Revision as of 11:31, 17 October 2022

Back to Top

Section editor transclusions Are you looking for a regimen, but can't find it here? It is possible that we've moved it to the historical regimens page. If you still can't find it, please let us know so we can add it! Note: certain regimens have been moved to dedicated pages:

0 regimens on this page 0 variants on this page

Please note, mature B-cell ALL (L3) is now classified as Burkitt lymphoma/leukemia. Regimens for this variant are available here

Guidelines

ESMO

2016: Hoelzer et al. Acute lymphoblastic leukaemia in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

EWALL/EBMT

2019: Giebel et al. Hematopoietic stem cell transplantation for adults with Philadelphia chromosome-negative acute lymphoblastic leukemia in first remission: a position statement of the European Working Group for Adult Acute Lymphoblastic Leukemia (EWALL) and the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT)

"How I Treat"

2020: Aldoss I, Douer D. How I treat the toxicities of pegasparaginase in adults with acute lymphoblastic leukemia. Blood. 2020 Mar 26;135(13):987-995. link to original article PubMed
2020: Aldoss I, Forman SJ. How I treat adults with advanced acute lymphoblastic leukemia eligible for CD19-targeted immunotherapy. Blood. 2020 Mar 12;135(11):804-813. link to original article PubMed
2015: Curran E, Stock W. How I treat acute lymphoblastic leukemia in older adolescents and young adults. Blood. 2015 Jun 11;125(24):3702-10. Epub 2015 Mar 24. link to PMC article PubMed
2015: Frey NV, Luger SM. How I treat adults with relapsed or refractory Philadelphia chromosome-negative acute lymphoblastic leukemia. Blood. 2015 Jul 30;126(5):589-96. Epub 2015 May 12. link to original article PubMed

NCCN

NCCN Guidelines - Acute Lymphoblastic Leukemia

Prephase

Prednisone monotherapy

Regimen

Study	Years of enrollment	Evidence
Huguet et al. 2009 (GRAALL-2003)	2003-2005	Phase 2

Note: in GRAALL-2003, this regimen was meant for patients up to 60 years old. The original Huguet et al. 2009 article Table 1 has several errors which were corrected in the erratum and the online Table 1. These corrected doses are replicated here. See paper for details on CNS prophylaxis and treatment.

Glucocorticoid therapy

Prednisone (Sterapred) 60 mg/m²/day PO on days 1 to 7

CNS therapy, prophylaxis

Methotrexate (MTX) 15 mg IT once on day 1

7-day course

Subsequent treatment

Cyclophosphamide, Daunorubicin, L-asparaginase, Vincristine, Prednisone induction

References

GRAALL-2003: Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. link to original article contains dosing details in manuscript PubMed NCT00222027

Vincristine & Prednisone

VP: Vincristine & Prednisone

Regimen

Study	Years of enrollment	Evidence
McCredie et al. 1983 (SWOG-7416	1975-1977	Non-randomized portion of RCT

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Chemotherapy

Vincristine (Oncovin) 2 mg IV once on day 1

Glucocorticoid therapy

Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5

5-day course

References

SWOG-7416: McCredie KB, Gehan EA, Freireich EJ, Hewlett JS, Coltman CA Jr, Hussein KK, Balcerzak SP, Chen TT. Management of adult acute leukemia: a Southwest Oncology Group study. Cancer. 1983 Sep 15;52(6):958-66. link to original article contains dosing details in manuscript PubMed

Upfront induction therapy

Cyclophosphamide, Cytarabine, Mercaptopurine

Regimen

Study	Evidence
Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)	Non-randomized portion of RCT

Preceding treatment

MRC UKALL XII/ECOG E2993, Ph-: "Phase 1" induction: DOLP
MRC UKALL XII/ECOG E2993, Ph+: "Phase 1" induction: Daunorubicin, L-asparaginase, Vincristine, Prednisone, Imatinib

Chemotherapy

Cyclophosphamide (Cytoxan) 650 mg/m² IV once per day on days 1, 15, 29
Cytarabine (Ara-C) 75 mg/m² IV once per day on days 1 to 4, 8 to 11, 15 to 18, 22 to 25
Mercaptopurine (6-MP) 6 mg/m² PO once per day on days 1 to 28

CNS therapy, prophylaxis

Methotrexate (MTX) 12 mg IT once per day on days 1, 8, 15, 22

29-day course

Subsequent treatment

L-asparaginase & Methotrexate early intensification

References

MRC UKALL XII/ECOG E2993: Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. link to original article contains dosing details in manuscript PubMed NCT00002514
1. Update: Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, Burnett AK, Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J, McMillan A, Franklin IM, Luger S, Ciobanu N, Rowe JM. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008 Feb 15;111(4):1827-33. Epub 2007 Nov 29. link to original article PubMed
2. Update: Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, Marks DI, McMillan AK, Litzow MR, Lazarus HM, Foroni L, Dewald G, Franklin IM, Luger SM, Paietta E, Wiernik PH, Tallman MS, Goldstone AH. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009 May 7;113(19):4489-96. Epub 2009 Feb 24. link to original article link to PMC article PubMed
3. Update: Fielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow MR, Lazarus H, Luger SM, Marks DI, McMillan AK, Moorman AV, Patel B, Paietta E, Tallman MS, Goldstone AH. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014 Feb 6;123(6):843-50. Epub 2013 Nov 25. link to original article contains dosing details in manuscript link to PMC article PubMed

Cyclophosphamide, Daunorubicin, Vincristine, Prednisone

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Thomas et al. 2004 (LALA-94)	1994-2002	Phase 3 (C)	Cyclophosphamide, Idarubicin, Vincristine, Prednisone	Seems to have inferior DFS

Chemotherapy

Cyclophosphamide (Cytoxan) 750 mg/m² IV once per day on days 1 & 8
Daunorubicin (Cerubidine) 30 mg/m² IV once per day on days 1 to 3, 15, 16
Vincristine (Oncovin) 2 mg IV once per day on days 1, 8, 15, 22

Glucocorticoid therapy

Prednisone (Sterapred) 60 mg/m²/day IV or PO on days 1 to 7, 15 to 21

28-day course

Subsequent treatment

Consolidation (see paper for details)

References

LALA-94: Thomas X, Boiron JM, Huguet F, Dombret H, Bradstock K, Vey N, Kovacsovics T, Delannoy A, Fegueux N, Fenaux P, Stamatoullas A, Vernant JP, Tournilhac O, Buzyn A, Reman O, Charrin C, Boucheix C, Gabert J, Lhéritier V, Fiere D. Outcome of treatment in adults with acute lymphoblastic leukemia: analysis of the LALA-94 trial. J Clin Oncol. 2004 Oct 15;22(20):4075-86. Epub 2004 Sep 7. link to original article contains dosing details in manuscript PubMed NCT00002700
1. Update: Vey N, Thomas X, Picard C, Kovascovicz T, Charin C, Cayuela JM, Dombret H, Dastugue N, Huguet F, Bastard C, Stamatoulas A, Giollant M, Tournilhac O, Macintyre E, Buzyn A, Bories D, Kuentz M, Dreyfus F, Delannoy A, Raynaud S, Gratecos N, Bordessoule D, de Botton S, Preudhomme C, Reman O, Troussard X, Pigneux A, Bilhou C, Vernant JP, Boucheix C, Gabert J; GET-LALA Group the Swiss Group for Clinical Cancer Research (SAKK). Allogeneic stem cell transplantation improves the outcome of adults with t(1;19)/E2A-PBX1 and t(4;11)/MLL-AF4 positive B-cell acute lymphoblastic leukemia: results of the prospective multicenter LALA-94 study. Leukemia. 2006 Dec;20(12):2155-61. Epub 2006 Oct 12. link to original article PubMed

Cyclophosphamide, Daunorubicin, Vincristine, Prednisolone

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Labar et al. 2010 (EORTC ALL-4)	1995-2003	Phase 3 (C)	Cyclophosphamide, Daunorubicin, Vincristine, Dexamethasone	Did not meet primary endpoint of EFS72

Chemotherapy

Cyclophosphamide (Cytoxan) 750 mg/m² IV once per day on days 1 & 8
Daunorubicin (Cerubidine) 30 mg/m² IV once per day on days 1 to 3, 15, 16
Vincristine (Oncovin) 2 mg IV once per day on days 1, 8, 15, 23

Glucocorticoid therapy

Prednisolone (Millipred) 60 mg/m²/day IV or PO on days 1 to 8, 15 to 22

CNS therapy, prophylaxis

Methotrexate (MTX) 15 mg IT once per day on days 1, 8, 15, 22, 28

28-day course

Subsequent treatment

HAM consolidation

References

EORTC ALL-4: Labar B, Suciu S, Willemze R, Muus P, Marie JP, Fillet G, Berneman Z, Jaksic B, Feremans W, Bron D, Sinnige H, Mistrik M, Vreugdenhil G, De Bock R, Nemet D, Gilotay C, Amadori S, de Witte T; EORTC Leukemia Group. Dexamethasone compared to prednisolone for adults with acute lymphoblastic leukemia or lymphoblastic lymphoma: final results of the ALL-4 randomized, phase III trial of the EORTC Leukemia Group. Haematologica. 2010 Sep;95(9):1489-95. Epub 2010 Apr 7. link to original article link to PMC article contains dosing details in manuscript PubMed

Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone

Regimen variant #1

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Huguet et al. 2009 (GRAALL-2003)	2003-2005	Phase 2
Maury et al. 2016 (GRAALL-2005/R)	2006-2014	Phase 3 (C)	Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone, Rituximab	Seems to have inferior EFS
Huguet et al. 2018 (GRAALL-2005)	2006-2014	Phase 3 (C)	Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone; hyperfractionated cyclophosphamide	Did not meet primary endpoint of EFS

Note: this "pediatric-like" regimen was meant for patients up to 60 years old. The original Huguet et al. 2009 article Table 1 has several errors which were corrected in the erratum and the online Table 1. These corrected doses are replicated here. See paper for details on CNS treatment. This is the "standard-dose cyclophosphamide" arm of GRAALL-2005.

Preceding treatment

Prednisone prephase

Chemotherapy

Cyclophosphamide (Cytoxan) by the following criteria:
- "Good early responders" (GRAALL-2003) and all patients (GRAALL-2005): 750 mg/m² IV over 3 hours once per day on days 1 & 15
- "Poor early responders" (GRAALL-2003): 750 mg/m² IV once on day 1, then 500 mg/m² IV every 12 hours on days 15 & 16
Daunorubicin (Cerubidine) 50 mg/m² IV once per day on days 1 to 3, then 30 mg/m² IV once per day on days 15 & 16
Asparaginase (Elspar) 6000 units/m² IV over 60 minutes once per day on days 8, 10, 12, 20, 22, 24, 26, 28
Vincristine (Oncovin) 2 mg IV once per day on days 1, 8, 15, 22

Glucocorticoid therapy

Prednisone (Sterapred) 60 mg/m²/day PO on days 1 to 14

CNS therapy, prophylaxis

Methotrexate (MTX) 15 mg IT once per day on days 1 & 8
Cytarabine (Ara-C) 40 mg IT once per day on days 1 & 8
Methylprednisolone (Solumedrol) 40 mg IT once per day on days 1 & 8

Supportive therapy

Lenograstim (Granocyte) by the following study-specific criteria:
- GRAALL-2003: 150 mcg/m² SC once per day from day 17 until myeloid recovery
- GRAALL-2005: 263 mcg SC once per day from day 18 until first day with ANC greater than 1000/uL

Subsequent treatment

Patients with resistant disease: Cytarabine & idarubicin salvage prior to further consolidation
All others: Pediatric-like GRAALL consolidation

Regimen variant #2, "HyperC"

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Maury et al. 2016 (GRAALL-2005/R)	2006-2014	Phase 3 (C)	Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone, Rituximab	Seems to have inferior EFS
Huguet et al. 2018 (GRAALL-2005)	2006-2014	Phase 3 (E-esc)	Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone; standard-dose cyclophosphamide	Did not meet primary endpoint of EFS

This is the "HyperC" arm of GRAALL-2005. Given the negative report in 2018, this experimental arm should be considered as historic reference.

Preceding treatment

Prednisone prephase

Chemotherapy

Cyclophosphamide (Cytoxan) 750 mg/m² IV over 3 hours once on day 1, then 300 mg/m² IV over 3 hours every 12 hours on days 15 to 17 (total dose: 2550 mg/m²)
Daunorubicin (Cerubidine) 50 mg/m² IV once per day on days 1 to 3, then 30 mg/m² IV once per day on days 15 & 16
Asparaginase (Elspar) 6000 units/m² IV over 60 minutes once per day on days 8, 10, 12, 20, 22, 24, 26, 28
Vincristine (Oncovin) 2 mg IV once per day on days 1, 8, 15, 22

Glucocorticoid therapy

Prednisone (Sterapred) 60 mg/m²/day PO on days 1 to 14

CNS therapy, prophylaxis

Methotrexate (MTX) 15 mg IT once per day on days 1 & 8
Cytarabine (Ara-C) 40 mg IT once per day on days 1 & 8
Methylprednisolone (Solumedrol) 40 mg IT once per day on days 1 & 8

Supportive therapy

Lenograstim (Granocyte) 263 mcg SC once per day from day 18 until first day with ANC greater than 1000/uL

28-day course

Subsequent treatment

Patients with resistant disease: Cytarabine & idarubicin salvage prior to further consolidation
Responders: Pediatric-like GRAALL consolidation

Regimen variant #3

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Annino et al. 2002 (GIMEMA ALL 0288)	1988-1996	Phase 3 (E-esc)	DOLP	Did not meet primary endpoint of CR rate

Note: vincristine is clearly shown as 2 mg/m² in Table 1, but this is an unusual dose; consider discussing with the authors if you are going to utilize this regimen.

Chemotherapy, "Induction phase I"

Cyclophosphamide (Cytoxan) 800 mg/m² IV once per day on days 1 & 2
Daunorubicin (Cerubidine) 40 mg/m² IV once per day on days 1, 8, 15, 22
L-Asparaginase 6000 units/m² SC once per day on days 22 to 31
Vincristine (Oncovin) 2 mg/m² IV once per day on days 1, 8, 15, 22

Glucocorticoid therapy

Prednisone (Sterapred) 60 mg/m²/day PO on days 1 to 14, then 40 mg/m²/day PO on days 15 to 31

31-day course

Subsequent treatment

Induction phase II or salvage, see paper for details

Regimen variant #4, "Larson regimen"

Study	Evidence
Larson et al. 1995 (CALGB 8811)	Phase 2

Chemotherapy, "Course I"

Cyclophosphamide (Cytoxan) by the following age-based criteria:
- Younger than 60: 1200 mg/m² IV once on day 1
- 60 or older: 800 mg/m² IV once on day 1
Daunorubicin (Cerubidine) by the following age-based criteria:
- Younger than 60: 45 mg/m² IV once per day on days 1 to 3
- 60 or older: 30 mg/m² IV once per day on days 1 to 3
Asparaginase (Elspar) 6000 units/m² SC once per day on days 5, 8, 11, 15, 18, 22
Vincristine (Oncovin) 2 mg IV once per day on days 1, 8, 15, 22

Glucocorticoid therapy

Prednisone (Sterapred) by the following age-based criteria:
- Younger than 60: 60 mg/m² PO once per day on days 1 to 21
- 60 or older: 60 mg/m² PO once per day on days 1 to 7

28-day course

Subsequent treatment

Larson regimen (CALGB 8811) early intensification ("Course II")

References

CALGB 8811: Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR, Hooberman AL, Westbrook CA, Arthur DC, George SL, Bloomfield CD, Schiffer CA. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: Cancer and Leukemia Group B study 8811. Blood. 1995 Apr 15;85(8):2025-37. link to original article contains dosing details in manuscript PubMed
GIMEMA ALL 0288: Annino L, Vegna ML, Camera A, Specchia G, Visani G, Fioritoni G, Ferrara F, Peta A, Ciolli S, Deplano W, Fabbiano F, Sica S, Di Raimondo F, Cascavilla N, Tabilio A, Leoni P, Invernizzi R, Baccarani M, Rotoli B, Amadori S, Mandelli F; GIMEMA. Treatment of adult acute lymphoblastic leukemia (ALL): long-term follow-up of the GIMEMA ALL 0288 randomized study. Blood. 2002 Feb 1;99(3):863-71. link to original article contains dosing details in manuscript PubMed
GRAALL-2003: Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. link to original article contains dosing details in manuscript PubMed NCT00222027
GRAALL-2005/R: Maury S, Chevret S, Thomas X, Heim D, Leguay T, Huguet F, Chevallier P, Hunault M, Boissel N, Escoffre-Barbe M, Hess U, Vey N, Pignon JM, Braun T, Marolleau JP, Cahn JY, Chalandon Y, Lhéritier V, Beldjord K, Béné MC, Ifrah N, Dombret H; GRAALL. Rituximab in B-lineage adult acute lymphoblastic leukemia. N Engl J Med. 2016 Sep 15;375(11):1044-53. link to original article link to supplement contains dosing details in supplement PubMed NCT00327678
GRAALL-2005: Huguet F, Chevret S, Leguay T, Thomas X, Boissel N, Escoffre-Barbe M, Chevallier P, Hunault M, Vey N, Bonmati C, Lepretre S, Marolleau JP, Pabst T, Rousselot P, Buzyn A, Cahn JY, Lhéritier V, Béné MC, Asnafi V, Delabesse E, Macintyre E, Chalandon Y, Ifrah N, Dombret H; Group of Research on Adult ALL. Intensified therapy of acute lymphoblastic leukemia in adults: report of the randomized GRAALL-2005 clinical trial. J Clin Oncol. 2018 Aug 20;36(24):2514-2523. Epub 2018 Jun 4. link to original article PubMed NCT00327678

Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone, Rituximab

Regimen variant #1

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Maury et al. 2016 (GRAALL-2005/R)	2006-2014	Phase 3 (E-esc)	Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone	Seems to have superior EFS

Note: this regimen was meant for CD20+ patients less than 60 years old. This is the "standard" arm of GRAALL-2005/R.

Preceding treatment

Prednisone prephase

Chemotherapy

Cyclophosphamide (Cytoxan) 750 mg/m² IV over 3 hours once per day on days 1 & 15
Daunorubicin (Cerubidine) 50 mg/m² IV once per day on days 1 to 3, then 30 mg/m² IV once per day on days 15 & 16
Asparaginase (Elspar) 6000 units/m² IV over 60 minutes once per day on days 8, 10, 12, 20, 22, 24, 26, 28
Vincristine (Oncovin) 2 mg IV once per day on days 1, 8, 15, 22

Glucocorticoid therapy

Prednisone (Sterapred) 60 mg/m²/day PO on days 1 to 14

Targeted therapy

Rituximab (Rituxan) 375 mg/m² IV once per day on days 1 & 7

CNS therapy, prophylaxis

Methotrexate (MTX) 15 mg IT once per day on days 1 & 8
Cytarabine (Ara-C) 40 mg IT once per day on days 1 & 8
Methylprednisolone (Solumedrol) 40 mg IT once per day on days 1 & 8

Supportive therapy

Lenograstim (Granocyte) by the following study-specific criteria:
- GRAALL-2003: 150 mcg/m² SC once per day from day 17 until myeloid recovery
- GRAALL-2005: 263 mcg SC once per day from day 18 until first day with ANC greater than 1000/uL

Subsequent treatment

Patients with resistant disease: Cytarabine, idarubicin, rituximab salvage prior to further consolidation
All others: Pediatric-like GRAALL consolidation with rituximab

References

GRAALL-2005/R: Maury S, Chevret S, Thomas X, Heim D, Leguay T, Huguet F, Chevallier P, Hunault M, Boissel N, Escoffre-Barbe M, Hess U, Vey N, Pignon JM, Braun T, Marolleau JP, Cahn JY, Chalandon Y, Lhéritier V, Beldjord K, Béné MC, Ifrah N, Dombret H; GRAALL. Rituximab in B-lineage adult acute lymphoblastic leukemia. N Engl J Med. 2016 Sep 15;375(11):1044-53. link to original article link to supplement contains dosing details in supplement PubMed NCT00327678

Cyclophosphamide, Idarubicin, Vincristine, Prednisone

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Thomas et al. 2004 (LALA-94)	1994-2002	Phase 3 (E-switch-ic)	Cyclophosphamide, Daunorubicin, Vincristine, Prednisone	Seems to have superior DFS

Chemotherapy

Cyclophosphamide (Cytoxan) 750 mg/m² IV once per day on days 1 & 8
Idarubicin (Idamycin) 9 mg/m² IV once per day on days 1, 2, 3, 8
Vincristine (Oncovin) 2 mg IV once per day on days 1, 8, 15, 22

Glucocorticoid therapy

Prednisone (Sterapred) 60 mg/m²/day IV or PO on days 1 to 7, 15 to 21

28-day course

Subsequent treatment

Consolidation (see paper for details)

References

LALA-94: Thomas X, Boiron JM, Huguet F, Dombret H, Bradstock K, Vey N, Kovacsovics T, Delannoy A, Fegueux N, Fenaux P, Stamatoullas A, Vernant JP, Tournilhac O, Buzyn A, Reman O, Charrin C, Boucheix C, Gabert J, Lhéritier V, Fiere D; SAKK. Outcome of treatment in adults with acute lymphoblastic leukemia: analysis of the LALA-94 trial. J Clin Oncol. 2004 Oct 15;22(20):4075-86. Epub 2004 Sep 7. link to original article contains dosing details in manuscript PubMed NCT00002700
1. Update: Vey N, Thomas X, Picard C, Kovascovicz T, Charin C, Cayuela JM, Dombret H, Dastugue N, Huguet F, Bastard C, Stamatoulas A, Giollant M, Tournilhac O, Macintyre E, Buzyn A, Bories D, Kuentz M, Dreyfus F, Delannoy A, Raynaud S, Gratecos N, Bordessoule D, de Botton S, Preudhomme C, Reman O, Troussard X, Pigneux A, Bilhou C, Vernant JP, Boucheix C, Gabert J; GET-LALA Group the Swiss Group for Clinical Cancer Research (SAKK). Allogeneic stem cell transplantation improves the outcome of adults with t(1;19)/E2A-PBX1 and t(4;11)/MLL-AF4 positive B-cell acute lymphoblastic leukemia: results of the prospective multicenter LALA-94 study. Leukemia. 2006 Dec;20(12):2155-61. Epub 2006 Oct 12. link to original article PubMed

DOLP

DOLP: Daunorubicin, Oncovin (Vincristine), L-Asparaginase, Prednisone
DVPA: Daunorubicin, Vincristine, Prednisone, Asparaginase

Regimen variant #1, 25/5000/1.5/60

Study	Evidence
Hoelzer et al. 1984	Non-randomized

Of historic interest. This is "Phase 1" of induction.

Chemotherapy

Daunorubicin (Cerubidine) 25 mg/m² IV once per day on days 1, 8, 15, 22
Vincristine (Oncovin) 1.5 mg/m² IV once per day on days 1, 8, 15, 22
Asparaginase (Elspar) 5000 units IV once per day on days 1 to 14

Glucocorticoid therapy

Prednisone (Sterapred) 60 mg/m²/day PO on days 1 to 28

4-week course

Subsequent treatment

See paper for details of treatment beyond induction

Regimen variant #2, 40/6000/2/60-40 ("Phase I" of GIMEMA ALL 0288)

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Annino et al. 2002 (GIMEMA ALL 0288)	1988-1996	Phase 3 (C)	Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone	Did not meet primary endpoint of CR rate

Note: vincristine is clearly shown as 2 mg/m² in Table 1, but this is an unusual dose; consider discussing with the authors if you are going to utilize this regimen.

Chemotherapy

Daunorubicin (Cerubidine) 40 mg/m² IV once per day on days 1, 8, 15, 22
Vincristine (Oncovin) 2 mg/m² IV once per day on days 1, 8, 15, 22
L-Asparaginase 6000 units/m² SC once per day on days 22 to 31

Glucocorticoid therapy

Prednisone (Sterapred) 60 mg/m²/day PO on days 1 to 14, then 40 mg/m²/day PO on days 15 to 31

31-day course

Subsequent treatment

Induction phase II or salvage (see paper for details)

Regimen variant #3, 45/500/2/40

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Gottlieb et al. 1984 (CALGB 7612)	1976-1980	Randomized (E-RT-esc)	L-asparaginase, Vincristine, Prednisone	Superior CR rate

Chemotherapy

Daunorubicin (Cerubidine) 45 mg/m² IV once per day on days 1 to 3
Vincristine (Oncovin) 2 mg IV once per day on days 1, 8, 15
Asparaginase (Elspar) 500 units/kg IV once per day on days 22 to 31

Glucocorticoid therapy

Prednisone (Sterapred) 40 mg/m²/day PO on days 1 to 22, then tapered to off by day 29

31-day course

Subsequent treatment

See paper for details of treatment beyond induction

Regimen variant #4, 50/6000/2/60 ("Linker regimen")

Study	Years of enrollment	Evidence
Linker et al. 1987	1980-1986	Phase 2

Chemotherapy

Daunorubicin (Cerubidine) by the following criteria:
- All patients: 50 mg/m² IV once per day on days 1 to 3
- Bone marrow on day 14 has residual leukemia: 50 mg/m² IV once on day 15
- Bone marrow on day 28 has residual leukemia: 50 mg/m² IV once per day on days 29 & 30
Vincristine (Oncovin) by the following criteria:
- All patients: 2 mg IV once per day on days 1, 8, 15, 22
- Bone marrow on day 28 has residual leukemia: 2 mg IV once per day on days 29 & 36
Asparaginase (Elspar) by the following criteria:
- All patients: 6000 units/m² IM once per day on days 17 to 28
- Bone marrow on day 28 has residual leukemia: 6000 units/m² IM once per day on days 29 to 35

Glucocorticoid therapy

Prednisone (Sterapred) by the following criteria:
- All patients: 60 mg/m² PO once per day on days 1 to 28
- Bone marrow on day 28 has residual leukemia: 60 mg/m² PO once per day on days 29 to 42

CNS therapy, prophylaxis

This is for patients without CNS involvement at diagnosis, and is started within 1 week of achieving complete remission:
Cranial radiation, 18 Gy total given in 10 fractions over 12 to 14 days
Methotrexate (MTX) 12 mg IT once per week x 6 doses concurrent with radiation

CNS therapy, treatment

This is for patients with CNS involvement at diagnosis:
Cranial radiation, 28 Gy total given
Methotrexate (MTX) 12 mg IT once per week x 10 doses that starts while they are receiving induction therapy, then given once per month during the first year of therapy

Subsequent treatment

Linker regimen consolidation therapy

Regimen variant #5, 60/10,000/1.4/60, daily dauno

Study	Evidence
Pullarkat et al. 2008 (SWOG S9400)	Phase 2

Note: this was the dosing used after the protocol amendment of September 1, 1999.

Chemotherapy

Daunorubicin (Cerubidine) by the following response-based criteria:
- All patients: 60 mg/m² IV once per day on days 1 to 3
- Persistent leukemia on day 21: 60 mg/m² IV once per day on days 22 & 23
Vincristine (Oncovin) by the following response-based criteria:
- All patients: 1.4 mg/m² (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
- Persistent leukemia on day 21: 1.4 mg/m² (maximum dose of 2 mg) IV once per day on days 29 & 36
Asparaginase (Elspar) 10,000 units IM or IV once per day on days 15 to 24

Glucocorticoid therapy

Prednisone (Sterapred) by the following response-based criteria:
- All patients: 60 mg/m²/day PO on days 1 to 28
- No leukemia on day 21: taper to off by day 42
- Persistent leukemia on day 21: 60 mg/m²/day PO on days 29 to 42

6-week course

Subsequent treatment

See paper for details

Regimen variant #6, 60/10,000/1.4/60, weekly dauno ("Phase I" of E2993 regimen)

Study	Evidence
Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)	Non-randomized portion of RCT

To our knowledge, this is the largest induction trial in adult ALL, N=1,646. CR rate was 91%.

Chemotherapy

Daunorubicin (Cerubidine) 60 mg/m² IV once per day on days 1, 8, 15, 22
Vincristine (Oncovin) 1.4 mg/m² IV once per day on days 1, 8, 15, 22
Asparaginase (Elspar) 10,000 units IM or IV once per day on days 17 to 28

Glucocorticoid therapy

Prednisone (Sterapred) 60 mg/m²/day PO in divided doses on days 1 to 28

CNS therapy, prophylaxis

Methotrexate (MTX) 12.5 mg IT once on day 15

4-week course

Subsequent treatment

Cyclophosphamide, Cytarabine, Mercaptopurine induction ("Phase 2")

References

Hoelzer D, Thiel E, Löffler H, Bodenstein H, Plaumann L, Büchner T, Urbanitz D, Koch P, Heimpel H, Engelhardt R, Muller U, Wendt FC, Sodomann H, Ruhl H, Herrmann F, Kaboth W, Dietzfelbinger H, Pralle H, Lunscken Ch, Hellriegel KP, Spors S, Nowrousian RM, Fischer J, Fulle H, Mitrou PS, Pfreundschuh M, Gorg Ch, Emmerich B, Queisser W, Meyer P, Labedzki L, Essers U, Konig H, Mainzer K, Herrmann R, Messerer D, Zwingers T. Intensified therapy in acute lymphoblastic and acute undifferentiated leukemia in adults. Blood. 1984 Jul;64(1):38-47. link to original article contains dosing details in manuscript PubMed
CALGB 7612: Gottlieb AJ, Weinberg V, Ellison RR, Henderson ES, Terebelo H, Rafla S, Cuttner J, Silver RT, Carey RW, Levy RN, Hutchinson JL, Raich P, Cooper MR, Wiernik P, Anderson JR, Holland JF. Efficacy of daunorubicin in the therapy of adult acute lymphocytic leukemia: a prospective randomized trial by Cancer and Leukemia Group B. Blood. 1984 Jul;64(1):267-74. link to original article contains dosing details in manuscript PubMed
Linker CA, Levitt LJ, O'Donnell M, Ries CA, Link MP, Forman SJ, Farbstein MJ. Improved results of treatment of adult acute lymphoblastic leukemia. Blood. 1987 Apr;69(4):1242-8. link to original article contains dosing details in manuscript PubMed
1. Update: Linker CA, Levitt LJ, O'Donnell M, Forman SJ, Ries CA. Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report. Blood. 1991 Dec 1;78(11):2814-22. link to original article contains dosing details in manuscript PubMed
GIMEMA ALL 0288: Annino L, Vegna ML, Camera A, Specchia G, Visani G, Fioritoni G, Ferrara F, Peta A, Ciolli S, Deplano W, Fabbiano F, Sica S, Di Raimondo F, Cascavilla N, Tabilio A, Leoni P, Invernizzi R, Baccarani M, Rotoli B, Amadori S, Mandelli F; GIMEMA. Treatment of adult acute lymphoblastic leukemia (ALL): long-term follow-up of the GIMEMA ALL 0288 randomized study. Blood. 2002 Feb 1;99(3):863-71. link to original article contains dosing details in manuscript PubMed
MRC UKALL XII/ECOG E2993: Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. link to original article contains dosing details in manuscript PubMed NCT00002514
1. Update: Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, Burnett AK, Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J, McMillan A, Franklin IM, Luger S, Ciobanu N, Rowe JM. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008 Feb 15;111(4):1827-33. Epub 2007 Nov 29. link to original article PubMed
2. Update: Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, Marks DI, McMillan AK, Litzow MR, Lazarus HM, Foroni L, Dewald G, Franklin IM, Luger SM, Paietta E, Wiernik PH, Tallman MS, Goldstone AH. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009 May 7;113(19):4489-96. Epub 2009 Feb 24. link to original article link to PMC article PubMed
3. Update: Fielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow MR, Lazarus H, Luger SM, Marks DI, McMillan AK, Moorman AV, Patel B, Paietta E, Tallman MS, Goldstone AH. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014 Feb 6;123(6):843-50. Epub 2013 Nov 25. link to original article contains dosing details in manuscript link to PMC article PubMed
SWOG S9400: Pullarkat V, Slovak ML, Kopecky KJ, Forman SJ, Appelbaum FR. Impact of cytogenetics on the outcome of adult acute lymphoblastic leukemia: results of Southwest Oncology Group 9400 study. Blood. 2008 Mar 1;111(5):2563-72. Epub 2007 Dec 21. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00002665

Daunorubicin, Pegaspargase, Vincristine, Dexamethasone

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Marks et al. 2022 (UKALL14)	2012-2017	Phase 3 (C)	Daunorubicin, Pegaspargase, Vincristine, Dexamethasone, Rituximab	Did not meet primary endpoint of EFS

Note: the manuscript contains an error in the timing of daunorubicin and vincristine; the correct schedule is available in the supplement. The authors have been notified of the error, and the correct schedule is used below.

Preceding treatment

Pre-phase dexamethasone

Chemotherapy

Daunorubicin (Cerubidine) 30 mg/m² IV over 1 to 15 minutes once per day on days 1, 8, 15, 22
Pegaspargase (Oncaspar) by the following age-based criteria:
- Age 40 years and younger: 1000 units/m² IV once per day on days 4 & 18
- Age 41 years or older: 1000 units/m² IV once on day 18
Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22

Glucocorticoid therapy

Dexamethasone (Decadron) 10 mg/m²/day PO on days 1 to 4, 8 to 11, 15 to 18

CNS therapy, prophylaxis

Methotrexate (MTX) 12.5 mg IT once on day 14

Subsequent treatment

See paper for protocol details

References

UKALL14: Marks DI, Kirkwood AA, Rowntree CJ, Aguiar M, Bailey KE, Beaton B, Cahalin P, Castleton AZ, Clifton-Hadley L, Copland M, Goldstone AH, Kelly R, Lawrie E, Lee S, McMillan AK, McMullin MF, Menne TF, Mitchell RJ, Moorman AV, Patel B, Patrick P, Smith P, Taussig D, Yallop D, Alapi KZ, Fielding AK. Addition of four doses of rituximab to standard induction chemotherapy in adult patients with precursor B-cell acute lymphoblastic leukaemia (UKALL14): a phase 3, multicentre, randomised controlled trial. Lancet Haematol. 2022 Apr;9(4):e262-e275. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01085617

Daunorubicin, Pegaspargase, Vincristine, Prednisone

Regimen variant #1, "ABFM"

Study	Evidence
Rytting et al. 2014	Non-randomized
Stock et al. 2019 (CALGB 10403)	Non-randomized

ABFM: Augmented Berlin-Frankfurt-Münster regimen

Chemotherapy

Daunorubicin (Cerubidine) 25 mg/m² IV over 1 to 15 minutes once per day on days 1, 8, 15, 22
Pegaspargase (Oncaspar) 2500 units/m² IM or IV over 1 to 2 hours once on day 4
Vincristine (Oncovin) 1.5 mg/m² (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22

Glucocorticoid therapy

Prednisone (Sterapred) 30 mg/m² IV or PO twice per day on days 1 to 28

CNS therapy, prophylaxis

Cytarabine (Ara-C) by the following age-based criteria:
- Ages 1 to 1.99: 30 mg IT once on day 1
- Ages 2 to 2.99: 50 mg IT once on day 1
- Age 3 and older: 70 mg IT once on day 1
Methotrexate (MTX) by the following age-based criteria:
- Ages 1 to 1.99: 8 mg IT once per day on days 8 & 29
- Ages 2 to 2.99: 10 mg IT once per day on days 8 & 29
- Ages 3 to 8.99: 12 mg IT once per day on days 8 & 29
- Age 9 and older: 15 mg IT once per day on days 8 & 29

4-week course

Subsequent treatment

Rytting et al. 2014: See protocol for details of treatment beyond induction
CALGB 10403, CR: AALL0232 consolidation
CALGB 10403, not CR: ABFM extended induction

Regimen variant #2, higher-dose dauno

Study	Evidence
Pullarkat et al. 2008 (SWOG S9400)	Non-randomized

Note: Table 1 lists vincristine as being given PO, which is surely an error. Likewise, prednisone is listed as IV. Pegaspargase was only given until the protocol amendment of September 1, 1999.

Chemotherapy

Daunorubicin (Cerubidine) by the following response-based criteria:
- Part 1 (all patients): 60 mg/m² IV once per day on days 1 to 3
- Part 2 (persistent leukemia on d21): 60 mg/m² IV once per day on days 22 & 23
Pegaspargase (Oncaspar) by the following response-based criteria:
- Part 1 (all patients): 2000 units/m² IV once on day 15
- Part 2 (persistent leukemia on d21): 2000 units/m² IV once on day 38
Vincristine (Oncovin) by the following response-based criteria:
- Part 1 (all patients): 1.4 mg/m² (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
- Part 2 (persistent leukemia on d21): 1.4 mg/m² (maximum dose of 2 mg) IV once per day on days 29 & 36

Glucocorticoid therapy

Prednisone (Sterapred) by the following response-based criteria:
- Part 1 (all patients): 60 mg/m²/day PO on days 1 to 28
- Part 2 (CR on d21): tapered from day 29 to 42
- Part 2 (persistent leukemia on d21): 60 mg/m²/day PO on days 29 to 42

42-day course

Subsequent treatment

See protocol for details of treatment beyond induction

References

SWOG S9400: Pullarkat V, Slovak ML, Kopecky KJ, Forman SJ, Appelbaum FR. Impact of cytogenetics on the outcome of adult acute lymphoblastic leukemia: results of Southwest Oncology Group 9400 study. Blood. 2008 Mar 1;111(5):2563-72. Epub 2007 Dec 21. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00002665
Rytting ME, Thomas DA, O'Brien SM, Ravandi-Kashani F, Jabbour EJ, Franklin AR, Kadia TM, Pemmaraju N, Daver NG, Ferrajoli A, Garcia-Manero G, Konopleva MY, Cortes JE, Borthakur G, Garris R, Cardenas-Turanzas M, Schroeder K, Jorgensen JL, Kornblau SM, Kantarjian HM. Augmented Berlin-Frankfurt-Münster therapy in adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL). Cancer. 2014 Dec 1;120(23):3660-8. Epub 2014 Jul 17. link to original article contains dosing details in manuscript link to PMC article PubMed
1. Update: Rytting ME, Jabbour EJ, Jorgensen JL, Ravandi F, Franklin AR, Kadia TM, Pemmaraju N, Daver NG, Ferrajoli A, Garcia-Manero G, Konopleva MY, Borthakur G, Garris R, Wang S, Pierce S, Schroeder K, Kornblau SM, Thomas DA, Cortes JE, O'Brien SM, Kantarjian HM. Final results of a single institution experience with a pediatric-based regimen, the augmented Berlin-Frankfurt-Münster (ABFM), in adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL), and comparison to the hyper-CVAD regimen. Am J Hematol. 2016 Aug;91(8):819-23. Epub 2016 May 14. link to original article link to PMC article PubMed
CALGB 10403: Stock W, Luger SM, Advani AS, Yin J, Harvey RC, Mullighan CG, Willman CL, Fulton N, Laumann KM, Malnassy G, Paietta E, Parker E, Geyer S, Mrózek K, Bloomfield CD, Sanford B, Marcucci G, Liedtke M, Claxton DF, Foster MC, Bogart JA, Grecula JC, Appelbaum FR, Erba H, Litzow MR, Tallman MS, Stone RM, Larson RA. A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403. Blood. 2019 Apr 4;133(14):1548-1559. Epub 2019 Jan 18. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00558519

Hyper-CVAD/MA

Hyper-CVAD/MA: Hyperfractionated Cyclophosphamide, Vincristine, Adriamycin (Doxorubicin), Dexamethasone alternating with Methotrexate, Ara-C (Cytarabine)

Protocol

Study	Evidence
Koller et al. 1997	Non-randomized
Thomas et al. 1999	Phase 2
Kantarjian et al. 2000	Phase 2
Thomas et al. 2004	Non-randomized

Chemotherapy, Part A (cycles 1, 3, 5, 7)

Cyclophosphamide (Cytoxan) 300 mg/m² IV over 2 hours every 12 hours on days 1 to 3 (total dose per cycle: 1800 mg/m²)
Vincristine (Oncovin) 2 mg IV once per day on days 4 & 11
Doxorubicin (Adriamycin) by the following criteria:
- Normal EF: 50 mg/m² IV continuous infusion over 24 hours, started on day 4
- EF less than 50%: 25 mg/m²/day IV continuous infusion over 48 hours, started on day 4 (total dose per cycle: 50 mg/m²)

Glucocorticoid therapy

Dexamethasone (Decadron) 40 mg IV or PO once per day on days 1 to 4, 11 to 14

Supportive therapy

Mesna (Mesnex) 600 mg/m²/day IV continuous infusion over 72 hours, started on day 1, starting 1 hour before Cyclophosphamide (Cytoxan) and completed 12 hours after the last dose of Cyclophosphamide (Cytoxan)
ONE of the following antibiotics:
- Ciprofloxacin (Cipro) 500 mg PO twice per day
- Levofloxacin (Levaquin) 500 mg PO once per day
- Trimethoprim-Sulfamethoxazole (Bactrim DS) 160/800 mg PO twice per day
Fluconazole (Diflucan) 200 mg PO once per day
ONE of the following antivirals:
- Acyclovir (Zovirax) 200 mg PO twice per day
- Valacyclovir (Valtrex) 500 mg PO once per day
Filgrastim (Neupogen) 10 mcg/kg SC once per day, starting 24 hours after completion of intensive courses of chemotherapy (day 5 for part A, day 4 for part B), given until ANC greater than 1000/uL

Next cycle to start as soon as ANC is greater than 1000/uL at least 24 hours off of G-CSF and platelet count greater than 60 x 10⁹/L

Chemotherapy, Part B (cycles 2, 4, 6, 8)

Methotrexate (MTX) 200 mg/m² IV over 2 hours once on day 1, then 800 mg/m² IV over 22 hours (total dose per cycle: 1000 mg/m²)
Cytarabine (Ara-C) by the following age-based criteria:
- Younger than 60: 3000 mg/m² IV over 2 hours every 12 hours on days 2 & 3 (total dose per cycle: 12,000 mg/m²)
- 60 or older: 1000 mg/m² IV over 2 hours every 12 hours on days 2 & 3 (total dose per cycle: 4000 mg/m²)

Glucocorticoid therapy

Methylprednisolone (Solumedrol) 50 mg IV every 12 hours on days 1 to 3 (see note)
- Note: This is only mentioned in the Kantarjian et al. 2010 publication, and it isn't clear if it's meant to be a supportive or antineoplastic medication.

Supportive therapy

Folinic acid (Leucovorin) 50 mg IV once on day 3, 12 hours after Methotrexate (MTX) is complete, then 15 mg IV every 6 hours until serum methotrexate level less than 100 nmol/L
ONE of the following antibiotics:
- Ciprofloxacin (Cipro) 500 mg PO twice per day
- Levofloxacin (Levaquin) 500 mg PO once per day
- Trimethoprim-Sulfamethoxazole (Bactrim DS) 160/800 mg PO twice per day
Fluconazole (Diflucan) 200 mg PO once per day
ONE of the following antivirals:
- Acyclovir (Zovirax) 200 mg PO twice per day
- Valacyclovir (Valtrex) 500 mg PO once per day
Filgrastim (Neupogen) 10 mcg/kg SC once per day, starting 24 hours after completion of intensive courses of chemotherapy (day 5 for part A, day 4 for part B), given until ANC greater than 1000/uL

Next cycle to start as soon as ANC is greater than 1000/uL at least 24 hours off of G-CSF and platelet count greater than 60 x 10⁹/L

CNS therapy, prophylaxis

Methotrexate (MTX) by the following criteria:
- LP: 12 mg IT once on day 2
- Ommaya reservoir: 6 mg IT once on day 2
Cytarabine (Ara-C) 100 mg IT once on either day 7 or 8

Given each cycle for a total of 6 or 8 intrathecal treatments (i.e. 3 each of methotrexate and cytarabine or 4 each of methotrexate and cytarabine), depending on risk for CNS relapse based serum lactate dehydrogenase (LDH) greater than 1400 IU/L and/or proliferative index percentage of S + G2M greater than or equal to 14%

CNS therapy, treatment

Methotrexate (MTX) 12 mg (6 mg if given via Ommaya reservoir) IT alternating with Cytarabine (Ara-C) 100 mg IT, with both given every week until cell count in CSF normalizes and cytology is negative for malignancy
Then Methotrexate (MTX) 12 mg (6 mg if given via Ommaya reservoir) IT given weeks 1 & 3 and Cytarabine (Ara-C) 100 mg IT, given weeks 2 & 4
Once those 4 weeks are complete, then intrathecal treatment is given similar to the prophylactic schedule, with each drug given once during every remaining cycle of induction therapy:
- Methotrexate (MTX) 12 mg (6 mg if given via Ommaya reservoir) IT once on day 2
- Cytarabine (Ara-C) 100 mg IT once on either day 7 or 8

Subsequent treatment

Certain patient populations (see e.g. Kantarjian et al. 2004) proceed to receive POMP maintenance

References

Review: Cortes J, O'Brien SM, Pierce S, Keating MJ, Freireich EJ, Kantarjian HM. The value of high-dose systemic chemotherapy and intrathecal therapy for central nervous system prophylaxis in different risk groups of adult acute lymphoblastic leukemia. Blood. 1995 Sep 15;86(6):2091-7. link to original article PubMed
Koller CA, Kantarjian HM, Thomas D, O'Brien S, Rios MB, Kornblau S, Murphy S, Keating M. The hyper-CVAD regimen improves outcome in relapsed acute lymphoblastic leukemia. Leukemia. 1997 Dec;11(12):2039-44. link to original article PubMed
Thomas DA, Cortes J, O'Brien S, Pierce S, Faderl S, Albitar M, Hagemeister FB, Cabanillas FF, Murphy S, Keating MJ, Kantarjian H. Hyper-CVAD program in Burkitt's-type adult acute lymphoblastic leukemia. J Clin Oncol. 1999 Aug;17(8):2461-70. link to original article contains dosing details in manuscript PubMed
Kantarjian HM, O'Brien S, Smith TL, Cortes J, Giles FJ, Beran M, Pierce S, Huh Y, Andreeff M, Koller C, Ha CS, Keating MJ, Murphy S, Freireich EJ. Results of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia. J Clin Oncol. 2000 Feb;18(3):547-61. link to original article contains dosing details in manuscript PubMed
1. Update: Kantarjian H, Thomas D, O'Brien S, Cortes J, Giles F, Jeha S, Bueso-Ramos CE, Pierce S, Shan J, Koller C, Beran M, Keating M, Freireich EJ. Long-term follow-up results of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD), a dose-intensive regimen, in adult acute lymphocytic leukemia. Cancer. 2004 Dec 15;101(12):2788-801. link to original article contains dosing details in manuscript PubMed
Thomas DA, O'Brien S, Cortes J, Giles FJ, Faderl S, Verstovsek S, Ferrajoli A, Koller C, Beran M, Pierce S, Ha CS, Cabanillas F, Keating MJ, Kantarjian H. Outcome with the hyper-CVAD regimens in lymphoblastic lymphoma. Blood. 2004 Sep 15;104(6):1624-30. Epub 2004 Jun 3. link to original article contains dosing details in manuscript PubMed

Mini-Hyper-CVD/MA & Inotuzumab ozogamicin

Mini-Hyper-CVD/MA & Inotuzumab ozogamicin: Mini (lower intensity) Hyperfractionated Cyclophosphamide, Vincristine, Dexamethasone alternating with Methotrexate and Ara-C (Cytarabine) & Inotuzumab ozogamicin

Protocol

Study	Years of enrollment	Evidence
Kantarjian et al. 2018 (MDACC 2010-0991)	2011-2017	Phase 2

==

Chemotherapy, Part A

Cyclophosphamide (Cytoxan) as follows:
- Cycles 1, 3, 5, 7: 150 mg/m² IV every 12 hours on days 1 to 3 (total dose per cycle: 900 mg/m²)
Vincristine (Oncovin) as follows:
- Cycles 1, 3, 5, 7: 2 mg IV once per day on days 1 & 8

Glucocorticoid therapy, Part A

Dexamethasone (Decadron) as follows:
- Cycles 1, 3, 5, 7: 20 mg IV or PO once per day on days 1 to 4, 11 to 14

Antibody-drug conjugate therapy, Part A

Inotuzumab ozogamicin (Besponsa) as follows:
- Cycles 1 & 3: 1.3 to 1.8 mg/m² IV once on day 3
- Cycles 5 & 7: 1 to 1.3 mg/m² IV once on day 3

==

Chemotherapy, Part B

Methotrexate (MTX) as follows:
- Cycles 2, 4, 6, 8: 250 mg/m² IV once on day 1
Cytarabine (Ara-C) as follows:
- Cycles 2, 4, 6, 8: 500 mg/m² IV every 12 hours on days 2 & 3 (total dose per cycle: 2000 mg/m²)

Antibody-drug conjugate therapy, Part B

Inotuzumab ozogamicin (Besponsa) as follows:
- Cycles 2 & 4: 1.3 to 1.8 mg/m² IV once on day 3
- Cycles 6 & 8: 1 to 1.3 mg/m² IV once on day 3

28-day cycle for 8 cycles

Subsequent treatment

Dose-reduced POMP x 3 y

References

MDACC 2010-0991: Kantarjian H, Ravandi F, Short NJ, Huang X, Jain N, Sasaki K, Daver N, Pemmaraju N, Khoury JD, Jorgensen J, Alvarado Y, Konopleva M, Garcia-Manero G, Kadia T, Yilmaz M, Bortakhur G, Burger J, Kornblau S, Wierda W, DiNardo C, Ferrajoli A, Jacob J, Garris R, O'Brien S, Jabbour E. Inotuzumab ozogamicin in combination with low-intensity chemotherapy for older patients with Philadelphia chromosome-negative acute lymphoblastic leukaemia: a single-arm, phase 2 study. Lancet Oncol. 2018 Feb;19(2):240-248. Epub 2018 Jan 16. link to original article PubMed NCT01371630

R-Hyper-CVAD/R-MA

R-Hyper-CVAD/R-MA: Rituximab, Hyperfractionated Cyclophosphamide, Vincristine, Adriamycin (Doxorubicin), Dexamethasone alternating with Rituximab, Methotrexate, Ara-C (Cytarabine)

Protocol

Study	Evidence
Thomas et al. 2006	Pilot, <20 patients reported
Thomas et al. 2010 (MDACC ID02-230)	Non-randomized

See papers for details of treatment beyond induction/consolidation, which differ substantially between "standard" and "modified" protocols.

Targeted therapy, Part A (cycles 1, 3, 5, 7)

Rituximab (Rituxan) as follows:
- Cycles 1 & 3: 375 mg/m² IV over 2 to 6 hours once per day on days 1 & 11

Chemotherapy, Part A (cycles 1, 3, 5, 7)

Cyclophosphamide (Cytoxan) 300 mg/m² IV over 2 hours every 12 hours on days 1 to 3 (total dose per cycle: 1800 mg/m²)
Vincristine (Oncovin) 2 mg IV once per day on days 4 & 11
Doxorubicin (Adriamycin) 50 mg/m² IV continuous infusion over 24 hours, started on day 4

Glucocorticoid therapy, Part A (cycles 1, 3, 5, 7)

Dexamethasone (Decadron) 40 mg IV or PO once per day on days 1 to 4, 11 to 14

Supportive therapy, Part A (cycles 1, 3, 5, 7)

Mesna (Mesnex) 600 mg/m²/day IV continuous infusion over 72 hours, started on day 1, starting 1 hour before Cyclophosphamide (Cytoxan) and completed 12 hours after the last dose of Cyclophosphamide (Cytoxan) (total dose per cycle: 1800 mg/m²)
Filgrastim (Neupogen) 10 mcg/kg SC once per day, starting 24 hours after completion of chemotherapy, given until WBC greater than 3 x 10⁹/L or bone pain present
ONE of the following antibiotics:
- Fluoroquinolone
- Trimethoprim-Sulfamethoxazole (Bactrim DS) 160/800 mg dose/route not specified
Fluconazole (Diflucan) dose/route not specified
ONE of the following antivirals:
- Acyclovir (Zovirax) dose/route not specified
- Valacyclovir (Valtrex) dose/route not specified

Next cycle to start no sooner than 14 days or as soon as "unmaintained" WBC count is greater than 3 x 10⁹/L and platelet count greater than 50 x 10⁹/L

Targeted therapy, Part B (cycles 2, 4, 6, 8)

Rituximab (Rituxan) as follows:
- Cycles 2 & 4: 375 mg/m² IV over 2 to 6 hours once per day on days 2 & 8

Chemotherapy, Part B (cycles 2, 4, 6, 8)

Methotrexate (MTX) 1000 mg/m² IV continuous infusion over 24 hours, started on day 1
Cytarabine (Ara-C) 3000 mg/m² IV over 2 hours every 12 hours on days 2 & 3 (total dose per cycle: 12,000 mg/m²)

Supportive therapy, Part B (cycles 2, 4, 6, 8)

Folinic acid (Leucovorin) 50 mg IV once on day 3, 12 hours after Methotrexate (MTX) is complete, then 15 mg IV every 6 hours until serum methotrexate level less than 100 nmol/L
Filgrastim (Neupogen) 10 mcg/kg SC once per day, starting on day 4, 24 hours after completion of chemotherapy, given until WBC greater than 3 x 10⁹/L or bone pain present
ONE of the following antibiotics:
- Fluoroquinolone
- Trimethoprim-Sulfamethoxazole (Bactrim DS) 160/800 mg dose/route not specified
Fluconazole (Diflucan) dose/route not specified
ONE of the following antivirals:
- Acyclovir (Zovirax) dose/route not specified
- Valacyclovir (Valtrex) dose/route not specified

Next cycle to start no sooner than 14 days or as soon as "unmaintained" WBC count is greater than 3 x 10⁹/L and platelet count greater than 50 x 10⁹/L

CNS therapy, prophylaxis

Methotrexate (MTX) 12 mg (6 mg if given via Ommaya reservoir) IT once on day 2
Cytarabine (Ara-C) 100 mg IT once on day 7

Given each cycle for a total of 16 intrathecal treatments. If CNS disease present, therapy augmented to twice per week alternating (MTX, ara-C) treatments until CSF cell count normalizes and cytology is negative, then continues for 4 more alternating once per week treatments; prophylaxis course then resumes. 8 alternating cycles

Dose modifications

Cytarabine (Ara-C) reduced to 1000 mg/m² for patients greater than or equal to 60 years old, creatinine greater than or equal to 1.5 mg/dL or 0 hour MTX level greater than or equal to 20,000 nmol/L
Vincristine (Oncovin) reduced to 1 mg for bilirubin greater than 2 mg/dL or NCI common toxicity criteria Grade 2+ peripheral neuropathy, omitted for bilirubin greater than 3 mg/dL or for ileus
Doxorubicin (Adriamycin) reduced by 50% for bilirubin 2 to 3 mg/dL, by 75% for bilirubin 3 to 5 mg/dL (eliminated for bilirubin greater than 5 mg/dL or for gastric/small-bowel involvement with Course 1 to reduce duration of myelosuppression given risk of perforation)
Methotrexate (MTX) reduced by 50% for CrCl 10 to 50 mL/min/1.73m² (eliminated for CrCl less than 10 mL/min/1.73m²), by 25% to 75% for delayed excretion and/or nephrotoxicity with prior course (dependent on severity) or by 50% for pleural effusions/ascites with drainage of fluid as feasible.

References

Thomas DA, Faderl S, O'Brien S, Bueso-Ramos C, Cortes J, Garcia-Manero G, Giles FJ, Verstovsek S, Wierda WG, Pierce SA, Shan J, Brandt M, Hagemeister FB, Keating MJ, Cabanillas F, Kantarjian H. Chemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia. Cancer. 2006 Apr 1;106(7):1569-80. link to original article contains dosing details in manuscript PubMed
1. Update: Fayad L, Thomas D, Romaguera J. Update of the MD Anderson Cancer Center experience with hyper-CVAD and rituximab for the treatment of mantle cell and Burkitt-type lymphomas. Clin Lymphoma Myeloma. 2007 Dec;8 Suppl 2:S57-62. link to original article PubMed
MDACC ID02-230: Thomas DA, O'Brien S, Faderl S, Garcia-Manero G, Ferrajoli A, Wierda W, Ravandi F, Verstovsek S, Jorgensen JL, Bueso-Ramos C, Andreeff M, Pierce S, Garris R, Keating MJ, Cortes J, Kantarjian HM. Chemoimmunotherapy with a modified hyper-CVAD and rituximab regimen improves outcome in de novo Philadelphia chromosome-negative precursor B-lineage acute lymphoblastic leukemia. J Clin Oncol. 2010 Aug 20;28(24):3880-9. Epub 2010 Jul 26. link to original article link to PMC article PubMed NCT00671658

Extended induction therapy

Note: these regimens are used when a pre-specified endpoint during remission induction was not achieved.

Daunorubicin, Pegaspargase, Vincristine, Prednisone

Regimen, "ABFM"

Study	Evidence
Stock et al. 2019 (CALGB 10403)	Non-randomized

ABFM: Augmented Berlin-Frankfurt-Münster regimen

Preceding treatment

ABFM induction, with inadequate response

Chemotherapy

Daunorubicin (Cerubidine) 25 mg/m² IV once on day 1
Pegaspargase (Oncaspar) 2500 units/m² IM or IV once on day 4
Vincristine (Oncovin) 1.5 mg/m² (maximum dose of 2 mg) IV once per day on days 1 & 8

Glucocorticoid therapy

Prednisone (Sterapred) 30 mg/m² IV or PO twice per day on days 1 to 14

2-week course

Subsequent treatment

AALL0232 consolidation

References

CALGB 10403: Stock W, Luger SM, Advani AS, Yin J, Harvey RC, Mullighan CG, Willman CL, Fulton N, Laumann KM, Malnassy G, Paietta E, Parker E, Geyer S, Mrózek K, Bloomfield CD, Sanford B, Marcucci G, Liedtke M, Claxton DF, Foster MC, Bogart JA, Grecula JC, Appelbaum FR, Erba H, Litzow MR, Tallman MS, Stone RM, Larson RA. A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403. Blood. 2019 Apr 4;133(14):1548-1559. Epub 2019 Jan 18. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00558519

Early intensification therapy

CALGB 8811 early intensification

Regimen

Study	Evidence
Larson et al. 1995 (CALGB 8811)	Phase 2

Preceding treatment

Cyclophosphamide, Daunorubicin, L-asparaginase, Vincristine, Prednisone induction ("Course I")

Chemotherapy, "Course II"

Cyclophosphamide (Cytoxan) 1000 mg/m² IV once on day 1
Mercaptopurine (6-MP) 60 mg/m² PO once per day on days 1 to 14
Cytarabine (Ara-C) 75 mg/m² SC once per day on days 1 to 4, 8 to 11
Vincristine (Oncovin) 2 mg IV once per day on days 15 & 22
Asparaginase (Elspar) 6000 units/m² SC once per day on days 15, 18, 22, 25

CNS therapy, prophylaxis

Methotrexate (MTX) 15 mg IT once on day 1

28-day cycle for 2 cycles

Subsequent treatment

Mercaptopurine, Methotrexate, WB-XRT interim maintenance ("Course III")

References

CALGB 8811: Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR, Hooberman AL, Westbrook CA, Arthur DC, George SL, Bloomfield CD, Schiffer CA. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: Cancer and Leukemia Group B study 8811. Blood. 1995 Apr 15;85(8):2025-37. link to original article contains dosing details in manuscript PubMed

L-Asparaginase & Methotrexate

Note: Asparaginase (Elspar) was discontinued by the manufacturer in December 2012, and is now essentially out of stock. Alternatives include Pegaspargase (Oncaspar) or Asparaginase Erwinia chrysanthemi (Erwinaze).

Regimen

Study	Evidence
Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)	Non-randomized portion of RCT

Preceding treatment

Cyclophosphamide, Cytarabine, Mercaptopurine induction ("Phase 2")

Chemotherapy

Methotrexate (MTX) 3000 mg/m² IV once per day on days 1, 8, 22
Asparaginase (Elspar) 10,000 units (route not specified) once per day on days 2, 9, 23

Supportive therapy

Folinic acid (Leucovorin) at "standard" doses

3 cycles (length of cycle not specified in original reference)

Subsequent treatment

Patients who were younger than 50 years of age and had an HLA-matched sibling donor, as well as Ph+ patients with any donor: Etoposide & TBI, then allo HSCT
All others: Etoposide & TBI, then auto HSCT versus International ALL Trial consolidation

References

MRC UKALL XII/ECOG E2993: Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. link to original article contains dosing details in manuscript PubMed NCT00002514
1. Update: Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, Burnett AK, Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J, McMillan A, Franklin IM, Luger S, Ciobanu N, Rowe JM. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008 Feb 15;111(4):1827-33. Epub 2007 Nov 29. link to original article PubMed
2. Update: Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, Marks DI, McMillan AK, Litzow MR, Lazarus HM, Foroni L, Dewald G, Franklin IM, Luger SM, Paietta E, Wiernik PH, Tallman MS, Goldstone AH. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009 May 7;113(19):4489-96. Epub 2009 Feb 24. link to original article link to PMC article PubMed
3. Update: Fielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow MR, Lazarus H, Luger SM, Marks DI, McMillan AK, Moorman AV, Patel B, Paietta E, Tallman MS, Goldstone AH. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014 Feb 6;123(6):843-50. Epub 2013 Nov 25. link to original article contains dosing details in manuscript link to PMC article PubMed

Consolidation after upfront therapy (including post-remission therapy)

Note that many of these regimens are complex and as such will be referred to by their study name, not by the individual drug names. This is also a phase of treatment often referred to as post-remission or postinduction therapy.

AALL0232 consolidation

Regimen

Study	Evidence
Stock et al. 2019 (CALGB 10403)	Non-randomized

Preceding treatment

ABFM induction

Chemotherapy

Cyclophosphamide (Cytoxan) 1000 mg/m² IV once per day on days 1 & 29
Cytarabine (Ara-C) 75 mg/m² IV or SC once per day on days 1 to 4, 8 to 11, 29 to 32, 36 to 39
Mercaptopurine (6-MP) 60 mg/m² PO once per day on days 1 to 14, 29 to 42
Pegaspargase (Oncaspar) 2500 units/m² IM or IV once per day on days 15 & 43
Vincristine (Oncovin) 1.5 mg/m² (maximum dose of 2 mg) IV once per day on days 15, 22, 43, 50

50-day course

Subsequent treatment

6-MP, Capizzi MTX, Pegaspargase interim maintenance

References

CALGB 10403: Stock W, Luger SM, Advani AS, Yin J, Harvey RC, Mullighan CG, Willman CL, Fulton N, Laumann KM, Malnassy G, Paietta E, Parker E, Geyer S, Mrózek K, Bloomfield CD, Sanford B, Marcucci G, Liedtke M, Claxton DF, Foster MC, Bogart JA, Grecula JC, Appelbaum FR, Erba H, Litzow MR, Tallman MS, Stone RM, Larson RA. A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403. Blood. 2019 Apr 4;133(14):1548-1559. Epub 2019 Jan 18. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00558519

Blinatumomab monotherapy

Regimen

Study	Years of enrollment	Evidence	Efficacy
Gökbuget et al. 2018 (BLAST)	2010-2014	Phase 2 (RT)	CR after 1 cycle: 78%

Note: these patients had MRD after induction; also note that this is BSA-based dosing.

Preceding treatment

"A minimum of 3 blocks of intensive chemotherapy"

Immunotherapy

Blinatumomab (Blincyto) 15 mcg/m²/day IV continuous infusion over 28 days, started on day 1 (total dose per cycle: 420 mcg/m²)

42-day cycle for up to 4 cycles

Subsequent treatment

Patients who had an allogeneic donor could proceed to allogeneic hematopoietic stem cell transplant any time after cycle 1

References

BLAST: Gökbuget N, Dombret H, Bonifacio M, Reichle A, Graux C, Faul C, Diedrich H, Topp MS, Brüggemann M, Horst HA, Havelange V, Stieglmaier J, Wessels H, Haddad V, Benjamin JE, Zugmaier G, Nagorsen D, Bargou RC. Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood. 2018 Apr 5;131(14):1522-1531. Epub 2018 Jan 22. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01207388
1. Update: Gökbuget N, Zugmaier G, Dombret H, Stein A, Bonifacio M, Graux C, Faul C, Brüggemann M, Taylor K, Mergen N, Reichle A, Horst HA, Havelange V, Topp MS, Bargou RC. Curative outcomes following blinatumomab in adults with minimal residual disease B-cell precursor acute lymphoblastic leukemia. Leuk Lymphoma. 2020 Nov;61(11):2665-2673. Epub 2020 Jul 3. link to original article PubMed

Cyclophosphamide & TBI, then allo HSCT

Cy/TBI: Cyclophosphamide & Total Body Irradiation

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Thomas et al. 1979	1976-1977	Non-randomized
Sebban et al. 1994 (LALA 87)	1986-1991	Phase 3 (E-esc)	Chemotherapy or Auto HSCT	Did not meet primary endpoint of OS60
Thomas et al. 2004 (LALA-94)	1994-2002	Non-randomized portion of RCT

Details in most of the manuscripts are limited.

Chemotherapy

Cyclophosphamide (Cytoxan) 60 mg/kg IV once per day on days -3 & -2

Radiotherapy

Total body irradiation by the following study-specific criteria:
- Zhang et al. 2023: 450 cGy once per day on days -5 & -4 (900 cGy total)
- Other studies: 10 to 1200 cGy total

Immunotherapy

Allogeneic stem cells transfused on day 0

One course

Immunotherapy

Allogeneic stem cells

Stem cells transfused on day 0

References

Thomas ED, Sanders JE, Flournoy N, Johnson FL, Buckner CD, Clift RA, Fefer A, Goodell BW, Storb R, Weiden PL. Marrow transplantation for patients with acute lymphoblastic leukemia in remission. Blood. 1979 Aug;54(2):468-76. link to original article contains dosing details in abstract PubMed
LALA 87: Sebban C, Lepage E, Vernant JP, Gluckman E, Attal M, Reiffers J, Sutton L, Racadot E, Michallet M, Maraninchi D, Dreyfus F, Fiere D; French Group of Therapy of Adult Acute Lymphoblastic Leukemia. Allogeneic bone marrow transplantation in adult acute lymphoblastic leukemia in first complete remission: a comparative study. J Clin Oncol. 1994 Dec;12(12):2580-7. link to original article PubMed
1. Update: Thiebaut A, Vernant JP, Degos L, Huguet FR, Reiffers J, Sebban C, Lepage E, Thomas X, Fière D. Adult acute lymphocytic leukemia study testing chemotherapy and autologous and allogeneic transplantation: a follow-up report of the French protocol LALA 87. Hematol Oncol Clin North Am. 2000 Dec;14(6):1353-66. link to original article PubMed
LALA-94: Thomas X, Boiron JM, Huguet F, Dombret H, Bradstock K, Vey N, Kovacsovics T, Delannoy A, Fegueux N, Fenaux P, Stamatoullas A, Vernant JP, Tournilhac O, Buzyn A, Reman O, Charrin C, Boucheix C, Gabert J, Lhéritier V, Fiere D. Outcome of treatment in adults with acute lymphoblastic leukemia: analysis of the LALA-94 trial. J Clin Oncol. 2004 Oct 15;22(20):4075-86. Epub 2004 Sep 7. link to original article contains dosing details in manuscript PubMed NCT00002700
1. Update: Vey N, Thomas X, Picard C, Kovascovicz T, Charin C, Cayuela JM, Dombret H, Dastugue N, Huguet F, Bastard C, Stamatoulas A, Giollant M, Tournilhac O, Macintyre E, Buzyn A, Bories D, Kuentz M, Dreyfus F, Delannoy A, Raynaud S, Gratecos N, Bordessoule D, de Botton S, Preudhomme C, Reman O, Troussard X, Pigneux A, Bilhou C, Vernant JP, Boucheix C, Gabert J; GET-LALA Group the Swiss Group for Clinical Cancer Research (SAKK). Allogeneic stem cell transplantation improves the outcome of adults with t(1;19)/E2A-PBX1 and t(4;11)/MLL-AF4 positive B-cell acute lymphoblastic leukemia: results of the prospective multicenter LALA-94 study. Leukemia. 2006 Dec;20(12):2155-61. Epub 2006 Oct 12. link to original article PubMed

Etoposide & TBI, then allo HSCT

Regimen

Study	Evidence
Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)	Non-randomized portion of RCT

Chemotherapy

Etoposide (Vepesid) 60 mg/kg IV once on day -3

Radiotherapy

Total body irradiation (TBI) 220 cGy twice per day in 6 fractions on days -6 to -4 (total dose: 1320 cGy)

Immunotherapy

Allogeneic stem cells transfused on day 0

One course

Immunotherapy

Allogeneic stem cells

Stem cells transfused on day 0

References

MRC UKALL XII/ECOG E2993: Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. link to original article contains dosing details in manuscript PubMed NCT00002514
1. Update: Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, Burnett AK, Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J, McMillan A, Franklin IM, Luger S, Ciobanu N, Rowe JM. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008 Feb 15;111(4):1827-33. Epub 2007 Nov 29. link to original article PubMed
2. Update: Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, Marks DI, McMillan AK, Litzow MR, Lazarus HM, Foroni L, Dewald G, Franklin IM, Luger SM, Paietta E, Wiernik PH, Tallman MS, Goldstone AH. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009 May 7;113(19):4489-96. Epub 2009 Feb 24. link to original article link to PMC article PubMed
3. Update: Fielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow MR, Lazarus H, Luger SM, Marks DI, McMillan AK, Moorman AV, Patel B, Paietta E, Tallman MS, Goldstone AH. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014 Feb 6;123(6):843-50. Epub 2013 Nov 25. link to original article contains dosing details in manuscript link to PMC article PubMed

International ALL Trial

Protocol

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)	1993-2003	Phase 3 (C)	Etoposide & TBI, then auto HSCT	Seems to have superior OS

Preceding treatment

L-asparaginase & Methotrexate intensification

Chemotherapy, Cycle 1

Cytarabine (Ara-C) 75 mg/m² IV once per day on days 1 to 5
Etoposide (Vepesid) 100 mg/m² IV once per day on days 1 to 5
Vincristine (Oncovin) 1.4 mg/m² IV once per day on days 1, 8, 15, 22

Glucocorticoid therapy

Dexamethasone (Decadron) 10 mg/m² PO once per day on days 1 to 28

4-week course, followed by:

Chemotherapy, Cycle 2

Cytarabine (Ara-C) 75 mg/m² IV once per day on days 1 to 5
Etoposide (Vepesid) 100 mg/m² IV once per day on days 1 to 5

4-week course, followed by:

Chemotherapy, Cycle 3

Daunorubicin (Cerubidine) 25 mg/m² IV once per day on days 1, 8, 15, 22
Cyclophosphamide (Cytoxan) 650 mg/m² IV once on day 29
Cytarabine (Ara-C) 75 mg/m² IV once per day on days 31 to 34, 38 to 41
Thioguanine (Tabloid) 60 mg/m² PO once per day on days 29 to 42

8-week course, followed by:

Chemotherapy, Cycle 4

Cytarabine (Ara-C) 75 mg/m² IV once per day on days 1 to 5
Etoposide (Vepesid) 100 mg/m² IV once per day on days 1 to 5

CNS therapy, prophylaxis

Cytarabine (Ara-C) 50 mg IT once per week for 4 weeks, then once per quarter for 4 doses
Whole-brain irradiation to 2400 cGy

Subsequent treatment

POMP maintenance

References

MRC UKALL XII/ECOG E2993: Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. link to original article contains dosing details in manuscript PubMed NCT00002514
1. Update: Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, Burnett AK, Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J, McMillan A, Franklin IM, Luger S, Ciobanu N, Rowe JM. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008 Feb 15;111(4):1827-33. Epub 2007 Nov 29. link to original article PubMed
2. Update: Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, Marks DI, McMillan AK, Litzow MR, Lazarus HM, Foroni L, Dewald G, Franklin IM, Luger SM, Paietta E, Wiernik PH, Tallman MS, Goldstone AH. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009 May 7;113(19):4489-96. Epub 2009 Feb 24. link to original article link to PMC article PubMed
3. Update: Fielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow MR, Lazarus H, Luger SM, Marks DI, McMillan AK, Moorman AV, Patel B, Paietta E, Tallman MS, Goldstone AH. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014 Feb 6;123(6):843-50. Epub 2013 Nov 25. link to original article contains dosing details in manuscript link to PMC article PubMed

Mercaptopurine, Methotrexate, Vincristine

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Sakura et al. 2017 (JALSG ALL202-O)	2002-2011	Phase 3 (E-esc)	MTX, 6-MP, Vincristine; intermediate-dose MTX	Seems to have superior DFS

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment. Given as cycles 2 and 5 of consolidation for patients younger than 50.

Chemotherapy

Mercaptopurine (6-MP) 25 mg/m² PO once per day on days 1 to 21
Methotrexate (MTX) 3000 mg/m² IV once per day on days 1 & 15
Vincristine (Oncovin) 1.3 mg/m² (maximum dose of 2 mg) IV once per day on days 1 & 15

CNS therapy

Methotrexate (MTX) 15 mg IT once per day on days 1 & 15
Dexamethasone (Decadron) 4 mg IT once per day on days 1 & 15

Supportive therapy

Folinic acid (Leucovorin) 50 mg IV once, then 15 mg IV every 6 hours for a total of 8 doses, beginning 36 h after the start of Methotrexate (MTX) infusion

References

JALSG ALL202-O: Sakura T, Hayakawa F, Sugiura I, Murayama T, Imai K, Usui N, Fujisawa S, Yamauchi T, Yujiri T, Kakihana K, Ito Y, Kanamori H, Ueda Y, Miyata Y, Kurokawa M, Asou N, Ohnishi K, Ohtake S, Kobayashi Y, Matsuo K, Kiyoi H, Miyazaki Y, Naoe T. High-dose methotrexate therapy significantly improved survival of adult acute lymphoblastic leukemia: a phase III study by JALSG. Leukemia. 2018 Mar;32(3):626-632. Epub 2017 Sep 15.link to original article contains dosing details in manuscript PubMed UMIN C000000063

Linker regimen (consolidation)

Protocol

Study	Years of enrollment	Evidence
Linker et al. 1987	1980-1986	Phase 2

Each cycle is approximately one month, based on recovery of ANC to greater than 1000/uL and platelet count to greater than 100 x 10⁹/L.

Preceding treatment

DOLP induction

Chemotherapy, Treatment A (cycles 1, 3, 5, 7)

Daunorubicin (Cerubidine) 50 mg/m² IV once per day on days 1 & 2
Vincristine (Oncovin) 2 mg IV once per day on days 1 & 8
Asparaginase (Elspar) 12,000 units/m² IM once per day on days 2, 4, 7, 9, 11, 14

Glucocorticoid therapy

Prednisone (Sterapred) 60 mg/m² PO once per day on days 1 to 14

Approximately one-month cycle

Chemotherapy, Treatment B (cycles 2, 4, 6, 8)

Teniposide (Vumon) 165 mg/m² IV once per day on days 1, 4, 8, 11
Cytarabine (Ara-C) 300 mg/m² IV once per day on days 1, 4, 8, 11

Approximately one-month cycle

Chemotherapy, Treatment C (cycle 9)

Methotrexate (MTX) 690 mg/m² IV continuous infusion over 42 hours, started on day 1
Asparaginase (Elspar) 12,000 units/m² IM once per day on days 2, 4, 7, 9, 11, 14

Glucocorticoid therapy

Prednisone (Sterapred) 60 mg/m² PO once per day on days 1 to 14

Approximately one-month cycle

Supportive therapy

Folinic acid (Leucovorin) 15 mg/m² IV every 6 hours on days 3 to 5, starting after Methotrexate (MTX) is complete (at 42 hours)

Subsequent treatment

6-MP & MTX maintenance

References

Linker CA, Levitt LJ, O'Donnell M, Ries CA, Link MP, Forman SJ, Farbstein MJ. Improved results of treatment of adult acute lymphoblastic leukemia. Blood. 1987 Apr;69(4):1242-8. link to original article contains dosing details in manuscript PubMed content property of HemOnc.org
1. Update: Linker CA, Levitt LJ, O'Donnell M, Forman SJ, Ries CA. Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report. Blood. 1991 Dec 1;78(11):2814-22. link to original article contains dosing details in manuscript PubMed

Pediatric-like GRAALL consolidation

Protocol

Study	Years of enrollment	Evidence
Huguet et al. 2009 (GRAALL-2003)	2003-2005	Phase 2

Note: the original article Table 1 has several errors which were corrected in the erratum and the online Table 1. These corrected doses are replicated here. Also note that each consolidation "block" flows into the next A->B->C and days are scheduled thusly.

Preceding treatment

Cyclophosphamide, Daunorubicin, L-asparaginase, Vincristine, Prednisone induction or Cytarabine & Idarubicin salvage

Chemotherapy, Consolidation A (Cycles 1, 4, 7)

Cytarabine (Ara-C) 2000 mg/m² IV every 12 hours on days 1 & 2
Asparaginase (Elspar) 10,000 units/m² (route not specified) once on day 3

Glucocorticoid therapy

Dexamethasone (Decadron) 10 mg (route not specified) every 12 hours on days 1 & 2

Supportive therapy

Lenograstim (Granocyte) 150 mcg/m² SC once per day on days 7 to 13

Chemotherapy, Consolidation B (Cycles 2, 5, 8)

Methotrexate (MTX) 3000 mg/m² IV continuous infusion (duration not specified), started on day 15
Vincristine (Oncovin) 2 mg IV once on day 15
Asparaginase (Elspar) 10,000 units/m² (route not specified) once on day 16
Mercaptopurine (6-MP) 60 mg/m² PO once per day on days 15 to 21

Supportive therapy

Lenograstim (Granocyte) 150 mcg/m² SC once per day on days 22 to 27

Chemotherapy, Consolidation C (Cycles 3, 6, 9)

Cyclophosphamide (Cytoxan) 500 mg/m² IV once per day on days 29 & 30
Etoposide (Vepesid) 75 mg/m² IV once per day on days 29 & 30
Methotrexate (MTX) 25 mg/m² (route not specified) once on day 29

Supportive therapy

Lenograstim (Granocyte) 150 mcg/m² SC once per day from day 31 until myeloid recovery

Subsequent treatment

Patients with CR after induction: Cyclophosphamide, daunorubicin, L-asparaginase, vincristine, prednisone late intensification between cycles 6 and 7
Patients with CR after salvage: Cytarabine & idarubicin late intensification between cycles 6 and 7
All patients: POMP maintenance after completion of consolidation

References

GRAALL-2003: Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. link to original article contains dosing details in manuscript PubMed NCT00222027

Interim maintenance

Mercaptopurine, Methotrexate, WB-XRT

Regimen

Study	Evidence
Larson et al. 1995 (CALGB 8811)	Phase 2

Preceding treatment

Larson regimen (CALGB 8811) early intensification ("Course II")

Chemotherapy, ("Course III")

Mercaptopurine (6-MP) 60 mg/m² PO once per day on days 1 to 70
Methotrexate (MTX) 20 mg/m² PO once per day on days 36, 43, 50, 57, 64

Radiotherapy

Cranial radiation, 24 Gy total given in 10 fractions from days 1 to 12

CNS therapy, prophylaxis

Methotrexate (MTX) 15 mg IT once per day on days 1, 8, 15, 22, 29

12-week course

Subsequent treatment

Larson regimen (CALGB 8811) late intensification ("Course IV")

References

CALGB 8811: Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR, Hooberman AL, Westbrook CA, Arthur DC, George SL, Bloomfield CD, Schiffer CA. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: Cancer and Leukemia Group B study 8811. Blood. 1995 Apr 15;85(8):2025-37. link to original article contains dosing details in manuscript PubMed

Methotrexate & Pegaspargase

Regimen

Study	Evidence
Stock et al. 2019 (CALGB 10403)	Non-randomized

Note: the instructions for dose escalation of MTX in the manuscript are confusing; the authors have been contacted for clarification.

Preceding treatment

AALL0232 consolidation ("Course II")

Chemotherapy

Methotrexate (MTX) 100 mg/m² IV once on day 1, then 150 mg/m² IV once on day 11, then 200 mg/m² IV once on day 21, then 250 mg/m² IV once on day 31, then 300 mg/m² IV once on day 41
Pegaspargase (Oncaspar) 2500 units IM or IV once per day on days 2 & 22

CNS therapy, prophylaxis

Methotrexate (MTX) 15 mg IT once per day on days 1 & 31

42-day course

Subsequent treatment

Delayed intensification ("Course IV")

References

CALGB 10403: Stock W, Luger SM, Advani AS, Yin J, Harvey RC, Mullighan CG, Willman CL, Fulton N, Laumann KM, Malnassy G, Paietta E, Parker E, Geyer S, Mrózek K, Bloomfield CD, Sanford B, Marcucci G, Liedtke M, Claxton DF, Foster MC, Bogart JA, Grecula JC, Appelbaum FR, Erba H, Litzow MR, Tallman MS, Stone RM, Larson RA. A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403. Blood. 2019 Apr 4;133(14):1548-1559. Epub 2019 Jan 18. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00558519

Late intensification

Cyclophosphamide, Cytarabine, Pegaspargase, Thioguanine, Vincristine, Dexamethasone

Regimen

Study	Evidence
Stock et al. 2019 (CALGB 10403)	Non-randomized

Note: also known as delayed intensification "Course IV".

Preceding treatment

MTX & Pegaspargase interim maintenance

Chemotherapy

Cyclophosphamide (Cytoxan) 1000 mg/m² IV once on day 29
Cytarabine (Ara-C) 75 mg/m² IV or SC once per day on days 29 to 32, 36 to 39
Pegaspargase (Oncaspar) 2500 units/m² IM or IV once per day on days 4 +/-1 day & 43
Thioguanine (Tabloid) 60 mg/m² PO once per day on days 29 to 42
Vincristine (Oncovin) 1.5 mg/m² (maximum dose of 2 mg) IV once per day on days 1, 8, 43, 50

Glucocorticoid therapy

Dexamethasone (Decadron) 5 mg/m² PO or IV twice per day on days 1 to 7, 15 to 21

CNS therapy, prophylaxis

Methotrexate (MTX) 15 mg IT once per day on days 1, 29, 36

50-day course

Subsequent treatment

Mercaptopurine, Methotrexate, Vincristine, Dexamethasone maintenance

References

CALGB 10403: Stock W, Luger SM, Advani AS, Yin J, Harvey RC, Mullighan CG, Willman CL, Fulton N, Laumann KM, Malnassy G, Paietta E, Parker E, Geyer S, Mrózek K, Bloomfield CD, Sanford B, Marcucci G, Liedtke M, Claxton DF, Foster MC, Bogart JA, Grecula JC, Appelbaum FR, Erba H, Litzow MR, Tallman MS, Stone RM, Larson RA. A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403. Blood. 2019 Apr 4;133(14):1548-1559. Epub 2019 Jan 18. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00558519

Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone

Regimen

Study	Years of enrollment	Evidence
Huguet et al. 2009 (GRAALL-2003)	2003-2005	Phase 2

Note: the original article Table 1 has several errors which were corrected in the erratum and the online Table 1. These corrected doses are replicated here.

Preceding treatment

Pediatric-like GRAALL consolidation cycle 6, if patients achieved CR1 after cyclophosphamide, daunorubicin, L-asparaginase, vincristine, prednisone induction

Chemotherapy

Cyclophosphamide (Cytoxan) 500 mg/m² IV every 12 hours on day 15
Daunorubicin (Cerubidine) 30 mg/m² IV once per day on days 1 to 3
Asparaginase (Elspar) 6000 units/m²/day (route not specified) on days 8, 10, 12, 18, 20, 22
Vincristine (Oncovin) 2 mg IV once per day on days 1, 8, 15

Glucocorticoid therapy

Prednisone (Sterapred) 60 mg/m²/day PO on days 1 to 14

Supportive therapy

Lenograstim (Granocyte) 150 mcg/m² SC once per day if ANC less than 500/uL until myeloid recovery

Subsequent treatment

Pediatric-like GRAALL consolidation

References

GRAALL-2003: Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. link to original article contains dosing details in manuscript PubMed NCT00222027

Cytarabine & Idarubicin

Regimen

Study	Years of enrollment	Evidence
Huguet et al. 2009 (GRAALL-2003)	2003-2005	Phase 2

Note: the original article Table 1 has several errors which were corrected in the erratum and the online Table 1. These corrected doses are replicated here.

Preceding treatment

Pediatric-like GRAALL consolidation cycle 6, if patients achieved CR1 after cytarabine & idarubicin salvage

Chemotherapy

Cytarabine (Ara-C) 2000 mg/m² IV every 12 hours on days 1 to 4
Idarubicin (Idamycin) 9 mg/m² IV once per day on days 1 to 3

Supportive therapy

Lenograstim (Granocyte) 150 mcg/m² SC once per day from day 9 until myeloid recovery

Subsequent treatment

Pediatric-like GRAALL consolidation

References

GRAALL-2003: Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. link to original article contains dosing details in manuscript PubMed NCT00222027

CALGB 8811 late intensification

Regimen

Study	Evidence
Larson et al. 1995 (CALGB 8811)	Phase 2

Preceding treatment

Mercaptopurine, Methotrexate, WB-XRT interim maintenance ("Course III")

Chemotherapy, "Course IV"

Doxorubicin (Adriamycin) 30 mg/m² IV once per day on days 1, 8, 15
Vincristine (Oncovin) 2 mg IV once per day on days 1, 8, 15
Cyclophosphamide (Cytoxan) 1000 mg/m² IV once on day 29
Thioguanine (Tabloid) 60 mg/m² PO once per day on days 29 to 42
Cytarabine (Ara-C) 75 mg/m² SC once per day on days 29 to 32, 36 to 39

Glucocorticoid therapy

Dexamethasone (Decadron) 10 mg/m² PO once per day on days 1 to 14

8-week course

Subsequent treatment

POMP maintenance ("Course V")

References

CALGB 8811: Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR, Hooberman AL, Westbrook CA, Arthur DC, George SL, Bloomfield CD, Schiffer CA. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: Cancer and Leukemia Group B study 8811. Blood. 1995 Apr 15;85(8):2025-37. link to original article contains dosing details in manuscript PubMed

Maintenance after upfront therapy

Mercaptopurine, Methotrexate, Vincristine, Dexamethasone

Regimen variant #1, 2 years

Study	Evidence
Stock et al. 2019 (CALGB 10403)	Non-randomized

Note: also known as maintenance "Course V". This duration was intended for female patients.

Preceding treatment

Delayed intensification "Course IV"

Chemotherapy

Mercaptopurine (6-MP) 75 mg/m² PO once per day
Methotrexate (MTX) as follows:
- Cycles 1 to 4: 20 mg/m² PO once per day on days 8, 15, 22, 36, 43, 50, 57, 64, 71, 78
- Cycles 5 to 8: 20 mg/m² PO once per day on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78
Vincristine (Oncovin) 1.5 mg (maximum dose of 2 mg) IV once per day on days 1, 29, 57

Glucocorticoid therapy

Dexamethasone (Decadron) 3 mg/m² PO or IV twice per day on days 1 to 5, 29 to 33, 57 to 61

CNS therapy, prophylaxis

Methotrexate (MTX) as follows:
- Cycles 1 to 4: 15 mg IT once per day on days 1 & 29
- Cycles 5 to 8: 15 mg IT once on day 1

12-week cycle for 8 cycles (2 years)

Regimen variant #2, 3 years

Study	Evidence
Stock et al. 2019 (CALGB 10403)	Non-randomized

Note: also known as maintenance "Course V". This duration was intended for male patients.

Preceding treatment

Delayed intensification "Course IV"

Chemotherapy

Mercaptopurine (6-MP) 75 mg/m² PO once per day
Methotrexate (MTX) as follows:
- Cycles 1 to 4: 20 mg/m² PO once per day on days 8, 15, 22, 36, 43, 50, 57, 64, 71, 78
- Cycles 5 to 12: 20 mg/m² PO once per day on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78
Vincristine (Oncovin) 1.5 mg (maximum dose of 2 mg) IV once per day on days 1, 29, 57

Glucocorticoid therapy

Dexamethasone (Decadron) 3 mg/m² PO or IV twice per day on days 1 to 5, 29 to 33, 57 to 61

CNS therapy, prophylaxis

Methotrexate (MTX) as follows:
- Cycles 1 to 4: 15 mg IT once per day on days 1 & 29
- Cycles 5 to 12: 15 mg IT once on day 1

12-week cycle for 12 cycles (3 years)

References

CALGB 10403: Stock W, Luger SM, Advani AS, Yin J, Harvey RC, Mullighan CG, Willman CL, Fulton N, Laumann KM, Malnassy G, Paietta E, Parker E, Geyer S, Mrózek K, Bloomfield CD, Sanford B, Marcucci G, Liedtke M, Claxton DF, Foster MC, Bogart JA, Grecula JC, Appelbaum FR, Erba H, Litzow MR, Tallman MS, Stone RM, Larson RA. A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403. Blood. 2019 Apr 4;133(14):1548-1559. Epub 2019 Jan 18. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00558519

Mercaptopurine & Methotrexate

Regimen

Study	Years of enrollment	Evidence
Linker et al. 1987	1980-1986	Phase 2

Preceding treatment

Linker regimen consolidation

Chemotherapy

Mercaptopurine (6-MP) 75 mg/m² PO once per day
Methotrexate (MTX) 20 mg/m² PO once on day 1

7-day cycle for 130 cycles (30 months)

References

Linker CA, Levitt LJ, O'Donnell M, Ries CA, Link MP, Forman SJ, Farbstein MJ. Improved results of treatment of adult acute lymphoblastic leukemia. Blood. 1987 Apr;69(4):1242-8. link to original article contains dosing details in manuscript PubMed
1. Update: Linker CA, Levitt LJ, O'Donnell M, Forman SJ, Ries CA. Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report. Blood. 1991 Dec 1;78(11):2814-22. link to original article contains dosing details in manuscript PubMed

POMP

POMP: Purinethol (Mercaptopurine), Oncovin (Vincristine), Methotrexate, Prednisone

Regimen variant #1

Study	Years of enrollment	Evidence
Huguet et al. 2009 (GRAALL-2003)	2003-2005	Phase 2

Preceding treatment

Pediatric-like GRAALL consolidation

Chemotherapy

Mercaptopurine (6-MP) 60 mg/m² PO once per day
Vincristine (Oncovin) as follows:
- Months 1 to 12: 2 mg IV once on day 1
Methotrexate (MTX) 25 mg/m² PO once per day on days 1, 8, 15, 22

Glucocorticoid therapy

Prednisone (Sterapred) as follows:
- Months 1 to 12: 40 mg/m²/day PO on days 1 to 7

1-month cycle for 24 cycles (2 years)

Regimen variant #2

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)	1993-2003	Phase 3 (C)	Etoposide & TBI, then auto HSCT	Seems to have superior OS

Preceding treatment

International ALL Trial consolidation

Chemotherapy

Mercaptopurine (6-MP) 75 mg/m² PO once per day
Vincristine (Oncovin) 1.4 mg/m² IV once on day 1
Methotrexate (MTX) 20 mg/m² IV or PO once per week

Glucocorticoid therapy

Prednisone (Sterapred) 60 mg/m² PO once per day on days 1 to 5

3-month cycle for 10 cycles (2.5 years from the start of phase III)

Regimen variant #3

Study	Evidence
Kantarjian et al. 2000	Phase 2

Note: this is the IV POMP used from 1995 onwards. Exact timing of drugs is not given, for example, that certain drugs are taken on days 1 to 5 of the cycle.

Preceding treatment

Hyper-CVAD/MA x 8

Chemotherapy

Mercaptopurine (6-MP) 1000 mg/m² IV over 60 minutes once per day on days 1 to 5
Vincristine (Oncovin) 2 mg IV once on day 1
Methotrexate (MTX) 10 mg/m² IV over 60 minutes once per day on days 1 to 5

Glucocorticoid therapy

Prednisone (Sterapred) 200 mg PO once per day on days 1 to 5

Supportive therapy

Trimethoprim/Sulfamethoxazole (dose not specified) PO twice per day on Saturday and Sunday for the first 6 months
ONE of the following antivirals, for the first 6 months:
- Acyclovir (Zovirax) 200 mg PO once per day or 3 times per week
- Valacyclovir (Valtrex) 500 mg PO once per day or 3 times per week

1-month cycle for 24 cycles (2 years)

Regimen variant #4

Study	Evidence
Larson et al. 1995 (CALGB 8811)	Phase 2

Preceding treatment

Larson regimen (CALGB 8811) late intensification ("Course IV")

Chemotherapy, "Course V"

Mercaptopurine (6-MP) 60 mg/m² PO once per day on days 1 to 28
Vincristine (Oncovin) 2 mg IV once on day 1
Methotrexate (MTX) 20 mg/m² PO once per day on days 1, 8, 15, 22

Glucocorticoid therapy

Prednisone (Sterapred) 60 mg/m² PO once per day on days 1 to 5

28-day cycles, continue until 24 months from diagnosis

References

CALGB 8811: Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR, Hooberman AL, Westbrook CA, Arthur DC, George SL, Bloomfield CD, Schiffer CA. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: Cancer and Leukemia Group B study 8811. Blood. 1995 Apr 15;85(8):2025-37. link to original article contains dosing details in manuscript PubMed
Kantarjian HM, O'Brien S, Smith TL, Cortes J, Giles FJ, Beran M, Pierce S, Huh Y, Andreeff M, Koller C, Ha CS, Keating MJ, Murphy S, Freireich EJ. Results of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia. J Clin Oncol. 2000 Feb;18(3):547-61. link to original article contains dosing details in manuscript PubMed
1. Update: Kantarjian H, Thomas D, O'Brien S, Cortes J, Giles F, Jeha S, Bueso-Ramos CE, Pierce S, Shan J, Koller C, Beran M, Keating M, Freireich EJ. Long-term follow-up results of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD), a dose-intensive regimen, in adult acute lymphocytic leukemia. Cancer. 2004 Dec 15;101(12):2788-801. link to original article contains dosing details in manuscript PubMed
MRC UKALL XII/ECOG E2993: Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. link to original article contains dosing details in manuscript PubMed NCT00002514
1. Update: Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, Burnett AK, Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J, McMillan A, Franklin IM, Luger S, Ciobanu N, Rowe JM. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008 Feb 15;111(4):1827-33. Epub 2007 Nov 29. link to original article PubMed
2. Update: Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, Marks DI, McMillan AK, Litzow MR, Lazarus HM, Foroni L, Dewald G, Franklin IM, Luger SM, Paietta E, Wiernik PH, Tallman MS, Goldstone AH. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009 May 7;113(19):4489-96. Epub 2009 Feb 24. link to original article link to PMC article PubMed
3. Update: Fielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow MR, Lazarus H, Luger SM, Marks DI, McMillan AK, Moorman AV, Patel B, Paietta E, Tallman MS, Goldstone AH. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014 Feb 6;123(6):843-50. Epub 2013 Nov 25. link to original article contains dosing details in manuscript link to PMC article PubMed
GRAALL-2003: Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. link to original article contains dosing details in manuscript PubMed NCT00222027

Relapsed or refractory

Augmented Hyper-CVAD & Asparaginase

Regimen

Study	Evidence
Faderl et al. 2011	Phase 2

To be completed

Chemotherapy

Glucocorticoid therapy

Dexamethasone (Decadron)

References

Faderl S, Thomas DA, O'Brien S, Ravandi F, Garcia-Manero G, Borthakur G, Ferrajoli A, Verstovsek S, Ayoubi M, Rytting M, Feliu J, Kantarjian HM. Augmented hyper-CVAD based on dose-intensified vincristine, dexamethasone, and asparaginase in adult acute lymphoblastic leukemia salvage therapy. Clin Lymphoma Myeloma Leuk. 2011 Feb;11(1):54-9. link to original article PubMed

Blinatumomab monotherapy

Regimen variant #1

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Topp et al. 2014 (MT103-211)	2012-2013	Phase 2 (RT)
Kantarjian et al. 2017 (TOWER)	2014-2015	Phase 3 (E-RT-switch-ooc)	Standard re-induction chemotherapy	Superior OS

The most common comparator in TOWER was FLAG +/- anthracycline.

Immunotherapy

Blinatumomab (Blincyto) as follows:
- Cycle 1: 9 mcg/day IV continuous infusion over 7 days, started on day 1, then 28 mcg/day IV continuous infusion over 21 days, started on day 8 (total dose: 651 mcg)
- Cycles 2 to 5: 28 mcg/day IV continuous infusion over 28 days, started on day 1 (total dose per cycle: 784 mcg)

42-day cycle for up to 5 cycles (2 cycles for induction and 3 additional cycles for consolidation)

Subsequent treatment

TOWER: Optional blinatumomab maintenance

Regimen variant #2

Study	Evidence
Topp et al. 2011 (MT103-202)	Phase 2
Topp et al. 2014 (MT103-206)	Phase 2

Immunotherapy

Blinatumomab (Blincyto) 15 mcg/m²/day IV continuous infusion over 28 days, started on day 1 (total dose per cycle: 420 mcg/m²)

42-day course

Subsequent treatment

Patients who had an allogeneic donor could receive an allogeneic hematopoietic stem cell transplant any time after cycle 1. Patients who had response could receive up to an additional 3 cycles of consolidation therapy--same as above.

References

MT103-202: Topp MS, Kufer P, Gökbuget N, Goebeler M, Klinger M, Neumann S, Horst HA, Raff T, Viardot A, Schmid M, Stelljes M, Schaich M, Degenhard E, Köhne-Volland R, Brüggemann M, Ottmann O, Pfeifer H, Burmeister T, Nagorsen D, Schmidt M, Lutterbuese R, Reinhardt C, Baeuerle PA, Kneba M, Einsele H, Riethmüller G, Hoelzer D, Zugmaier G, Bargou RC. Targeted therapy with the T-cell-engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival. J Clin Oncol. 2011 Jun 20;29(18):2493-8. Epub 2011 May 16. link to original article contains dosing details in manuscript PubMed NCT00560794
1. Update: Topp MS, Gökbuget N, Zugmaier G, Degenhard E, Goebeler ME, Klinger M, Neumann SA, Horst HA, Raff T, Viardot A, Stelljes M, Schaich M, Köhne-Volland R, Brüggemann M, Ottmann OG, Burmeister T, Baeuerle PA, Nagorsen D, Schmidt M, Einsele H, Riethmüller G, Kneba M, Hoelzer D, Kufer P, Bargou RC. Long-term follow-up of hematologic relapse-free survival in a phase 2 study of blinatumomab in patients with MRD in B-lineage ALL. Blood. 2012 Dec 20;120(26):5185-7. link to original article PubMed
2. Update: Gökbuget N, Zugmaier G, Klinger M, Kufer P, Stelljes M, Viardot A, Horst HA, Neumann S, Brüggemann M, Ottmann OG, Burmeister T, Wessiepe D, Topp MS, Bargou R. Long-term relapse-free survival in a phase 2 study of blinatumomab for the treatment of patients with minimal residual disease in B-lineage acute lymphoblastic leukemia. Haematologica. 2017 Apr;102(4):e132-e135. Epub 2017 Jan 12. link to original article link to PMC article PubMed
MT103-206: Topp MS, Gökbuget N, Zugmaier G, Klappers P, Stelljes M, Neumann S, Viardot A, Marks R, Diedrich H, Faul C, Reichle A, Horst HA, Brüggemann M, Wessiepe D, Holland C, Alekar S, Mergen N, Einsele H, Hoelzer D, Bargou RC. Phase II trial of the anti-CD19 bispecific T cell-engager blinatumomab shows hematologic and molecular remissions in patients with relapsed or refractory B-precursor acute lymphoblastic leukemia. J Clin Oncol. 2014 Dec 20;32(36):4134-40. Epub 2014 Nov 10. link to original article PubMed NCT01209286
1. Update: Zugmaier G, Gökbuget N, Klinger M, Viardot A, Stelljes M, Neumann S, Horst HA, Marks R, Faul C, Diedrich H, Reichle A, Brüggemann M, Holland C, Schmidt M, Einsele H, Bargou RC, Topp MS. Long-term survival and T-cell kinetics in relapsed/refractory ALL patients who achieved MRD response after blinatumomab treatment. Blood. 2015 Dec 10;126(24):2578-84. Epub 2015 Oct 19. link to original article link to PMC article PubMed
MT103-211: Topp MS, Gökbuget N, Stein AS, Zugmaier G, O'Brien S, Bargou RC, Dombret H, Fielding AK, Heffner L, Larson RA, Neumann S, Foà R, Litzow M, Ribera JM, Rambaldi A, Schiller G, Brüggemann M, Horst HA, Holland C, Jia C, Maniar T, Huber B, Nagorsen D, Forman SJ, Kantarjian HM. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol. 2015 Jan;16(1):57-66. Epub 2014 Dec 16. Erratum in: Lancet Oncol. 2015 Apr;16(4):e158. link to original article PubMed NCT01466179
TOWER: Kantarjian H, Stein A, Gökbuget N, Fielding AK, Schuh AC, Ribera JM, Wei A, Dombret H, Foà R, Bassan R, Arslan Ö, Sanz MA, Bergeron J, Demirkan F, Lech-Maranda E, Rambaldi A, Thomas X, Horst HA, Brüggemann M, Klapper W, Wood BL, Fleishman A, Nagorsen D, Holland C, Zimmerman Z, Topp MS. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017 Mar 2;376(9):836-847. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02013167
1. HRQoL analysis: Topp MS, Zimmerman Z, Cannell P, Dombret H, Maertens J, Stein A, Franklin J, Tran Q, Cong Z, Schuh AC. Health-related quality of life in adults with relapsed/refractory acute lymphoblastic leukemia treated with blinatumomab. Blood. 2018 Jun 28;131(26):2906-2914. Epub 2018 May 8. link to original article link to PMC article PubMed

Brexucabtagene autoleucel monotherapy

Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence
Shah et al. 2021 (ZUMA-3)	2018-2019	Phase 2 (RT)

Preceding treatment

FC conditioning

Immunotherapy

Brexucabtagene autoleucel (Tecartus) 1 x 10⁶ CAR T cells/kg IV once on day 0

References

ZUMA-3: Shah BD, Ghobadi A, Oluwole OO, Logan AC, Boissel N, Cassaday RD, Leguay T, Bishop MR, Topp MS, Tzachanis D, O'Dwyer KM, Arellano ML, Lin Y, Baer MR, Schiller GJ, Park JH, Subklewe M, Abedi M, Minnema MC, Wierda WG, DeAngelo DJ, Stiff P, Jeyakumar D, Feng C, Dong J, Shen T, Milletti F, Rossi JM, Vezan R, Masouleh BK, Houot R. KTE-X19 for relapsed or refractory adult B-cell acute lymphoblastic leukaemia: phase 2 results of the single-arm, open-label, multicentre ZUMA-3 study. Lancet. 2021 Aug 7;398(10299):491-502. Epub 2021 Jun 4. link to original article contains dosing details in abstract PubMed NCT02614066

Clofarabine monotherapy

Regimen

Study	Evidence
Kantarjian et al. 2003	Phase 2, <20 patients in this arm

Chemotherapy

Clofarabine (Clolar) 40 mg/m² IV over 60 minutes once per day on days 1 to 5

3- to 6-week cycles, depending on response count recovery

References

Kantarjian H, Gandhi V, Cortes J, Verstovsek S, Du M, Garcia-Manero G, Giles F, Faderl S, O'Brien S, Jeha S, Davis J, Shaked Z, Craig A, Keating M, Plunkett W, Freireich EJ. Phase 2 clinical and pharmacologic study of clofarabine in patients with refractory or relapsed acute leukemia. Blood. 2003 Oct 1;102(7):2379-86. Epub 2003 Jun 5. link to original article contains dosing details in manuscript PubMed

Cytarabine monotherapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Kantarjian et al. 2016 (INO-VATE ALL)	2012-2014	Phase 3 (C)	Inotuzumab ozogamicin	Seems to have inferior OS

Chemotherapy

Cytarabine (Ara-C) by the following criteria:
- Younger than 55: 3000 mg/m² IV every 12 hours on days 1 to 6 (total dose: 36,000 mg/m²)
- 55 or older: 1500 mg/m² IV every 12 hours on days 1 to 6 (total dose: 18,000 mg/m²)

6-day course

References

INO-VATE ALL: Kantarjian HM, DeAngelo DJ, Stelljes M, Martinelli G, Liedtke M, Stock W, Gökbuget N, O'Brien S, Wang K, Wang T, Paccagnella ML, Sleight B, Vandendries E, Advani AS. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016 Aug 25;375(8):740-53. Epub 2016 Jun 12. link to original article contains dosing details in abstract link to PMC article PubMed NCT01564784
1. Update: Kantarjian HM, DeAngelo DJ, Stelljes M, Liedtke M, Stock W, Gökbuget N, O'Brien SM, Jabbour E, Wang T, Liang White J, Sleight B, Vandendries E, Advani AS. Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia: Final report and long-term survival follow-up from the randomized, phase 3 INO-VATE study. Cancer. 2019 Jul 15;125(14):2474-2487. Epub 2019 Mar 28. link to original article link to PMC article PubMed

Cytarabine & Idarubicin

Regimen

Study	Years of enrollment	Evidence
Huguet et al. 2009 (GRAALL-2003)	2003-2005	Phase 2
Maury et al. 2016 (GRAALL-2005/R)	2006-2014	Non-randomized portion of phase 3 RCT

Note: the original GRAALL-2003 article Table 1 has several errors which were corrected in the erratum and the online Table 1. These corrected doses are replicated here. This regimen is for patients not achieving CR1 with induction.

Preceding treatment

Cyclophosphamide, Daunorubicin, L-aspariginase, Vincristine, Prednisone induction

Chemotherapy

Cytarabine (Ara-C) 2000 mg/m² IV over 3 hours every 12 hours on days 1 to 4 (total dose: 16,000 mg/m²)
Idarubicin (Idamycin) 12 mg/m² IV over 60 minutes once per day on days 1 to 3

Supportive therapy

Lenograstim (Granocyte) by the following study-specific criteria:
- GRAALL-2003: 150 mcg/m² SC once per day from day 9 until myeloid recovery
- GRAALL-2005: 263 mcg IV or SC once per day from day 9 until first day with ANC greater than 1000/uL

One course

Subsequent treatment

Patients achieving CR1 after salvage: Pediatric-like GRAALL consolidation

References

GRAALL-2003: Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. link to original article contains dosing details in manuscript PubMed NCT00222027
GRAALL-2005/R: Maury S, Chevret S, Thomas X, Heim D, Leguay T, Huguet F, Chevallier P, Hunault M, Boissel N, Escoffre-Barbe M, Hess U, Vey N, Pignon JM, Braun T, Marolleau JP, Cahn JY, Chalandon Y, Lhéritier V, Beldjord K, Béné MC, Ifrah N, Dombret H; GRAALL. Rituximab in B-lineage adult acute lymphoblastic leukemia. N Engl J Med. 2016 Sep 15;375(11):1044-53. link to original article link to supplement contains dosing details in supplement PubMed NCT00327678

Cytarabine, Idarubicin, Rituximab

Regimen

Study	Years of enrollment	Evidence
Maury et al. 2016 (GRAALL-2005/R)	2006-2014	Non-randomized portion of RCT

This regimen is for patients not achieving CR1 with induction.

Preceding treatment

Cyclophosphamide, Daunorubicin, L-aspariginase, Vincristine, Prednisone, Rituximab induction

Chemotherapy

Cytarabine (Ara-C) 2000 mg/m² IV over 3 hours every 12 hours on days 1 to 4 (total dose: 16,000 mg/m²)
Idarubicin (Idamycin) 12 mg/m² IV over 60 minutes once per day on days 1 to 3

Targeted therapy

Rituximab (Rituxan) 375 mg/m² IV once per day on days 1 & 7

Supportive therapy

Lenograstim (Granocyte) 263 mcg IV or SC once per day, starting on day 9, continuing until first day with ANC greater than 1000/uL

One course

Subsequent treatment

Patients achieving CR1 after salvage: Pediatric-like GRAALL consolidation with rituximab

References

GRAALL-2005/R: Maury S, Chevret S, Thomas X, Heim D, Leguay T, Huguet F, Chevallier P, Hunault M, Boissel N, Escoffre-Barbe M, Hess U, Vey N, Pignon JM, Braun T, Marolleau JP, Cahn JY, Chalandon Y, Lhéritier V, Beldjord K, Béné MC, Ifrah N, Dombret H; GRAALL. Rituximab in B-lineage adult acute lymphoblastic leukemia. N Engl J Med. 2016 Sep 15;375(11):1044-53. link to original article link to supplement contains dosing details in supplement PubMed NCT00327678

Cytarabine & Mitoxantrone (MC)

MC: Mitoxantrone & Cytarabine

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Kantarjian et al. 2016 (INO-VATE ALL)	2012-2014	Phase 3 (C)	Inotuzumab ozogamicin	Seems to have inferior OS

Chemotherapy

Cytarabine (Ara-C) 200 mg/m²/day IV continuous infusion over 7 days, started on day 1 (total dose per cycle: 1400 mg/m²)
Mitoxantrone (Novantrone) 12 mg/m² IV over 20 minutes once per day on days 1 to 3

15- to 20-day cycle for up to 4 cycles

Dose modifications

Mitoxantrone (Novantrone) dose reduction to 8 mg/m² allowed on the basis of age, coexisting conditions, and previous anthracycline use

References

INO-VATE ALL: Kantarjian HM, DeAngelo DJ, Stelljes M, Martinelli G, Liedtke M, Stock W, Gökbuget N, O'Brien S, Wang K, Wang T, Paccagnella ML, Sleight B, Vandendries E, Advani AS. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016 Aug 25;375(8):740-53. Epub 2016 Jun 12. link to original article link to original protocol contains dosing details in supplement link to PMC article PubMed NCT01564784
1. Update: Kantarjian HM, DeAngelo DJ, Stelljes M, Liedtke M, Stock W, Gökbuget N, O'Brien SM, Jabbour E, Wang T, Liang White J, Sleight B, Vandendries E, Advani AS. Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia: Final report and long-term survival follow-up from the randomized, phase 3 INO-VATE study. Cancer. 2019 Jul 15;125(14):2474-2487. Epub 2019 Mar 28. link to original article link to PMC article PubMed

FLAG

FLAG: FLudarabine, Ara-C (Cytarabine), G-CSF

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Kantarjian et al. 2016 (INO-VATE ALL)	2012-2014	Phase 3 (C)	Inotuzumab ozogamicin	Seems to have inferior OS

Chemotherapy

Fludarabine (Fludara) 30 mg/m² IV over 30 minutes once per day on days 2 to 6
Cytarabine (Ara-C) 2000 mg/m² IV once per day on days 1 to 6

Growth factor therapy

G-CSF 5 mcg/kg or at the institutional standard dose once per day (interval not specified)

28-day cycle for up to 4 cycles

References

INO-VATE ALL: Kantarjian HM, DeAngelo DJ, Stelljes M, Martinelli G, Liedtke M, Stock W, Gökbuget N, O'Brien S, Wang K, Wang T, Paccagnella ML, Sleight B, Vandendries E, Advani AS. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016 Aug 25;375(8):740-53. Epub 2016 Jun 12. link to original article contains dosing details in abstract link to PMC article PubMed NCT01564784
1. Update: Kantarjian HM, DeAngelo DJ, Stelljes M, Liedtke M, Stock W, Gökbuget N, O'Brien SM, Jabbour E, Wang T, Liang White J, Sleight B, Vandendries E, Advani AS. Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia: Final report and long-term survival follow-up from the randomized, phase 3 INO-VATE study. Cancer. 2019 Jul 15;125(14):2474-2487. Epub 2019 Mar 28. link to original article link to PMC article PubMed

Hyper-CVAD/MA & Everolimus

Hyper-CVAD/MA & Everolimus: Hyperfractionated Cyclophosphamide, Vincristine, Adriamycin (Doxorubicin), Dexamethasone alternating with Methotrexate, Ara-C (Cytarabine), with Everolimus

Protocol

Study	Years of enrollment	Evidence
Daver et al. 2015 (MDACC 2009-0100)	2010-2014	Phase 1/2

Note: there are some difference between this protocol and other published Hyper-CVAD protocols, including flexibility in the timing of vincristine and dexamethasone. Some details were missing, in particular the supportive medications for the B cycles. The everolimus dose is the MTD.

Targeted therapy, all cycles

Everolimus (Afinitor) 5 mg PO once per day

Chemotherapy, Part A (cycles 1, 3, 5, 7)

Cyclophosphamide (Cytoxan) 300 mg/m² IV over 3 hours every 12 hours on days 1 to 3 (total dose per cycle: 1800 mg/m²)
Vincristine (Oncovin) by the following age-based criteria:
- Younger than 18: 1.5 mg/m² (maximum dose of 2 mg) IV once per day on days 4 & 11 (+/- 2 days)
- 18 and older: 2 mg IV once per day on days 4 & 11 (+/- 2 days)
Doxorubicin (Adriamycin) 50 mg/m² IV continuous infusion over 24 hours, started on day 4

Glucocorticoid therapy, Part A (cycles 1, 3, 5, 7)

Dexamethasone (Decadron) by the following age-based criteria:
- Younger than 18: 20 mg/m² (maximum dose of 40 mg) IV or PO once per day on days 1 to 4, 11 to 14 (+/- 2 days)
- 18 and older: 40 mg IV or PO once per day on days 1 to 4, 11 to 14 (+/- 2 days)

Supportive therapy, Part A (cycles 1, 3, 5, 7)

Mesna (Mesnex) 600 mg/m²/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 1800 mg/m²)
Pegfilgrastim (Neulasta) 6 mg SC once, approximately 24 hours after completion of chemotherapy

Chemotherapy, Part A (cycles 1, 3, 5, 7)

Methotrexate (MTX) 200 mg/m² IV over 2 hours once on day 1, then 800 mg/m² IV over 22 hours (total dose per cycle: 1000 mg/m²)
Cytarabine (Ara-C) by the following age-based criteria:
- Younger than 60: 3000 mg/m² IV over 2 hours every 12 hours on days 2 & 3 (total dose per cycle: 12,000 mg/m²)
- 60 and older, or with creatinine at least 1.5 x the upper limit of normal: 1000 mg/m² IV over 2 hours every 12 hours on days 2 & 3 (total dose per cycle: 4000 mg/m²)

Glucocorticoid therapy, Part A (cycles 1, 3, 5, 7)

Methylprednisolone (Solumedrol) by the following age-based criteria:
- Younger than 18: 25 mg/m² (maximum dose of 50 mg) IV over 2 hours every 12 hours on days 1 to 3 (total dose per cycle: 150 mg/m²)
- 18 and older: 50 mg IV over 2 hours every 12 hours on days 1 to 3 (total dose per cycle: 300 mg/m²)
  - It isn't clear if this is meant to be a supportive or antineoplastic medication.

References

MDACC 2009-0100: Daver N, Boumber Y, Kantarjian H, Ravandi F, Cortes J, Rytting ME, Kawedia JD, Basnett J, Culotta KS, Zeng Z, Lu H, Richie MA, Garris R, Xiao L, Liu W, Baggerly KA, Jabbour E, O'Brien S, Burger J, Bendall LJ, Thomas D, Konopleva M. A Phase I/II study of the mTOR inhibitor everolimus in combination with HyperCVAD chemotherapy in patients with relapsed/refractory acute lymphoblastic leukemia. Clin Cancer Res. 2015 Jun 15;21(12):2704-14. Epub 2015 Feb 27. link to original article link to PMC article contains partial protocol in supplement PubMed NCT00968253

Inotuzumab ozogamicin monotherapy

Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Kantarjian et al. 2012 (MDACC 2009-0872)	2010-2011	Phase 2
Kantarjian et al. 2016 (INO-VATE ALL)	2012-2014	Phase 3 (E-RT-switch-ooc)	Investigator's choice of: 1. Cytarabine 2. MC 3. FLAG	Seems to have superior OS

Note: the protocol in the text of Kantarjian et al. 2016 is confusing, as it does not specify BSA-based dosing; the original protocol is clear on this, as is the FDA package insert.

Antibody-drug conjugate therapy

Inotuzumab ozogamicin (Besponsa) as follows:
- Cycle 1: 0.8 mg/m² IV once on day 1, then 0.5 mg/m² IV once per day on days 8 & 15
- Cycles 2 to 6, patients achieving CR or CRi: 0.5 mg/m² IV once per day on days 1, 8, 15
- Cycles 2 to 6, less than CR: 0.8 mg/m² IV once on day 1, then 0.5 mg/m² IV once per day on days 8 & 15

21-day cycle for 1 cycle, then 28-day cycle for up to 5 cycles

References

MDACC 2009-0872: Kantarjian H, Thomas D, Jorgensen J, Jabbour E, Kebriaei P, Rytting M, York S, Ravandi F, Kwari M, Faderl S, Rios MB, Cortes J, Fayad L, Tarnai R, Wang SA, Champlin R, Advani A, O'Brien S. Inotuzumab ozogamicin, an anti-CD22-calecheamicin conjugate, for refractory and relapsed acute lymphocytic leukaemia: a phase 2 study. Lancet Oncol. 2012 Apr;13(4):403-11. Epub 2012 Feb 21. link to original article contains dosing details in abstract PubMed NCT01134575
INO-VATE ALL: Kantarjian HM, DeAngelo DJ, Stelljes M, Martinelli G, Liedtke M, Stock W, Gökbuget N, O'Brien S, Wang K, Wang T, Paccagnella ML, Sleight B, Vandendries E, Advani AS. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016 Aug 25;375(8):740-53. Epub 2016 Jun 12. link to original article link to original protocol contains dosing details in supplement link to PMC article PubMed NCT01564784
1. Update: Kantarjian HM, DeAngelo DJ, Stelljes M, Liedtke M, Stock W, Gökbuget N, O'Brien SM, Jabbour E, Wang T, Liang White J, Sleight B, Vandendries E, Advani AS. Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia: Final report and long-term survival follow-up from the randomized, phase 3 INO-VATE study. Cancer. 2019 Jul 15;125(14):2474-2487. Epub 2019 Mar 28. link to original article link to PMC article PubMed

Tisagenlecleucel monotherapy

Regimen

Study	Years of enrollment	Evidence	Efficacy
Maude et al. 2014 (UPCC04409)	2012-2014	Phase 1/2a
Maude et al. 2018 (ELIANA)	2015-2017	Phase 2 (RT)	ORR: 81%

Note: dosing instructions are based on ELIANA.

Preceding treatment

Lymphodepleting therapy with FC or CYVE

Immunotherapy

Tisagenlecleucel (Kymriah) by the following criteria:
- Up to 50 kg: 2 to 5 x 10⁶ CTL019 transduced viable T-cells per kg body weight IV once on day 0
- Greater than 50 kg: 1.0 to 2.5 x 10⁸ CTL019 transduced viable T-cells IV once on day 0

One course

References

UPCC04409: Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, Chew A, Gonzalez VE, Zheng Z, Lacey SF, Mahnke YD, Melenhorst JJ, Rheingold SR, Shen A, Teachey DT, Levine BL, June CH, Porter DL, Grupp SA. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014 Oct 16;371(16):1507-17. Erratum in: N Engl J Med. 2016 Mar 10;374(10):998. link to original article link to PMC article PubMed NCT01029366
ELIANA: Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, Bader P, Verneris MR, Stefanski HE, Myers GD, Qayed M, De Moerloose B, Hiramatsu H, Schlis K, Davis KL, Martin PL, Nemecek ER, Yanik GA, Peters C, Baruchel A, Boissel N, Mechinaud F, Balduzzi A, Krueger J, June CH, Levine BL, Wood P, Taran T, Leung M, Mueller KT, Zhang Y, Sen K, Lebwohl D, Pulsipher MA, Grupp SA. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018 Feb 1;378(5):439-448. link to original article link to supplementary protocol contains dosing details in supplement link to PMC article PubMed NCT02435849

Consolidation after salvage therapy

Blinatumomab monotherapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Brown et al. 2021 (COG AALL1331)	2014-2019	Phase 3 (E-switch-ooc)	Standard salvage consolidation chemotherapy	Might have superior DFS

Immunotherapy

Blinatumomab (Blincyto) 15 mcg/m²/day IV continuous infusion over 28 days, started on day 1 (total dose per cycle: 420 mcg/m²)

35-day cycle for 2 cycles

Subsequent treatment

Allogeneic hematopoietic stem cell transplant

References

COG AALL1331: Brown PA, Ji L, Xu X, Devidas M, Hogan LE, Borowitz MJ, Raetz EA, Zugmaier G, Sharon E, Bernhardt MB, Terezakis SA, Gore L, Whitlock JA, Pulsipher MA, Hunger SP, Loh ML. Effect of Postreinduction Therapy Consolidation With Blinatumomab vs Chemotherapy on Disease-Free Survival in Children, Adolescents, and Young Adults With First Relapse of B-Cell Acute Lymphoblastic Leukemia: A Randomized Clinical Trial. JAMA. 2021 Mar 2;325(9):833-842. link to original article link to PMC article contains dosing details in manuscript PubMed NCT02101853

Cyclophosphamide & TBI, then allo HSCT

Cy/TBI: Cyclophosphamide & Total Body Irradiation

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Rudolph et al. 1973	1968-1970	Non-randomized, <20 pts in subgroup
Kersey et al. 1987	1982-1985	Quasi-randomized	Auto HSCT	Superior RFS

Details in most of the manuscripts are limited.

Chemotherapy

Cyclophosphamide (Cytoxan) 60 mg/kg IV once per day on days -3 & -2

Radiotherapy

Total body irradiation by the following study-specific criteria:
- Zhang et al. 2023: 450 cGy once per day on days -5 & -4 (900 cGy total)
- Other studies: 10 to 1200 cGy total

Immunotherapy

Allogeneic stem cells transfused on day 0

One course

Immunotherapy

Allogeneic stem cells

Stem cells transfused on day 0

References

Rudolph RH, Fefer A, Thomas ED, Buckner CD, Clift RA, Storb R. Isogeneic marrow grafts for hematologic malignancy in man. Arch Intern Med. 1973 Aug;132(2):279-85. link to original article PubMed
1. Update: Fefer A, Einstein AB, Thomas ED, Buckner CD, Clift RA, Glucksberg H, Neiman PE, Storb R. Bone-marrow transplantation for hematologic neoplasia in 16 patients with identical twins. N Engl J Med. 1974 Jun 20;290(25):1389-93. link to original article PubMed
Kersey JH, Weisdorf D, Nesbit ME, LeBien TW, Woods WG, McGlave PB, Kim T, Vallera DA, Goldman AI, Bostrom B, Hurd D, Ramsay NKC. Comparison of autologous and allogeneic bone marrow transplantation for treatment of high-risk refractory acute lymphoblastic leukemia. N Engl J Med. 1987 Aug 20;317(8):461-7. link to original article PubMed

Maintenance after subsequent lines of therapy

Blinatumomab monotherapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Kantarjian et al. 2017 (TOWER)	2014-2015	Phase 3 (E-RT-switch-ooc)	Standard maintenance chemotherapy	Superior OS

The most common comparator was not specified but is presumably POMP.

Preceding treatment

Blinatumomab induction and consolidation

Immunotherapy

Blinatumomab (Blincyto) 28 mcg/day IV continuous infusion over 28 days, started on day 1 (total dose per cycle: 784 mcg)

12-week cycle for up to 5 cycles (1 year)

References

TOWER: Kantarjian H, Stein A, Gökbuget N, Fielding AK, Schuh AC, Ribera JM, Wei A, Dombret H, Foà R, Bassan R, Arslan Ö, Sanz MA, Bergeron J, Demirkan F, Lech-Maranda E, Rambaldi A, Thomas X, Horst HA, Brüggemann M, Klapper W, Wood BL, Fleishman A, Nagorsen D, Holland C, Zimmerman Z, Topp MS. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017 Mar 2;376(9):836-847. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02013167
1. HRQoL analysis: Topp MS, Zimmerman Z, Cannell P, Dombret H, Maertens J, Stein A, Franklin J, Tran Q, Cong Z, Schuh AC. Health-related quality of life in adults with relapsed/refractory acute lymphoblastic leukemia treated with blinatumomab. Blood. 2018 Jun 28;131(26):2906-2914. Epub 2018 May 8. link to original article link to PMC article PubMed

Investigational agents

These are drugs under study with at least some promising results for this disease.

Epratuzumab (humanised anti-CD22 antibody)

@@ Line 3: / Line 3: @@
 [[#top|Back to Top]]
 </div>
-{{#lst:Section editor transclusions|mcl}}
+{{#lst:Section editor transclusions|leuk}}
-''Are you looking for a regimen but can't find it here? It is possible that we've moved it to the [[Mantle_cell_lymphoma_-_historical|historical regimens page]]. For placebo or observational studies in this condition, please visit [[Mantle cell lymphoma - null regimens|this page]]. If you still can't find it, please let us know so we can add it!''.
+''Are you looking for a regimen, but can't find it here? It is possible that we've moved it to the [[B-cell acute lymphoblastic leukemia_-_historical|historical regimens page]]. If you still can't find it, please let us know so we can add it!''
+<big>'''Note: certain regimens have been moved to dedicated pages:
+*'''[[B-cell acute lymphoblastic leukemia,_Ph-positive|B-cell ALL, Ph-positive]]
+*'''[[CNS leukemia]]
+*'''[[T-cell acute lymphoblastic leukemia]]
+*'''[[B-cell acute lymphoblastic leukemia, pediatric|Pediatric B-cell ALL]]
+*'''[[B-cell acute lymphoblastic leukemia,_Ph-positive,_pediatric|Pediatric B-cell ALL, Ph-positive]]
+</big>
 {| class="wikitable" style="float:right; margin-right: 5px;"
 |-
@@ Line 11: / Line 18: @@
 |}
 {{TOC limit|limit=3}}
+''Please note, mature B-cell ALL (L3) is now classified as Burkitt lymphoma/leukemia. Regimens for this variant are available [http://hemonc.org/wiki/Aggressive_Non-Hodgkin_lymphoma#BL_or_Burkitt-like_lymphoma.2C_untreated here]''
 =Guidelines=
 ==[http://www.esmo.org/ ESMO]==
-*'''2017:''' Dreyling et al. [https://www.esmo.org/Guidelines/Haematological-Malignancies/Newly-Diagnosed-and-Relapsed-Mantle-Cell-Lymphoma Newly diagnosed and relapsed mantle cell lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]
+*'''2016:''' Hoelzer et al. [https://www.esmo.org/Guidelines/Haematological-Malignancies/Acute-Lymphoblastic-Leukaemia Acute lymphoblastic leukaemia in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]
-===Older===
+==EWALL/EBMT==
-*'''2014:''' Dreyling et al. [https://academic.oup.com/annonc/article-lookup/doi/10.1093/annonc/mdu264 Newly diagnosed and relapsed mantle cell lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.] [https://pubmed.ncbi.nlm.nih.gov/25210087 PubMed]
+*'''2019:''' Giebel et al. [https://www.nature.com/articles/s41409-018-0373-4 Hematopoietic stem cell transplantation for adults with Philadelphia chromosome-negative acute lymphoblastic leukemia in first remission: a position statement of the European Working Group for Adult Acute Lymphoblastic Leukemia (EWALL) and the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT)]
+=="How I Treat"==
+*'''2020:''' Aldoss I, Douer D. How I treat the toxicities of pegasparaginase in adults with acute lymphoblastic leukemia. Blood. 2020 Mar 26;135(13):987-995. [https://doi.org/10.1182/blood.2019002477 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31977001 PubMed]
+*'''2020:''' Aldoss I, Forman SJ. How I treat adults with advanced acute lymphoblastic leukemia eligible for CD19-targeted immunotherapy. Blood. 2020 Mar 12;135(11):804-813. [https://doi.org/10.1182/blood.2019002132 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31899793 PubMed]
+*'''2015:''' Curran E, Stock W. How I treat acute lymphoblastic leukemia in older adolescents and young adults. Blood. 2015 Jun 11;125(24):3702-10. Epub 2015 Mar 24. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4463735/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25805810 PubMed]
+*'''2015:''' Frey NV, Luger SM. How I treat adults with relapsed or refractory Philadelphia chromosome-negative acute lymphoblastic leukemia. Blood. 2015 Jul 30;126(5):589-96. Epub 2015 May 12. [http://www.bloodjournal.org/content/126/5/589.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/25966988 PubMed]
 ==[https://www.nccn.org/ NCCN]==
-*[https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf NCCN Guidelines - B-Cell Lymphomas]
+*[https://www.nccn.org/professionals/physician_gls/pdf/all.pdf NCCN Guidelines - Acute Lymphoblastic Leukemia]
-=First-line therapy, pre-phase=
+=Prephase=
-==CVP (Prednisolone) {{#subobject:1c1228|Regimen=1}}==
+==Prednisone monotherapy {{#subobject:8ca13b|Regimen=1}}==
-CVP: '''<u>C</u>'''yclophosphamide, '''<u>O</u>'''ncovin (Vincristine), '''<u>P</u>'''rednisolone
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:bd8596|Variant=1}}===
+===Regimen {{#subobject:2fd1d7|Variant=1}}===
 {| class="wikitable sortable" style="width: 60%; text-align:center;"
 !style="width: 33%"|Study
@@ Line 28: / Line 40: @@
 !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://doi.org/10.1056/NEJMoa1701769 Le Gouill et al. 2017 (LyMa)]
+|[https://doi.org/10.1200/JCO.2008.18.6916 Huguet et al. 2009 (GRAALL-2003)]
-|2008-2012
+|2003-2005
-|style="background-color:#91cf61"|Non-randomized portion of RCT
+|style="background-color:#91cf61"|Phase 2
 |-
 |}
-''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''
+''Note: in GRAALL-2003, this regimen was meant for patients up to 60 years old. The original Huguet et al. 2009 article Table 1 has several errors which were corrected in the erratum and the online Table 1. These corrected doses are replicated here. See paper for details on CNS prophylaxis and treatment.''
 <div class="toccolours" style="background-color:#b3e2cd">
-====Chemotherapy====
-*[[Cyclophosphamide (Cytoxan)]] 750 mg/m<sup>2</sup> IV once on day 1
-*[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1
 ====Glucocorticoid therapy====
-*[[Prednisolone (Millipred)]] 80 mg/m<sup>2</sup> PO once per day on days 1 to 5
+*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup>/day PO on days 1 to 7
-'''21-day course'''
+====CNS therapy, prophylaxis====
+*[[Methotrexate (MTX)]] 15 mg IT once on day 1
+'''7-day course'''
 </div>
 <div class="toccolours" style="background-color:#cbd5e7">
 ====Subsequent treatment====
-*[[#R-DHAC|R-DHAC]] x 4 or [[#R-DHAOx|R-DHAOx]] x 4 or [[#R-DHAP|R-DHAP]] x 4
+*[[#Cyclophosphamide.2C_Daunorubicin.2C_L-Asparaginase.2C_Vincristine.2C_Prednisone|Cyclophosphamide, Daunorubicin, L-asparaginase, Vincristine, Prednisone]] induction
 </div></div>
 ===References===
-<!-- # '''Abstract:''' Steven Le Gouill, MD, PhD, Catherine Thieblemont, MD, PhD, Lucie Oberic, Krimo Bouabdallah, MD, Emmanuel Gyan, MD, PhD, Gandhi Damaj, MD, Vincent Ribrag, MD, Serge Bologna, MD, Remy Gressin, MD, Olivier Casasnovas, MD, Corinne Haioun, MD, PhD, Philippe Solal-Celigny, MD, Herve Maisonneuve, MD, Eric Van Den Neste, MD, PhD, Anne Moreau, MD, Marie C Bene, Gilles Salles, MD PhD, Hervé Tilly, MD, PhD, Thierry Lamy, MD, PhD and Olivier Hermine, MD, PhD. Rituximab Maintenance Versus Wait and Watch after Four Courses of R-DHAP Followed By Autologous Stem Cell transplantation in Previously Untreated Young Patients with Mantle Cell Lymphoma: First Interim Analysis of the Phase III Prospective Lyma Trial, a Lysa Study. Blood 2014 124:146. [http://www.bloodjournal.org/content/124/21/146 link to abstract] -->
+# '''GRAALL-2003:''' Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. [https://doi.org/10.1200/JCO.2008.18.6916 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19124805 PubMed] NCT00222027
-# '''LyMa:''' Le Gouill S, Thieblemont C, Oberic L, Moreau A, Bouabdallah K, Dartigeas C, Damaj G, Gastinne T, Ribrag V, Feugier P, Casasnovas O, Zerazhi H, Haioun C, Maisonneuve H, Houot R, Jardin F, Van Den Neste E, Tournilhac O, Le Dû K, Morschhauser F, Cartron G, Fornecker LM, Canioni D, Callanan M, Béné MC, Salles G, Tilly H, Lamy T, Gressin R, Hermine O; LYSA. Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma. N Engl J Med. 2017 Sep 28;377(13):1250-1260. [https://doi.org/10.1056/NEJMoa1701769 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1701769/suppl_file/nejmoa1701769_appendix.pdf link to protocol] '''contains dosing details in supplement''' [https://pubmed.ncbi.nlm.nih.gov/28953447 PubMed] NCT00921414
+==Vincristine & Prednisone {{#subobject:663781|Regimen=1}}==
-=First-line therapy, randomized data=
+VP: '''<u>V</u>'''incristine & '''<u>P</u>'''rednisone
-==Bendamustine & Rituximab (BR) {{#subobject:b7779c|Regimen=1}}==
-BR: '''<u>B</u>'''endamustine, '''<u>R</u>'''ituximab
-<br>RB: '''<u>R</u>'''ituximab, '''<u>B</u>'''endamustine
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #1, 6 cycles {{#subobject:68b17c|Variant=1}}===
+===Regimen {{#subobject:78gjc7|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
-!style="width: 20%"|Study
+!style="width: 33%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 33%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
+|-
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|[https://doi.org/10.1002/1097-0142(19830915)52:6%3C958::aid-cncr2820520604%3E3.0.co;2-z McCredie et al. 1983 (SWOG-7416]
+|1975-1977
+|style="background-color:#91cf61"|Non-randomized portion of RCT
 |-
-|[https://doi.org/10.1016/S0140-6736(12)61763-2 Rummel et al. 2013 (StiL NHL1)]
+|}
-|2003-2008
+''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''
-|style="background-color:#1a9851"|Phase 3 (E-switch-ic)
+<div class="toccolours" style="background-color:#b3e2cd">
-|[[#R-CHOP|R-CHOP]]
+====Chemotherapy====
-|style="background-color:#1a9850"|Superior PFS<br>Median PFS: 69.5 vs 31.2 mo<br>(HR 0.58, 95% CI 0.44-0.74)
+*[[Vincristine (Oncovin)]] 2 mg IV once on day 1
+====Glucocorticoid therapy====
+*[[Prednisone (Sterapred)]] 100 mg PO once per day on days 1 to 5
+'''5-day course'''
+</div></div>
+===References===
+# '''SWOG-7416:''' McCredie KB, Gehan EA, Freireich EJ, Hewlett JS, Coltman CA Jr, Hussein KK, Balcerzak SP, Chen TT. Management of adult acute leukemia: a Southwest Oncology Group study. Cancer. 1983 Sep 15;52(6):958-66. [https://doi.org/10.1002/1097-0142(19830915)52:6%3C958::aid-cncr2820520604%3E3.0.co;2-z link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/6883280 PubMed]
+=Upfront induction therapy=
+==Cyclophosphamide, Cytarabine, Mercaptopurine {{#subobject:317919|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:d69105|Variant=1}}===
+{| class="wikitable" style="width: 40%; text-align:center;"
+!style="width: 25%"|Study
+!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5318240/ Chen et al. 2016 (SWOG S1106)]
+|[http://www.bloodjournal.org/content/106/12/3760.long Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)]
-|2012-2013
+|style="background-color:#91cf61"|Non-randomized portion of RCT
-|style="background-color:#1a9851"|Randomized Phase 2 (E-de-esc)
-|[[#R-Hyper-CVAD.2FR-MA|R-Hyper-CVAD/R-MA]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS24
 |-
 |}
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*MRC UKALL XII/ECOG E2993, Ph-: "Phase 1" induction: [[#DOLP|DOLP]]
+*MRC UKALL XII/ECOG E2993, Ph+: "Phase 1" induction: [[B-cell_acute_lymphoblastic_leukemia,_Ph-positive#Daunorubicin.2C_L-Asparaginase.2C_Vincristine.2C_Prednisone.2C_Imatinib|Daunorubicin, L-asparaginase, Vincristine, Prednisone, Imatinib]]
+</div>
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Bendamustine]] 90 mg/m<sup>2</sup> IV once per day on days 1 & 2
+*[[Cyclophosphamide (Cytoxan)]] 650 mg/m<sup>2</sup> IV once per day on days 1, 15, 29
-====Targeted therapy====
+*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> IV once per day on days 1 to 4, 8 to 11, 15 to 18, 22 to 25
-*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1
+*[[Mercaptopurine (6-MP)]] 6 mg/m<sup>2</sup> PO once per day on days 1 to 28
-====Supportive therapy====
+====CNS therapy, prophylaxis====
-*Antiemetics, antipyretics, and antibiotics according to local standard of care
+*[[Methotrexate (MTX)]] 12 mg IT once per day on days 1, 8, 15, 22
-*Prophylactic use of [[:Category:Granulocyte_colony-stimulating_factors|G-CSF]] allowed according [https://doi.org/10.1200/jco.2006.06.4451 ASCO guidelines] (2006)
+'''29-day course'''
-'''28-day cycle for up to 6 cycles'''
 </div>
 <div class="toccolours" style="background-color:#cbd5e7">
 ====Subsequent treatment====
-*SWOG S1106, responders: [[#BEAM.2C_then_auto_HSCT|BEAM, then auto HSCT]] or [[#CBV.2C_then_auto_HSCT|CBV, then auto HSCT]] or [[#Cyclophosphamide.2C_Etoposide.2C_TBI.2C_then_auto_HSCT_88|cyclophosphamide, etoposide, TBI, then auto HSCT]], depending on age and center
+*[[#L-Asparaginase_.26_Methotrexate|L-asparaginase & Methotrexate]] early intensification
-</div></div><br>
+</div></div>
+===References===
+# '''MRC UKALL XII/ECOG E2993:''' Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. [http://www.bloodjournal.org/content/106/12/3760.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16105981 PubMed] NCT00002514
+## '''Update:''' Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, Burnett AK, Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J, McMillan A, Franklin IM, Luger S, Ciobanu N, Rowe JM. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008 Feb 15;111(4):1827-33. Epub 2007 Nov 29. [http://www.bloodjournal.org/content/111/4/1827.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/18048644 PubMed]
+## '''Update:''' Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, Marks DI, McMillan AK, Litzow MR, Lazarus HM, Foroni L, Dewald G, Franklin IM, Luger SM, Paietta E, Wiernik PH, Tallman MS, Goldstone AH. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009 May 7;113(19):4489-96. Epub 2009 Feb 24. [http://www.bloodjournal.org/content/113/19/4489.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4188540/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19244158 PubMed]
+## '''Update:''' Fielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow MR, Lazarus H, Luger SM, Marks DI, McMillan AK, Moorman AV, Patel B, Paietta E, Tallman MS, Goldstone AH. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014 Feb 6;123(6):843-50. Epub 2013 Nov 25. [http://www.bloodjournal.org/content/123/6/843.full link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3916877/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24277073 PubMed]
+==Cyclophosphamide, Daunorubicin, Vincristine, Prednisone {{#subobject:29d427|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #2, 8 cycles {{#subobject:1483a3|Variant=1}}===
+===Regimen {{#subobject:7ff1ac|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
@@ Line 98: / Line 128: @@
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4260975/ Flinn et al. 2014 (BRIGHT)]
+|[https://doi.org/10.1200/jco.2004.10.050 Thomas et al. 2004 (LALA-94)]
-|2009-2012
+|1994-2002
-|style="background-color:#1a9851"|Phase 3 (E-switch-ic)
+|style="background-color:#1a9851"|Phase 3 (C)
-|1. [[#R-CHOP|R-CHOP]]<br> 2. [[#R-CVP|R-CVP]]
+|[[#Cyclophosphamide.2C_Idarubicin.2C_Vincristine.2C_Prednisone|Cyclophosphamide, Idarubicin, Vincristine, Prednisone]]
-|style="background-color:#1a9850"|Superior PFS<sup>1</sup><br>PFS60: 65.5% vs 55.8%<br>(HR 0.61, 95% CI 0.45-0.85)
+|style="background-color:#fc8d59"|Seems to have inferior DFS
 |-
 |}
-''<sup>1</sup>Reported efficacy is based on the 2019 update.''
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Bendamustine]] 90 mg/m<sup>2</sup> IV once per day on days 1 & 2
+*[[Cyclophosphamide (Cytoxan)]] 750 mg/m<sup>2</sup> IV once per day on days 1 & 8
-====Targeted therapy====
+*[[Daunorubicin (Cerubidine)]] 30 mg/m<sup>2</sup> IV once per day on days 1 to 3, 15, 16
-*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1
+*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 1, 8, 15, 22
-====Supportive therapy====
+====Glucocorticoid therapy====
-*Antiemetics, antipyretics, and antibiotics according to local standard of care
+*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup>/day IV or PO on days 1 to 7, 15 to 21
-*Prophylactic use of [[:Category:Granulocyte_colony-stimulating_factors|G-CSF]] allowed according [https://doi.org/10.1200/jco.2006.06.4451 ASCO guidelines] (2006)
+'''28-day course'''
-'''28-day cycle for up to 8 cycles'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*Consolidation (see paper for details)
 </div></div>
 ===References===
-<!--
+# '''LALA-94:''' Thomas X, Boiron JM, Huguet F, Dombret H, Bradstock K, Vey N, Kovacsovics T, Delannoy A, Fegueux N, Fenaux P, Stamatoullas A, Vernant JP, Tournilhac O, Buzyn A, Reman O, Charrin C, Boucheix C, Gabert J, Lhéritier V, Fiere D. Outcome of treatment in adults with acute lymphoblastic leukemia: analysis of the LALA-94 trial. J Clin Oncol. 2004 Oct 15;22(20):4075-86. Epub 2004 Sep 7. [https://doi.org/10.1200/jco.2004.10.050 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15353542 PubMed] NCT00002700
-# Mathias J Rummel, MD, PhD, Norbert Niederle, Georg Maschmeyer, Andre Banat, MD, MBA, Ulrich von Gruenhagen, MD, Christoph Losem, Gerhard Heil, Manfred Welslau, Christina Balser, Ulrich Kaiser, Harald Ballo, Eckhart Weidmann, Heinz A Duerk, Dorothea Kofahl-Krause, Fritz Roller, Juergen Barth, Dieter Hoelzer, MD, PhD, Axel Hinke and Wolfram Brugger. Bendamustine Plus Rituximab Is Superior in Respect of Progression Free Survival and CR Rate When Compared to CHOP Plus Rituximab as First-Line Treatment of Patients with Advanced Follicular, Indolent, and Mantle Cell Lymphomas: Final Results of a Randomized Phase III Study of the StiL (Study Group Indolent Lymphomas, Germany). 2009 ASH Annual Meeting abstract 405. [http://www.bloodjournal.org/content/114/22/405 link to abstract]
+## '''Update:''' Vey N, Thomas X, Picard C, Kovascovicz T, Charin C, Cayuela JM, Dombret H, Dastugue N, Huguet F, Bastard C, Stamatoulas A, Giollant M, Tournilhac O, Macintyre E, Buzyn A, Bories D, Kuentz M, Dreyfus F, Delannoy A, Raynaud S, Gratecos N, Bordessoule D, de Botton S, Preudhomme C, Reman O, Troussard X, Pigneux A, Bilhou C, Vernant JP, Boucheix C, Gabert J; GET-LALA Group the Swiss Group for Clinical Cancer Research (SAKK). Allogeneic stem cell transplantation improves the outcome of adults with t(1;19)/E2A-PBX1 and t(4;11)/MLL-AF4 positive B-cell acute lymphoblastic leukemia: results of the prospective multicenter LALA-94 study. Leukemia. 2006 Dec;20(12):2155-61. Epub 2006 Oct 12. [https://doi.org/10.1038/sj.leu.2404420 link to original article] [https://pubmed.ncbi.nlm.nih.gov/17039234 PubMed]
-# Mathias J. Rummel, Norbert Niederle, Georg Maschmeyer, Andre G. Banat, Ulrich von Gruenhagen, Christoph Losem, Dorothea Kofahl-Krause, Gerhard Heil, Manfred Welslau, Christina Balser, Ulrich Kaiser, Eckhart Weidmann, Heinz A. Duerk, Harald Ballo, Martina Stauch, Juergen Barth, Axel Hinke, Wolfram Brugger, Study Group Indolent Lymphomas (StiL). Bendamustine plus rituximab (B-R) versus CHOP plus rituximab (CHOP-R) as first-line treatment in patients with indolent and mantle cell lymphomas (MCL): Updated results from the StiL NHL1 study. 2012 ASCO Annual Meeting abstract 3. [http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview==abst_detail_view&confID==114&abstractID==95807 link to abstract] [http://www.ascopost.com/issues/july-1-2012/german-study-finds-bendamustine-improves-progression-free-survival-in-patients-with-non-hodgkin-lymphoma.aspx ASCO Post article] [http://www.asco.org/ASCOv2/MultiMedia/Virtual%20Meeting?&vmview==vm_session_presentations_view&confID==114&sessionID==4807 ASCO plenary session video] -->
+==Cyclophosphamide, Daunorubicin, Vincristine, Prednisolone {{#subobject:30z427|Regimen=1}}==
-# '''StiL NHL1:''' Rummel MJ, Niederle N, Maschmeyer G, Banat GA, von Grünhagen U, Losem C, Kofahl-Krause D, Heil G, Welslau M, Balser C, Kaiser U, Weidmann E, Dürk H, Ballo H, Stauch M, Roller F, Barth J, Hoelzer D, Hinke A, Brugger W; StiL. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013 Apr 6;381(9873):1203-10. Epub 2013 Feb 20. Erratum in: Lancet. 2013 Apr 6;381(9873):1184. [https://doi.org/10.1016/S0140-6736(12)61763-2 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23433739 PubMed] NCT00991211
-## '''Update: Abstract:''' Mathias J. Rummel, MD, Georg Maschmeyer, MD, Arnold Ganser, Andrea Heider, PhD, Ulrich von Grünhagen, MD, PhD5, Christoph Losem, Gerhard Heil, MD, Manfred Welslau, Christina Balser, MD, Ulrich Kaiser, MD, Eckhart Weidmann, Heinz Dürk, MD, Hans Peter Böck, Martina Beate Stauch, MD, Jürgen Barth, Wolfgang Blau, MD, Alexander Burchardt, MD, Frank Kauff, PhD, Axel Hinke, PhD and Wolfram Brugger, MD. Bendamustine Plus Rituximab (B-R) Versus CHOP Plus Rituximab (CHOP-R) As First-Line Treatment in Patients with Indolent and Mantle Cell Lymphomas (MCL) – 7 Year Updated Results from the StiL NHL1 Study. Blood 2014 124:4407. [http://www.bloodjournal.org/content/124/21/4407 link to abstract]
-<!-- # Ian Flinn et al. An Open-Label, Randomized Study of Bendamustine and Rituximab (BR) Compared with Rituximab, Cyclophosphamide, Vincristine, and Prednisone (R-CVP) or Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) in First-Line Treatment of Patients with Advanced Indolent Non-Hodgkin’s Lymphoma (NHL) or Mantle Cell Lymphoma (MCL): The Bright Study. 2012 ASH Annual Meeting abstract 902. [https://ash.confex.com/ash/2012/webprogram/Paper51442.html link to abstract] -->
-# '''BRIGHT:''' Flinn IW, van der Jagt R, Kahl BS, Wood P, Hawkins TE, Macdonald D, Hertzberg M, Kwan YL, Simpson D, Craig M, Kolibaba K, Issa S, Clementi R, Hallman DM, Munteanu M, Chen L, Burke JM. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood. 2014 May 8;123(19):2944-52. Epub 2014 Mar 3. [https://doi.org/10.1182/blood-2013-11-531327 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4260975/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24591201 PubMed] NCT00877006
-<!-- ## '''Update: Abstract:''' Ian Flinn, Richard van der Jagt, Julie E. Chang, Peter Wood, Tim E. Hawkins, David MacDonald, Judith Trotman, David Simpson, Kathryn S. Kolibaba, Samar Issa, Doreen M. Hallman, Ling Chen, and John M. Burke. First-line treatment of iNHL or MCL patients with BR or R-CHOP/R-CVP: Results of the BRIGHT 5-year follow-up study. Journal of Clinical Oncology 2017 35:15_suppl, 7500-7500 [https://doi.org/10.1200/JCO.2017.35.15_suppl.7500 link to abstract] -->
-## '''Update:''' Flinn IW, van der Jagt R, Kahl B, Wood P, Hawkins T, MacDonald D, Simpson D, Kolibaba K, Issa S, Chang J, Trotman J, Hallman D, Chen L, Burke JM. First-line treatment of patients with indolent non-Hodgkin lymphoma or mantle-cell lymphoma with bendamustine plus rituximab versus R-CHOP or R-CVP: results of the BRIGHT 5-year follow-up study. J Clin Oncol. 2019 Apr 20;37(12):984-991. Epub 2019 Feb 27. [https://doi.org/10.1200/JCO.18.00605 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494265/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30811293 PubMed]
-# '''SWOG S1106:''' Chen RW, Li H, Bernstein SH, Kahwash S, Rimsza LM, Forman SJ, Constine L, Shea TC, Cashen AF, Blum KA, Fenske TS, Barr PM, Phillips T, Leblanc M, Fisher RI, Cheson BD, Smith SM, Faham M, Wilkins J, Leonard JP, Kahl BS, Friedberg JW. RB but not R-HCVAD is a feasible induction regimen prior to auto-HCT in frontline MCL: results of SWOG Study S1106. Br J Haematol. 2017 Mar;176(5):759-769. Epub 2016 Dec 19. [https://doi.org/full/10.1111/bjh.14480 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5318240/ link to PMC article] '''does not contain dosing details''' [https://pubmed.ncbi.nlm.nih.gov/27992063 PubMed] NCT01412879
-## '''Update:''' Kamdar M, Li H, Chen RW, Rimsza LM, Leblanc ML, Fenske TS, Shea TC, Barr PM, Phillips TJ, Leonard JP, Kahl BS, Friedberg JW, Smith SM. Five-year outcomes of the S1106 study of R-hyper-CVAD vs R-bendamustine in transplant-eligible patients with mantle cell lymphoma. Blood Adv. 2019 Oct 22;3(20):3132-3135. [https://ashpublications.org/bloodadvances/article/3/20/3132/422496/Fiveyear-outcomes-of-the-S1106-study-of-RhyperCVAD link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849956/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31648328 PubMed]
-#'''ACE-LY-308:''' NCT02972840
-#'''BGB-3111-306:''' NCT04002297
-==R-CHOP {{#subobject:ca52ab|Regimen=1}}==
-R-CHOP: '''<u>R</u>'''ituximab, '''<u>C</u>'''yclophosphamide, '''<u>H</u>'''ydroxydaunorubicin (Doxorubicin), '''<u>O</u>'''ncovin (Vincristine), '''<u>P</u>'''rednisone
-===Example orders===
-*[[Example orders for R-CHOP in lymphoma]]
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #1, prednisone 100 mg {{#subobject:f5db72|Variant=1}}===
+===Regimen {{#subobject:adf38f|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
@@ Line 143: / Line 161: @@
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1056/NEJMoa1200920 Kluin-Nelemans et al. 2012 (MCLelderly)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2930949/ Labar et al. 2010 (EORTC ALL-4)]
-|2004-2010
+|1995-2003
 |style="background-color:#1a9851"|Phase 3 (C)
-|[[Mantle_cell_lymphoma_-_historical#FCR|R-FC]]
+|[[#Cyclophosphamide.2C_Daunorubicin.2C_Vincristine.2C_Dexamethasone_99|Cyclophosphamide, Daunorubicin, Vincristine, Dexamethasone]]
-|style="background-color:#1a9850"|Superior OS<br>OS48: 62% vs 47%<br>(HR 0.67, 95% CI 0.50-0.88)
+| style="background-color:#ffffbf" |Did not meet primary endpoint of EFS72
-|-
-|[https://doi.org/10.1016/S0140-6736(16)00739-X Hermine et al. 2016 (MCL Younger)]
-|2004-2010
-|style="background-color:#1a9851"|Phase 3 (C)
-|[[Complex_multipart_regimens#MCL_Younger|See link]]
-| style="background-color:#fc8d59" |[[Complex_multipart_regimens#MCL_Younger|See link]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4260975/ Flinn et al. 2014 (BRIGHT)]
-|2009-2012
-|style="background-color:#1a9851"|Phase 3 (C)
-|[[#Bendamustine_.26_Rituximab_.28BR.29|BR]]
-|style="background-color:#eeee01"|Seems to have non-inferior CR rate
 |-
 |}
 <div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
-*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1
 ====Chemotherapy====
-*[[Cyclophosphamide (Cytoxan)]] 750 mg/m<sup>2</sup> IV once on day 1
+*[[Cyclophosphamide (Cytoxan)]] 750 mg/m<sup>2</sup> IV once per day on days 1 & 8
-*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV once on day 1
+*[[Daunorubicin (Cerubidine)]] 30 mg/m<sup>2</sup> IV once per day on days 1 to 3, 15, 16
-*[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1
+*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 1, 8, 15, 23
 ====Glucocorticoid therapy====
-*[[Prednisone (Sterapred)]] 100 mg PO once per day on days 1 to 5
+*[[Prednisolone (Millipred)]] 60 mg/m<sup>2</sup>/day IV or PO on days 1 to 8, 15 to 22
-====Supportive therapy====
+====CNS therapy, prophylaxis====
-*Antiemetics, antipyretics, and antibiotics per local standard of care
+*[[Methotrexate (MTX)]] 15 mg IT once per day on days 1, 8, 15, 22, 28
-*[[:Category:Granulocyte_colony-stimulating_factors|G-CSF]] "according to the [https://doi.org/10.1200/jco.2000.18.20.3558 American Society of Clinical Oncology guidelines]"
+'''28-day course'''
-'''21-day cycle for up to 8 cycles'''
 </div>
 <div class="toccolours" style="background-color:#cbd5e7">
 ====Subsequent treatment====
-*MCLelderly: [[#Rituximab_monotherapy|Rituximab]] versus [[Mantle_cell_lymphoma_-_historical#Interferon_alfa_monotherapy|interferon alfa]] maintenance
+*[[#HAM_88|HAM]] consolidation
-*MCL Younger: [[Stem_cell_mobilization#DexaBEAM_.26_G-CSF|Dexa-BEAM]], then [[Mantle_cell_lymphoma#Cyclophosphamide_.26_TBI.2C_then_auto_HSCT|Cy/TBI auto HSCT]]
+</div></div>
-</div></div><br>
+===References===
+# '''EORTC ALL-4:''' Labar B, Suciu S, Willemze R, Muus P, Marie JP, Fillet G, Berneman Z, Jaksic B, Feremans W, Bron D, Sinnige H, Mistrik M, Vreugdenhil G, De Bock R, Nemet D, Gilotay C, Amadori S, de Witte T; [[Study_Groups#EORTC|EORTC]] Leukemia Group. Dexamethasone compared to prednisolone for adults with acute lymphoblastic leukemia or lymphoblastic lymphoma: final results of the ALL-4 randomized, phase III trial of the EORTC Leukemia Group. Haematologica. 2010 Sep;95(9):1489-95. Epub 2010 Apr 7. [http://www.haematologica.org/content/95/9/1489.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2930949/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20378563 PubMed]
+==Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone {{#subobject:0cee78|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #2, prednisone 100 mg/m<sup>2</sup> {{#subobject:6eca9e|Variant=1}}===
+===Regimen variant #1 {{#subobject:2aaaf3|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
@@ Line 190: / Line 195: @@
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1200/jco.2005.08.133 Lenz et al. 2005]
+|[https://doi.org/10.1200/JCO.2008.18.6916 Huguet et al. 2009 (GRAALL-2003)]
-|2000-2002
+|2003-2005
-|style="background-color:#1a9851"|Phase 3 (E-esc)
+|style="background-color:#91cf61"|Phase 2
-|[[Mantle_cell_lymphoma_-_historical#CHOP|CHOP]]
+|style="background-color:#d3d3d3"|
-|style="background-color:#1a9850"|Superior ORR
+|style="background-color:#d3d3d3"|
+|-
+|[https://doi.org/10.1056/NEJMoa1605085 Maury et al. 2016 (GRAALL-2005/R)]
+|2006-2014
+|style="background-color:#1a9851"|Phase 3 (C)
+|[[#Cyclophosphamide.2C_Daunorubicin.2C_L-Asparaginase.2C_Vincristine.2C_Prednisone.2C_Rituximab|Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone, Rituximab]]
+|style="background-color:#fc8d59"|Seems to have inferior EFS
 |-
-|[https://doi.org/10.1056/NEJMoa1412096 Robak et al. 2015 (LYM-3002)]
+|[https://doi.org/10.1200/JCO.2017.76.8192 Huguet et al. 2018 (GRAALL-2005)]
-|2008-2011
+|2006-2014
 |style="background-color:#1a9851"|Phase 3 (C)
-|[[#VR-CAP|VR-CAP]]
+|[[#Cyclophosphamide.2C_Daunorubicin.2C_L-Asparaginase.2C_Vincristine.2C_Prednisone|Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone]]; hyperfractionated cyclophosphamide
-|style="background-color:#d73027"|Inferior OS<sup>1</sup>
+| style="background-color:#ffffbf" |Did not meet primary endpoint of EFS
 |-
 |}
-''<sup>1</sup>Reported efficacy for LYM-3002 is based on the 2018 update.''<br>
+''Note: this "pediatric-like" regimen was meant for patients up to 60 years old. The original Huguet et al. 2009 article Table 1 has several errors which were corrected in the erratum and the online Table 1. These corrected doses are replicated here. See paper for details on CNS treatment. This is the "standard-dose cyclophosphamide" arm of GRAALL-2005.''
-''Note: there is a slight difference between the two studies in terms of rituximab timing.''
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*[[#Prednisone_monotherapy|Prednisone prephase]]
+</div>
 <div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
-*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day -1 ('''Lenz et al. 2005''') or day 1 ('''LYM-3002''')
 ====Chemotherapy====
-*[[Cyclophosphamide (Cytoxan)]] 750 mg/m<sup>2</sup> IV once on day 1
+*[[Cyclophosphamide (Cytoxan)]] by the following criteria:
-*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV once on day 1
+**"Good early responders" (GRAALL-2003) and all patients (GRAALL-2005): 750 mg/m<sup>2</sup> IV over 3 hours once per day on days 1 & 15
-*[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1
+**"Poor early responders" (GRAALL-2003): 750 mg/m<sup>2</sup> IV once on day 1, then 500 mg/m<sup>2</sup> IV every 12 hours on days 15 & 16
+*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV once per day on days 1 to 3, then 30 mg/m<sup>2</sup> IV once per day on days 15 & 16
+*[[Asparaginase (Elspar)]] 6000 units/m<sup>2</sup> IV over 60 minutes once per day on days 8, 10, 12, 20, 22, 24, 26, 28
+*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 1, 8, 15, 22
 ====Glucocorticoid therapy====
-*[[Prednisone (Sterapred)]] 100 mg/m<sup>2</sup> PO once per day on days 1 to 5
+*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup>/day PO on days 1 to 14
-'''21-day cycle for 6 cycles (Lenz et al. 2005) or up to 8 cycles (LYM-3002)'''
+====CNS therapy, prophylaxis====
+*[[Methotrexate (MTX)]] 15 mg IT once per day on days 1 & 8
+*[[Cytarabine (Ara-C)]] 40 mg IT once per day on days 1 & 8
+*[[Methylprednisolone (Solumedrol)]] 40 mg IT once per day on days 1 & 8
+====Supportive therapy====
+*[[Lenograstim (Granocyte)]] by the following study-specific criteria:
+**GRAALL-2003: 150 mcg/m<sup>2</sup> SC once per day from day 17 until myeloid recovery
+**GRAALL-2005: 263 mcg SC once per day from day 18 until first day with ANC greater than 1000/uL
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*Patients with resistant disease: [[#Cytarabine_.26_Idarubicin_2|Cytarabine & idarubicin]] salvage prior to further consolidation
+*All others: [[#Pediatric-like_GRAALL_consolidation|Pediatric-like GRAALL]] consolidation
 </div></div><br>
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #3, uncapped vincristine {{#subobject:360915|Variant=1}}===
+===Regimen variant #2, "HyperC" {{#subobject:7096ea|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
@@ Line 225: / Line 252: @@
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1016/S0140-6736(12)61763-2 Rummel et al. 2013 (StiL NHL1)]
+|[https://doi.org/10.1056/NEJMoa1605085 Maury et al. 2016 (GRAALL-2005/R)]
-|2003-2008
+|2006-2014
 |style="background-color:#1a9851"|Phase 3 (C)
-|[[#Bendamustine_.26_Rituximab_.28BR.29|BR]]
+|[[#Cyclophosphamide.2C_Daunorubicin.2C_L-Asparaginase.2C_Vincristine.2C_Prednisone.2C_Rituximab|Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone, Rituximab]]
-|style="background-color:#d73027"|Inferior PFS
+|style="background-color:#fc8d59"|Seems to have inferior EFS
 |-
-|}
+|[https://doi.org/10.1200/JCO.2017.76.8192 Huguet et al. 2018 (GRAALL-2005)]
-<div class="toccolours" style="background-color:#b3e2cd">
+|2006-2014
-====Targeted therapy====
+|style="background-color:#1a9851"|Phase 3 (E-esc)
-*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1
+|[[#Cyclophosphamide.2C_Daunorubicin.2C_L-Asparaginase.2C_Vincristine.2C_Prednisone|Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone]]; standard-dose cyclophosphamide
-====Chemotherapy====
+| style="background-color:#ffffbf" |Did not meet primary endpoint of EFS
-*[[Cyclophosphamide (Cytoxan)]] 750 mg/m<sup>2</sup> IV once on day 1
-*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV once on day 1
-*[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> IV once on day 1
-====Glucocorticoid therapy====
-*[[Prednisone (Sterapred)]] 100 mg PO once per day on days 1 to 5
-'''21-day cycle up to maximum of 6 cycles'''
-</div></div><br>
-<div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #4, 3 cycles, rituximab in cycle 3 only {{#subobject:53c52a|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
-!style="width: 33%"|Study
-!style="width: 33%"|Years of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[http://www.bloodjournal.org/content/121/1/48.full Delarue et al. 2012]
-|2000-2003
-|style="background-color:#91cf61"|Phase 2
 |-
 |}
+''This is the "HyperC" arm of GRAALL-2005. Given the negative report in 2018, this experimental arm should be considered as historic reference.''
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*[[#Prednisone_monotherapy|Prednisone prephase]]
+</div>
 <div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
-*[[Rituximab (Rituxan)]] as follows:
-**Cycles 1 & 2: none
-**Cycle 3: 375 mg/m<sup>2</sup> IV once on day 1
 ====Chemotherapy====
-*[[Cyclophosphamide (Cytoxan)]] 750 mg/m<sup>2</sup> IV once on day 1
+*[[Cyclophosphamide (Cytoxan)]] 750 mg/m<sup>2</sup> IV over 3 hours once on day 1, then 300 mg/m<sup>2</sup> IV over 3 hours every 12 hours on days 15 to 17 (total dose: 2550 mg/m<sup>2</sup>)
-*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV once on day 1
+*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV once per day on days 1 to 3, then 30 mg/m<sup>2</sup> IV once per day on days 15 & 16
-*[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> IV once on day 1
+*[[Asparaginase (Elspar)]] 6000 units/m<sup>2</sup> IV over 60 minutes once per day on days 8, 10, 12, 20, 22, 24, 26, 28
+*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 1, 8, 15, 22
 ====Glucocorticoid therapy====
-*[[Prednisone (Sterapred)]] 40 mg/m<sup>2</sup> PO once per day on days 1 to 5
+*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup>/day PO on days 1 to 14
 ====CNS therapy, prophylaxis====
-''Intrathecal prophylaxis with the following was given per physician discretion; no timeframe or total number of doses is described:''
+*[[Methotrexate (MTX)]] 15 mg IT once per day on days 1 & 8
-*[[Methotrexate (MTX)]] 15 mg IT
+*[[Cytarabine (Ara-C)]] 40 mg IT once per day on days 1 & 8
-*[[Cytarabine (Ara-C)]] 40 mg IT
+*[[Methylprednisolone (Solumedrol)]] 40 mg IT once per day on days 1 & 8
-*Corticosteroids
+====Supportive therapy====
-'''21-day cycle for up to 3 cycles'''
+*[[Lenograstim (Granocyte)]] 263 mcg SC once per day from day 18 until first day with ANC greater than 1000/uL
+'''28-day course'''
 </div>
 <div class="toccolours" style="background-color:#cbd5e7">
 ====Subsequent treatment====
-*[[#R-DHAP|R-DHAP]]; patients who progress after first 2 cycles go directly to R-DHAP
+*Patients with resistant disease: [[#Cytarabine_.26_Idarubicin_2|Cytarabine & idarubicin]] salvage prior to further consolidation
+*Responders: [[#Pediatric-like_GRAALL_consolidation|Pediatric-like GRAALL]] consolidation
 </div></div><br>
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #5, 4 cycles {{#subobject:b10fa8|Variant=1}}===
+===Regimen variant #3 {{#subobject:1bf42b|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 33%"|Study
+!style="width: 20%"|Study
-!style="width: 33%"|Years of enrollment
+!style="width: 20%"|Years of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3732008/ Smith et al. 2012 (ECOG E1499)]
+|[http://www.bloodjournal.org/content/99/3/863.long Annino et al. 2002 (GIMEMA ALL 0288)]
-|2003-2005
+|1988-1996
-|style="background-color:#91cf61"|Phase 2
+|style="background-color:#1a9851"|Phase 3 (E-esc)
+|[[#DOLP|DOLP]]
+|style="background-color:#ffffbf"|Did not meet primary endpoint of CR rate
 |-
 |}
-''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''
+''Note: vincristine is clearly shown as 2 mg/m<sup>2</sup> in Table 1, but this is an unusual dose; consider discussing with the authors if you are going to utilize this regimen.''
 <div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
+====Chemotherapy, "Induction phase I"====
-*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1
+*[[Cyclophosphamide (Cytoxan)]] 800 mg/m<sup>2</sup> IV once per day on days 1 & 2
-====Chemotherapy====
+*[[Daunorubicin (Cerubidine)]] 40 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
-*[[Cyclophosphamide (Cytoxan)]] 750 mg/m<sup>2</sup> IV once on day 1
+*[[Asparaginase (Elspar)|L-Asparaginase]] 6000 units/m<sup>2</sup> SC once per day on days 22 to 31
-*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV once on day 1
+*[[Vincristine (Oncovin)]] 2 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
-*[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1
 ====Glucocorticoid therapy====
-*[[Prednisone (Sterapred)]] 100 mg PO once per day on days 1 to 5
+*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup>/day PO on days 1 to 14, then 40 mg/m<sup>2</sup>/day PO on days 15 to 31
-'''21-day cycle for 4 cycles'''
+'''31-day course'''
 </div>
 <div class="toccolours" style="background-color:#cbd5e7">
 ====Subsequent treatment====
-*[[#Ibritumomab_tiuxetan_protocol|Ibritumomab tiuxetan]] consolidation, in 4 to 8 weeks
+*Induction phase II or salvage, see paper for details
-</div></div>
+</div></div><br>
-===References===
-# Lenz G, Dreyling M, Hoster E, Wörmann B, Dührsen U, Metzner B, Eimermacher H, Neubauer A, Wandt H, Steinhauer H, Martin S, Heidemann E, Aldaoud A, Parwaresch R, Hasford J, Unterhalt M, Hiddemann W; German Low Grade Lymphoma Study Group. Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone significantly improves response and time to treatment failure, but not long-term outcome in patients with previously untreated mantle cell lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG). J Clin Oncol. 2005 Mar 20;23(9):1984-92. Epub 2005 Jan 24. [https://doi.org/10.1200/jco.2005.08.133 link to original article] [https://pubmed.ncbi.nlm.nih.gov/15668467 PubMed]
-# Delarue R, Haioun C, Ribrag V, Brice P, Delmer A, Tilly H, Salles G, Van Hoof A, Casasnovas O, Brousse N, Lefrere F, Hermine O; Groupe d'Etude des Lymphomes de l'Adulte. CHOP and DHAP plus rituximab followed by autologous stem cell transplantation in mantle cell lymphoma: a phase 2 study from the Groupe d'Etude des Lymphomes de l'Adulte. Blood. 2013 Jan 3;121(1):48-53. Epub 2012 Jun 20. [http://www.bloodjournal.org/content/121/1/48.full link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22718839 PubMed]
-# '''MCLelderly:''' Kluin-Nelemans HC, Hoster E, Hermine O, Walewski J, Trneny M, Geisler CH, Stilgenbauer S, Thieblemont C, Vehling-Kaiser U, Doorduijn JK, Coiffier B, Forstpointner R, Tilly H, Kanz L, Feugier P, Szymczyk M, Hallek M, Kremers S, Lepeu G, Sanhes L, Zijlstra JM, Bouabdallah R, Lugtenburg PJ, Macro M, Pfreundschuh M, Procházka V, Di Raimondo F, Ribrag V, Uppenkamp M, André M, Klapper W, Hiddemann W, Unterhalt M, Dreyling MH. Treatment of older patients with mantle-cell lymphoma. N Engl J Med. 2012 Aug 9;367(6):520-31. [https://doi.org/10.1056/NEJMoa1200920 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22873532 PubMed] NCT00209209
-## '''Update:''' Kluin-Nelemans HC, Hoster E, Hermine O, Walewski J, Geisler CH, Trneny M, Stilgenbauer S, Kaiser F, Doorduijn JK, Salles G, Szymczyk M, Tilly H, Kanz L, Schmidt C, Feugier P, Thieblemont C, Zijlstra JM, Ribrag V, Klapper W, Pott C, Unterhalt M, Dreyling MH. Treatment of Older Patients With Mantle Cell Lymphoma (MCL): Long-Term Follow-Up of the Randomized European MCL Elderly Trial. J Clin Oncol. 2020 Jan 20;38(3):248-256. Epub 2019 Dec 5. [https://doi.org/10.1200/jco.19.01294 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31804876 PubMed]
-<!-- Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, June 2-6, 2006; the 47th Annual Meeting of the American Society of Hematology, Atlanta, GA, December 8-11, 2007; and the 11th International Conference on Malignant Lymphoma, Lugano, Switzerland, June 15-18, 2011. -->
-# '''ECOG E1499:''' Smith MR, Li H, Gordon L, Gascoyne RD, Paietta E, Forero-Torres A, Kahl BS, Advani R, Hong F, Horning SJ. Phase II study of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone immunochemotherapy followed by yttrium-90-ibritumomab tiuxetan in untreated mantle-cell lymphoma: Eastern Cooperative Oncology Group Study E1499. J Clin Oncol. 2012 Sep 1;30(25):3119-26. Epub 2012 Jul 30. [https://doi.org/10.1200/jco.2012.42.2444 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3732008/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22851557 PubMed] NCT00070447
-## '''Update:''' Smith MR, Hong F, Li H, Gordon LI, Gascoyne RD, Paietta EM, Advani RH, Forero-Torres A, Horning SJ, Kahl BS. Mantle cell lymphoma initial therapy with abbreviated R-CHOP followed by (90)Y-ibritumomab tiuxetan: 10-year follow-up of the phase 2 ECOG-ACRIN study E1499. Leukemia. 2017 Feb;31(2):517-519. Epub 2016 Oct 26. [https://doi.org/10.1038/leu.2016.305 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5288271/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27780968 PubMed]
-<!--
-# Mathias J Rummel, MD, PhD, Norbert Niederle, Georg Maschmeyer, Andre Banat, MD, MBA, Ulrich von Gruenhagen, MD, Christoph Losem, Gerhard Heil, Manfred Welslau, Christina Balser, Ulrich Kaiser, Harald Ballo, Eckhart Weidmann, Heinz A Duerk, Dorothea Kofahl-Krause, Fritz Roller, Juergen Barth, Dieter Hoelzer, MD, PhD, Axel Hinke and Wolfram Brugger. Bendamustine Plus Rituximab Is Superior in Respect of Progression Free Survival and CR Rate When Compared to CHOP Plus Rituximab as First-Line Treatment of Patients with Advanced Follicular, Indolent, and Mantle Cell Lymphomas: Final Results of a Randomized Phase III Study of the StiL (Study Group Indolent Lymphomas, Germany). 2009 ASH Annual Meeting abstract 405. [https://ash.confex.com/ash/2009/webprogram/Paper20178.html link to abstract]
-# Mathias J. Rummel, Norbert Niederle, Georg Maschmeyer, Andre G. Banat, Ulrich von Gruenhagen, Christoph Losem, Dorothea Kofahl-Krause, Gerhard Heil, Manfred Welslau, Christina Balser, Ulrich Kaiser, Eckhart Weidmann, Heinz A. Duerk, Harald Ballo, Martina Stauch, Juergen Barth, Axel Hinke, Wolfram Brugger, Study Group Indolent Lymphomas (StiL). Bendamustine plus rituximab (B-R) versus CHOP plus rituximab (CHOP-R) as first-line treatment in patients with indolent and mantle cell lymphomas (MCL): Updated results from the StiL NHL1 study. 2012 ASCO Annual Meeting abstract 3. [http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview==abst_detail_view&confID==114&abstractID==95807 link to abstract] [http://www.ascopost.com/issues/july-1-2012/german-study-finds-bendamustine-improves-progression-free-survival-in-patients-with-non-hodgkin-lymphoma.aspx ASCO Post article] [http://www.asco.org/ASCOv2/MultiMedia/Virtual%20Meeting?&vmview==vm_session_presentations_view&confID==114&sessionID==4807 ASCO plenary session video] -->
-# '''StiL NHL1:''' Rummel MJ, Niederle N, Maschmeyer G, Banat GA, von Grünhagen U, Losem C, Kofahl-Krause D, Heil G, Welslau M, Balser C, Kaiser U, Weidmann E, Dürk H, Ballo H, Stauch M, Roller F, Barth J, Hoelzer D, Hinke A, Brugger W; StiL. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013 Apr 6;381(9873):1203-10. Epub 2013 Feb 20. Erratum in: Lancet. 2013 Apr 6;381(9873):1184. [https://doi.org/10.1016/S0140-6736(12)61763-2 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23433739 PubMed] NCT00991211
-## '''Update: Abstract:''' Mathias J. Rummel, MD, Georg Maschmeyer, MD, Arnold Ganser, Andrea Heider, PhD, Ulrich von Grünhagen, MD, PhD5, Christoph Losem, Gerhard Heil, MD, Manfred Welslau, Christina Balser, MD, Ulrich Kaiser, MD, Eckhart Weidmann, Heinz Dürk, MD, Hans Peter Böck, Martina Beate Stauch, MD, Jürgen Barth, Wolfgang Blau, MD, Alexander Burchardt, MD, Frank Kauff, PhD, Axel Hinke, PhD and Wolfram Brugger, MD. Bendamustine Plus Rituximab (B-R) Versus CHOP Plus Rituximab (CHOP-R) As First-Line Treatment in Patients with Indolent and Mantle Cell Lymphomas (MCL) – 7 Year Updated Results from the StiL NHL1 Study. Blood 2014 124:4407. [http://www.bloodjournal.org/content/124/21/4407 link to abstract]
-<!-- # Ian Flinn et al. An Open-Label, Randomized Study of Bendamustine and Rituximab (BR) Compared with Rituximab, Cyclophosphamide, Vincristine, and Prednisone (R-CVP) or Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) in First-Line Treatment of Patients with Advanced Indolent Non-Hodgkin’s Lymphoma (NHL) or Mantle Cell Lymphoma (MCL): The Bright Study. 2012 ASH Annual Meeting abstract 902. [https://ash.confex.com/ash/2012/webprogram/Paper51442.html link to abstract] -->
-# '''BRIGHT:''' Flinn IW, van der Jagt R, Kahl BS, Wood P, Hawkins TE, Macdonald D, Hertzberg M, Kwan YL, Simpson D, Craig M, Kolibaba K, Issa S, Clementi R, Hallman DM, Munteanu M, Chen L, Burke JM. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood. 2014 May 8;123(19):2944-52. Epub 2014 Mar 3. [https://doi.org/10.1182/blood-2013-11-531327 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4260975/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24591201 PubMed] NCT00877006
-<!-- ## '''Update: Abstract:''' Ian Flinn, Richard van der Jagt, Julie E. Chang, Peter Wood, Tim E. Hawkins, David MacDonald, Judith Trotman, David Simpson, Kathryn S. Kolibaba, Samar Issa, Doreen M. Hallman, Ling Chen, and John M. Burke. First-line treatment of iNHL or MCL patients with BR or R-CHOP/R-CVP: Results of the BRIGHT 5-year follow-up study. Journal of Clinical Oncology 2017 35:15_suppl, 7500-7500 [https://doi.org/10.1200/JCO.2017.35.15_suppl.7500 link to abstract] -->
-## '''Update:''' Flinn IW, van der Jagt R, Kahl B, Wood P, Hawkins T, MacDonald D, Simpson D, Kolibaba K, Issa S, Chang J, Trotman J, Hallman D, Chen L, Burke JM. First-line treatment of patients with indolent non-Hodgkin lymphoma or mantle-cell lymphoma with bendamustine plus rituximab versus R-CHOP or R-CVP: results of the BRIGHT 5-year follow-up study. J Clin Oncol. 2019 Apr 20;37(12):984-991. Epub 2019 Feb 27. [https://doi.org/10.1200/JCO.18.00605 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494265/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30811293 PubMed]
-<!-- # '''Abstract:''' Franco Cavalli, Brendan Rooney, Lixia Pei, Helgi Van De Velde, Tadeusz Robak, on behalf of the LYM-3002 Investigators. Randomized phase 3 study of rituximab, cyclophosphamide, doxorubicin, and prednisone plus vincristine (R-CHOP) or bortezomib (VR-CAP) in newly diagnosed mantle cell lymphoma (MCL) patients (pts) ineligible for bone marrow transplantation (BMT). 2014 ASCO Annual Meeting abstract 8500. [http://meetinglibrary.asco.org/content/129206-144 link to abstract] -->
-# '''LYM-3002:''' Robak T, Huang H, Jin J, Zhu J, Liu T, Samoilova O, Pylypenko H, Verhoef G, Siritanaratkul N, Osmanov E, Alexeeva J, Pereira J, Drach J, Mayer J, Hong X, Okamoto R, Pei L, Rooney B, van de Velde H, Cavalli F; the LYM-3002 Investigators. Bortezomib-based therapy for newly diagnosed mantle-cell lymphoma. N Engl J Med. 2015 Mar 5;372(10):944-953. [https://doi.org/10.1056/NEJMoa1412096 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25738670 PubMed] NCT00722137
-## '''Update:''' Robak T, Jin J, Pylypenko H, Verhoef G, Siritanaratkul N, Drach J, Raderer M, Mayer J, Pereira J, Tumyan G, Okamoto R, Nakahara S, Hu P, Appiani C, Nemat S, Cavalli F; LYM-3002 investigators. Frontline bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in transplantation-ineligible patients with newly diagnosed mantle cell lymphoma: final overall survival results of a randomised, open-label, phase 3 study. Lancet Oncol. 2018 Nov;19(11):1449-58. Epub 2018 Oct 18. [https://doi.org/10.1016/S1470-2045(18)30685-5 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30348538 PubMed]
-# '''MCL Younger:''' Hermine O, Hoster E, Walewski J, Bosly A, Stilgenbauer S, Thieblemont C, Szymczyk M, Bouabdallah R, Kneba M, Hallek M, Salles G, Feugier P, Ribrag V, Birkmann J, Forstpointner R, Haioun C, Hänel M, Casasnovas RO, Finke J, Peter N, Bouabdallah K, Sebban C, Fischer T, Dührsen U, Metzner B, Maschmeyer G, Kanz L, Schmidt C, Delarue R, Brousse N, Klapper W, Macintyre E, Delfau-Larue MH, Pott C, Hiddemann W, Unterhalt M, Dreyling M; European Mantle Cell Lymphoma Network. Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open-label, phase 3 trial of the European Mantle Cell Lymphoma Network. Lancet. 2016 Aug 6;388(10044):565-75. Epub 2016 Jun 14. [https://doi.org/10.1016/S0140-6736(16)00739-X link to original article] [https://pubmed.ncbi.nlm.nih.gov/27313086 PubMed] NCT00209222
-==R-CHOP (Prednisolone) {{#subobject:ug72ab|Regimen=1}}==
-R-CHOP: '''<u>R</u>'''ituximab, '''<u>C</u>'''yclophosphamide, '''<u>H</u>'''ydroxydaunorubicin (Doxorubicin), '''<u>O</u>'''ncovin (Vincristine), '''<u>P</u>'''rednisolone
-===Example orders===
-*[[Example orders for R-CHOP in lymphoma]]
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:c7982b|Variant=1}}===
+===Regimen variant #4, "Larson regimen" {{#subobject:e460e0|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
+{| class="wikitable" style="width: 40%; text-align:center;"
-!style="width: 33%"|Study
+!style="width: 25%"|Study
-!style="width: 33%"|Years of enrollment
+!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://doi.org/10.1111/j.1365-2141.2008.07498.x Van 't Veer et al. 2008 (HOVON 45)]
+|[http://www.bloodjournal.org/content/85/8/2025.full Larson et al. 1995 (CALGB 8811)]
-|2002-2005
 |style="background-color:#91cf61"|Phase 2
 |-
 |}
-''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''
 <div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
+====Chemotherapy, "Course I"====
-*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1
+*[[Cyclophosphamide (Cytoxan)]] by the following age-based criteria:
-====Chemotherapy====
+**Younger than 60: 1200 mg/m<sup>2</sup> IV once on day 1
-*[[Cyclophosphamide (Cytoxan)]] 750 mg/m<sup>2</sup> IV once on day 1
+**60 or older: 800 mg/m<sup>2</sup> IV once on day 1
-*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV once on day 1
+*[[Daunorubicin (Cerubidine)]] by the following age-based criteria:
-*[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> IV once on day 1
+**Younger than 60: 45 mg/m<sup>2</sup> IV once per day on days 1 to 3
+**60 or older: 30 mg/m<sup>2</sup> IV once per day on days 1 to 3
+*[[Asparaginase (Elspar)]] 6000 units/m<sup>2</sup> SC once per day on days 5, 8, 11, 15, 18, 22
+*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 1, 8, 15, 22
 ====Glucocorticoid therapy====
-*[[Prednisolone (Millipred)]] 100 mg PO once per day on days 1 to 5
+*[[Prednisone (Sterapred)]] by the following age-based criteria:
-'''21-day cycle for 3 cycles'''
+**Younger than 60: 60 mg/m<sup>2</sup> PO once per day on days 1 to 21
+**60 or older: 60 mg/m<sup>2</sup> PO once per day on days 1 to 7
+'''28-day course'''
 </div>
 <div class="toccolours" style="background-color:#cbd5e7">
 ====Subsequent treatment====
-*Patients with at least PR: [[#R-HiDAC|R-HiDAC]]
+*[[#CALGB_8811_early_intensification|Larson regimen (CALGB 8811)]] early intensification ("Course II")
 </div></div>
 ===References===
-# '''HOVON 45:''' Van 't Veer MB, de Jong D, MacKenzie M, Kluin-Nelemans HC, van Oers MH, Zijlstra J, Hagenbeek A, van Putten WL. High-dose Ara-C and BEAM with autograft rescue in R-CHOP responsive mantle cell lymphoma patients. Br J Haematol. 2009 Feb;144(4):524-30. Epub 2008 Nov 26. [https://doi.org/10.1111/j.1365-2141.2008.07498.x link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19036081 PubMed]
+# '''CALGB 8811:''' Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR, Hooberman AL, Westbrook CA, Arthur DC, George SL, Bloomfield CD, Schiffer CA. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: Cancer and Leukemia Group B study 8811. Blood. 1995 Apr 15;85(8):2025-37. [http://www.bloodjournal.org/content/85/8/2025.full.pdf+html link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/7718875 PubMed]
-==R-CHOP-14 (Prednisolone) {{#subobject:50294c|Regimen=1}}==
+# '''GIMEMA ALL 0288:''' Annino L, Vegna ML, Camera A, Specchia G, Visani G, Fioritoni G, Ferrara F, Peta A, Ciolli S, Deplano W, Fabbiano F, Sica S, Di Raimondo F, Cascavilla N, Tabilio A, Leoni P, Invernizzi R, Baccarani M, Rotoli B, Amadori S, Mandelli F; GIMEMA. Treatment of adult acute lymphoblastic leukemia (ALL): long-term follow-up of the GIMEMA ALL 0288 randomized study. Blood. 2002 Feb 1;99(3):863-71. [http://www.bloodjournal.org/content/99/3/863.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11806988 PubMed]
-R-CHOP-14: '''<u>R</u>'''ituximab, '''<u>C</u>'''yclophosphamide, '''<u>H</u>'''ydroxydaunorubicin (Doxorubicin), '''<u>O</u>'''ncovin (Vincristine), '''<u>P</u>'''rednisolone every '''<u>14</u>''' days
+# '''GRAALL-2003:''' Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. [https://doi.org/10.1200/JCO.2008.18.6916 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19124805 PubMed] NCT00222027
+<!-- # '''Abstract:''' Maury et al. Addition of Rituximab Improves the Outcome of Adult Patients with CD20-Positive, Ph-Negative, B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL): Results of the Randomized Graall-R 2005 Study. ASH 2015 Annual Meeting Abstract 1.[https://ash.confex.com/ash/2015/webprogram/Paper82882.html link to abstract] -->
+# '''GRAALL-2005/R:''' Maury S, Chevret S, Thomas X, Heim D, Leguay T, Huguet F, Chevallier P, Hunault M, Boissel N, Escoffre-Barbe M, Hess U, Vey N, Pignon JM, Braun T, Marolleau JP, Cahn JY, Chalandon Y, Lhéritier V, Beldjord K, Béné MC, Ifrah N, Dombret H; GRAALL. Rituximab in B-lineage adult acute lymphoblastic leukemia. N Engl J Med. 2016 Sep 15;375(11):1044-53. [https://doi.org/10.1056/NEJMoa1605085 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1605085/suppl_file/nejmoa1605085_protocol.pdf link to supplement] '''contains dosing details in supplement''' [https://pubmed.ncbi.nlm.nih.gov/27626518 PubMed] NCT00327678
+# '''GRAALL-2005:''' Huguet F, Chevret S, Leguay T, Thomas X, Boissel N, Escoffre-Barbe M, Chevallier P, Hunault M, Vey N, Bonmati C, Lepretre S, Marolleau JP, Pabst T, Rousselot P, Buzyn A, Cahn JY, Lhéritier V, Béné MC, Asnafi V, Delabesse E, Macintyre E, Chalandon Y, Ifrah N, Dombret H; Group of Research on Adult ALL. Intensified therapy of acute lymphoblastic leukemia in adults: report of the randomized GRAALL-2005 clinical trial. J Clin Oncol. 2018 Aug 20;36(24):2514-2523. Epub 2018 Jun 4. [https://doi.org/10.1200/JCO.2017.76.8192 link to original article] [https://pubmed.ncbi.nlm.nih.gov/29863974 PubMed] NCT00327678
+==Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone, Rituximab {{#subobject:18fec2|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:4b4e17|Variant=1}}===
+===Regimen variant #1 {{#subobject:aa59d3|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 33%"|Study
+!style="width: 20%"|Study
-!style="width: 33%"|Years of enrollment
+!style="width: 20%"|Years of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1056/NEJMoa1701769 Le Gouill et al. 2017 (LyMa)]
+|[https://doi.org/10.1056/NEJMoa1605085 Maury et al. 2016 (GRAALL-2005/R)]
-|2008-2012
+|2006-2014
-|style="background-color:#91cf61"|Non-randomized portion of RCT
+|style="background-color:#1a9851"|Phase 3 (E-esc)
+|[[#Cyclophosphamide.2C_Daunorubicin.2C_L-Asparaginase.2C_Vincristine.2C_Prednisone|Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone]]
+|style="background-color:#91cf60"|Seems to have superior EFS
 |-
 |}
-''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''
+''Note: this regimen was meant for CD20+ patients less than 60 years old. This is the "standard" arm of '''GRAALL-2005/R'''.''
 <div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
-*[[#R-DHAC|R-DHAC]] x 4 or [[#R-DHAOx|R-DHAOx]] x 4 or [[#R-DHAP|R-DHAP]] x 4, with PR
+*[[#Prednisone_monotherapy|Prednisone prephase]]
 </div>
 <div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
-*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1
 ====Chemotherapy====
-*[[Cyclophosphamide (Cytoxan)]] 750 mg/m<sup>2</sup> IV once on day 1
+*[[Cyclophosphamide (Cytoxan)]] 750 mg/m<sup>2</sup> IV over 3 hours once per day on days 1 & 15
-*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV once on day 1
+*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV once per day on days 1 to 3, then 30 mg/m<sup>2</sup> IV once per day on days 15 & 16
-*[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1
+*[[Asparaginase (Elspar)]] 6000 units/m<sup>2</sup> IV over 60 minutes once per day on days 8, 10, 12, 20, 22, 24, 26, 28
+*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 1, 8, 15, 22
 ====Glucocorticoid therapy====
-*[[Prednisolone (Millipred)]] 80 mg/m<sup>2</sup> PO once per day on days 1 to 5
+*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup>/day PO on days 1 to 14
+====Targeted therapy====
+*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once per day on days 1 & 7
+====CNS therapy, prophylaxis====
+*[[Methotrexate (MTX)]] 15 mg IT once per day on days 1 & 8
+*[[Cytarabine (Ara-C)]] 40 mg IT once per day on days 1 & 8
+*[[Methylprednisolone (Solumedrol)]] 40 mg IT once per day on days 1 & 8
 ====Supportive therapy====
-*Not specified
+*[[Lenograstim (Granocyte)]] by the following study-specific criteria:
-'''14-day cycle for 4 cycles'''
+**GRAALL-2003: 150 mcg/m<sup>2</sup> SC once per day from day 17 until myeloid recovery
+**GRAALL-2005: 263 mcg SC once per day from day 18 until first day with ANC greater than 1000/uL
 </div>
 <div class="toccolours" style="background-color:#cbd5e7">
 ====Subsequent treatment====
-*[[#R-BEAM.2C_then_auto_HSCT|R-BEAM with autologous HSCT]]
+*Patients with resistant disease: [[#Cytarabine.2C_Idarubicin.2C_Rituximab|Cytarabine, idarubicin, rituximab]] salvage prior to further consolidation
+*All others: Pediatric-like GRAALL consolidation with rituximab
 </div></div>
 ===References===
-<!-- # '''Abstract:''' Steven Le Gouill, MD, PhD, Catherine Thieblemont, MD, PhD, Lucie Oberic, Krimo Bouabdallah, MD, Emmanuel Gyan, MD, PhD, Gandhi Damaj, MD, Vincent Ribrag, MD, Serge Bologna, MD, Remy Gressin, MD, Olivier Casasnovas, MD, Corinne Haioun, MD, PhD, Philippe Solal-Celigny, MD, Herve Maisonneuve, MD, Eric Van Den Neste, MD, PhD, Anne Moreau, MD, Marie C Bene, Gilles Salles, MD PhD, Hervé Tilly, MD, PhD, Thierry Lamy, MD, PhD and Olivier Hermine, MD, PhD. Rituximab Maintenance Versus Wait and Watch after Four Courses of R-DHAP Followed By Autologous Stem Cell transplantation in Previously Untreated Young Patients with Mantle Cell Lymphoma: First Interim Analysis of the Phase III Prospective Lyma Trial, a Lysa Study. Blood 2014 124:146. [http://www.bloodjournal.org/content/124/21/146 link to abstract] -->
+<!-- # '''Abstract:''' Maury et al. Addition of Rituximab Improves the Outcome of Adult Patients with CD20-Positive, Ph-Negative, B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL): Results of the Randomized Graall-R 2005 Study. ASH 2015 Annual Meeting Abstract 1.[https://ash.confex.com/ash/2015/webprogram/Paper82882.html link to abstract] -->
-# '''LyMa:''' Le Gouill S, Thieblemont C, Oberic L, Moreau A, Bouabdallah K, Dartigeas C, Damaj G, Gastinne T, Ribrag V, Feugier P, Casasnovas O, Zerazhi H, Haioun C, Maisonneuve H, Houot R, Jardin F, Van Den Neste E, Tournilhac O, Le Dû K, Morschhauser F, Cartron G, Fornecker LM, Canioni D, Callanan M, Béné MC, Salles G, Tilly H, Lamy T, Gressin R, Hermine O; LYSA. Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma. N Engl J Med. 2017 Sep 28;377(13):1250-1260. [https://doi.org/10.1056/NEJMoa1701769 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1701769/suppl_file/nejmoa1701769_appendix.pdf link to protocol] '''contains dosing details in supplement''' [https://pubmed.ncbi.nlm.nih.gov/28953447 PubMed] NCT00921414
+# '''GRAALL-2005/R:''' Maury S, Chevret S, Thomas X, Heim D, Leguay T, Huguet F, Chevallier P, Hunault M, Boissel N, Escoffre-Barbe M, Hess U, Vey N, Pignon JM, Braun T, Marolleau JP, Cahn JY, Chalandon Y, Lhéritier V, Beldjord K, Béné MC, Ifrah N, Dombret H; GRAALL. Rituximab in B-lineage adult acute lymphoblastic leukemia. N Engl J Med. 2016 Sep 15;375(11):1044-53. [https://doi.org/10.1056/NEJMoa1605085 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1605085/suppl_file/nejmoa1605085_protocol.pdf link to supplement] '''contains dosing details in supplement''' [https://pubmed.ncbi.nlm.nih.gov/27626518 PubMed] NCT00327678
-==R-CHOP/R-DHAP {{#subobject:989434|Regimen=1}}==
+==Cyclophosphamide, Idarubicin, Vincristine, Prednisone {{#subobject:4c1f91|Regimen=1}}==
-R-CHOP/R-DHAP: '''<u>R</u>'''ituximab, '''<u>C</u>'''yclophosphamide, '''<u>H</u>'''ydroxydaunorubicin (Doxorubicin), '''<u>O</u>'''ncovin (Vincristine), '''<u>P</u>'''redniso(lo)ne alternating with '''<u>R</u>'''ituximab, '''<u>D</u>'''examethasone, '''<u>H</u>'''igh-dose '''<u>A</u>'''ra-C (Cytarabine), '''<u>P</u>'''latinol (Cisplatin)
 <div class="toccolours" style="background-color:#eeeeee">
-===Protocol {{#subobject:dea6ec|Variant=1}}===
+===Regimen {{#subobject:435069|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
@@ Line 410: / Line 418: @@
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1016/S0140-6736(16)00739-X Hermine et al. 2016 (MCL Younger)]
+|[https://doi.org/10.1200/jco.2004.10.050 Thomas et al. 2004 (LALA-94)]
-|2004-2010
+|1994-2002
-|style="background-color:#1a9851"|Phase 3 (E-esc)
+|style="background-color:#1a9851"|Phase 3 (E-switch-ic)
-|[[Complex_multipart_regimens#MCL_Younger|See link]]
+|[[#Cyclophosphamide.2C_Daunorubicin.2C_Vincristine.2C_Prednisone|Cyclophosphamide, Daunorubicin, Vincristine, Prednisone]]
-|style="background-color:#91cf60"|[[Complex_multipart_regimens#MCL_Younger|See link]]
+|style="background-color:#91cf60"|Seems to have superior DFS
 |-
 |}
 <div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
+====Chemotherapy====
-*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1
+*[[Cyclophosphamide (Cytoxan)]] 750 mg/m<sup>2</sup> IV once per day on days 1 & 8
-====Chemotherapy, CHOP portion (Cycles 1, 3, 5)====
+*[[Idarubicin (Idamycin)]] 9 mg/m<sup>2</sup> IV once per day on days 1, 2, 3, 8
-*[[Cyclophosphamide (Cytoxan)]] as follows:
+*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 1, 8, 15, 22
-**Cycles 1, 3, 5: 750 mg/m<sup>2</sup> IV once on day 1
+====Glucocorticoid therapy====
-*[[Doxorubicin (Adriamycin)]] as follows:
+*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup>/day IV or PO on days 1 to 7, 15 to 21
-**Cycles 1, 3, 5: 50 mg/m<sup>2</sup> IV once on day 1
+'''28-day course'''
-*[[Vincristine (Oncovin)]] as follows:
-**Cycles 1, 3, 5: 1.4 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1
-====Glucocorticoid therapy, CHOP portion (Cycles 1, 3, 5)====
-*[[Prednisone (Sterapred)]] as follows:
-**Cycles 1, 3, 5: 100 mg PO once per day on days 1 to 5
-====Glucocorticoid therapy, DHAP portion (Cycles 2, 4, 6)====
-*[[Dexamethasone (Decadron)]] as follows:
-**Cycles 2, 4, 6: 40 mg PO once per day on days 1 to 4
-====Chemotherapy, DHAP portion (Cycles 2, 4, 6)====
-*[[Cytarabine (Ara-C)]] as follows:
-**Cycles 2, 4, 6: 2000 mg/m<sup>2</sup> IV every 12 hours on day 2 (total dose per cycle: 4000 mg/m<sup>2</sup>)
-*[[Cisplatin (Platinol)]] as follows:
-**Cycles 2, 4, 6: 100 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 1
-'''21-day cycle for 6 cycles'''
 </div>
 <div class="toccolours" style="background-color:#cbd5e7">
 ====Subsequent treatment====
-*[[#Cytarabine.2C_Melphalan.2C_TBI.2C_then_auto_HSCT_88|Cytarabine, Melphalan, TBI with autologous hematopoietic stem cell transplant]]
+*Consolidation (see paper for details)
 </div></div>
 ===References===
-# '''MCL Younger:''' Hermine O, Hoster E, Walewski J, Bosly A, Stilgenbauer S, Thieblemont C, Szymczyk M, Bouabdallah R, Kneba M, Hallek M, Salles G, Feugier P, Ribrag V, Birkmann J, Forstpointner R, Haioun C, Hänel M, Casasnovas RO, Finke J, Peter N, Bouabdallah K, Sebban C, Fischer T, Dührsen U, Metzner B, Maschmeyer G, Kanz L, Schmidt C, Delarue R, Brousse N, Klapper W, Macintyre E, Delfau-Larue MH, Pott C, Hiddemann W, Unterhalt M, Dreyling M; European Mantle Cell Lymphoma Network. Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open-label, phase 3 trial of the European Mantle Cell Lymphoma Network. Lancet. 2016 Aug 6;388(10044):565-75. Epub 2016 Jun 14. [https://doi.org/10.1016/S0140-6736(16)00739-X link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/27313086 PubMed] NCT00209222
+# '''LALA-94:''' Thomas X, Boiron JM, Huguet F, Dombret H, Bradstock K, Vey N, Kovacsovics T, Delannoy A, Fegueux N, Fenaux P, Stamatoullas A, Vernant JP, Tournilhac O, Buzyn A, Reman O, Charrin C, Boucheix C, Gabert J, Lhéritier V, Fiere D; SAKK. Outcome of treatment in adults with acute lymphoblastic leukemia: analysis of the LALA-94 trial. J Clin Oncol. 2004 Oct 15;22(20):4075-86. Epub 2004 Sep 7. [https://doi.org/10.1200/jco.2004.10.050 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15353542 PubMed] NCT00002700
-#'''TRIANGLE:''' NCT02858258
+## '''Update:''' Vey N, Thomas X, Picard C, Kovascovicz T, Charin C, Cayuela JM, Dombret H, Dastugue N, Huguet F, Bastard C, Stamatoulas A, Giollant M, Tournilhac O, Macintyre E, Buzyn A, Bories D, Kuentz M, Dreyfus F, Delannoy A, Raynaud S, Gratecos N, Bordessoule D, de Botton S, Preudhomme C, Reman O, Troussard X, Pigneux A, Bilhou C, Vernant JP, Boucheix C, Gabert J; GET-LALA Group the Swiss Group for Clinical Cancer Research (SAKK). Allogeneic stem cell transplantation improves the outcome of adults with t(1;19)/E2A-PBX1 and t(4;11)/MLL-AF4 positive B-cell acute lymphoblastic leukemia: results of the prospective multicenter LALA-94 study. Leukemia. 2006 Dec;20(12):2155-61. Epub 2006 Oct 12. [https://doi.org/10.1038/sj.leu.2404420 link to original article] [https://pubmed.ncbi.nlm.nih.gov/17039234 PubMed]
-==R-CVP {{#subobject:d4a808|Regimen=1}}==
+==DOLP {{#subobject:3c9897|Regimen=1}}==
-R-CVP: '''<u>R</u>'''ituximab, '''<u>C</u>'''yclophosphamide, '''<u>V</u>'''incristine, '''<u>P</u>'''rednisone
+DOLP: '''<u>D</u>'''aunorubicin, '''<u>O</u>'''ncovin (Vincristine), '''<u>L</u>'''-Asparaginase, '''<u>P</u>'''rednisone
+<br>DVPA: '''<u>D</u>'''aunorubicin, '''<u>V</u>'''incristine, '''<u>P</u>'''rednisone, '''<u>A</u>'''sparaginase
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:8c0109|Variant=1}}===
+===Regimen variant #1, 25/5000/1.5/60 {{#subobject:7b55e1|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
+{| class="wikitable" style="width: 40%; text-align:center;"
-!style="width: 20%"|Study
+!style="width: 25%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4260975/ Flinn et al. 2014 (BRIGHT)]
+|[http://www.bloodjournal.org/content/64/1/38.long Hoelzer et al. 1984]
-|2009-2012
+|style="background-color:#91cf61"|Non-randomized
-|style="background-color:#1a9851"|Phase 3 (C)
-|[[#Bendamustine_.26_Rituximab_.28BR.29|BR]]
-|style="background-color:#eeee01"|Seems to have non-inferior CR rate
 |-
 |}
-<div class="toccolours" style="background-color:#b3e2cd">
+''Of historic interest. This is "Phase 1" of induction.''
-====Targeted therapy====
-*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1
 ====Chemotherapy====
-*[[Cyclophosphamide (Cytoxan)]] 750 mg/m<sup>2</sup> or 1000 mg/m<sup>2</sup> IV once on day 1
+*[[Daunorubicin (Cerubidine)]] 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
-*[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
+*[[Asparaginase (Elspar)]] 5000 units IV once per day on days 1 to 14
 ====Glucocorticoid therapy====
-*[[Prednisone (Sterapred)]] 100 mg PO once per day on days 1 to 5
+*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup>/day PO on days 1 to 28
-====Supportive therapy====
+'''4-week course'''
-*Antiemetics, antipyretics, and antibiotics per local standard of care
+</div>
-*[[:Category:Granulocyte_colony-stimulating_factors|G-CSF]] "according to the [https://doi.org/10.1200/jco.2000.18.20.3558 American Society of Clinical Oncology guidelines]"
+<div class="toccolours" style="background-color:#cbd5e7">
-'''21-day cycle for up to 8 cycles'''
+====Subsequent treatment====
-</div></div>
+*See paper for details of treatment beyond induction
-===References===
+</div></div><br>
-<!-- # '''Abstract:''' Ian Flinn et al. An Open-Label, Randomized Study of Bendamustine and Rituximab (BR) Compared with Rituximab, Cyclophosphamide, Vincristine, and Prednisone (R-CVP) or Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) in First-Line Treatment of Patients with Advanced Indolent Non-Hodgkin’s Lymphoma (NHL) or Mantle Cell Lymphoma (MCL): The Bright Study. 2012 ASH Annual Meeting abstract 902. [https://ash.confex.com/ash/2012/webprogram/Paper51442.html link to abstract] -->
-# '''BRIGHT:''' Flinn IW, van der Jagt R, Kahl BS, Wood P, Hawkins TE, Macdonald D, Hertzberg M, Kwan YL, Simpson D, Craig M, Kolibaba K, Issa S, Clementi R, Hallman DM, Munteanu M, Chen L, Burke JM. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood. 2014 May 8;123(19):2944-52. Epub 2014 Mar 3. [https://doi.org/10.1182/blood-2013-11-531327 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4260975/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24591201 PubMed] NCT00877006
-<!-- ## '''Update: Abstract:''' Ian Flinn, Richard van der Jagt, Julie E. Chang, Peter Wood, Tim E. Hawkins, David MacDonald, Judith Trotman, David Simpson, Kathryn S. Kolibaba, Samar Issa, Doreen M. Hallman, Ling Chen, and John M. Burke. First-line treatment of iNHL or MCL patients with BR or R-CHOP/R-CVP: Results of the BRIGHT 5-year follow-up study. Journal of Clinical Oncology 2017 35:15_suppl, 7500-7500 [https://doi.org/10.1200/JCO.2017.35.15_suppl.7500 link to abstract] -->
-## '''Update:''' Flinn IW, van der Jagt R, Kahl B, Wood P, Hawkins T, MacDonald D, Simpson D, Kolibaba K, Issa S, Chang J, Trotman J, Hallman D, Chen L, Burke JM. First-line treatment of patients with indolent non-Hodgkin lymphoma or mantle-cell lymphoma with bendamustine plus rituximab versus R-CHOP or R-CVP: results of the BRIGHT 5-year follow-up study. J Clin Oncol. 2019 Apr 20;37(12):984-991. Epub 2019 Feb 27. [https://doi.org/10.1200/JCO.18.00605 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494265/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30811293 PubMed]
-==R-Hyper-CVAD/R-MA {{#subobject:a76238|Regimen=1}}==
-R-Hyper-CVAD/R-MA: '''<u>R</u>'''ituximab, '''<u>Hyper</u>'''fractionated '''<u>C</u>'''yclophosphamide, '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>D</u>'''examethasone alternating with '''<u>R</u>'''ituximab, '''<u>M</u>'''ethotrexate, '''<u>A</u>'''ra-C (Cytarabine)
 <div class="toccolours" style="background-color:#eeeeee">
-===Protocol {{#subobject:abb9f1|Variant=1}}===
+===Regimen variant #2, 40/6000/2/60-40 ("Phase I" of GIMEMA ALL 0288) {{#subobject:6da40d|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
@@ Line 494: / Line 476: @@
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1200/jco.2005.01.1825 Romaguera et al. 2005]
+|[http://www.bloodjournal.org/content/99/3/863.long Annino et al. 2002 (GIMEMA ALL 0288)]
-|1999-2002
+|1988-1996
-|style="background-color:#91cf61"|Phase 2
+|style="background-color:#1a9851"|Phase 3 (C)
-| style="background-color:#d3d3d3" |
+|[[#Cyclophosphamide.2C_Daunorubicin.2C_L-Asparaginase.2C_Vincristine.2C_Prednisone|Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone]]
-| style="background-color:#d3d3d3" |
+|style="background-color:#ffffbf"|Did not meet primary endpoint of CR rate
-|-
-|[https://doi.org/10.1002/cncr.23880 Wang et al. 2008]
-|NR
-|style="background-color:#91cf61"|Phase 2
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3660082/ Bernstein et al. 2013 (SWOG S0213)]
-|2002-2006
-|style="background-color:#91cf61"|Phase 2
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|-
-|[https://doi.org/full/10.1111/j.1365-2141.2011.08958.x Merli et al. 2012]
-|2005-2010
-|style="background-color:#91cf61"|Phase 2
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5318240/ Chen et al. 2016 (SWOG S1106)]
-|2012-2013
-|style="background-color:#1a9851"|Randomized Phase 2 (E-esc)
-|[[#Bendamustine_.26_Rituximab_.28BR.29|BR]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS24
 |-
 |}
-''Note: Romaguera et al. 2005 had slightly different doxorubicin dosages in the text vs. table 1. SWOG S0213 used the original protocol as specified in Romaguera et al. 2005.''
+''Note: vincristine is clearly shown as 2 mg/m<sup>2</sup> in Table 1, but this is an unusual dose; consider discussing with the authors if you are going to utilize this regimen.''
 <div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
+====Chemotherapy====
-*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1, '''given first'''
+*[[Daunorubicin (Cerubidine)]] 40 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
-**Patients with peripheral blood involvement could have the cycle 1 dose of rituximab delayed or omitted by clinician discretion
+*[[Vincristine (Oncovin)]] 2 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
-====Chemotherapy, Part A (cycles 1, 3, 5, 7)====
+*[[Asparaginase (Elspar)|L-Asparaginase]] 6000 units/m<sup>2</sup> SC once per day on days 22 to 31
-*[[Cyclophosphamide (Cytoxan)]] as follows:
-**Cycles 1, 3, 5, 7: 300 mg/m<sup>2</sup> IV over 3 hours every 12 hours on days 2 to 4, '''given second''' (total dose per cycle: 1800 mg/m<sup>2</sup>)
-*[[Vincristine (Oncovin)]] as follows:
-**Cycles 1, 3, 5, 7: 1.4 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 5 & 12, '''given 12 hours after the last dose of [[Cyclophosphamide (Cytoxan)]] on day 5'''
-*[[Doxorubicin (Adriamycin)]] as follows:
-**Cycles 1, 3, 5, 7: 16.6 to 16.7 mg/m<sup>2</sup>/day IV continuous infusion over 72 hours, started on day 5 (total dose per cycle: 49.8 to 50.1 mg/m<sup>2</sup>)
 ====Glucocorticoid therapy====
-*[[Dexamethasone (Decadron)]] as follows:
+*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup>/day PO on days 1 to 14, then 40 mg/m<sup>2</sup>/day PO on days 15 to 31
-**Cycles 1, 3, 5, 7: 40 mg IV or PO once per day on days 2 to 5, 12 to 15
+'''31-day course'''
-====Supportive therapy, Part A====
-*[[Mesna (Mesnex)]] as follows:
-**Cycles 1, 3, 5, 7: 600 mg/m<sup>2</sup>/day IV continuous infusion over 76 hours, started on day 2, 1 hour before [[Cyclophosphamide (Cytoxan)]] and completed 12 hours after the last dose of [[Cyclophosphamide (Cytoxan)]]
-***"Over 76 hours" is not exactly specified in Romaguera et al. 2005; Wang et al. 2008. It is based on the assumption that "completed 12 hours after the last dose of cyclophosphamide" means that it would finish 12 hours after the last dose of cyclophosphamide completes.
-====Chemotherapy, Part B (cycles 2, 4, 6, 8)====
-*[[Methotrexate (MTX)]] as follows, by the following criteria:
-**Cycles 2, 4, 6, 8, patients with creatinine up to 1.5 mg/dL: 200 mg/m<sup>2</sup> IV over 2 hours once on day 2, then 800 mg/m<sup>2</sup> IV over 22 hours (total dose per cycle: 1000 mg/m<sup>2</sup>)
-**Cycles 2, 4, 6, 8, patients with creatinine greater than 1.5 mg/dL: 100 mg/m<sup>2</sup> IV over 2 hours once on day 2, then 400 mg/m<sup>2</sup> IV over 22 hours (total dose per cycle: 500 mg/m<sup>2</sup>)
-***Urine alkalinized to pH of 6.8 or more prior to the start of methotrexate and kept within that range until methotrexate is cleared
-*[[Cytarabine (Ara-C)]] as follows, by the following criteria:
-**Cycles 2, 4, 6, 8, standard patients: 3000 mg/m<sup>2</sup> IV over 2 hours every 12 hours on days 3 & 4 (total dose per cycle: 12,000 mg/m<sup>2</sup>)
-**Cycles 2, 4, 6, 8, patients older than 60 or with creatinine greater than 1.5 mg/dL: 1000 mg/m<sup>2</sup> IV over 2 hours every 12 hours on days 3 & 4 (total dose per cycle: 4000 mg/m<sup>2</sup>)
-====Supportive therapy, Part B====
-*[[Folinic acid (Leucovorin)]] as follows:
-**Cycles 2, 4, 6, 8: 50 mg PO once on day 3, 12 hours after [[Methotrexate (MTX)]] is complete, then 15 mg PO every 6 hours for 8 doses. If serum methotrexate level at 24 hours is greater than 1000 nmol/L or at 48 hours is greater than 100 nmol/L, dose is increased to 100 mg IV Q3H.
-*[[Prednisolone (Millipred) | Prednisolone]] as follows:
-**Cycles 2, 4, 6, 8: 1% ophthalmic solution 2 drops in each eye four times per day on days 3 to 9 was started on the day of the start of [[Cytarabine (Ara-C)]] infusion and was continued for 7 days to prevent chemical conjunctivitis.
-====Supportive therapy, all cycles====
-''All growth factors and antibiotics given for 10 days, starting 24 to 36 hours after doxorubicin infusion is complete in A cycles and not specified in B cycles''
-*[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day
-*[[Valacyclovir (Valtrex)]] 500 mg PO once per day
-*[[Fluconazole (Diflucan)]] 100 mg PO once per day
-*ONE of the following fluoroquinolones:
-**[[Levofloxacin (Levaquin)]] 500 mg PO once per day
-**[[Ciprofloxacin (Cipro)]] 500 mg PO twice per day
-*[[:Category:Erythrocyte_growth_factors|Erythropoietin]] was permitted throughout therapy
-'''21-day cycle for 8 cycles'''
 </div>
 <div class="toccolours" style="background-color:#cbd5e7">
 ====Subsequent treatment====
-*Merli et al. 2012, responders: [[Regimen_classes#High-dose_chemotherapy_with_auto_HSCT|autologous HSCT (regimen not specified)]]
+*Induction phase II or salvage (see paper for details)
-</div></div>
+</div></div><br>
-===References===
-# Romaguera JE, Fayad L, Rodriguez MA, Broglio KR, Hagemeister FB, Pro B, McLaughlin P, Younes A, Samaniego F, Goy A, Sarris AH, Dang NH, Wang M, Beasley V, Medeiros LJ, Katz RL, Gagneja H, Samuels BI, Smith TL, Cabanillas FF. High rate of durable remissions after treatment of newly diagnosed aggressive mantle-cell lymphoma with rituximab plus hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine. J Clin Oncol. 2005 Oct 1;23(28):7013-23. Epub 2005 Sep 6. [https://doi.org/10.1200/jco.2005.01.1825 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16145068 PubMed]
-## '''Update:''' Romaguera JE, Fayad LE, Feng L, Hartig K, Weaver P, Rodriguez MA, Hagemeister FB, Pro B, McLaughlin P, Younes A, Samaniego F, Goy A, Cabanillas F, Kantarjian H, Kwak L, Wang M. Ten-year follow-up after intense chemoimmunotherapy with Rituximab-HyperCVAD alternating with Rituximab-high dose methotrexate/cytarabine (R-MA) and without stem cell transplantation in patients with untreated aggressive mantle cell lymphoma. Br J Haematol. 2010 Jul;150(2):200-8. Epub 2010 May 26. Review. Erratum in: Br J Haematol.n 2010 Oct;151(1):111. [https://doi.org/10.1111/j.1365-2141.2010.08228.x link to original article] [https://pubmed.ncbi.nlm.nih.gov/20528872 PubMed]
-## '''Update:''' Chihara D, Cheah CY, Westin JR, Fayad LE, Rodriguez MA, Hagemeister FB, Pro B, McLaughlin P, Younes A, Samaniego F, Goy A, Cabanillas F, Kantarjian H, Kwak LW, Wang ML, Romaguera JE. Rituximab plus hyper-CVAD alternating with MTX/Ara-C in patients with newly diagnosed mantle cell lymphoma: 15-year follow-up of a phase II study from the MD Anderson Cancer Center. Br J Haematol. 2016 Jan;172(1):80-8. Epub 2015 Dec 9. [https://doi.org/10.1111/bjh.13796 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5471614/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26648336 PubMed]
-# Wang M, Fayad L, Cabanillas F, Hagemeister F, McLaughlin P, Rodriguez MA, Kwak LW, Zhou Y, Kantarjian H, Romaguera J. Phase 2 trial of rituximab plus hyper-CVAD alternating with rituximab plus methotrexate-cytarabine for relapsed or refractory aggressive mantle cell lymphoma. Cancer. 2008 Nov 15;113(10):2734-41.[https://doi.org/10.1002/cncr.23880 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18973182 PubMed]
-# Merli F, Luminari S, Ilariucci F, Petrini M, Visco C, Ambrosetti A, Stelitano C, Caracciolo F, Di Renzo N, Angrilli F, Carella AM, Capodanno I, Barbolini E, Galimberti S, Federico M. Rituximab plus HyperCVAD alternating with high dose cytarabine and methotrexate for the initial treatment of patients with mantle cell lymphoma, a multicentre trial from Gruppo Italiano Studio Linfomi. Br J Haematol. 2012 Feb;156(3):346-53. Epub 2011 Dec 7. [https://doi.org/full/10.1111/j.1365-2141.2011.08958.x link to original article] [https://pubmed.ncbi.nlm.nih.gov/22145911 PubMed]
-# '''SWOG S0213:''' Bernstein SH, Epner E, Unger JM, Leblanc M, Cebula E, Burack R, Rimsza L, Miller TP, Fisher RI. A phase II multicenter trial of hyperCVAD MTX/Ara-C and rituximab in patients with previously untreated mantle cell lymphoma; SWOG 0213. Ann Oncol. 2013 Jun;24(6):1587-93. Epub 2013 Mar 15. [https://doi.org/10.1093/annonc/mdt070 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3660082/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23504948 PubMed] NCT00041132
-# '''SWOG S1106:''' Chen RW, Li H, Bernstein SH, Kahwash S, Rimsza LM, Forman SJ, Constine L, Shea TC, Cashen AF, Blum KA, Fenske TS, Barr PM, Phillips T, Leblanc M, Fisher RI, Cheson BD, Smith SM, Faham M, Wilkins J, Leonard JP, Kahl BS, Friedberg JW. RB but not R-HCVAD is a feasible induction regimen prior to auto-HCT in frontline MCL: results of SWOG Study S1106. Br J Haematol. 2017 Mar;176(5):759-769. Epub 2016 Dec 19. [https://doi.org/full/10.1111/bjh.14480 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5318240/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27992063 PubMed] NCT01412879
-## '''Update:''' Kamdar M, Li H, Chen RW, Rimsza LM, Leblanc ML, Fenske TS, Shea TC, Barr PM, Phillips TJ, Leonard JP, Kahl BS, Friedberg JW, Smith SM. Five-year outcomes of the S1106 study of R-hyper-CVAD vs R-bendamustine in transplant-eligible patients with mantle cell lymphoma. Blood Adv. 2019 Oct 22;3(20):3132-3135. [https://ashpublications.org/bloodadvances/article/3/20/3132/422496/Fiveyear-outcomes-of-the-S1106-study-of-RhyperCVAD link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849956/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31648328 PubMed]
-==VR-CAP {{#subobject:de09c8|Regimen=1}}==
-VR-CAP: '''<u>V</u>'''elcade (Bortezomib), '''<u>R</u>'''ituximab, '''<u>C</u>'''yclophosphamide, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>P</u>'''rednisone
-<br>VcR-CAP: '''<u>V</u>'''el'''<u>c</u>'''ade (Bortezomib), '''<u>R</u>'''ituximab, '''<u>C</u>'''yclophosphamide, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>P</u>'''rednisone
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:8ab61|Variant=1}}===
+===Regimen variant #3, 45/500/2/40 {{#subobject:1e5376|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
@@ Line 593: / Line 506: @@
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1056/NEJMoa1412096 Robak et al. 2015 (LYM-3002)]
+|[http://www.bloodjournal.org/content/64/1/267.long Gottlieb et al. 1984 (CALGB 7612)]
-|2008-2011
+|1976-1980
-|style="background-color:#1a9851"|Phase 3 (E-RT-esc)
+|style="background-color:#1a9851"|Randomized (E-RT-esc)
-|[[#R-CHOP|R-CHOP]]
+|[[B-cell acute lymphoblastic leukemia_-_historical#L-Asparaginase.2C_Vincristine.2C_Prednisone|L-asparaginase, Vincristine, Prednisone]]
-|style="background-color:#1a9850"|Superior OS<sup>1</sup><br>Median OS: 90.7 vs 55.7 mo<br>(HR 0.66, 95% CI 0.51-0.85)
+|style="background-color:#1a9850"|Superior CR rate
 |-
 |}
-''<sup>1</sup>Reported efficacy is based on the 2018 update.''
 <div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
-*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11, '''given first'''
-*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1, '''given second'''
 ====Chemotherapy====
-*[[Cyclophosphamide (Cytoxan)]] 750 mg/m<sup>2</sup> IV once on day 1
+*[[Daunorubicin (Cerubidine)]] 45 mg/m<sup>2</sup> IV once per day on days 1 to 3
-*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV once on day 1
+*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 1, 8, 15
+*[[Asparaginase (Elspar)]] 500 units/kg IV once per day on days 22 to 31
 ====Glucocorticoid therapy====
-*[[Prednisone (Sterapred)]] 100 mg/m<sup>2</sup> PO once per day on days 1 to 5
+*[[Prednisone (Sterapred)]] 40 mg/m<sup>2</sup>/day PO on days 1 to 22, then tapered to off by day 29
-'''21-day cycle for up to 8 cycles'''
+'''31-day course'''
-</div></div>
+</div>
-===References===
+<div class="toccolours" style="background-color:#cbd5e7">
-<!-- # '''Abstract:''' Franco Cavalli, Brendan Rooney, Lixia Pei, Helgi Van De Velde, Tadeusz Robak, on behalf of the LYM-3002 Investigators. Randomized phase 3 study of rituximab, cyclophosphamide, doxorubicin, and prednisone plus vincristine (R-CHOP) or bortezomib (VR-CAP) in newly diagnosed mantle cell lymphoma (MCL) patients (pts) ineligible for bone marrow transplantation (BMT). 2014 ASCO Annual Meeting abstract 8500. [http://meetinglibrary.asco.org/content/129206-144 link to abstract] -->
+====Subsequent treatment====
-# '''LYM-3002:''' Robak T, Huang H, Jin J, Zhu J, Liu T, Samoilova O, Pylypenko H, Verhoef G, Siritanaratkul N, Osmanov E, Alexeeva J, Pereira J, Drach J, Mayer J, Hong X, Okamoto R, Pei L, Rooney B, van de Velde H, Cavalli F; the LYM-3002 Investigators. Bortezomib-based therapy for newly diagnosed mantle-cell lymphoma. N Engl J Med. 2015 Mar 5;372(10):944-953. [https://doi.org/10.1056/NEJMoa1412096 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25738670 PubMed] NCT00722137
+*See paper for details of treatment beyond induction
-## '''Update:''' Robak T, Jin J, Pylypenko H, Verhoef G, Siritanaratkul N, Drach J, Raderer M, Mayer J, Pereira J, Tumyan G, Okamoto R, Nakahara S, Hu P, Appiani C, Nemat S, Cavalli F; LYM-3002 investigators. Frontline bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in transplantation-ineligible patients with newly diagnosed mantle cell lymphoma: final overall survival results of a randomised, open-label, phase 3 study. Lancet Oncol. 2018 Nov;19(11):1449-58. Epub 2018 Oct 18. [https://doi.org/10.1016/S1470-2045(18)30685-5 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30348538 PubMed]
+</div></div><br>
-=First-line therapy, non-randomized or retrospective data=
-==BR/RC {{#subobject:1gc79c|Regimen=1}}==
-BR/RC: '''<u>B</u>'''endamustine & '''<u>R</u>'''ituximab alternating with '''<u>R</u>'''ituximab & '''<u>C</u>'''ytarabine
-<br>BR/CR: '''<u>B</u>'''endamustine & '''<u>R</u>'''ituximab alternating with '''<u>C</u>'''ytarabine & '''<u>R</u>'''ituximab
-<br>RB/RC: '''<u>R</u>'''ituximab & '''<u>B</u>'''endamustine alternating with '''<u>R</u>'''ituximab & '''<u>C</u>'''ytarabine
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #1 {{#subobject:baugaa|Variant=1}}===
+===Regimen variant #4, 50/6000/2/60 ("Linker regimen") {{#subobject:9ce40a|Variant=1}}===
 {| class="wikitable sortable" style="width: 60%; text-align:center;"
 !style="width: 33%"|Study
@@ Line 628: / Line 533: @@
 !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://doi.org/10.1111/bjh.13929 Armand et al. 2016 (DFCI 12-168)]
+|[https://doi.org/10.1182/blood.V69.4.1242.1242 Linker et al. 1987]
-|2012-2014
+|1980-1986
 |style="background-color:#91cf61"|Phase 2
 |-
 |}
 <div class="toccolours" style="background-color:#b3e2cd">
-====Chemotherapy, BR portion====
+====Chemotherapy====
-*[[Bendamustine]] as follows:
+*[[Daunorubicin (Cerubidine)]] by the following criteria:
-**Cycles 1 to 3: 90 mg/m<sup>2</sup> IV once per day on days 1 & 2
+**All patients: 50 mg/m<sup>2</sup> IV once per day on days 1 to 3
-====Chemotherapy, RC portion====
+**Bone marrow on day 14 has residual leukemia: 50 mg/m<sup>2</sup> IV once on day 15
-*[[Cytarabine (Cytosar)]] by the following criteria:
+**Bone marrow on day 28 has residual leukemia: 50 mg/m<sup>2</sup> IV once per day on days 29 & 30
-**Cycles 4 to 6, standard patients: 3000 mg/m<sup>2</sup> twice per day on days 1 & 2
+*[[Vincristine (Oncovin)]] by the following criteria:
-**Cycles 4 to 6, patients older than 60: 2000 mg/m<sup>2</sup> twice per day on days 1 & 2
+**All patients: 2 mg IV once per day on days 1, 8, 15, 22
-**Cycles 4 to 6, patients older than 60 with either renal dysfunction (Cr 1.3 to 2.0) or preexisting neurotoxicity: 1500 mg/m<sup>2</sup> twice per day on days 1 & 2
+**Bone marrow on day 28 has residual leukemia: 2 mg IV once per day on days 29 & 36
-**Cycles 4 to 6, patients older than 60 with both renal dysfunction (Cr 1.3 to 2.0) and preexisting neurotoxicity: 1000 mg/m<sup>2</sup> twice per day on days 1 & 2
+*[[Asparaginase (Elspar)]] by the following criteria:
-====Targeted therapy====
+**All patients: 6000 units/m<sup>2</sup> IM once per day on days 17 to 28
-*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1
+**Bone marrow on day 28 has residual leukemia: 6000 units/m<sup>2</sup> IM once per day on days 29 to 35
-'''28-day cycle for 3 cycles, then 21-day cycle for 3 cycles'''
+====Glucocorticoid therapy====
+*[[Prednisone (Sterapred)]] by the following criteria:
+**All patients: 60 mg/m<sup>2</sup> PO once per day on days 1 to 28
+**Bone marrow on day 28 has residual leukemia: 60 mg/m<sup>2</sup> PO once per day on days 29 to 42
+====CNS therapy, prophylaxis====
+*This is for patients without CNS involvement at diagnosis, and is started within 1 week of achieving complete remission:
+*Cranial radiation, 18 Gy total given in 10 fractions over 12 to 14 days
+*[[Methotrexate (MTX)]] 12 mg IT once per week x 6 doses concurrent with radiation
+====CNS therapy, treatment====
+*This is for patients with CNS involvement at diagnosis:
+*Cranial radiation, 28 Gy total given
+*[[Methotrexate (MTX)]] 12 mg IT once per week x 10 doses that starts while they are receiving induction therapy, then given once per month during the first year of therapy
 </div>
 <div class="toccolours" style="background-color:#cbd5e7">
 ====Subsequent treatment====
-*[[Regimen_classes#High-dose_chemotherapy_with_auto_HSCT|Auto HSCT]]
+*[[#Linker_regimen_.28consolidation.29|Linker regimen consolidation therapy]]
 </div></div><br>
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #2 {{#subobject:baugja|Variant=1}}===
+===Regimen variant #5, 60/10,000/1.4/60, daily dauno {{#subobject:8ad81b|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
+{| class="wikitable" style="width: 40%; text-align:center;"
-!style="width: 33%"|Study
+!style="width: 25%"|Study
-!style="width: 33%"|Years of enrollment
+!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7065472/ Merryman et al. 2020 (WUSTL 201603149)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2254550/ Pullarkat et al. 2008 (SWOG S9400)]
-|2016-2018
 |style="background-color:#91cf61"|Phase 2
 |-
 |}
-''Note: Merryman et al. 2020 is an update for DFCI 12-168 and the primary publication for WUSTL 201603149.''
+''Note: this was the dosing used after the protocol amendment of September 1, 1999.''
 <div class="toccolours" style="background-color:#b3e2cd">
-====Chemotherapy, BR portion====
+====Chemotherapy====
-*[[Bendamustine]] as follows:
+*[[Daunorubicin (Cerubidine)]] by the following response-based criteria:
-**Cycles 1, 3, 5: 90 mg/m<sup>2</sup> IV once per day on days 1 & 2
+**All patients: 60 mg/m<sup>2</sup> IV once per day on days 1 to 3
-====Chemotherapy, RC portion====
+**Persistent leukemia on day 21: 60 mg/m<sup>2</sup> IV once per day on days 22 & 23
-*[[Cytarabine (Cytosar)]] by the following criteria:
+*[[Vincristine (Oncovin)]] by the following response-based criteria:
-**Cycles 2, 4, 6, standard patients: 3000 mg/m<sup>2</sup> twice per day on days 1 & 2
+**All patients: 1.4 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
-**Cycles 2, 4, 6, patients older than 60 or with renal dysfunction (eGFR 40 to 59): 2000 mg/m<sup>2</sup> twice per day on days 1 & 2
+**Persistent leukemia on day 21: 1.4 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 29 & 36
-====Targeted therapy====
+*[[Asparaginase (Elspar)]] 10,000 units IM or IV once per day on days 15 to 24
-*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1
+====Glucocorticoid therapy====
-'''28-day cycle, then 21-day cycle, then then 28-day cycle, then 21-day cycle, then 28-day cycle, then 21-day cycle'''
+*[[Prednisone (Sterapred)]] by the following response-based criteria:
+**All patients: 60 mg/m<sup>2</sup>/day PO on days 1 to 28
+**No leukemia on day 21: taper to off by day 42
+**Persistent leukemia on day 21: 60 mg/m<sup>2</sup>/day PO on days 29 to 42
+'''6-week course'''
 </div>
 <div class="toccolours" style="background-color:#cbd5e7">
 ====Subsequent treatment====
-*[[Regimen_classes#High-dose_chemotherapy_with_auto_HSCT|Auto HSCT]]
+*See paper for details
-</div></div>
+</div></div><br>
-===References===
-# '''DFCI 12-168:''' Armand P, Redd R, Bsat J, Mayuram S, Giardino A, Fisher DC, LaCasce AS, Jacobson C, Davids MS, Brown JR, Weng L, Wilkins J, Faham M, Freedman AS, Joyce R, Jacobsen ED. A phase 2 study of rituximab-bendamustine and rituximab-cytarabine for transplant-eligible patients with mantle cell lymphoma. Br J Haematol. 2016 Apr;173(1):89-95. Epub 2016 Jan 5. [https://doi.org/10.1111/bjh.13929 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26729345 PubMed] NCT01661881
-##'''Update:''' Merryman RW, Edwin N, Redd R, Bsat J, Chase M, LaCasce A, Freedman A, Jacobson C, Fisher D, Ng S, Crombie J, Kim A, Odejide O, Davids MS, Brown JR, Jacene H, Cashen A, Bartlett NL, Mehta-Shah N, Ghobadi A, Kahl B, Joyce R, Armand P, Jacobsen E. Rituximab/bendamustine and rituximab/cytarabine induction therapy for transplant-eligible mantle cell lymphoma. Blood Adv. 2020 Mar 10;4(5):858-867. [https://doi.org/10.1182/bloodadvances.2019001355 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7065472/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/32126141/ PubMed] NCT01661881
-#'''WUSTL 201603149:''' Merryman RW, Edwin N, Redd R, Bsat J, Chase M, LaCasce A, Freedman A, Jacobson C, Fisher D, Ng S, Crombie J, Kim A, Odejide O, Davids MS, Brown JR, Jacene H, Cashen A, Bartlett NL, Mehta-Shah N, Ghobadi A, Kahl B, Joyce R, Armand P, Jacobsen E. Rituximab/bendamustine and rituximab/cytarabine induction therapy for transplant-eligible mantle cell lymphoma. Blood Adv. 2020 Mar 10;4(5):858-867. [https://doi.org/10.1182/bloodadvances.2019001355 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7065472/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/32126141/ PubMed] NCT02728531
-==Chlorambucil & Rituximab (RClb) {{#subobject:f5fb55|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:e9fbd5|Variant=1}}===
+===Regimen variant #6, 60/10,000/1.4/60, weekly dauno ("Phase I" of E2993 regimen) {{#subobject:6d5745|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
+{| class="wikitable" style="width: 40%; text-align:center;"
-!style="width: 33%"|Study
+!style="width: 25%"|Study
-!style="width: 33%"|Years of enrollment
+!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://doi.org/10.3109/10428194.2010.534518 Sachanas et al. 2011]
+|[http://www.bloodjournal.org/content/106/12/3760.long Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)]
-|NR in abstract
+|style="background-color:#91cf61"|Non-randomized portion of RCT
-|style="background-color:#91cf61"|Phase 2
 |-
 |}
-<div class="toccolours" style="background-color:#b3e2cd">
+''To our knowledge, this is the largest induction trial in adult ALL, N=1,646. CR rate was 91%.''
 ====Chemotherapy====
-*[[Chlorambucil (Leukeran)]] as follows:
+*[[Daunorubicin (Cerubidine)]] 60 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
-**Cycles 1 to 8: 10 mg PO once per day on days 2 to 11
+*[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
-**Cycles 9 to 12: 10 mg PO once per day on days 1 to 10
+*[[Asparaginase (Elspar)]] 10,000 units IM or IV once per day on days 17 to 28
-====Targeted therapy====
+====Glucocorticoid therapy====
-*[[Rituximab (Rituxan)]] as follows:
+*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup>/day PO in divided doses on days 1 to 28
-**Cycles 1 to 8: 375 mg/m<sup>2</sup> IV once on day 1
+====CNS therapy, prophylaxis====
-'''28-day cycle for 12 cycles'''
+*[[Methotrexate (MTX)]] 12.5 mg IT once on day 15
+'''4-week course'''
 </div>
 <div class="toccolours" style="background-color:#cbd5e7">
 ====Subsequent treatment====
-*PR/CR: [[#Rituximab_monotherapy|Rituximab]] maintenance
+*[[#Cyclophosphamide.2C_Cytarabine.2C_Mercaptopurine|Cyclophosphamide, Cytarabine, Mercaptopurine]] induction ("Phase 2")
 </div></div>
 ===References===
-# Sachanas S, Pangalis GA, Vassilakopoulos TP, Korkolopoulou P, Kontopidou FN, Athanasoulia M, Yiakoumis X, Kalpadakis C, Georgiou G, Masouridis S, Moschogiannis M, Tsirkinidis P, Pappis V, Kokoris SI, Siakantaris MP, Panayiotidis P, Angelopoulou MK. Combination of rituximab with chlorambucil as first line treatment in patients with mantle cell lymphoma: a highly effective regimen. Leuk Lymphoma. 2011 Mar;52(3):387-93. Epub 2010 Dec 6. [https://doi.org/10.3109/10428194.2010.534518 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21133713 PubMed]
+# Hoelzer D, Thiel E, Löffler H, Bodenstein H, Plaumann L, Büchner T, Urbanitz D, Koch P, Heimpel H, Engelhardt R, Muller U, Wendt FC, Sodomann H, Ruhl H, Herrmann F, Kaboth W, Dietzfelbinger H, Pralle H, Lunscken Ch, Hellriegel KP, Spors S, Nowrousian RM, Fischer J, Fulle H, Mitrou PS, Pfreundschuh M, Gorg Ch, Emmerich B, Queisser W, Meyer P, Labedzki L, Essers U, Konig H, Mainzer K, Herrmann R, Messerer D, Zwingers T. Intensified therapy in acute lymphoblastic and acute undifferentiated leukemia in adults. Blood. 1984 Jul;64(1):38-47. [http://www.bloodjournal.org/content/64/1/38.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/6375764 PubMed]
-==Cladribine monotherapy {{#subobject:f729d6|Regimen=1}}==
+# '''CALGB 7612:''' Gottlieb AJ, Weinberg V, Ellison RR, Henderson ES, Terebelo H, Rafla S, Cuttner J, Silver RT, Carey RW, Levy RN, Hutchinson JL, Raich P, Cooper MR, Wiernik P, Anderson JR, Holland JF. Efficacy of daunorubicin in the therapy of adult acute lymphocytic leukemia: a prospective randomized trial by Cancer and Leukemia Group B. Blood. 1984 Jul;64(1):267-74. [http://www.bloodjournal.org/content/64/1/267.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/6375760 PubMed]
+# Linker CA, Levitt LJ, O'Donnell M, Ries CA, Link MP, Forman SJ, Farbstein MJ. Improved results of treatment of adult acute lymphoblastic leukemia. Blood. 1987 Apr;69(4):1242-8. [https://doi.org/10.1182/blood.V69.4.1242.1242 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/3470055 PubMed]
+## '''Update:''' Linker CA, Levitt LJ, O'Donnell M, Forman SJ, Ries CA. Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report. Blood. 1991 Dec 1;78(11):2814-22. [http://www.bloodjournal.org/content/78/11/2814.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/1835410 PubMed]
+# '''GIMEMA ALL 0288:''' Annino L, Vegna ML, Camera A, Specchia G, Visani G, Fioritoni G, Ferrara F, Peta A, Ciolli S, Deplano W, Fabbiano F, Sica S, Di Raimondo F, Cascavilla N, Tabilio A, Leoni P, Invernizzi R, Baccarani M, Rotoli B, Amadori S, Mandelli F; GIMEMA. Treatment of adult acute lymphoblastic leukemia (ALL): long-term follow-up of the GIMEMA ALL 0288 randomized study. Blood. 2002 Feb 1;99(3):863-71. [http://www.bloodjournal.org/content/99/3/863.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11806988 PubMed]
+# '''MRC UKALL XII/ECOG E2993:''' Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. [http://www.bloodjournal.org/content/106/12/3760.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16105981 PubMed] NCT00002514
+## '''Update:''' Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, Burnett AK, Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J, McMillan A, Franklin IM, Luger S, Ciobanu N, Rowe JM. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008 Feb 15;111(4):1827-33. Epub 2007 Nov 29. [http://www.bloodjournal.org/content/111/4/1827.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/18048644 PubMed]
+## '''Update:''' Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, Marks DI, McMillan AK, Litzow MR, Lazarus HM, Foroni L, Dewald G, Franklin IM, Luger SM, Paietta E, Wiernik PH, Tallman MS, Goldstone AH. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009 May 7;113(19):4489-96. Epub 2009 Feb 24. [http://www.bloodjournal.org/content/113/19/4489.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4188540/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19244158 PubMed]
+## '''Update:''' Fielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow MR, Lazarus H, Luger SM, Marks DI, McMillan AK, Moorman AV, Patel B, Paietta E, Tallman MS, Goldstone AH. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014 Feb 6;123(6):843-50. Epub 2013 Nov 25. [http://www.bloodjournal.org/content/123/6/843.full link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3916877/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24277073 PubMed]
+# '''SWOG S9400:''' Pullarkat V, Slovak ML, Kopecky KJ, Forman SJ, Appelbaum FR. Impact of cytogenetics on the outcome of adult acute lymphoblastic leukemia: results of Southwest Oncology Group 9400 study. Blood. 2008 Mar 1;111(5):2563-72. Epub 2007 Dec 21. [http://www.bloodjournal.org/content/111/5/2563.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2254550/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18156492 PubMed] NCT00002665
+==Daunorubicin, Pegaspargase, Vincristine, Dexamethasone {{#subobject:1526yg|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:986eae|Variant=1}}===
+===Regimen {{#subobject:cf4hg1|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 33%"|Study
+!style="width: 20%"|Study
-!style="width: 33%"|Years of enrollment
+!style="width: 20%"|Years of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3465670/ Inwards et al. 2008 (NCCTG 95-80-53)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8969057/ Marks et al. 2022 (UKALL14)]
-|2003-2005
+|2012-2017
-|style="background-color:#91cf61"|Phase 2
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Daunorubicin.2C_Pegaspargase.2C_Vincristine.2C_Dexamethasone.2C_Rituximab_99|Daunorubicin, Pegaspargase, Vincristine, Dexamethasone, Rituximab]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of EFS
 |-
 |}
+''Note: the manuscript contains an error in the timing of daunorubicin and vincristine; the correct schedule is available in the supplement. The authors have been notified of the error, and the correct schedule is used below.''
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*[[#Dexamethasone_monotherapy_88|Pre-phase dexamethasone]]
+</div>
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
-*[[Cladribine (Leustatin)]] 5 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 to 5
+*[[Daunorubicin (Cerubidine)]] 30 mg/m<sup>2</sup> IV over 1 to 15 minutes once per day on days 1, 8, 15, 22
-'''28-day cycle for up to 6 cycles'''
+*[[Pegaspargase (Oncaspar)]] by the following age-based criteria:
+**Age 40 years and younger: 1000 units/m<sup>2</sup> IV once per day on days 4 & 18
+**Age 41 years or older: 1000 units/m<sup>2</sup> IV once on day 18
+*[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
+====Glucocorticoid therapy====
+*[[Dexamethasone (Decadron)]] 10 mg/m<sup>2</sup>/day PO on days 1 to 4, 8 to 11, 15 to 18
+====CNS therapy, prophylaxis====
+*[[Methotrexate (MTX)]] 12.5 mg IT once on day 14
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*See paper for protocol details
 </div></div>
 ===References===
-# '''NCCTG 95-80-53:''' Inwards DJ, Fishkin PA, Hillman DW, Brown DW, Ansell SM, Kurtin PJ, Fonseca R, Morton RF, Veeder MH, Witzig TE. Long-term results of the treatment of patients with mantle cell lymphoma with cladribine (2-CDA) alone (95-80-53) or 2-CDA and rituximab (N0189) in the North Central Cancer Treatment Group. Cancer. 2008 Jul 1;113(1):108-16. [https://doi.org/10.1002/cncr.23537 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3465670/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18470909 PubMed]
+#'''UKALL14:''' Marks DI, Kirkwood AA, Rowntree CJ, Aguiar M, Bailey KE, Beaton B, Cahalin P, Castleton AZ, Clifton-Hadley L, Copland M, Goldstone AH, Kelly R, Lawrie E, Lee S, McMillan AK, McMullin MF, Menne TF, Mitchell RJ, Moorman AV, Patel B, Patrick P, Smith P, Taussig D, Yallop D, Alapi KZ, Fielding AK. Addition of four doses of rituximab to standard induction chemotherapy in adult patients with precursor B-cell acute lymphoblastic leukaemia (UKALL14): a phase 3, multicentre, randomised controlled trial. Lancet Haematol. 2022 Apr;9(4):e262-e275. [https://doi.org/10.1016/s2352-3026(22)00038-2 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8969057/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35358441/ PubMed] NCT01085617
-==Cladribine & Rituximab {{#subobject:9dabc7|Regimen=1}}==
+==Daunorubicin, Pegaspargase, Vincristine, Prednisone {{#subobject:1524a2|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:ab63a9|Variant=1}}===
+===Regimen variant #1, "ABFM" {{#subobject:cf403e|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
+{| class="wikitable" style="width: 40%; text-align:center;"
-!style="width: 33%"|Study
+!style="width: 25%"|Study
-!style="width: 33%"|Years of enrollment
+!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239168/ Rytting et al. 2014]
+|style="background-color:#91cf61"|Non-randomized
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3465670/ Inwards et al. 2008 (NCCTG N0189)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6450431/ Stock et al. 2019 (CALGB 10403)]
-|2003-2005
+| style="background-color:#91cf61" |Non-randomized
-|style="background-color:#91cf61"|Phase 2
 |-
 |}
-<div class="toccolours" style="background-color:#b3e2cd">
+ABFM: '''<u>A</u>'''ugmented '''<u>B</u>'''erlin-'''<u>F</u>'''rankfurt-'''<u>M</u>'''ünster regimen<br>
 ====Chemotherapy====
-*[[Cladribine (Leustatin)]] 5 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 to 5
+*[[Daunorubicin (Cerubidine)]] 25 mg/m<sup>2</sup> IV over 1 to 15 minutes once per day on days 1, 8, 15, 22
-====Targeted therapy====
+*[[Pegaspargase (Oncaspar)]] 2500 units/m<sup>2</sup> IM or IV over 1 to 2 hours once on day 4
-*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
-====Supportive therapy====
+====Glucocorticoid therapy====
-*[[Pegfilgrastim (Neulasta)]] 6 mg SC once on day 6
+*[[Prednisone (Sterapred)]] 30 mg/m<sup>2</sup> IV or PO twice per day on days 1 to 28
-''OR''
+====CNS therapy, prophylaxis====
-*[[Filgrastim (Neupogen)]] (dose not specified) SC once per day on days 6 to 15
+*[[Cytarabine (Ara-C)]] by the following age-based criteria:
-'''28-day cycle for up to 6 cycles'''
+**Ages 1 to 1.99: 30 mg IT once on day 1
-</div></div>
+**Ages 2 to 2.99: 50 mg IT once on day 1
-===References===
+**Age 3 and older: 70 mg IT once on day 1
-# '''NCCTG N0189:''' Inwards DJ, Fishkin PA, Hillman DW, Brown DW, Ansell SM, Kurtin PJ, Fonseca R, Morton RF, Veeder MH, Witzig TE. Long-term results of the treatment of patients with mantle cell lymphoma with cladribine (2-CDA) alone (95-80-53) or 2-CDA and rituximab (N0189) in the North Central Cancer Treatment Group. Cancer. 2008 Jul 1;113(1):108-16. [https://doi.org/10.1002/cncr.23537 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3465670/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18470909 PubMed]
+*[[Methotrexate (MTX)]] by the following age-based criteria:
-==Lenalidomide & Rituximab (R<sup>2</sup>) {{#subobject:517896|Regimen=1}}==
+**Ages 1 to 1.99: 8 mg IT once per day on days 8 & 29
-LR: '''<u>L</u>'''enalidomide & '''<u>R</u>'''ituximab
+**Ages 2 to 2.99: 10 mg IT once per day on days 8 & 29
+**Ages 3 to 8.99: 12 mg IT once per day on days 8 & 29
+**Age 9 and older: 15 mg IT once per day on days 8 & 29
+'''4-week course'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*Rytting et al. 2014: See protocol for details of treatment beyond induction
+*CALGB 10403, CR: [[#AALL0232_consolidation|AALL0232]] consolidation
+*CALGB 10403, not CR: [[#Daunorubicin.2C_Pegaspargase.2C_Vincristine.2C_Prednisone|ABFM extended]] induction
+</div></div><br>
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:c021ff|Variant=1}}===
+===Regimen variant #2, higher-dose dauno {{#subobject:e88a83|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
+{| class="wikitable" style="width: 40%; text-align:center;"
-!style="width: 33%"|Study
+!style="width: 25%"|Study
-!style="width: 33%"|Years of enrollment
+!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4710541/ Ruan et al. 2015 (Cornell 1103011566)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2254550/ Pullarkat et al. 2008 (SWOG S9400)]
-|2011-2014
+|style="background-color:#91cf61"|Non-randomized
-|style="background-color:#91cf61"|Phase 2
 |-
 |}
+''Note: Table 1 lists vincristine as being given PO, which is surely an error. Likewise, prednisone is listed as IV. Pegaspargase was only given until the protocol amendment of September 1, 1999.''
 <div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
+====Chemotherapy====
-*[[Lenalidomide (Revlimid)]] as follows:
+*[[Daunorubicin (Cerubidine)]] by the following response-based criteria:
-**Cycle 1: 20 mg PO once per day on days 1 to 21
+**Part 1 (all patients): 60 mg/m<sup>2</sup> IV once per day on days 1 to 3
-**Cycle 2 onwards (if no dose-limiting adverse events in cycle 1): 25 mg PO once per day on days 1 to 21
+**Part 2 (persistent leukemia on d21): 60 mg/m<sup>2</sup> IV once per day on days 22 & 23
-*[[Rituximab (Rituxan)]] as follows:
+*[[Pegaspargase (Oncaspar)]] by the following response-based criteria:
-**Cycle 1: 375 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
+**Part 1 (all patients): 2000 units/m<sup>2</sup> IV once on day 15
-**Cycles 4, 6, 8, 10, 12: 375 mg/m<sup>2</sup> IV once on day 1
+**Part 2 (persistent leukemia on d21): 2000 units/m<sup>2</sup> IV once on day 38
-====Supportive therapy====
+*[[Vincristine (Oncovin)]] by the following response-based criteria:
-*Thromboprophylaxis: [[Aspirin]] or [[:Category:Low molecular weight heparins|low molecular weight heparin]] unless on treatment for known thrombosis
+**Part 1 (all patients): 1.4 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
-'''28-day cycle for 12 cycles'''
+**Part 2 (persistent leukemia on d21): 1.4 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 29 & 36
+====Glucocorticoid therapy====
+*[[Prednisone (Sterapred)]] by the following response-based criteria:
+**Part 1 (all patients): 60 mg/m<sup>2</sup>/day PO on days 1 to 28
+**Part 2 (CR on d21): tapered from day 29 to 42
+**Part 2 (persistent leukemia on d21): 60 mg/m<sup>2</sup>/day PO on days 29 to 42
+'''42-day course'''
 </div>
 <div class="toccolours" style="background-color:#cbd5e7">
 ====Subsequent treatment====
-*[[#Lenalidomide_.26_Rituximab_.28R2.29_2|Lenalidomide & rituximab]] maintenance
+*See protocol for details of treatment beyond induction
 </div></div>
 ===References===
-<!-- # '''Abstract:''' Jia Ruan, Peter Martin, Bijal D. Shah, Stephen J. Schuster, Sonali M. Smith, Richard R. Furman, Paul Christos, Amelyn Rodriguez, Paige Wolstencroft, Jakub Svoboda, Alison Bender, Jessica Lewis, Morton Coleman, John P. Leonard. Combination Biologic Therapy Without Chemotherapy As Initial Treatment For Mantle Cell Lymphoma: Multi-Center Phase II Study Of Lenalidomide Plus Rituximab. Blood Nov 2013,122(21)247 [http://www.bloodjournal.org/content/122/21/247 link to abstract]
+# '''SWOG S9400:''' Pullarkat V, Slovak ML, Kopecky KJ, Forman SJ, Appelbaum FR. Impact of cytogenetics on the outcome of adult acute lymphoblastic leukemia: results of Southwest Oncology Group 9400 study. Blood. 2008 Mar 1;111(5):2563-72. Epub 2007 Dec 21. [http://www.bloodjournal.org/content/111/5/2563.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2254550/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18156492 PubMed] NCT00002665
-## '''Update Abstract:''' Jia Ruan, MD, PhD, Peter Martin, MD, Bijal D. Shah, MD, Stephen J. Schuster, MD, Sonali M. Smith, MD, Richard R Furman, MD, Paul Christos, DrPH, Amelyn Rodriguez, RN, Louisa Drake, Jakub Svoboda, MD, Jessica Lewis, PA-C, Orel Katz, PA-C, Morton Coleman, MD and John P. Leonard, MD. Sustained Remission with the Combination Biologic Doublet of Lenalidomide Plus Rituximab As Initial Treatment for Mantle Cell Lymphoma: A Multi-Center Phase II Study Report. ASH Annual Meeting 2014 Abstract 625 [https://ash.confex.com/ash/2014/webprogram/Paper73280.html link to abstract] -->
+# Rytting ME, Thomas DA, O'Brien SM, Ravandi-Kashani F, Jabbour EJ, Franklin AR, Kadia TM, Pemmaraju N, Daver NG, Ferrajoli A, Garcia-Manero G, Konopleva MY, Cortes JE, Borthakur G, Garris R, Cardenas-Turanzas M, Schroeder K, Jorgensen JL, Kornblau SM, Kantarjian HM. Augmented Berlin-Frankfurt-Münster therapy in adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL). Cancer. 2014 Dec 1;120(23):3660-8. Epub 2014 Jul 17. [https://doi.org/10.1002/cncr.28930 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239168/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25042398 PubMed]
-# '''Cornell 1103011566:''' Ruan J, Martin P, Shah B, Schuster SJ, Smith SM, Furman RR, Christos P, Rodriguez A, Svoboda J, Lewis J, Katz O, Coleman M, Leonard JP. Lenalidomide plus rituximab as initial treatment for mantle-cell lymphoma. N Engl J Med. 2015 Nov 5;373(19):1835-44. [https://doi.org/10.1056/NEJMoa1505237 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4710541/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26535512 PubMed] NCT01472562
+## '''Update:''' Rytting ME, Jabbour EJ, Jorgensen JL, Ravandi F, Franklin AR, Kadia TM, Pemmaraju N, Daver NG, Ferrajoli A, Garcia-Manero G, Konopleva MY, Borthakur G, Garris R, Wang S, Pierce S, Schroeder K, Kornblau SM, Thomas DA, Cortes JE, O'Brien SM, Kantarjian HM. Final results of a single institution experience with a pediatric-based regimen, the augmented Berlin-Frankfurt-Münster (ABFM), in adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL), and comparison to the hyper-CVAD regimen. Am J Hematol. 2016 Aug;91(8):819-23. Epub 2016 May 14. [https://doi.org/10.1002/ajh.24419 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5558853/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27178680 PubMed]
-## '''Update:''' Ruan J, Martin P, Christos P, Cerchietti L, Tam W, Shah B, Schuster SJ, Rodriguez A, Hyman D, Calvo-Vidal MN, Smith SM, Svoboda J, Furman RR, Coleman M, Leonard JP. Five-year follow-up of lenalidomide plus rituximab as initial treatment of mantle cell lymphoma. Blood. 2018 Nov 8;132(19):2016-2025. Epub 2018 Sep 4. [http://www.bloodjournal.org/content/132/19/2016.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/30181173 PubMed]
+# '''CALGB 10403:''' Stock W, Luger SM, Advani AS, Yin J, Harvey RC, Mullighan CG, Willman CL, Fulton N, Laumann KM, Malnassy G, Paietta E, Parker E, Geyer S, Mrózek K, Bloomfield CD, Sanford B, Marcucci G, Liedtke M, Claxton DF, Foster MC, Bogart JA, Grecula JC, Appelbaum FR, Erba H, Litzow MR, Tallman MS, Stone RM, Larson RA. A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403. Blood. 2019 Apr 4;133(14):1548-1559. Epub 2019 Jan 18. [http://www.bloodjournal.org/content/133/14/1548.long link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6450431/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30658992 PubMed] NCT00558519
-==Observation==
+==Hyper-CVAD/MA {{#subobject:8e1d75|Regimen=1}}==
+Hyper-CVAD/MA: '''<u>Hyper</u>'''fractionated '''<u>C</u>'''yclophosphamide, '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>D</u>'''examethasone alternating with '''<u>M</u>'''ethotrexate, '''<u>A</u>'''ra-C (Cytarabine)
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen===
+===Protocol {{#subobject:70e9ec|Variant=1}}===
 {| class="wikitable" style="width: 40%; text-align:center;"
 !style="width: 25%"|Study
 !style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://doi.org/10.1200/jco.2008.19.6121 Martin et al. 2009]
+|[https://www.nature.com/articles/2400861 Koller et al. 1997]
-|style="background-color:#ffffbe"|Retrospective
+|style="background-color:#91cf61"|Non-randomized
 |-
-|}
+|[https://doi.org/10.1200/jco.1999.17.8.2461 Thomas et al. 1999]
-''Also known as "watchful waiting".''
+|style="background-color:#91cf61"|Phase 2
-</div></div>
-===References===
-# '''Retrospective:''' Martin P, Chadburn A, Christos P, Weil K, Furman RR, Ruan J, Elstrom R, Niesvizky R, Ely S, Diliberto M, Melnick A, Knowles DM, Chen-Kiang S, Coleman M, Leonard JP. Outcome of deferred initial therapy in mantle-cell lymphoma. J Clin Oncol. 2009 Mar 10;27(8):1209-13. [https://doi.org/10.1200/jco.2008.19.6121 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19188674 PubMed]
-# '''Retrospective:''' Cohen JB, Han X, Jemal A, Ward EM, Flowers CR. Deferred therapy is associated with improved overall survival in patients with newly diagnosed mantle cell lymphoma. Cancer. 2016 Aug 1;122(15):2356-63. Epub 2016 May 6. [https://onlinelibrary.wiley.com/wol1/doi/10.1002/cncr.30068 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27153197 PubMed]
-==R-BAC {{#subobject:3d5221|Regimen=1}}==
-R-BAC: '''<u>R</u>'''ituximab, '''<u>B</u>'''endamustine, '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine)
-<div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #1, 375/70/500 ("RBAC500") {{#subobject:737eac|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
-!style="width: 33%"|Study
-!style="width: 33%"|Years of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://doi.org/10.1016/S2352-3026(16)30185-5 Visco et al. 2016 (FIL-RBAC500)]
+|[https://doi.org/10.1200/jco.2000.18.3.547 Kantarjian et al. 2000]
-|2012-2014
 |style="background-color:#91cf61"|Phase 2
+|-
+|[http://www.bloodjournal.org/content/104/6/1624.long Thomas et al. 2004]
+|style="background-color:#91cf61"|Non-randomized
 |-
 |}
 <div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
+====Chemotherapy, Part A (cycles 1, 3, 5, 7)====
-*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1
+*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> IV over 2 hours every 12 hours on days 1 to 3 (total dose per cycle: 1800 mg/m<sup>2</sup>)
-====Chemotherapy====
+*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 4 & 11
-*[[Bendamustine]] 70 mg/m<sup>2</sup> IV once per day on days 2 & 3
+*[[Doxorubicin (Adriamycin)]] by the following criteria:
-*[[Cytarabine (Ara-C)]] 500 mg/m<sup>2</sup> IV once per day on days 2 to 4
+**Normal EF: 50 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 4
-'''28-day cycle for up to 6 cycles'''
+**EF less than 50%: 25 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on day 4 (total dose per cycle: 50 mg/m<sup>2</sup>)
-</div></div><br>
+====Glucocorticoid therapy====
-<div class="toccolours" style="background-color:#eeeeee">
+*[[Dexamethasone (Decadron)]] 40 mg IV or PO once per day on days 1 to 4, 11 to 14
-===Regimen variant #2, 375/70/800 {{#subobject:1f05e1|Variant=1}}===
+====Supportive therapy====
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
+*[[Mesna (Mesnex)]] 600 mg/m<sup>2</sup>/day IV continuous infusion over 72 hours, started on day 1, starting 1 hour before [[Cyclophosphamide (Cytoxan)]] and completed 12 hours after the last dose of [[Cyclophosphamide (Cytoxan)]]
-!style="width: 33%"|Study
+*ONE of the following antibiotics:
-!style="width: 33%"|Years of enrollment
+**[[Ciprofloxacin (Cipro)]] 500 mg PO twice per day
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+**[[Levofloxacin (Levaquin)]] 500 mg PO once per day
-|-
+**[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] 160/800 mg PO twice per day
-|[https://doi.org/10.1200/jco.2012.45.9842 Visco et al. 2013 (VI-1903)]
+*[[Fluconazole (Diflucan)]] 200 mg PO once per day
-|2009-2011
+*ONE of the following antivirals:
-|style="background-color:#91cf61"|Phase 2
+**[[Acyclovir (Zovirax)]] 200 mg PO twice per day
-|-
+**[[Valacyclovir (Valtrex)]] 500 mg PO once per day
-|}
+*[[Filgrastim (Neupogen)]] 10 mcg/kg SC once per day, starting 24 hours after completion of intensive courses of chemotherapy (day 5 for part A, day 4 for part B), given until ANC greater than 1000/uL
-''Note: up to 6 cycles were given for newly diagnosed patients under the age of 80, who tolerated treatment, or had regression of disease between cycles 2 and 4.''
+'''Next cycle to start as soon as ANC is greater than 1000/uL at least 24 hours off of G-CSF and platelet count greater than 60 x 10<sup>9</sup>/L'''
+====Chemotherapy, Part B (cycles 2, 4, 6, 8)====
+*[[Methotrexate (MTX)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1, then 800 mg/m<sup>2</sup> IV over 22 hours (total dose per cycle: 1000 mg/m<sup>2</sup>)
+*[[Cytarabine (Ara-C)]] by the following age-based criteria:
+**Younger than 60: 3000 mg/m<sup>2</sup> IV over 2 hours every 12 hours on days 2 & 3 (total dose per cycle: 12,000 mg/m<sup>2</sup>)
+**60 or older: 1000 mg/m<sup>2</sup> IV over 2 hours every 12 hours on days 2 & 3 (total dose per cycle: 4000 mg/m<sup>2</sup>)
+====Glucocorticoid therapy====
+*[[Methylprednisolone (Solumedrol)]] 50 mg IV every 12 hours on days 1 to 3 (see note)
+**''Note: This is only mentioned in the Kantarjian et al. 2010 publication, and it isn't clear if it's meant to be a supportive or antineoplastic medication.''
 <div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
+====Supportive therapy====
-*[[Rituximab (Rituxan)]] as follows:
+*[[Folinic acid (Leucovorin)]] 50 mg IV once on day 3, 12 hours after [[Methotrexate (MTX)]] is complete, then 15 mg IV every 6 hours until serum methotrexate level less than 100 nmol/L
-**Cycle 1: 375 mg/m<sup>2</sup> IV once on day 1
+*ONE of the following antibiotics:
-**Cycle 2 onwards: 375 mg/m<sup>2</sup> IV once on day 2
+**[[Ciprofloxacin (Cipro)]] 500 mg PO twice per day
-====Chemotherapy====
+**[[Levofloxacin (Levaquin)]] 500 mg PO once per day
-*[[Bendamustine]] 70 mg/m<sup>2</sup> IV once per day on days 2 & 3
+**[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] 160/800 mg PO twice per day
-*[[Cytarabine (Ara-C)]] 800 mg/m<sup>2</sup> IV over 2 hours once per day on days 2 to 4, '''starting 2 hours after bendamustine on days 2 & 3'''
+*[[Fluconazole (Diflucan)]] 200 mg PO once per day
-'''28-day cycle for 4 to 6 cycles (see note)'''
+*ONE of the following antivirals:
+**[[Acyclovir (Zovirax)]] 200 mg PO twice per day
+**[[Valacyclovir (Valtrex)]] 500 mg PO once per day
+*[[Filgrastim (Neupogen)]] 10 mcg/kg SC once per day, starting 24 hours after completion of intensive courses of chemotherapy (day 5 for part A, day 4 for part B), given until ANC greater than 1000/uL
+'''Next cycle to start as soon as ANC is greater than 1000/uL at least 24 hours off of G-CSF and platelet count greater than 60 x 10<sup>9</sup>/L'''
+====CNS therapy, prophylaxis====
+*[[Methotrexate (MTX)]] by the following criteria:
+**LP: 12 mg IT once on day 2
+**Ommaya reservoir: 6 mg IT once on day 2
+*[[Cytarabine (Ara-C)]] 100 mg IT once on either day 7 or 8
+'''Given each cycle for a total of 6 or 8 intrathecal treatments (i.e. 3 each of methotrexate and cytarabine or 4 each of methotrexate and cytarabine), depending on risk for CNS relapse based serum lactate dehydrogenase (LDH) greater than 1400 IU/L and/or proliferative index percentage of S + G2M greater than or equal to 14%'''
+====CNS therapy, treatment====
+*[[Methotrexate (MTX)]] 12 mg (6 mg if given via Ommaya reservoir) IT alternating with [[Cytarabine (Ara-C)]] 100 mg IT, with both given every week until cell count in CSF normalizes and cytology is negative for malignancy
+*Then [[Methotrexate (MTX)]] 12 mg (6 mg if given via Ommaya reservoir) IT given weeks 1 & 3 and [[Cytarabine (Ara-C)]] 100 mg IT, given weeks 2 & 4
+*Once those 4 weeks are complete, then intrathecal treatment is given similar to the prophylactic schedule, with each drug given once during every remaining cycle of induction therapy:
+**[[Methotrexate (MTX)]] 12 mg (6 mg if given via Ommaya reservoir) IT once on day 2
+**[[Cytarabine (Ara-C)]] 100 mg IT once on either day 7 or 8
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*Certain patient populations (see e.g. Kantarjian et al. 2004) proceed to receive [[#POMP|POMP]] maintenance
 </div></div>
 ===References===
-# '''VI-1903:''' Visco C, Finotto S, Zambello R, Paolini R, Menin A, Zanotti R, Zaja F, Semenzato G, Pizzolo G, D'Amore ES, Rodeghiero F. Combination of rituximab, bendamustine, and cytarabine for patients with mantle-cell non-Hodgkin lymphoma ineligible for intensive regimens or autologous transplantation. J Clin Oncol. 2013 Apr 10;31(11):1442-9. Epub 2013 Feb 11. [https://doi.org/10.1200/jco.2012.45.9842 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23401442 PubMed] NCT00992134
+# '''Review:''' Cortes J, O'Brien SM, Pierce S, Keating MJ, Freireich EJ, Kantarjian HM. The value of high-dose systemic chemotherapy and intrathecal therapy for central nervous system prophylaxis in different risk groups of adult acute lymphoblastic leukemia. Blood. 1995 Sep 15;86(6):2091-7. [http://www.bloodjournal.org/content/86/6/2091.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/7662956 PubMed]
-# '''FIL-RBAC500:''' Visco C, Chiappella A, Nassi L, Patti C, Ferrero S, Barbero D, Evangelista A, Spina M, Molinari A, Rigacci L, Tani M, Di Rocco A, Pinotti G, Fabbri A, Zambello R, Finotto S, Gotti M, Carella AM, Salvi F, Pileri SA, Ladetto M, Ciccone G, Gaidano G, Ruggeri M, Martelli M, Vitolo U. Rituximab, bendamustine, and low-dose cytarabine as induction therapy in elderly patients with mantle cell lymphoma: a multicentre, phase 2 trial from Fondazione Italiana Linfomi. Lancet Haematol. 2017 Jan;4(1):e15-e23. Epub 2016 Dec 2. [https://doi.org/10.1016/S2352-3026(16)30185-5 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/27927586 PubMed] NCT01662050
+# Koller CA, Kantarjian HM, Thomas D, O'Brien S, Rios MB, Kornblau S, Murphy S, Keating M. The hyper-CVAD regimen improves outcome in relapsed acute lymphoblastic leukemia. Leukemia. 1997 Dec;11(12):2039-44. [https://www.nature.com/articles/2400861 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9447817 PubMed]
-==maxi-R-CHOP/R-HiDAC {{#subobject:360f9d|Regimen=1}}==
+# Thomas DA, Cortes J, O'Brien S, Pierce S, Faderl S, Albitar M, Hagemeister FB, Cabanillas FF, Murphy S, Keating MJ, Kantarjian H. Hyper-CVAD program in Burkitt's-type adult acute lymphoblastic leukemia. J Clin Oncol. 1999 Aug;17(8):2461-70. [https://doi.org/10.1200/jco.1999.17.8.2461 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/10561310 PubMed]
-maxi-R-CHOP/R-HiDAC: '''<u>maxi</u>'''mum-strength '''<u>R</u>'''ituximab, '''<u>C</u>'''yclophosphamide, '''<u>H</u>'''ydroxydaunorubicin (Doxorubicin), '''<u>O</u>'''ncovin (Vincristine), '''<u>P</u>'''redniso(lo)ne alternating with '''<u>R</u>'''ituximab, '''<u>Hi</u>'''gh-'''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine)
+# Kantarjian HM, O'Brien S, Smith TL, Cortes J, Giles FJ, Beran M, Pierce S, Huh Y, Andreeff M, Koller C, Ha CS, Keating MJ, Murphy S, Freireich EJ. Results of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia. J Clin Oncol. 2000 Feb;18(3):547-61. [https://doi.org/10.1200/jco.2000.18.3.547 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/10653870 PubMed]
+## '''Update:''' Kantarjian H, Thomas D, O'Brien S, Cortes J, Giles F, Jeha S, Bueso-Ramos CE, Pierce S, Shan J, Koller C, Beran M, Keating M, Freireich EJ. Long-term follow-up results of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD), a dose-intensive regimen, in adult acute lymphocytic leukemia. Cancer. 2004 Dec 15;101(12):2788-801. [https://doi.org/10.1002/cncr.20668 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15481055 PubMed]
+# Thomas DA, O'Brien S, Cortes J, Giles FJ, Faderl S, Verstovsek S, Ferrajoli A, Koller C, Beran M, Pierce S, Ha CS, Cabanillas F, Keating MJ, Kantarjian H. Outcome with the hyper-CVAD regimens in lymphoblastic lymphoma. Blood. 2004 Sep 15;104(6):1624-30. Epub 2004 Jun 3. [http://www.bloodjournal.org/content/104/6/1624.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15178574 PubMed]
+==Mini-Hyper-CVD/MA & Inotuzumab ozogamicin {{#subobject:c0320b|Regimen=1}}==
+Mini-Hyper-CVD/MA & Inotuzumab ozogamicin: '''<u>Mini</u>''' (lower intensity) '''<u>Hyper</u>'''fractionated '''<u>C</u>'''yclophosphamide, '''<u>V</u>'''incristine, '''<u>D</u>'''examethasone alternating with '''<u>M</u>'''ethotrexate and '''<u>A</u>'''ra-C (Cytarabine) & Inotuzumab ozogamicin
 <div class="toccolours" style="background-color:#eeeeee">
-===Protocol {{#subobject:b65317|Variant=1}}===
+===Protocol {{#subobject:c32f4a|Variant=1}}===
 {| class="wikitable sortable" style="width: 60%; text-align:center;"
 !style="width: 33%"|Study
@@ Line 867: / Line 847: @@
 !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2556606/ Geisler et al. 2008 (NLG MCL2)]
+|[https://doi.org/10.1016/S1470-2045(18)30011-1 Kantarjian et al. 2018 (MDACC 2010-0991)]
-|2000-2006
+|2011-2017
-|style="background-color:#91cf61"|Phase 2
+| style="background-color:#91cf61" |Phase 2
 |-
 |}
-''Note: This is also known as the "Nordic regimen". Protocol originally started rituximab during cycle 4, but the protocol was amended to start it on cycle 2.''
 <div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy, maxi-R-CHOP portion====
+========
-*[[Rituximab (Rituxan)]] as follows:
+====Chemotherapy, Part A====
-**Cycles 3 & 5: 375 mg/m<sup>2</sup> IV once on day 1
+*[[Cyclophosphamide (Cytoxan)]] as follows:
-====Chemotherapy, maxi-R-CHOP portion====
+**Cycles 1, 3, 5, 7: 150 mg/m<sup>2</sup> IV every 12 hours on days 1 to 3 (total dose per cycle: 900 mg/m<sup>2</sup>)
-*[[Cyclophosphamide (Cytoxan)]] 1200 mg/m<sup>2</sup> IV once on day 1
+*[[Vincristine (Oncovin)]] as follows:
-*[[Doxorubicin (Adriamycin)]] 75 mg/m<sup>2</sup> IV once on day 1
+**Cycles 1, 3, 5, 7: 2 mg IV once per day on days 1 & 8
-*[[Vincristine (Oncovin)]] 2 mg IV once on day 1
+====Glucocorticoid therapy, Part A====
-====Glucocorticoid therapy, maxi-R-CHOP portion====
+*[[Dexamethasone (Decadron)]] as follows:
-*[[Prednisone (Sterapred)]] 100 mg PO once per day on days 1 to 5
+**Cycles 1, 3, 5, 7: 20 mg IV or PO once per day on days 1 to 4, 11 to 14
-'''21-day cycle for 3 cycles, alternating with R-HiDAC (6 cycles total)'''
+====Antibody-drug conjugate therapy, Part A====
-====Targeted therapy, R-HiDAC portion====
+*[[Inotuzumab ozogamicin (Besponsa)]] as follows:
-*[[Rituximab (Rituxan)]] as follows:
+**Cycles 1 & 3: 1.3 to 1.8 mg/m<sup>2</sup> IV once on day 3
-**Cycles 2 & 4: 375 mg/m<sup>2</sup> IV once on day 1
+**Cycles 5 & 7: 1 to 1.3 mg/m<sup>2</sup> IV once on day 3
-**Cycle 6: 375 mg/m<sup>2</sup> IV once per day on days 1 & 9
+========
-====Chemotherapy, R-HiDAC portion====
+====Chemotherapy, Part B====
-*[[Cytarabine (Ara-C)]] by the following age-based criteria:
+*[[Methotrexate (MTX)]] as follows:
-**60 and younger: 3000 mg/m<sup>2</sup> IV over 3 hours every 12 hours on days 1 & 2 (total dose per cycle: 12,000 mg/m<sup>2</sup>)
+**Cycles 2, 4, 6, 8: 250 mg/m<sup>2</sup> IV once on day 1
-**Older than 60: 2000 mg/m<sup>2</sup> IV over 3 hours every 12 hours on days 1 & 2 (total dose per cycle: 8000 mg/m<sup>2</sup>)
+*[[Cytarabine (Ara-C)]] as follows:
-====Supportive therapy, R-HiDAC portion====
+**Cycles 2, 4, 6, 8: 500 mg/m<sup>2</sup> IV every 12 hours on days 2 & 3 (total dose per cycle: 2000 mg/m<sup>2</sup>)
-*[[Filgrastim (Neupogen)]] given during cycle 6 as part of stem cell mobilization, with at least 2 million CD34+ cells/kg harvested
+====Antibody-drug conjugate therapy, Part B====
-'''21-day cycle for 3 cycles, alternating with maxi-R-CHOP (6 cycles total)'''
+*[[Inotuzumab ozogamicin (Besponsa)]] as follows:
+**Cycles 2 & 4: 1.3 to 1.8 mg/m<sup>2</sup> IV once on day 3
+**Cycles 6 & 8: 1 to 1.3 mg/m<sup>2</sup> IV once on day 3
+'''28-day cycle for 8 cycles'''
 </div>
 <div class="toccolours" style="background-color:#cbd5e7">
 ====Subsequent treatment====
-*[[#BEAC.2C_then_auto_HSCT|BEAC with autologous HSCT]] or [[#BEAM.2C_then_auto_HSCT|BEAM with autologous HSCT]], within 1 to 2 weeks. If transplant was delayed, an additional 1 to 2 cycles of chemotherapy with maxi-R-CHOP or R-HiDAC could be given.
+*[[#POMP|Dose-reduced POMP]] x 3 y
 </div></div>
 ===References===
-# '''NLG MCL2:''' Geisler CH, Kolstad A, Laurell A, Andersen NS, Pedersen LB, Jerkeman M, Eriksson M, Nordström M, Kimby E, Boesen AM, Kuittinen O, Lauritzsen GF, Nilsson-Ehle H, Ralfkiaer E, Akerman M, Ehinger M, Sundström C, Langholm R, Delabie J, Karjalainen-Lindsberg ML, Brown P, Elonen E; Nordic Lymphoma Group. Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo-purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group. Blood. 2008 Oct 1;112(7):2687-93. Epub 2008 Jul 14. [http://www.bloodjournal.org/content/112/7/2687.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2556606/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18625886 PubMed] ISRCTN87866680
+<!-- # '''Abstract:''' Susan O'Brien, Deborah A. Thomas, Elias Jabbour, Stefan Faderl, Farhad Ravandi, Gautam Borthakur, Sergernne York, Rebecca Garris, Jorge E. Cortes, Hagop M. Kantarjian. Inotuzumab Ozogamicin In Combination With Low-Intensity Chemotherapy (Mini-hyper-CVD) As Frontline Therapy For Older Patients (≥60 years) With Acute Lymphoblastic Leukemia (ALL). Blood Nov 2013,122(21)1432 [http://www.bloodjournal.org/content/122/21/1432 link to original abstract] -->
-## '''Update:''' Geisler CH, Kolstad A, Laurell A, Jerkeman M, Räty R, Andersen NS, Pedersen LB, Eriksson M, Nordström M, Kimby E, Bentzen H, Kuittinen O, Lauritzsen GF, Nilsson-Ehle H, Ralfkiaer E, Ehinger M, Sundström C, Delabie J, Karjalainen-Lindsberg ML, Brown P, Elonen E; Nordic Lymphoma Group. Nordic MCL2 trial update: six-year follow-up after intensive immunochemotherapy for untreated mantle cell lymphoma followed by BEAM or BEAC + autologous stem-cell support: still very long survival but late relapses do occur. Br J Haematol. 2012 Aug;158(3):355-62. Epub 2012 May 29. Erratum in: Br J Haematol. 2012 Sep;158(6):815-6. [https://doi.org/10.1111/j.1365-2141.2012.09174.x link to original article] [https://pubmed.ncbi.nlm.nih.gov/22640180 PubMed]
+# '''MDACC 2010-0991:''' Kantarjian H, Ravandi F, Short NJ, Huang X, Jain N, Sasaki K, Daver N, Pemmaraju N, Khoury JD, Jorgensen J, Alvarado Y, Konopleva M, Garcia-Manero G, Kadia T, Yilmaz M, Bortakhur G, Burger J, Kornblau S, Wierda W, DiNardo C, Ferrajoli A, Jacob J, Garris R, O'Brien S, Jabbour E. Inotuzumab ozogamicin in combination with low-intensity chemotherapy for older patients with Philadelphia chromosome-negative acute lymphoblastic leukaemia: a single-arm, phase 2 study. Lancet Oncol. 2018 Feb;19(2):240-248. Epub 2018 Jan 16. [https://doi.org/10.1016/S1470-2045(18)30011-1 link to original article] [https://pubmed.ncbi.nlm.nih.gov/29352703 PubMed] NCT01371630
-## '''Update:''' Eskelund CW, Kolstad A, Jerkeman M, Räty R, Laurell A, Eloranta S, Smedby KE, Husby S, Pedersen LB, Andersen NS, Eriksson M, Kimby E, Bentzen H, Kuittinen O, Lauritzsen GF, Nilsson-Ehle H, Ralfkiaer E, Ehinger M, Sundström C, Delabie J, Karjalainen-Lindsberg ML, Workman CT, Garde C, Elonen E, Brown P, Grønbaek K, Geisler CH. 15-year follow-up of the Second Nordic Mantle Cell Lymphoma trial (MCL2): prolonged remissions without survival plateau. Br J Haematol. 2016 Nov;175(3):410-418. Epub 2016 Jul 5. [https://doi.org/10.1111/bjh.14241 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27378674 PubMed]
+==R-Hyper-CVAD/R-MA {{#subobject:7daccd|Regimen=1}}==
-==R-DHAC {{#subobject:ed2a61|Regimen=1}}==
+R-Hyper-CVAD/R-MA: '''<u>R</u>'''ituximab, '''<u>Hyper</u>'''fractionated '''<u>C</u>'''yclophosphamide, '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>D</u>'''examethasone alternating with '''<u>R</u>'''ituximab, '''<u>M</u>'''ethotrexate, '''<u>A</u>'''ra-C (Cytarabine)
-R-DHAC: '''<u>R</u>'''ituximab, '''<u>D</u>'''examethasone, '''<u>H</u>'''igh-dose '''<u>A</u>'''ra-C (Cytarabine), '''<u>C</u>'''arboplatin
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:c89679|Variant=1}}===
+===Protocol {{#subobject:9af66b|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
+{| class="wikitable" style="width: 40%; text-align:center;"
-!style="width: 33%"|Study
+!style="width: 25%"|Study
-!style="width: 33%"|Years of enrollment
+!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+|-
+|[https://doi.org/10.1002/cncr.21776 Thomas et al. 2006]
+|style="background-color:#ffffbe"|Pilot, <20 patients reported
 |-
-|[https://doi.org/10.1056/NEJMoa1701769 Le Gouill et al. 2017 (LyMa)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2940403/ Thomas et al. 2010 (MDACC ID02-230)]
-|2008-2012
+|style="background-color:#91cf61"|Non-randomized
-|style="background-color:#91cf61"|Non-randomized portion of RCT
 |-
 |}
-''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''
+''See papers for details of treatment beyond induction/consolidation, which differ substantially between "standard" and "modified" protocols.''
-<div class="toccolours" style="background-color:#cbd5e8">
+====Targeted therapy, Part A (cycles 1, 3, 5, 7)====
-====Preceding treatment====
+*[[Rituximab (Rituxan)]] as follows:
-*[[#CVP_.28Prednisolone.29|Pre-phase CVP]] x 1 (optional)
+**Cycles 1 & 3: 375 mg/m<sup>2</sup> IV over 2 to 6 hours once per day on days 1 & 11
-</div>
+====Chemotherapy, Part A (cycles 1, 3, 5, 7)====
-<div class="toccolours" style="background-color:#b3e2cd">
+*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> IV over 2 hours every 12 hours on days 1 to 3 (total dose per cycle: 1800 mg/m<sup>2</sup>)
-====Targeted therapy====
+*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 4 & 11
-*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1
+*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 4
-====Glucocorticoid therapy====
+====Glucocorticoid therapy, Part A (cycles 1, 3, 5, 7)====
-*[[Dexamethasone (Decadron)]] 40 mg IV once per day on days 1 to 4
+*[[Dexamethasone (Decadron)]] 40 mg IV or PO once per day on days 1 to 4, 11 to 14
-====Chemotherapy====
+====Supportive therapy, Part A (cycles 1, 3, 5, 7)====
-*[[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV every 12 hours on day 2 (total dose per cycle: 4000 mg/m<sup>2</sup>)
+*[[Mesna (Mesnex)]] 600 mg/m<sup>2</sup>/day IV continuous infusion over 72 hours, started on day 1, starting 1 hour before [[Cyclophosphamide (Cytoxan)]] and completed 12 hours after the last dose of [[Cyclophosphamide (Cytoxan)]] (total dose per cycle: 1800 mg/m<sup>2</sup>)
-*[[Carboplatin (Paraplatin)]] AUC 5 IV once on day 1
+*[[Filgrastim (Neupogen)]] 10 mcg/kg SC once per day, starting 24 hours after completion of chemotherapy, given until WBC greater than 3 x 10<sup>9</sup>/L or bone pain present
-'''21-day cycle for 4 cycles'''
+*ONE of the following antibiotics:
-</div>
+**[[:Category:Fluoroquinolone|Fluoroquinolone]]
-<div class="toccolours" style="background-color:#cbd5e7">
+**[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] 160/800 mg dose/route not specified
-====Subsequent treatment====
+*[[Fluconazole (Diflucan)]] dose/route not specified
-*CR: [[#R-BEAM.2C_then_auto_HSCT|R-BEAM with autologous HSCT]]
+*ONE of the following antivirals:
-*PR: [[#R-CHOP-14_.28Prednisolone.29|R-CHOP-14]] x 4
+**[[Acyclovir (Zovirax)]] dose/route not specified
+**[[Valacyclovir (Valtrex)]] dose/route not specified
+'''Next cycle to start no sooner than 14 days or as soon as "unmaintained" WBC count is greater than 3 x 10<sup>9</sup>/L and platelet count greater than 50 x 10<sup>9</sup>/L'''
+====Targeted therapy, Part B (cycles 2, 4, 6, 8)====
+*[[Rituximab (Rituxan)]] as follows:
+**Cycles 2 & 4: 375 mg/m<sup>2</sup> IV over 2 to 6 hours once per day on days 2 & 8
+====Chemotherapy, Part B (cycles 2, 4, 6, 8)====
+*[[Methotrexate (MTX)]] 1000 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 1
+*[[Cytarabine (Ara-C)]] 3000 mg/m<sup>2</sup> IV over 2 hours every 12 hours on days 2 & 3 (total dose per cycle: 12,000 mg/m<sup>2</sup>)
+====Supportive therapy, Part B (cycles 2, 4, 6, 8)====
+*[[Folinic acid (Leucovorin)]] 50 mg IV once on day 3, 12 hours after [[Methotrexate (MTX)]] is complete, then 15 mg IV every 6 hours until serum methotrexate level less than 100 nmol/L
+*[[Filgrastim (Neupogen)]] 10 mcg/kg SC once per day, starting on day 4, 24 hours after completion of chemotherapy, given until WBC greater than 3 x 10<sup>9</sup>/L or bone pain present
+*ONE of the following antibiotics:
+**Fluoroquinolone
+**[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] 160/800 mg dose/route not specified
+*[[Fluconazole (Diflucan)]] dose/route not specified
+*ONE of the following antivirals:
+**[[Acyclovir (Zovirax)]] dose/route not specified
+**[[Valacyclovir (Valtrex)]] dose/route not specified
+'''Next cycle to start no sooner than 14 days or as soon as "unmaintained" WBC count is greater than 3 x 10<sup>9</sup>/L and platelet count greater than 50 x 10<sup>9</sup>/L'''
+====CNS therapy, prophylaxis====
+*[[Methotrexate (MTX)]] 12 mg (6 mg if given via Ommaya reservoir) IT once on day 2
+*[[Cytarabine (Ara-C)]] 100 mg IT once on day 7
+'''Given each cycle for a total of 16 intrathecal treatments.'''
+''If CNS disease present, therapy augmented to twice per week alternating (MTX, ara-C) treatments until CSF cell count normalizes and cytology is negative, then continues for 4 more alternating once per week treatments; prophylaxis course then resumes.''
+'''8 alternating cycles'''
+====Dose modifications====
+*[[Cytarabine (Ara-C)]] reduced to 1000 mg/m<sup>2</sup> for patients greater than or equal to 60 years old, creatinine greater than or equal to 1.5 mg/dL or 0 hour MTX level greater than or equal to 20,000 nmol/L
+*[[Vincristine (Oncovin)]] reduced to 1 mg for bilirubin greater than 2 mg/dL or NCI common toxicity criteria Grade 2+ peripheral neuropathy, omitted for bilirubin greater than 3 mg/dL or for ileus
+*[[Doxorubicin (Adriamycin)]] reduced by 50% for bilirubin 2 to 3 mg/dL, by 75% for bilirubin 3 to 5 mg/dL (eliminated for bilirubin greater than 5 mg/dL or for gastric/small-bowel involvement with Course 1 to reduce duration of myelosuppression given risk of perforation)
+*[[Methotrexate (MTX)]] reduced by 50% for CrCl 10 to 50 mL/min/1.73m<sup>2</sup> (eliminated for CrCl less than 10 mL/min/1.73m<sup>2</sup>), by 25% to 75% for delayed excretion and/or nephrotoxicity with prior course (dependent on severity) or by 50% for pleural effusions/ascites with drainage of fluid as feasible.
 </div></div>
 ===References===
-<!-- # '''Abstract:''' Steven Le Gouill, MD, PhD, Catherine Thieblemont, MD, PhD, Lucie Oberic, Krimo Bouabdallah, MD, Emmanuel Gyan, MD, PhD, Gandhi Damaj, MD, Vincent Ribrag, MD, Serge Bologna, MD, Remy Gressin, MD, Olivier Casasnovas, MD, Corinne Haioun, MD, PhD, Philippe Solal-Celigny, MD, Herve Maisonneuve, MD, Eric Van Den Neste, MD, PhD, Anne Moreau, MD, Marie C Bene, Gilles Salles, MD PhD, Hervé Tilly, MD, PhD, Thierry Lamy, MD, PhD and Olivier Hermine, MD, PhD. Rituximab Maintenance Versus Wait and Watch after Four Courses of R-DHAP Followed By Autologous Stem Cell transplantation in Previously Untreated Young Patients with Mantle Cell Lymphoma: First Interim Analysis of the Phase III Prospective Lyma Trial, a Lysa Study. Blood 2014 124:146. [http://www.bloodjournal.org/content/124/21/146 link to abstract] -->
+# Thomas DA, Faderl S, O'Brien S, Bueso-Ramos C, Cortes J, Garcia-Manero G, Giles FJ, Verstovsek S, Wierda WG, Pierce SA, Shan J, Brandt M, Hagemeister FB, Keating MJ, Cabanillas F, Kantarjian H. Chemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia. Cancer. 2006 Apr 1;106(7):1569-80. [https://doi.org/10.1002/cncr.21776 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16502413 PubMed]
-# '''LyMa:''' Le Gouill S, Thieblemont C, Oberic L, Moreau A, Bouabdallah K, Dartigeas C, Damaj G, Gastinne T, Ribrag V, Feugier P, Casasnovas O, Zerazhi H, Haioun C, Maisonneuve H, Houot R, Jardin F, Van Den Neste E, Tournilhac O, Le Dû K, Morschhauser F, Cartron G, Fornecker LM, Canioni D, Callanan M, Béné MC, Salles G, Tilly H, Lamy T, Gressin R, Hermine O; LYSA. Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma. N Engl J Med. 2017 Sep 28;377(13):1250-1260. [https://doi.org/10.1056/NEJMoa1701769 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1701769/suppl_file/nejmoa1701769_appendix.pdf link to protocol] '''contains dosing details in supplement''' [https://pubmed.ncbi.nlm.nih.gov/28953447 PubMed] NCT00921414
+## '''Update:''' Fayad L, Thomas D, Romaguera J. Update of the MD Anderson Cancer Center experience with hyper-CVAD and rituximab for the treatment of mantle cell and Burkitt-type lymphomas. Clin Lymphoma Myeloma. 2007 Dec;8 Suppl 2:S57-62. [https://doi.org/10.3816/clm.2007.s.034 link to original article] [https://pubmed.ncbi.nlm.nih.gov/18284717 PubMed]
-==R-DHAOx {{#subobject:16a22d|Regimen=1}}==
+# '''MDACC ID02-230:''' Thomas DA, O'Brien S, Faderl S, Garcia-Manero G, Ferrajoli A, Wierda W, Ravandi F, Verstovsek S, Jorgensen JL, Bueso-Ramos C, Andreeff M, Pierce S, Garris R, Keating MJ, Cortes J, Kantarjian HM. Chemoimmunotherapy with a modified hyper-CVAD and rituximab regimen improves outcome in de novo Philadelphia chromosome-negative precursor B-lineage acute lymphoblastic leukemia. J Clin Oncol. 2010 Aug 20;28(24):3880-9. Epub 2010 Jul 26. [https://doi.org/10.1200/jco.2009.26.9456 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2940403/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20660823 PubMed] NCT00671658
-R-DHAOx: '''<u>R</u>'''ituximab, '''<u>D</u>'''examethasone, '''<u>H</u>'''igh-dose '''<u>A</u>'''ra-C (Cytarabine), '''<u>Ox</u>'''aliplatin
+=Extended induction therapy=
+''Note: these regimens are used when a pre-specified endpoint during remission induction was not achieved.''
+==Daunorubicin, Pegaspargase, Vincristine, Prednisone {{#subobject:1734a2|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:3aa7db|Variant=1}}===
+===Regimen, "ABFM" {{#subobject:cbc322e|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
+{| class="wikitable" style="width: 40%; text-align:center;"
-!style="width: 33%"|Study
+!style="width: 25%"|Study
-!style="width: 33%"|Years of enrollment
+!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://doi.org/10.1056/NEJMoa1701769 Le Gouill et al. 2017 (LyMa)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6450431/ Stock et al. 2019 (CALGB 10403)]
-|2008-2012
+| style="background-color:#91cf61" |Non-randomized
-|style="background-color:#91cf61"|Non-randomized portion of RCT
 |-
 |}
-''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''
+ABFM: '''<u>A</u>'''ugmented '''<u>B</u>'''erlin-'''<u>F</u>'''rankfurt-'''<u>M</u>'''ünster regimen<br>
 <div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
-*[[#CVP_.28Prednisolone.29|Pre-phase CVP]] x 1 (optional)
+*[[#Daunorubicin.2C_Pegaspargase.2C_Vincristine.2C_Prednisone|ABFM]] induction, with inadequate response
 </div>
 <div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
+====Chemotherapy====
-*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1
+*[[Daunorubicin (Cerubidine)]] 25 mg/m<sup>2</sup> IV once on day 1
+*[[Pegaspargase (Oncaspar)]] 2500 units/m<sup>2</sup> IM or IV once on day 4
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1 & 8
 ====Glucocorticoid therapy====
-*[[Dexamethasone (Decadron)]] 40 mg IV once per day on days 1 to 4
+*[[Prednisone (Sterapred)]] 30 mg/m<sup>2</sup> IV or PO twice per day on days 1 to 14
-====Chemotherapy====
+'''2-week course'''
-*[[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV every 12 hours on day 2 (total dose per cycle: 4000 mg/m<sup>2</sup>)
-*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV once on day 1
-'''21-day cycle for 4 cycles'''
 </div>
 <div class="toccolours" style="background-color:#cbd5e7">
 ====Subsequent treatment====
-*CR: [[#R-BEAM.2C_then_auto_HSCT|R-BEAM with autologous HSCT]]
+*[[#AALL0232_consolidation|AALL0232]] consolidation
-*PR: [[#R-CHOP-14_.28Prednisolone.29|R-CHOP-14]] x 4
 </div></div>
 ===References===
-<!-- # '''Abstract:''' Steven Le Gouill, MD, PhD, Catherine Thieblemont, MD, PhD, Lucie Oberic, Krimo Bouabdallah, MD, Emmanuel Gyan, MD, PhD, Gandhi Damaj, MD, Vincent Ribrag, MD, Serge Bologna, MD, Remy Gressin, MD, Olivier Casasnovas, MD, Corinne Haioun, MD, PhD, Philippe Solal-Celigny, MD, Herve Maisonneuve, MD, Eric Van Den Neste, MD, PhD, Anne Moreau, MD, Marie C Bene, Gilles Salles, MD PhD, Hervé Tilly, MD, PhD, Thierry Lamy, MD, PhD and Olivier Hermine, MD, PhD. Rituximab Maintenance Versus Wait and Watch after Four Courses of R-DHAP Followed By Autologous Stem Cell transplantation in Previously Untreated Young Patients with Mantle Cell Lymphoma: First Interim Analysis of the Phase III Prospective Lyma Trial, a Lysa Study. Blood 2014 124:146. [http://www.bloodjournal.org/content/124/21/146 link to abstract] -->
+# '''CALGB 10403:''' Stock W, Luger SM, Advani AS, Yin J, Harvey RC, Mullighan CG, Willman CL, Fulton N, Laumann KM, Malnassy G, Paietta E, Parker E, Geyer S, Mrózek K, Bloomfield CD, Sanford B, Marcucci G, Liedtke M, Claxton DF, Foster MC, Bogart JA, Grecula JC, Appelbaum FR, Erba H, Litzow MR, Tallman MS, Stone RM, Larson RA. A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403. Blood. 2019 Apr 4;133(14):1548-1559. Epub 2019 Jan 18. [http://www.bloodjournal.org/content/133/14/1548.long link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6450431/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30658992 PubMed] NCT00558519
-# '''LyMa:''' Le Gouill S, Thieblemont C, Oberic L, Moreau A, Bouabdallah K, Dartigeas C, Damaj G, Gastinne T, Ribrag V, Feugier P, Casasnovas O, Zerazhi H, Haioun C, Maisonneuve H, Houot R, Jardin F, Van Den Neste E, Tournilhac O, Le Dû K, Morschhauser F, Cartron G, Fornecker LM, Canioni D, Callanan M, Béné MC, Salles G, Tilly H, Lamy T, Gressin R, Hermine O; LYSA. Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma. N Engl J Med. 2017 Sep 28;377(13):1250-1260. [https://doi.org/10.1056/NEJMoa1701769 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1701769/suppl_file/nejmoa1701769_appendix.pdf link to protocol] '''contains dosing details in supplement''' [https://pubmed.ncbi.nlm.nih.gov/28953447 PubMed] NCT00921414
+=Early intensification therapy=
-==R-DHAP {{#subobject:7bb19f|Regimen=1}}==
+==CALGB 8811 early intensification {{#subobject:225653|Regimen=1}}==
-R-DHAP: '''<u>R</u>'''ituximab, '''<u>D</u>'''examethasone, '''<u>H</u>'''igh-dose '''<u>A</u>'''ra-C (Cytarabine), '''<u>P</u>'''latinol (Cisplatin)
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #1, 3 cycles {{#subobject:b417da|Variant=1}}===
+===Regimen {{#subobject:b3e19a|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
+{| class="wikitable" style="width: 40%; text-align:center;"
-!style="width: 33%"|Study
+!style="width: 25%"|Study
-!style="width: 33%"|Years of enrollment
+!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[http://www.bloodjournal.org/content/121/1/48.full Delarue et al. 2012]
+|[http://www.bloodjournal.org/content/85/8/2025.full Larson et al. 1995 (CALGB 8811)]
-|2000-2003
 |style="background-color:#91cf61"|Phase 2
 |-
 |}
-''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment. The authors did not clearly specify the total dose/schedule of cytarabine; below is the dosing used in the [[Diffuse_large_B-cell_lymphoma#R-DHAP|NCIC-CTG LY.12 trial]]''
 <div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
-*[[#R-CHOP|R-CHOP]] x 2 to 3 cycles
+*[[#Cyclophosphamide.2C_Daunorubicin.2C_L-Asparaginase.2C_Vincristine.2C_Prednisone|Cyclophosphamide, Daunorubicin, L-asparaginase, Vincristine, Prednisone induction ("Course I")]]
 </div>
 <div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
+====Chemotherapy, "Course II"====
-*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1
+*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV once on day 1
-====Glucocorticoid therapy====
+*[[Mercaptopurine (6-MP)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 14
-*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4
+*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> SC once per day on days 1 to 4, 8 to 11
-====Chemotherapy====
+*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 15 & 22
-*[[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV every 12 hours on day 2 (total dose per cycle: 4000 mg/m<sup>2</sup>)
+*[[Asparaginase (Elspar)]] 6000 units/m<sup>2</sup> SC once per day on days 15, 18, 22, 25
-*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 1
 ====CNS therapy, prophylaxis====
-''Intrathecal prophylaxis with the following was given per physician discretion; no timeframe or total number of doses is described:''
+*[[Methotrexate (MTX)]] 15 mg IT once on day 1
-*[[Methotrexate (MTX)]] 15 mg IT
+'''28-day cycle for 2 cycles'''
-*[[Cytarabine (Ara-C)]] 40 mg IT
-*Corticosteroids
-'''21-day cycle for 3 cycles'''
 </div>
 <div class="toccolours" style="background-color:#cbd5e7">
 ====Subsequent treatment====
-*[[#TAM6.2C_then_auto_HSCT|TAM6 with auto HSCT]]
+*[[#Mercaptopurine.2C_Methotrexate.2C_WB-XRT|Mercaptopurine, Methotrexate, WB-XRT]] interim maintenance ("Course III")
-</div></div><br>
+</div></div>
+===References===
+# '''CALGB 8811:''' Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR, Hooberman AL, Westbrook CA, Arthur DC, George SL, Bloomfield CD, Schiffer CA. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: Cancer and Leukemia Group B study 8811. Blood. 1995 Apr 15;85(8):2025-37. [http://www.bloodjournal.org/content/85/8/2025.full.pdf+html link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/7718875 PubMed]
+==L-Asparaginase & Methotrexate {{#subobject:0c63ca|Regimen=1}}==
+'''Note: [[Asparaginase (Elspar)]] was discontinued by the manufacturer in December 2012, and is now essentially out of stock. Alternatives include [[Pegaspargase (Oncaspar)]] or [[Asparaginase Erwinia chrysanthemi (Erwinaze)]].'''
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #2, 4 cycles {{#subobject:10fd0a|Variant=1}}===
+===Regimen {{#subobject:51817e|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
+{| class="wikitable" style="width: 40%; text-align:center;"
-!style="width: 33%"|Study
+!style="width: 25%"|Study
-!style="width: 33%"|Years of enrollment
+!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://doi.org/10.1056/NEJMoa1701769 Le Gouill et al. 2017 (LyMa)]
+|[http://www.bloodjournal.org/content/106/12/3760.long Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)]
-|2008-2012
 |style="background-color:#91cf61"|Non-randomized portion of RCT
 |-
 |}
-''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''
 <div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
-*[[#CVP_.28Prednisolone.29|Pre-phase CVP]] x 1 (optional)
+*[[#Cyclophosphamide.2C_Cytarabine.2C_Mercaptopurine|Cyclophosphamide, Cytarabine, Mercaptopurine induction ("Phase 2")]]
 </div>
 <div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
-*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1
-====Glucocorticoid therapy====
-*[[Dexamethasone (Decadron)]] 40 mg IV once per day on days 1 to 4
 ====Chemotherapy====
-*[[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV every 12 hours on day 2 (total dose per cycle: 4000 mg/m<sup>2</sup>)
+*[[Methotrexate (MTX)]] 3000 mg/m<sup>2</sup> IV once per day on days 1, 8, 22
-*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 1
+*[[Asparaginase (Elspar)]] 10,000 units (route not specified) once per day on days 2, 9, 23
-'''21-day cycle for 4 cycles'''
+====Supportive therapy====
+*[[Folinic acid (Leucovorin)]] at "standard" doses
+'''3 cycles (length of cycle not specified in original reference)'''
 </div>
 <div class="toccolours" style="background-color:#cbd5e7">
 ====Subsequent treatment====
-*CR: [[#R-BEAM.2C_then_auto_HSCT|R-BEAM with autologous HSCT]]
+*Patients who were younger than 50 years of age and had an HLA-matched sibling donor, as well as Ph+ patients with any donor: [[Transplant_conditioning_regimens#Etoposide_.26_TBI_2|Etoposide & TBI, then allo HSCT]]
-*PR: [[#R-CHOP-14_.28Prednisolone.29|R-CHOP-14]] x 4
+*All others: [[Transplant_conditioning_regimens#Etoposide_.26_TBI|Etoposide & TBI, then auto HSCT]] versus [[#International_ALL_Trial|International ALL Trial]] consolidation
 </div></div>
 ===References===
-# '''Case series:''' de Guibert S, Jaccard A, Bernard M, Turlure P, Bordessoule D, Lamy T. Rituximab and DHAP followed by intensive therapy with autologous stem-cell transplantation as first-line therapy for mantle cell lymphoma. Haematologica. 2006 Mar;91(3):425-6. [http://www.haematologica.org/content/91/3/425 link to original article] '''does not contain dosing details''' [https://pubmed.ncbi.nlm.nih.gov/16531272 PubMed]
+# '''MRC UKALL XII/ECOG E2993:''' Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. [http://www.bloodjournal.org/content/106/12/3760.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16105981 PubMed] NCT00002514
-# Delarue R, Haioun C, Ribrag V, Brice P, Delmer A, Tilly H, Salles G, Van Hoof A, Casasnovas O, Brousse N, Lefrere F, Hermine O; Groupe d'Etude des Lymphomes de l'Adulte. CHOP and DHAP plus rituximab followed by autologous stem cell transplantation in mantle cell lymphoma: a phase 2 study from the Groupe d'Etude des Lymphomes de l'Adulte. Blood. 2013 Jan 3;121(1):48-53. Epub 2012 Jun 20. [http://www.bloodjournal.org/content/121/1/48.full link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22718839 PubMed]
+## '''Update:''' Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, Burnett AK, Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J, McMillan A, Franklin IM, Luger S, Ciobanu N, Rowe JM. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008 Feb 15;111(4):1827-33. Epub 2007 Nov 29. [http://www.bloodjournal.org/content/111/4/1827.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/18048644 PubMed]
-<!-- # '''Abstract:''' Steven Le Gouill, MD, PhD, Catherine Thieblemont, MD, PhD, Lucie Oberic, Krimo Bouabdallah, MD, Emmanuel Gyan, MD, PhD, Gandhi Damaj, MD, Vincent Ribrag, MD, Serge Bologna, MD, Remy Gressin, MD, Olivier Casasnovas, MD, Corinne Haioun, MD, PhD, Philippe Solal-Celigny, MD, Herve Maisonneuve, MD, Eric Van Den Neste, MD, PhD, Anne Moreau, MD, Marie C Bene, Gilles Salles, MD PhD, Hervé Tilly, MD, PhD, Thierry Lamy, MD, PhD and Olivier Hermine, MD, PhD. Rituximab Maintenance Versus Wait and Watch after Four Courses of R-DHAP Followed By Autologous Stem Cell transplantation in Previously Untreated Young Patients with Mantle Cell Lymphoma: First Interim Analysis of the Phase III Prospective Lyma Trial, a Lysa Study. Blood 2014 124:146. [http://www.bloodjournal.org/content/124/21/146 link to abstract] -->
+## '''Update:''' Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, Marks DI, McMillan AK, Litzow MR, Lazarus HM, Foroni L, Dewald G, Franklin IM, Luger SM, Paietta E, Wiernik PH, Tallman MS, Goldstone AH. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009 May 7;113(19):4489-96. Epub 2009 Feb 24. [http://www.bloodjournal.org/content/113/19/4489.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4188540/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19244158 PubMed]
-# '''LyMa:''' Le Gouill S, Thieblemont C, Oberic L, Moreau A, Bouabdallah K, Dartigeas C, Damaj G, Gastinne T, Ribrag V, Feugier P, Casasnovas O, Zerazhi H, Haioun C, Maisonneuve H, Houot R, Jardin F, Van Den Neste E, Tournilhac O, Le Dû K, Morschhauser F, Cartron G, Fornecker LM, Canioni D, Callanan M, Béné MC, Salles G, Tilly H, Lamy T, Gressin R, Hermine O; LYSA. Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma. N Engl J Med. 2017 Sep 28;377(13):1250-1260. [https://doi.org/10.1056/NEJMoa1701769 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1701769/suppl_file/nejmoa1701769_appendix.pdf link to protocol] '''contains dosing details in supplement''' [https://pubmed.ncbi.nlm.nih.gov/28953447 PubMed] NCT00921414
+## '''Update:''' Fielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow MR, Lazarus H, Luger SM, Marks DI, McMillan AK, Moorman AV, Patel B, Paietta E, Tallman MS, Goldstone AH. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014 Feb 6;123(6):843-50. Epub 2013 Nov 25. [http://www.bloodjournal.org/content/123/6/843.full link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3916877/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24277073 PubMed]
-==R-HiDAC {{#subobject:3a58eb|Regimen=1}}==
+=Consolidation after upfront therapy (including post-remission therapy)=
-R-HiDAC: '''<u>R</u>'''ituximab & '''<u>Hi</u>'''gh '''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine)
+''Note that many of these regimens are complex and as such will be referred to by their study name, not by the individual drug names. This is also a phase of treatment often referred to as post-remission or postinduction therapy.''
+==AALL0232 consolidation {{#subobject:065gg9|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:395100|Variant=1}}===
+===Regimen {{#subobject:342b6d|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
+{| class="wikitable" style="width: 40%; text-align:center;"
-!style="width: 33%"|Study
+!style="width: 50%"|Study
-!style="width: 33%"|Years of enrollment
+!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://doi.org/10.1111/j.1365-2141.2008.07498.x Van 't Veer et al. 2008 (HOVON 45)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6450431/ Stock et al. 2019 (CALGB 10403)]
-|2002-2005
+| style="background-color:#91cf61" |Non-randomized
-|style="background-color:#91cf61"|Phase 2
 |-
 |}
 <div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
-*[[#R-CHOP_.28Prednisolone.29|R-CHOP]] x 3
+*[[#Daunorubicin.2C_Pegaspargase.2C_Vincristine.2C_Prednisone|ABFM]] induction
 </div>
 <div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
-*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 11
 ====Chemotherapy====
-*[[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV every 12 hours on days 1 to 4 (total dose: 16,000 mg/m<sup>2</sup>)
+*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 29
-'''11-day course'''
+*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> IV or SC once per day on days 1 to 4, 8 to 11, 29 to 32, 36 to 39
+*[[Mercaptopurine (6-MP)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 14, 29 to 42
+*[[Pegaspargase (Oncaspar)]] 2500 units/m<sup>2</sup> IM or IV once per day on days 15 & 43
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 15, 22, 43, 50
+'''50-day course'''
 </div>
 <div class="toccolours" style="background-color:#cbd5e7">
 ====Subsequent treatment====
-*Stem cells were collected after this cycle with G-CSF given to "enhance" collection. Patients then proceeded to [[#BEAM.2C_then_auto_HSCT|BEAM with autologous HSCT]]
+*6-MP, Capizzi MTX, Pegaspargase interim maintenance
 </div></div>
 ===References===
-# '''HOVON 45:''' Van 't Veer MB, de Jong D, MacKenzie M, Kluin-Nelemans HC, van Oers MH, Zijlstra J, Hagenbeek A, van Putten WL. High-dose Ara-C and BEAM with autograft rescue in R-CHOP responsive mantle cell lymphoma patients. Br J Haematol. 2009 Feb;144(4):524-30. Epub 2008 Nov 26. [https://doi.org/10.1111/j.1365-2141.2008.07498.x link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19036081 PubMed]
+# '''CALGB 10403:''' Stock W, Luger SM, Advani AS, Yin J, Harvey RC, Mullighan CG, Willman CL, Fulton N, Laumann KM, Malnassy G, Paietta E, Parker E, Geyer S, Mrózek K, Bloomfield CD, Sanford B, Marcucci G, Liedtke M, Claxton DF, Foster MC, Bogart JA, Grecula JC, Appelbaum FR, Erba H, Litzow MR, Tallman MS, Stone RM, Larson RA. A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403. Blood. 2019 Apr 4;133(14):1548-1559. Epub 2019 Jan 18. [http://www.bloodjournal.org/content/133/14/1548.long link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6450431/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30658992 PubMed] NCT00558519
-==R-M-CHOP {{#subobject:358013|Regimen=1}}==
+==Blinatumomab monotherapy {{#subobject:065ff9|Regimen=1}}==
-R-M-CHOP: '''<u>R</u>'''ituximab, '''<u>MTX</u>''' (Methotrexate), '''<u>C</u>'''yclophosphamide, '''<u>H</u>'''ydroxydaunorubicin (Doxorubicin), '''<u>O</u>'''ncovin, '''<u>P</u>'''rednisone
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:e580e|Variant=1}}===
+===Regimen {{#subobject:687b6d|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
+{| class="wikitable sortable" style="width: 80%; text-align:center;"
-!style="width: 33%"|Study
+!style="width: 25%"|Study
-!style="width: 33%"|Years of enrollment
+!style="width: 25%"|Years of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2793032/ Damon et al. 2009 (CALGB 59909)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6027091/ Gökbuget et al. 2018 (BLAST)]
-|2001-2004
+|2010-2014
-|style="background-color:#91cf61"|Phase 2
+|style="background-color:#91cf61"|Phase 2 (RT)
+| style="background-color:#e0ecf4" |CR after 1 cycle: 78%
 |-
 |}
-''Note: this is the induction portion ("Treatments 1 & 2") of CALGB 59909. Median days between treatment 1 & 2 was 23 days, with a range of 16 to 41 days observed.''
+''Note: these patients had MRD after induction; also note that this is BSA-based dosing.''
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*"A minimum of 3 blocks of intensive [[Regimen_classes#Chemotherapy|chemotherapy]]"
+</div>
 <div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
+====Immunotherapy====
-*[[Rituximab (Rituxan)]] by the following criteria:
+*[[Blinatumomab (Blincyto)]] 15 mcg/m<sup>2</sup>/day IV continuous infusion over 28 days, started on day 1 (total dose per cycle: 420 mcg/m<sup>2</sup>)
-**Circulating mantle cells up to 10,000 cells/uL: 375 mg/m<sup>2</sup> IV once on day 1
+'''42-day cycle for up to 4 cycles'''
-====Chemotherapy====
-*[[Methotrexate (MTX)]] 300 mg/m<sup>2</sup> IV over 4 hours once on day 2
-*[[Cyclophosphamide (Cytoxan)]] 2000 mg/m<sup>2</sup> IV over 2 hours once on day 3
-*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV once on day 3
-*[[Vincristine (Oncovin)]] by the following age-based criteria:
-**Up to 40 years old: 1.4 mg/m<sup>2</sup> IV once on day 3
-**Older than 40: 1.4 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 3
-====Glucocorticoid therapy====
-*[[Prednisone (Sterapred)]] 100 mg/m<sup>2</sup> PO once per day on days 3 to 7
-====Supportive therapy====
-*[[Folinic acid (Leucovorin)]] 50 mg/m<sup>2</sup> IV every 6 hours for 3 doses, starting 24 hours after completion of methotrexate, then 10 mg/m<sup>2</sup> IV or PO every 6 hours until serum methotrexate level less than 50 nmol/L
-*[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting on day 4, to continue until ANC greater than 10,000/uL once or greater than 5000/uL twice
-*[[Levofloxacin (Levaquin)]] 500 mg PO once per day, starting on day 6, to continue until ANC is greater than or equal to 1500/uL
-*[[Fluconazole (Diflucan)]] 200 mg PO once per day, starting on day 6, to continue until ANC is greater than or equal to 1500/uL
-'''2 cycles, with interval between cycle 1 & 2 based on count recovery'''
 </div>
 <div class="toccolours" style="background-color:#cbd5e7">
 ====Subsequent treatment====
-*Patients with less than or equal to 15% involvement by disease in bone marrow biopsy after cycle 2: [[Stem_cell_mobilization#EAR_.26_G-CSF|EAR with stem cell mobilization]], 4 weeks after treatment 2, if ANC greater than or equal to 1000/uL, platelets greater than or equal to 100 x 10<sup>9</sup>/L, Cr less than 2 mg/dL, total bilirubin less than 2x upper limit of normal, and AST less than 3x upper limit of normal.
+*Patients who had an allogeneic donor could proceed to allogeneic hematopoietic stem cell transplant any time after cycle 1
-*Patients with bone marrow biopsy after treatment 2 has greater than 15% involvement by disease, repeat treatment 2 (identified as "treatment 2.5")
-*Patients with greater than 15% bone marrow involvement by disease after treatment 2.5 were removed from protocol
-====CNS therapy====
-If cerebrospinal fluid (CSF) contained disease with CSF WBC count greater than or equal to 5 cells/uL:
-*[[Methotrexate (MTX)]] 12 mg IT x 10 total doses during treatments 1 to 3; not given concurrently with intrathecal methotrexate or cytarabine
-If CSF contained greater than 5 cells/uL:
-*In addition to intrathecal chemotherapy above, patient also received 2 Gy x 12 fractions (total dose 24 Gy) [[External_beam_radiotherapy|cranial radiation]]
 </div></div>
 ===References===
-# '''CALGB 59909:''' Damon LE, Johnson JL, Niedzwiecki D, Cheson BD, Hurd DD, Bartlett NL, Lacasce AS, Blum KA, Byrd JC, Kelly M, Stock W, Linker CA, Canellos GP. Immunochemotherapy and autologous stem-cell transplantation for untreated patients with mantle-cell lymphoma: CALGB 59909. J Clin Oncol. 2009 Dec 20;27(36):6101-8. Epub 2009 Nov 16. [https://doi.org/10.1200/jco.2009.22.2554 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2793032/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19917845 PubMed] NCT00020943
+# '''BLAST:''' Gökbuget N, Dombret H, Bonifacio M, Reichle A, Graux C, Faul C, Diedrich H, Topp MS, Brüggemann M, Horst HA, Havelange V, Stieglmaier J, Wessels H, Haddad V, Benjamin JE, Zugmaier G, Nagorsen D, Bargou RC. Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood. 2018 Apr 5;131(14):1522-1531. Epub 2018 Jan 22. [https://doi.org/10.1182/blood-2017-08-798322 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6027091/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29358182 PubMed] NCT01207388
-==R-MACLO/R-IVAM {{#subobject:51391f|Regimen=1}}==
+## '''Update:''' Gökbuget N, Zugmaier G, Dombret H, Stein A, Bonifacio M, Graux C, Faul C, Brüggemann M, Taylor K, Mergen N, Reichle A, Horst HA, Havelange V, Topp MS, Bargou RC. Curative outcomes following blinatumomab in adults with minimal residual disease B-cell precursor acute lymphoblastic leukemia. Leuk Lymphoma. 2020 Nov;61(11):2665-2673. Epub 2020 Jul 3. [https://doi.org/10.1080/10428194.2020.1780583 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32619115/ PubMed]
-R-MACLO/R-IVAM: '''<u>R</u>'''ituximab, '''<u>MTX</u>''' (Methotrexate), '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''yclophosphamide, '''<u>L</u>'''eucovorin (Folinic acid), '''<u>O</u>'''ncovin (Vincristine) alternating with '''<u>R</u>'''ituximab, '''<u>I</u>'''fosfamide, '''<u>V</u>'''P-16 (Etoposide), '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine), '''<u>M</u>'''esna
+==Cyclophosphamide & TBI, then allo HSCT {{#subobject:a9f7e8|Regimen=1}}==
+Cy/TBI: '''<u>Cy</u>'''clophosphamide & '''<u>T</u>'''otal '''<u>B</u>'''ody '''<u>I</u>'''rradiation
 <div class="toccolours" style="background-color:#eeeeee">
-===Protocol variant #1 {{#subobject:fdf7f7|Variant=1}}===
+===Regimen {{#subobject:6ca28d|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 33%"|Study
+!style="width: 17%"|Study
-!style="width: 33%"|Years of enrollment
+!style="width: 15%"|Years of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 17%"|Comparator
+!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Non-relapse mortality]]
 |-
-|[http://www.tandfonline.com/doi/full/10.3109/10428190903518345 Lossos et al. 2010 (UM-MCL1)]
+|[http://www.bloodjournal.org/content/54/2/468.long Thomas et al. 1979]
-|2004-2013
+|1976-1977
-|style="background-color:#91cf61"|Phase 2
+| style="background-color:#91cf61" |Non-randomized
+| style="background-color:#d3d3d3" |
+| style="background-color:#d3d3d3" |
+| style="background-color:#d3d3d3" |
 |-
-|}
+|[https://doi.org/10.1200/JCO.1994.12.12.2580 Sebban et al. 1994 (LALA 87)]
-<div class="toccolours" style="background-color:#b3e2cd">
+|1986-1991
-====Targeted therapy, all cycles====
+|style="background-color:#1a9851"|Phase 3 (E-esc)
-*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1
+|Chemotherapy or Auto HSCT
-====Chemotherapy, R-MACLO portion (Cycles 1 & 3)====
+|style="background-color:#ffffbf"|Did not meet primary endpoint of OS60
-*[[Doxorubicin (Adriamycin)]] 45 mg/m<sup>2</sup> IV once on day 1
+|style="background-color:#d3d3d3"|
-*[[Cyclophosphamide (Cytoxan)]] 800 mg/m<sup>2</sup> IV once on day 1, then 200 mg/m<sup>2</sup> IV once per day on days 2 to 5
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1 & 8
-*[[Methotrexate (MTX)]] 1200 mg/m<sup>2</sup> IV over 60 minutes once on day 10, then 5520 mg/m<sup>2</sup> IV continuous infusion over 23 hours (total dose per cycle: 6720 mg/m<sup>2</sup>)
-====Supportive therapy, R-MACLO portion (Cycles 1 & 3)====
-*[[Folinic acid (Leucovorin)]] 180 mg/m<sup>2</sup> IV once 12 hours after [[Methotrexate (MTX)]] is complete, then 12 mg/m<sup>2</sup> IV every 6 hours for at least 10 doses or until serum methotrexate level is less than 50 nmol/L
-*[[:Category:Granulocyte_colony-stimulating_factors|G-CSF]] given starting on day 13, continued until ANC greater than 1500/uL for two consecutive days
-'''Next cycle to start after count recovery'''
-====Chemotherapy, R-IVAM portion (Cycles 2 & 4)====
-*[[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV every 12 hours on days 1 & 2 (total dose per cycle: 8000 mg/m<sup>2</sup>)
-*[[Etoposide (Vepesid)]] 60 mg/m<sup>2</sup> IV once per day on days 1 to 5
-*[[Ifosfamide (Ifex)]] 1500 mg/m<sup>2</sup> IV once per day on days 1 to 5
-====Supportive therapy, R-IVAM portion (Cycles 2 & 4)====
-*[[Mesna (Mesnex)]] 360 mg/m<sup>2</sup> IV every 3 hours on days 1 to 5, starting prior to [[Ifosfamide (Ifex)]] (total dose per cycle: 14,400 mg/m<sup>2</sup>)
-*[[:Category:Granulocyte_colony-stimulating_factors|G-CSF]] starting on day 7, continued until ANC greater than 1500/uL for two consecutive days
-'''Next cycle to start after count recovery + 2 weeks'''
-'''Total of 4 cycles'''
-</div>
-<div class="toccolours" style="background-color:#cbd5e7">
-====Subsequent treatment====
-*Patients achieving a CR: [[#Thalidomide_monotherapy|Thalidomide]] maintenance
-</div></div><br>
-<div class="toccolours" style="background-color:#eeeeee">
-===Protocol variant #2 {{#subobject:ee6728|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
-!style="width: 33%"|Study
-!style="width: 33%"|Years of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[http://www.tandfonline.com/doi/full/10.3109/10428190903518345 Lossos et al. 2010 (UM-MCL2)]
+|[https://doi.org/10.1200/jco.2004.10.050 Thomas et al. 2004 (LALA-94)]
-|2004-2013
+|1994-2002
-|style="background-color:#91cf61"|Phase 2
+| style="background-color:#91cf61" |Non-randomized portion of RCT
+| style="background-color:#d3d3d3" |
+| style="background-color:#d3d3d3" |
+| style="background-color:#d3d3d3" |
 |-
 |}
-''Note: The only difference between this protocol and protocol #1 above is the dose of the MTX and the maintenance portion. It is unclear from the text whether the total dose of MTX is reduced to 3000 mg/m<sup>2</sup> or if the 23 hour infusional portion is reduced to 3000 mg/m<sup>2</sup>.''
+{{#lst:Allogeneic HSCT|6ca28d}}
-<div class="toccolours" style="background-color:#b3e2cd">
+====Immunotherapy====
-====Targeted therapy, all cycles====
+*[[Allogeneic stem cells]]
-*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1
+'''Stem cells transfused on day 0'''
-====Chemotherapy, R-MACLO portion (Cycles 1 & 3)====
-*[[Doxorubicin (Adriamycin)]] 45 mg/m<sup>2</sup> IV once on day 1
-*[[Cyclophosphamide (Cytoxan)]] 800 mg/m<sup>2</sup> IV once on day 1, then 200 mg/m<sup>2</sup> IV once per day on days 2 to 5
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1 & 8
-*[[Methotrexate (MTX)]] 1200 mg/m<sup>2</sup> IV over 60 minutes once on day 10, then 3000 mg/m<sup>2</sup> IV continuous infusion over 23 hours (total dose per cycle: 4200 mg/m<sup>2</sup>)
-====Supportive therapy, R-MACLO portion (Cycles 1 & 3)====
-*[[Folinic acid (Leucovorin)]] 180 mg/m<sup>2</sup> IV once 12 hours after [[Methotrexate (MTX)]] is complete, then 12 mg/m<sup>2</sup> IV every 6 hours for at least 10 doses or until serum methotrexate level is less than 50 nmol/L
-*[[:Category:Granulocyte_colony-stimulating_factors|G-CSF]] given starting on day 13, continued until ANC greater than 1500/uL for two consecutive days
-'''Next cycle to start after count recovery'''
-====Chemotherapy, R-IVAM portion (Cycles 2 & 4)====
-*[[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV every 12 hours on days 1 & 2 (total dose per cycle: 8000 mg/m<sup>2</sup>)
-*[[Etoposide (Vepesid)]] 60 mg/m<sup>2</sup> IV once per day on days 1 to 5
-*[[Ifosfamide (Ifex)]] 1500 mg/m<sup>2</sup> IV once per day on days 1 to 5
-====Supportive therapy, R-IVAM portion (Cycles 2 & 4)====
-*[[Mesna (Mesnex)]] 360 mg/m<sup>2</sup> IV every 3 hours on days 1 to 5, starting prior to [[Ifosfamide (Ifex)]] (total dose per cycle: 14,400 mg/m<sup>2</sup>)
-*[[:Category:Granulocyte_colony-stimulating_factors|G-CSF]] starting on day 7, continued until ANC greater than 1500/uL for two consecutive days
-'''Next cycle to start after count recovery + 2 weeks'''
-'''Total of 4 cycles'''
-</div>
-<div class="toccolours" style="background-color:#cbd5e7">
-====Subsequent treatment====
-*Patients achieving a CR: [[#Rituximab_monotherapy|Rituximab]] maintenance
 </div></div>
 ===References===
-# '''UM-MCL1:''' Lossos IS, Hosein PJ, Morgensztern D, Coleman F, Escalón MP, Byrne GE Jr, Rosenblatt JD, Walker GR. High rate and prolonged duration of complete remissions induced by rituximab, methotrexate, doxorubicin, cyclophosphamide, vincristine, ifosfamide, etoposide, cytarabine, and thalidomide (R-MACLO-IVAM-T), a modification of the National Cancer Institute 89-C-41 regimen, in patients with newly diagnosed mantle cell lymphoma. Leuk Lymphoma. 2010 Mar;51(3):406-14. [http://www.tandfonline.com/doi/full/10.3109/10428190903518345 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20038221 PubMed] NCT00450801
+# Thomas ED, Sanders JE, Flournoy N, Johnson FL, Buckner CD, Clift RA, Fefer A, Goodell BW, Storb R, Weiden PL. Marrow transplantation for patients with acute lymphoblastic leukemia in remission. Blood. 1979 Aug;54(2):468-76. [http://www.bloodjournal.org/content/54/2/468.long link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/378292 PubMed]
-## '''Update:''' Hosein PJ, Sandoval-Sus JD, Goodman D, Arteaga AG, Reis I, Hoffman J, Stefanovic A, Rosenblatt JD, Lossos IS. Updated survival analysis of two sequential prospective trials of R-MACLO-IVAM followed by maintenance for newly diagnosed mantle cell lymphoma. Am J Hematol. 2015 Jun;90(6):E111-6. Epub 2015 Apr 2. [https://doi.org/10.1002/ajh.23996 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4439262/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25737247 PubMed]
+# '''LALA 87:''' Sebban C, Lepage E, Vernant JP, Gluckman E, Attal M, Reiffers J, Sutton L, Racadot E, Michallet M, Maraninchi D, Dreyfus F, Fiere D; French Group of Therapy of Adult Acute Lymphoblastic Leukemia. Allogeneic bone marrow transplantation in adult acute lymphoblastic leukemia in first complete remission: a comparative study. J Clin Oncol. 1994 Dec;12(12):2580-7. [https://doi.org/10.1200/JCO.1994.12.12.2580 link to original article] [https://pubmed.ncbi.nlm.nih.gov/7989932 PubMed]
-# '''UM-MCL2:''' Lossos IS, Hosein PJ, Morgensztern D, Coleman F, Escalón MP, Byrne GE Jr, Rosenblatt JD, Walker GR. High rate and prolonged duration of complete remissions induced by rituximab, methotrexate, doxorubicin, cyclophosphamide, vincristine, ifosfamide, etoposide, cytarabine, and thalidomide (R-MACLO-IVAM-T), a modification of the National Cancer Institute 89-C-41 regimen, in patients with newly diagnosed mantle cell lymphoma. Leuk Lymphoma. 2010 Mar;51(3):406-14. [http://www.tandfonline.com/doi/full/10.3109/10428190903518345 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20038221 PubMed] NCT00878254
+## '''Update:''' Thiebaut A, Vernant JP, Degos L, Huguet FR, Reiffers J, Sebban C, Lepage E, Thomas X, Fière D. Adult acute lymphocytic leukemia study testing chemotherapy and autologous and allogeneic transplantation: a follow-up report of the French protocol LALA 87. Hematol Oncol Clin North Am. 2000 Dec;14(6):1353-66. [https://doi.org/10.1016/s0889-8588(05)70190-8 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11147227 PubMed]
-## '''Update:''' Hosein PJ, Sandoval-Sus JD, Goodman D, Arteaga AG, Reis I, Hoffman J, Stefanovic A, Rosenblatt JD, Lossos IS. Updated survival analysis of two sequential prospective trials of R-MACLO-IVAM followed by maintenance for newly diagnosed mantle cell lymphoma. Am J Hematol. 2015 Jun;90(6):E111-6. Epub 2015 Apr 2. [https://doi.org/10.1002/ajh.23996 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4439262/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25737247 PubMed]
+# '''LALA-94:''' Thomas X, Boiron JM, Huguet F, Dombret H, Bradstock K, Vey N, Kovacsovics T, Delannoy A, Fegueux N, Fenaux P, Stamatoullas A, Vernant JP, Tournilhac O, Buzyn A, Reman O, Charrin C, Boucheix C, Gabert J, Lhéritier V, Fiere D. Outcome of treatment in adults with acute lymphoblastic leukemia: analysis of the LALA-94 trial. J Clin Oncol. 2004 Oct 15;22(20):4075-86. Epub 2004 Sep 7. [https://doi.org/10.1200/jco.2004.10.050 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15353542 PubMed] NCT00002700
-==RiPAD+C {{#subobject:438664|Regimen=1}}==
+## '''Update:''' Vey N, Thomas X, Picard C, Kovascovicz T, Charin C, Cayuela JM, Dombret H, Dastugue N, Huguet F, Bastard C, Stamatoulas A, Giollant M, Tournilhac O, Macintyre E, Buzyn A, Bories D, Kuentz M, Dreyfus F, Delannoy A, Raynaud S, Gratecos N, Bordessoule D, de Botton S, Preudhomme C, Reman O, Troussard X, Pigneux A, Bilhou C, Vernant JP, Boucheix C, Gabert J; GET-LALA Group the Swiss Group for Clinical Cancer Research (SAKK). Allogeneic stem cell transplantation improves the outcome of adults with t(1;19)/E2A-PBX1 and t(4;11)/MLL-AF4 positive B-cell acute lymphoblastic leukemia: results of the prospective multicenter LALA-94 study. Leukemia. 2006 Dec;20(12):2155-61. Epub 2006 Oct 12. [https://doi.org/10.1038/sj.leu.2404420 link to original article] [https://pubmed.ncbi.nlm.nih.gov/17039234 PubMed]
-RiPAD+C: '''<u>Ri</u>'''tuximab, '''<u>P</u>'''S-341 (Bortezomib), '''<u>A</u>'''driamycin (Doxorubicin), '''<u>D</u>'''examethasone, '''<u>C</u>'''hlorambucil
+==Etoposide & TBI, then allo HSCT {{#subobject:b389e1|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:c36f20|Variant=1}}===
+===Regimen {{#subobject:e4216b|Variant=1}}===
-{| class="wikitable" style="width: 60%; text-align:center;"
+{| class="wikitable" style="width: 40%; text-align:center;"
-!style="width: 33%"|Study
+!style="width: 25%"|Study
-!style="width: 33%"|Years of enrollment
+!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://doi.org/10.1093/annonc/mdr450 Houot et al. 2011 (ManteauRiBVD)]
+|[http://www.bloodjournal.org/content/106/12/3760.long Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)]
-|2007-2008
+| style="background-color:#91cf61" |Non-randomized portion of RCT
-|style="background-color:#91cf61"|Phase 2
 |-
 |}
-<div class="toccolours" style="background-color:#b3e2cd">
+{{#lst:Allogeneic HSCT|e4216b}}
-====Targeted therapy====
+====Immunotherapy====
-*[[Rituximab (Rituxan)]] as follows:
+*[[Allogeneic stem cells]]
-**Cycle 1: 375 mg/m<sup>2</sup> IV once per day on days 1 & 8
+'''Stem cells transfused on day 0'''
-**Cycle 2 onwards: 375 mg/m<sup>2</sup> IV once on day 1
-*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> (route not specified) once per day on days 1, 4, 8, 11
-====Chemotherapy====
-*[[Doxorubicin (Adriamycin)]] 9 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 36 mg/m<sup>2</sup>)
-*[[Chlorambucil (Leukeran)]] 12 mg PO once per day on days 20 to 29
-====Glucocorticoid therapy====
-*[[Dexamethasone (Decadron)]] 20 mg (route not specified) twice per day on days 1 to 4
-'''35-day cycle for up to 6 cycles'''
 </div></div>
 ===References===
-# '''ManteauRiBVD:''' Houot R, Le Gouill S, Ojeda Uribe M, Mounier C, Courby S, Dartigeas C, Bouabdallah K, Alexis Vigier M, Moles MP, Tournilhac O, Arakelyan N, Rodon P, El Yamani A, Sutton L, Fornecker L, Assouline D, Harousseau JL, Maisonneuve H, Caulet-Maugendre S, Gressin R; GOELAMS. Combination of rituximab, bortezomib, doxorubicin, dexamethasone and chlorambucil (RiPAD+C) as first-line therapy for elderly mantle cell lymphoma patients: results of a phase II trial from the GOELAMS. Ann Oncol. 2012 Jun;23(6):1555-61. Epub 2011 Oct 19. [https://doi.org/10.1093/annonc/mdr450 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22012966 PubMed] NCT00740415
+# '''MRC UKALL XII/ECOG E2993:''' Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. [http://www.bloodjournal.org/content/106/12/3760.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16105981 PubMed] NCT00002514
-==R-VAD+C {{#subobject:456435|Regimen=1}}==
+## '''Update:''' Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, Burnett AK, Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J, McMillan A, Franklin IM, Luger S, Ciobanu N, Rowe JM. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008 Feb 15;111(4):1827-33. Epub 2007 Nov 29. [http://www.bloodjournal.org/content/111/4/1827.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/18048644 PubMed]
-R-VAD+C: '''<u>R</u>'''ituximab, '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>D</u>'''examethasone, '''<u>C</u>'''hlorambucil
+## '''Update:''' Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, Marks DI, McMillan AK, Litzow MR, Lazarus HM, Foroni L, Dewald G, Franklin IM, Luger SM, Paietta E, Wiernik PH, Tallman MS, Goldstone AH. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009 May 7;113(19):4489-96. Epub 2009 Feb 24. [http://www.bloodjournal.org/content/113/19/4489.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4188540/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19244158 PubMed]
+## '''Update:''' Fielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow MR, Lazarus H, Luger SM, Marks DI, McMillan AK, Moorman AV, Patel B, Paietta E, Tallman MS, Goldstone AH. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014 Feb 6;123(6):843-50. Epub 2013 Nov 25. [http://www.bloodjournal.org/content/123/6/843.full link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3916877/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24277073 PubMed]
+==International ALL Trial {{#subobject:a1cf91|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:332e75|Variant=1}}===
+===Protocol {{#subobject:1d1710|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 33%"|Study
+!style="width: 20%"|Study
-!style="width: 33%"|Years of enrollment
+!style="width: 20%"|Years of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2913084/ Gressin et al. 2010 (GOELAMS LM2001)]
+|[http://www.bloodjournal.org/content/106/12/3760.long Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)]
-|2003-2005
+|1993-2003
-|style="background-color:#91cf61"|Phase 2
+|style="background-color:#1a9851"|Phase 3 (C)
+|[[Transplant_conditioning_regimens#Etoposide_.26_TBI|Etoposide & TBI, then auto HSCT]]
+|style="background-color:#91cf60"|Seems to have superior OS
 |-
 |}
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*[[#L-Asparaginase_.26_Methotrexate|L-asparaginase & Methotrexate intensification]]
+</div>
 <div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
+====Chemotherapy, Cycle 1====
-*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1
+*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> IV once per day on days 1 to 5
-====Chemotherapy====
+*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5
-*[[Vincristine (Oncovin)]] 0.4 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 1.6 mg/m<sup>2</sup>)
+*[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
-*[[Doxorubicin (Adriamycin)]] 9 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 36 mg/m<sup>2</sup>)
-*[[Chlorambucil (Leukeran)]] 12 mg PO once per day on days 20 to 29
 ====Glucocorticoid therapy====
-*[[Dexamethasone (Decadron)]] 20 mg IV or PO twice per day on days 1 to 4
+*[[Dexamethasone (Decadron)]] 10 mg/m<sup>2</sup> PO once per day on days 1 to 28
-'''35-day cycle for 4 to 8 cycles'''
+'''4-week course, followed by:'''
+====Chemotherapy, Cycle 2====
+*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> IV once per day on days 1 to 5
+*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5
+'''4-week course, followed by:'''
+====Chemotherapy, Cycle 3====
+*[[Daunorubicin (Cerubidine)]] 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
+*[[Cyclophosphamide (Cytoxan)]] 650 mg/m<sup>2</sup> IV once on day 29
+*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> IV once per day on days 31 to 34, 38 to 41
+*[[Thioguanine (Tabloid)]] 60 mg/m<sup>2</sup> PO once per day on days 29 to 42
+'''8-week course, followed by:'''
+====Chemotherapy, Cycle 4====
+*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> IV once per day on days 1 to 5
+*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5
+====CNS therapy, prophylaxis====
+*[[Cytarabine (Ara-C)]] 50 mg IT once per week for 4 weeks, then once per quarter for 4 doses
+*[[External_beam_radiotherapy|Whole-brain irradiation]] to 2400 cGy
 </div>
 <div class="toccolours" style="background-color:#cbd5e7">
 ====Subsequent treatment====
-*Transplant-eligible patients with more than partial response after 4 cycles: [[#Melphalan_.26_TBI.2C_then_auto_HSCT|High-dose melphalan & TBI, then autologous HSCT]] 4 weeks after the 6th cycle
+*[[#POMP|POMP]] maintenance
 </div></div>
 ===References===
-# '''GOELAMS LM2001:''' Gressin R, Caulet-Maugendre S, Deconinck E, Tournilhac O, Gyan E, Moles MP, El Yamani A, Cornillon J, Rossi JF, Le Gouill S, Lepeu G, Damaj G, Celigny PS, Maisonneuve H, Corront B, Vilque JP, Casassus P, Lamy T, Colonna M, Colombat P; GOELAMS. Evaluation of the (R)VAD+C regimen for the treatment of newly diagnosed mantle cell lymphoma: combined results of two prospective phase II trials from the French GOELAMS Group. Haematologica. 2010 Aug;95(8):1350-7. Epub 2010 Mar 10. [http://www.haematologica.org/content/95/8/1350.full link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2913084/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20220059 PubMed] NCT00285389
+# '''MRC UKALL XII/ECOG E2993:''' Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. [http://www.bloodjournal.org/content/106/12/3760.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16105981 PubMed] NCT00002514
-==VcR-CVAD {{#subobject:2494f3|Regimen=1}}==
+## '''Update:''' Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, Burnett AK, Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J, McMillan A, Franklin IM, Luger S, Ciobanu N, Rowe JM. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008 Feb 15;111(4):1827-33. Epub 2007 Nov 29. [http://www.bloodjournal.org/content/111/4/1827.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/18048644 PubMed]
-VcR-CVAD: '''<u>V</u>'''el'''<u>c</u>'''ade (Bortezomib), '''<u>R</u>'''ituximab, '''<u>C</u>'''yclophosphamide, '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>D</u>'''examethasone
+## '''Update:''' Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, Marks DI, McMillan AK, Litzow MR, Lazarus HM, Foroni L, Dewald G, Franklin IM, Luger SM, Paietta E, Wiernik PH, Tallman MS, Goldstone AH. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009 May 7;113(19):4489-96. Epub 2009 Feb 24. [http://www.bloodjournal.org/content/113/19/4489.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4188540/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19244158 PubMed]
+## '''Update:''' Fielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow MR, Lazarus H, Luger SM, Marks DI, McMillan AK, Moorman AV, Patel B, Paietta E, Tallman MS, Goldstone AH. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014 Feb 6;123(6):843-50. Epub 2013 Nov 25. [http://www.bloodjournal.org/content/123/6/843.full link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3916877/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24277073 PubMed]
+==Mercaptopurine, Methotrexate, Vincristine {{#subobject:72025a|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:bb2a6e|Variant=1}}===
+===Regimen {{#subobject:b9e09c|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 33%"|Study
+!style="width: 20%"|Study
-!style="width: 33%"|Years of enrollment
+!style="width: 20%"|Years of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3188692/ Chang et al. 2011]
+|[https://www.nature.com/articles/leu2017283 Sakura et al. 2017 (JALSG ALL202-O)]
-|2005-2008
+|2002-2011
-|style="background-color:#91cf61"|Phase 2
+| style="background-color:#1a9851" |Phase 3 (E-esc)
-|-
+|[[#Mercaptopurine.2C_Methotrexate.2C_Vincristine_88|MTX, 6-MP, Vincristine]]; intermediate-dose MTX
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3954048/ Chang et al. 2014 (ECOG E1405)]
+| style="background-color:#91cf60" |Seems to have superior DFS
-|2007-NR
-|style="background-color:#91cf61"|Phase 2
 |-
 |}
+''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment. Given as cycles 2 and 5 of consolidation for patients younger than 50.''
 <div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
-*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1 & 4
-*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1
 ====Chemotherapy====
-*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> IV over 3 hours every 12 hours on days 1 to 3 (total dose per cycle: 1800 mg/m<sup>2</sup>)
+*[[Mercaptopurine (6-MP)]] 25 mg/m<sup>2</sup> PO once per day on days 1 to 21
-*[[Vincristine (Oncovin)]] 1 mg IV once on day 3
+*[[Methotrexate (MTX)]] 3000 mg/m<sup>2</sup> IV once per day on days 1 & 15
-*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 100 mg/m<sup>2</sup>)
+*[[Vincristine (Oncovin)]] 1.3 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1 & 15
-====Glucocorticoid therapy====
+====CNS therapy====
-*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4
+*[[Methotrexate (MTX)]] 15 mg IT once per day on days 1 & 15
+*[[Dexamethasone (Decadron)]] 4 mg IT once per day on days 1 & 15
 ====Supportive therapy====
-*[[Mesna (Mesnex)]] dose not specified Chang et al. 2011; not mentioned in Chang et al. 2014
+*[[Folinic acid (Leucovorin)]] 50 mg IV once, then 15 mg IV every 6 hours for a total of 8 doses, beginning 36 h after the '''start''' of [[Methotrexate (MTX)]] infusion
-*Growth factor support with one of the following:
-**[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, started on day 5 or 6 and continued until absolute neutrophil count was at least 2000/uL past nadir
-**[[Pegfilgrastim (Neulasta)]] 6 mg SC once on day 5 or 6
-'''21-day cycle for 6 cycles'''
-</div>
-<div class="toccolours" style="background-color:#cbd5e7">
-====Subsequent treatment====
-*ECOG E1405, at least PR: [[#Rituximab_monotherapy|Rituximab]] maintenance or [[Regimen_classes#High-dose_chemotherapy_with_auto_HSCT|high-dose therapy with autologous HSCT (regimen not specified)]], patient choice
 </div></div>
 ===References===
-# Chang JE, Peterson C, Choi S, Eickhoff JC, Kim K, Yang DT, Gilbert LA, Rogers ES, Werndli JE, Huie MS, McFarland TA, Volk M, Blank J, Callander NS, Longo WL, Kahl BS; Wisconsin Oncology Network. VcR-CVAD induction chemotherapy followed by maintenance rituximab in mantle cell lymphoma: a Wisconsin Oncology Network study. Br J Haematol. 2011 Oct;155(2):190-7. Epub 2011 Aug 16. [https://doi.org/10.1111/j.1365-2141.2011.08820.x link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3188692/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21848883 PubMed]
+# '''JALSG ALL202-O:''' Sakura T, Hayakawa F, Sugiura I, Murayama T, Imai K, Usui N, Fujisawa S, Yamauchi T, Yujiri T, Kakihana K, Ito Y, Kanamori H, Ueda Y, Miyata Y, Kurokawa M, Asou N, Ohnishi K, Ohtake S, Kobayashi Y, Matsuo K, Kiyoi H, Miyazaki Y, Naoe T. High-dose methotrexate therapy significantly improved survival of adult acute lymphoblastic leukemia: a phase III study by JALSG. Leukemia. 2018 Mar;32(3):626-632. Epub 2017 Sep 15.[https://www.nature.com/articles/leu2017283 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28914260 PubMed] UMIN C000000063
-# '''ECOG E1405:''' Chang JE, Li H, Smith MR, Gascoyne RD, Paietta EM, Yang DT, Advani RH, Horning SJ, Kahl BS. Phase 2 study of VcR-CVAD with maintenance rituximab for untreated mantle cell lymphoma: an Eastern Cooperative Oncology Group study (E1405). Blood. 2014 Mar 13;123(11):1665-73. Epub 2014 Jan 23. [http://www.bloodjournal.org/content/123/11/1665.full link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3954048/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24458437 PubMed] NCT00433537
+==Linker regimen (consolidation) {{#subobject:3a5313|Regimen=1}}==
-==VR-CHOP {{#subobject:f5739b|Regimen=1}}==
-VR-CHOP: '''<u>V</u>'''elcade (Bortezomib), '''<u>R</u>'''ituximab, '''<u>C</u>'''yclophosphamide, '''<u>H</u>'''ydroxydaunorubicin (Doxorubicin), '''<u>O</u>'''ncovin (Vincristine), '''<u>P</u>'''redniso(lo)ne
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:e54ea1|Variant=1}}===
+===Protocol {{#subobject:33e7c0|Variant=1}}===
 {| class="wikitable sortable" style="width: 60%; text-align:center;"
 !style="width: 33%"|Study
@@ Line 1,327: / Line 1,278: @@
 !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://doi.org/10.1200/jco.2010.31.1142 Ruan et al. 2010 (Cornell 0309006313)]
+|[https://doi.org/10.1182/blood.V69.4.1242.1242 Linker et al. 1987]
-|2004-2007
+|1980-1986
-|style="background-color:#91cf61"|Phase 2
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4710555/ Till et al. 2015 (SWOG S0601)]
-|2006-2008
 |style="background-color:#91cf61"|Phase 2
 |-
 |}
-''Note: Doses here are the phase II dose of bortezomib and the R-CHOP protocol as specified in the phase I report by Furman et al. 2010''
+''Each cycle is approximately one month, based on recovery of ANC to greater than 1000/uL and platelet count to greater than 100 x 10<sup>9</sup>/L.''
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*[[#DOLP|DOLP]] induction
+</div>
 <div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
+====Chemotherapy, Treatment A (cycles 1, 3, 5, 7)====
-*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1 & 4, '''given first on day 1'''
+*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV once per day on days 1 & 2
-*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1
+*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 1 & 8
-====Chemotherapy====
+*[[Asparaginase (Elspar)]] 12,000 units/m<sup>2</sup> IM once per day on days 2, 4, 7, 9, 11, 14
-*[[Cyclophosphamide (Cytoxan)]] 750 mg/m<sup>2</sup> IV once on day 1
+====Glucocorticoid therapy====
-*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV once on day 1
+*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 14
-*[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1
+'''Approximately one-month cycle'''
+====Chemotherapy, Treatment B (cycles 2, 4, 6, 8)====
+*[[Teniposide (Vumon)]] 165 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
+*[[Cytarabine (Ara-C)]] 300 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
+'''Approximately one-month cycle'''
+====Chemotherapy, Treatment C (cycle 9)====
+*[[Methotrexate (MTX)]] 690 mg/m<sup>2</sup> IV continuous infusion over 42 hours, started on day 1
+*[[Asparaginase (Elspar)]] 12,000 units/m<sup>2</sup> IM once per day on days 2, 4, 7, 9, 11, 14
 ====Glucocorticoid therapy====
-*[[Prednisone (Sterapred)]] 100 mg PO once per day on days 1 to 5
+*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 14
+'''Approximately one-month cycle'''
 ====Supportive therapy====
-*[[Acetaminophen (Tylenol)]] (dose/route not specified) once on day 1, prior to [[Rituximab (Rituxan)]]
+*[[Folinic acid (Leucovorin)]] 15 mg/m<sup>2</sup> IV every 6 hours on days 3 to 5, starting after [[Methotrexate (MTX)]] is complete (at 42 hours)
-*[[Diphenhydramine (Benadryl)]] (dose/route not specified) once on day 1, prior to [[Rituximab (Rituxan)]]
-'''21-day cycle for 6 cycles'''
 </div>
 <div class="toccolours" style="background-color:#cbd5e7">
 ====Subsequent treatment====
-*SWOG S0601: [[#Bortezomib_monotherapy|Bortezomib]] maintenance
+*[[#Mercaptopurine_.26_Methotrexate_2|6-MP & MTX]] maintenance
 </div></div>
 ===References===
-# '''Cornell 0309006313:''' Ruan J, Martin P, Furman RR, Lee SM, Cheung K, Vose JM, Lacasce A, Morrison J, Elstrom R, Ely S, Chadburn A, Cesarman E, Coleman M, Leonard JP. Bortezomib plus CHOP-rituximab for previously untreated diffuse large B-cell lymphoma and mantle cell lymphoma. J Clin Oncol. 2011 Feb 20;29(6):690-7. Epub 2010 Dec 28. [https://doi.org/10.1200/jco.2010.31.1142 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21189393 PubMed] NCT00151320
+# Linker CA, Levitt LJ, O'Donnell M, Ries CA, Link MP, Forman SJ, Farbstein MJ. Improved results of treatment of adult acute lymphoblastic leukemia. Blood. 1987 Apr;69(4):1242-8. [https://doi.org/10.1182/blood.V69.4.1242.1242 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/3470055 PubMed] content property of [http://hemonc.org HemOnc.org]
-# '''SWOG S0601:''' Till BG, Li H, Bernstein SH, Fisher RI, Burack WR, Rimsza LM, Floyd JD, DaSilva MA, Moore DF Jr, Pozdnyakova O, Smith SM, LeBlanc M, Friedberg JW. Phase II trial of R-CHOP plus bortezomib induction therapy followed by bortezomib maintenance for newly diagnosed mantle cell lymphoma: SWOG S0601. Br J Haematol. 2016 Jan;172(2):208-18. Epub 2015 Oct 22. [https://doi.org/10.1111/bjh.13818 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4710555/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26492567 PubMed] NCT00376961
+## '''Update:''' Linker CA, Levitt LJ, O'Donnell M, Forman SJ, Ries CA. Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report. Blood. 1991 Dec 1;78(11):2814-22. [http://www.bloodjournal.org/content/78/11/2814.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/1835410 PubMed]
-=Consolidation after first-line therapy=
+==Pediatric-like GRAALL consolidation {{#subobject:32d4f7|Regimen=1}}==
-==BEAC, then auto HSCT {{#subobject:0341c3|Regimen=1}}==
-BEAC: '''<u>R</u>'''ituximab, '''<u>B</u>'''iCNU (Carmustine), '''<u>E</u>'''toposide, '''<u>A</u>'''ra-C (Cytarabine), '''<u>C</u>'''yclophosphamide
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:760828|Variant=1}}===
+===Protocol {{#subobject:5fe62b|Variant=1}}===
 {| class="wikitable sortable" style="width: 60%; text-align:center;"
 !style="width: 33%"|Study
@@ Line 1,369: / Line 1,324: @@
 !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2556606/ Geisler et al. 2008 (NLG MCL2)]
+|[https://doi.org/10.1200/JCO.2008.18.6916 Huguet et al. 2009 (GRAALL-2003)]
-|2000-2006
+|2003-2005
 |style="background-color:#91cf61"|Phase 2
 |-
 |}
+''Note: the original article Table 1 has several errors which were corrected in the erratum and the online Table 1. These corrected doses are replicated here. Also note that each consolidation "block" flows into the next A->B->C and days are scheduled thusly.
 <div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
-*[[#maxi-R-CHOP.2FR-HiDAC|maxi-R-CHOP/R-HiDAC]] x 6 to 8
+*[[#Cyclophosphamide.2C_Daunorubicin.2C_L-Asparaginase.2C_Vincristine.2C_Prednisone|Cyclophosphamide, Daunorubicin, L-asparaginase, Vincristine, Prednisone]] induction or [[#Cytarabine_.26_Idarubicin_2|Cytarabine & Idarubicin]] salvage
-{{#lst:Autologous HSCT conditioning regimens|1a6845}}
+</div>
-'''Stem cells reinfused after chemotherapy, unclear exactly which day'''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy, Consolidation A (Cycles 1, 4, 7)====
+*[[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV every 12 hours on days 1 & 2
+*[[Asparaginase (Elspar)]] 10,000 units/m<sup>2</sup> (route not specified) once on day 3
+====Glucocorticoid therapy====
+*[[Dexamethasone (Decadron)]] 10 mg (route not specified) every 12 hours on days 1 & 2
+====Supportive therapy====
+*[[Lenograstim (Granocyte)]] 150 mcg/m<sup>2</sup> SC once per day on days 7 to 13
+====Chemotherapy, Consolidation B (Cycles 2, 5, 8)====
+*[[Methotrexate (MTX)]] 3000 mg/m<sup>2</sup> IV continuous infusion (duration not specified), started on day 15
+*[[Vincristine (Oncovin)]] 2 mg IV once on day 15
+*[[Asparaginase (Elspar)]] 10,000 units/m<sup>2</sup> (route not specified) once on day 16
+*[[Mercaptopurine (6-MP)]] 60 mg/m<sup>2</sup> PO once per day on days 15 to 21
+====Supportive therapy====
+*[[Lenograstim (Granocyte)]] 150 mcg/m<sup>2</sup> SC once per day on days 22 to 27
+====Chemotherapy, Consolidation C (Cycles 3, 6, 9)====
+*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once per day on days 29 & 30
+*[[Etoposide (Vepesid)]] 75 mg/m<sup>2</sup> IV once per day on days 29 & 30
+*[[Methotrexate (MTX)]] 25 mg/m<sup>2</sup> (route not specified) once on day 29
+====Supportive therapy====
+*[[Lenograstim (Granocyte)]] 150 mcg/m<sup>2</sup> SC once per day from day 31 until myeloid recovery
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*Patients with CR after induction: [[#Cyclophosphamide.2C_Daunorubicin.2C_L-Asparaginase.2C_Vincristine.2C_Prednisone_2|Cyclophosphamide, daunorubicin, L-asparaginase, vincristine, prednisone late intensification]] between cycles 6 and 7
+*Patients with CR after salvage: [[#Cytarabine_.26_Idarubicin|Cytarabine & idarubicin late intensification]] between cycles 6 and 7
+*All patients: [[#POMP|POMP]] maintenance after completion of consolidation
 </div></div>
 ===References===
-# '''NLG MCL2:''' Geisler CH, Kolstad A, Laurell A, Andersen NS, Pedersen LB, Jerkeman M, Eriksson M, Nordström M, Kimby E, Boesen AM, Kuittinen O, Lauritzsen GF, Nilsson-Ehle H, Ralfkiaer E, Akerman M, Ehinger M, Sundström C, Langholm R, Delabie J, Karjalainen-Lindsberg ML, Brown P, Elonen E; Nordic Lymphoma Group. Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo-purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group. Blood. 2008 Oct 1;112(7):2687-93. Epub 2008 Jul 14. [http://www.bloodjournal.org/content/112/7/2687.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2556606/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18625886 PubMed] ISRCTN87866680
+# '''GRAALL-2003:''' Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. [https://doi.org/10.1200/JCO.2008.18.6916 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19124805 PubMed] NCT00222027
-## '''Update:''' Geisler CH, Kolstad A, Laurell A, Jerkeman M, Räty R, Andersen NS, Pedersen LB, Eriksson M, Nordström M, Kimby E, Bentzen H, Kuittinen O, Lauritzsen GF, Nilsson-Ehle H, Ralfkiaer E, Ehinger M, Sundström C, Delabie J, Karjalainen-Lindsberg ML, Brown P, Elonen E; Nordic Lymphoma Group. Nordic MCL2 trial update: six-year follow-up after intensive immunochemotherapy for untreated mantle cell lymphoma followed by BEAM or BEAC + autologous stem-cell support: still very long survival but late relapses do occur. Br J Haematol. 2012 Aug;158(3):355-62. Epub 2012 May 29. Erratum in: Br J Haematol. 2012 Sep;158(6):815-6. [https://doi.org/10.1111/j.1365-2141.2012.09174.x link to original article] [https://pubmed.ncbi.nlm.nih.gov/22640180 PubMed]
+=Interim maintenance=
-## '''Update:''' Eskelund CW, Kolstad A, Jerkeman M, Räty R, Laurell A, Eloranta S, Smedby KE, Husby S, Pedersen LB, Andersen NS, Eriksson M, Kimby E, Bentzen H, Kuittinen O, Lauritzsen GF, Nilsson-Ehle H, Ralfkiaer E, Ehinger M, Sundström C, Delabie J, Karjalainen-Lindsberg ML, Workman CT, Garde C, Elonen E, Brown P, Grønbaek K, Geisler CH. 15-year follow-up of the Second Nordic Mantle Cell Lymphoma trial (MCL2): prolonged remissions without survival plateau. Br J Haematol. 2016 Nov;175(3):410-418. Epub 2016 Jul 5. [https://doi.org/10.1111/bjh.14241 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27378674 PubMed]
+==Mercaptopurine, Methotrexate, WB-XRT {{#subobject:64a822|Regimen=1}}==
-==BEAM, then auto HSCT {{#subobject:ed61ad|Regimen=1}}==
-BEAM: '''<u>R</u>'''ituximab, '''<u>B</u>'''iCNU (Carmustine), '''<u>E</u>'''toposide, '''<u>A</u>'''ra-C (Cytarabine), '''<u>M</u>'''elphalan
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #1 {{#subobject:9fff3a|Variant=1}}===
+===Regimen {{#subobject:4011bd|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
+{| class="wikitable" style="width: 40%; text-align:center;"
-!style="width: 33%"|Study
+!style="width: 25%"|Study
-!style="width: 33%"|Years of enrollment
+!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2556606/ Geisler et al. 2008 (NLG MCL2)]
+|[http://www.bloodjournal.org/content/85/8/2025.full Larson et al. 1995 (CALGB 8811)]
-|2000-2006
 |style="background-color:#91cf61"|Phase 2
 |-
 |}
 <div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*[[#CALGB_8811_early_intensification|Larson regimen (CALGB 8811) early intensification ("Course II")]]
 </div>
 <div class="toccolours" style="background-color:#b3e2cd">
-====Preceding treatment====
+====Chemotherapy, ("Course III")====
-*[[#maxi-R-CHOP.2FR-HiDAC|maxi-R-CHOP/R-HiDAC]] x 6 to 8
+*[[Mercaptopurine (6-MP)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 70
-{{#lst:Autologous HSCT|2821aa}}
+*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> PO once per day on days 36, 43, 50, 57, 64
-'''Stem cells re-infused after chemotherapy, unclear exactly which day'''
+====Radiotherapy====
-</div></div><br>
+*[[External_beam_radiotherapy|Cranial radiation]], 24 Gy total given in 10 fractions from days 1 to 12
-<div class="toccolours" style="background-color:#eeeeee">
+====CNS therapy, prophylaxis====
-===Regimen variant #2 {{#subobject:970002|Variant=1}}===
+*[[Methotrexate (MTX)]] 15 mg IT once per day on days 1, 8, 15, 22, 29
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
+'''12-week course'''
-!style="width: 33%"|Study
-!style="width: 33%"|Years of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://doi.org/10.1111/j.1365-2141.2008.07498.x Van 't Veer et al. 2008 (HOVON 45)]
-|2002-2005
-|style="background-color:#91cf61"|Phase 2
-|-
-|}
-<div class="toccolours" style="background-color:#cbd5e8">
 </div>
-<div class="toccolours" style="background-color:#b3e2cd">
+<div class="toccolours" style="background-color:#cbd5e7">
-====Preceding treatment====
+====Subsequent treatment====
-*[[#R-CHOP|R-CHOP]] x 3, then [[#R-HiDAC|R-HiDAC]] x 1
+*[[#CALGB_8811_late_intensification|Larson regimen (CALGB 8811) late intensification ("Course IV")]]
-{{#lst:Autologous HSCT|f28f87}}
-'''Stem cells re-infused on day 0'''
 </div></div>
 ===References===
-# '''NLG MCL2:''' Geisler CH, Kolstad A, Laurell A, Andersen NS, Pedersen LB, Jerkeman M, Eriksson M, Nordström M, Kimby E, Boesen AM, Kuittinen O, Lauritzsen GF, Nilsson-Ehle H, Ralfkiaer E, Akerman M, Ehinger M, Sundström C, Langholm R, Delabie J, Karjalainen-Lindsberg ML, Brown P, Elonen E; Nordic Lymphoma Group. Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo-purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group. Blood. 2008 Oct 1;112(7):2687-93. Epub 2008 Jul 14. [http://www.bloodjournal.org/content/112/7/2687.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2556606/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18625886 PubMed] ISRCTN87866680
+# '''CALGB 8811:''' Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR, Hooberman AL, Westbrook CA, Arthur DC, George SL, Bloomfield CD, Schiffer CA. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: Cancer and Leukemia Group B study 8811. Blood. 1995 Apr 15;85(8):2025-37. [http://www.bloodjournal.org/content/85/8/2025.full.pdf+html link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/7718875 PubMed]
-## '''Update:''' Geisler CH, Kolstad A, Laurell A, Jerkeman M, Räty R, Andersen NS, Pedersen LB, Eriksson M, Nordström M, Kimby E, Bentzen H, Kuittinen O, Lauritzsen GF, Nilsson-Ehle H, Ralfkiaer E, Ehinger M, Sundström C, Delabie J, Karjalainen-Lindsberg ML, Brown P, Elonen E; Nordic Lymphoma Group. Nordic MCL2 trial update: six-year follow-up after intensive immunochemotherapy for untreated mantle cell lymphoma followed by BEAM or BEAC + autologous stem-cell support: still very long survival but late relapses do occur. Br J Haematol. 2012 Aug;158(3):355-62. Epub 2012 May 29. Erratum in: Br J Haematol. 2012 Sep;158(6):815-6. [https://doi.org/10.1111/j.1365-2141.2012.09174.x link to original article] [https://pubmed.ncbi.nlm.nih.gov/22640180 PubMed]
+==Methotrexate & Pegaspargase {{#subobject:0c25ba|Regimen=1}}==
-## '''Update:''' Eskelund CW, Kolstad A, Jerkeman M, Räty R, Laurell A, Eloranta S, Smedby KE, Husby S, Pedersen LB, Andersen NS, Eriksson M, Kimby E, Bentzen H, Kuittinen O, Lauritzsen GF, Nilsson-Ehle H, Ralfkiaer E, Ehinger M, Sundström C, Delabie J, Karjalainen-Lindsberg ML, Workman CT, Garde C, Elonen E, Brown P, Grønbaek K, Geisler CH. 15-year follow-up of the Second Nordic Mantle Cell Lymphoma trial (MCL2): prolonged remissions without survival plateau. Br J Haematol. 2016 Nov;175(3):410-418. Epub 2016 Jul 5. [https://doi.org/10.1111/bjh.14241 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27378674 PubMed]
-# '''HOVON 45:''' Van 't Veer MB, de Jong D, MacKenzie M, Kluin-Nelemans HC, van Oers MH, Zijlstra J, Hagenbeek A, van Putten WL. High-dose Ara-C and BEAM with autograft rescue in R-CHOP responsive mantle cell lymphoma patients. Br J Haematol. 2009 Feb;144(4):524-30. Epub 2008 Nov 26. [https://doi.org/10.1111/j.1365-2141.2008.07498.x link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19036081 PubMed]
-# '''SWOG S1106:''' Chen RW, Li H, Bernstein SH, Kahwash S, Rimsza LM, Forman SJ, Constine L, Shea TC, Cashen AF, Blum KA, Fenske TS, Barr PM, Phillips T, Leblanc M, Fisher RI, Cheson BD, Smith SM, Faham M, Wilkins J, Leonard JP, Kahl BS, Friedberg JW. RB but not R-HCVAD is a feasible induction regimen prior to auto-HCT in frontline MCL: results of SWOG Study S1106. Br J Haematol. 2017 Mar;176(5):759-769. Epub 2016 Dec 19. [https://doi.org/full/10.1111/bjh.14480 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5318240/ link to PMC article] '''does not contain dosing details''' [https://pubmed.ncbi.nlm.nih.gov/27992063 PubMed] NCT01412879
-## '''Update:''' Kamdar M, Li H, Chen RW, Rimsza LM, Leblanc ML, Fenske TS, Shea TC, Barr PM, Phillips TJ, Leonard JP, Kahl BS, Friedberg JW, Smith SM. Five-year outcomes of the S1106 study of R-hyper-CVAD vs R-bendamustine in transplant-eligible patients with mantle cell lymphoma. Blood Adv. 2019 Oct 22;3(20):3132-3135. [https://ashpublications.org/bloodadvances/article/3/20/3132/422496/Fiveyear-outcomes-of-the-S1106-study-of-RhyperCVAD link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849956/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31648328 PubMed]
-==CBV, then auto HSCT {{#subobject:292784|Regimen=1}}==
-CBV: '''<u>C</u>'''yclophosphamide, '''<u>B</u>'''iCNU (Carmustine), '''<u>V</u>'''P-16 (Etoposide)
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:55f221|Variant=1}}===
+===Regimen {{#subobject:5acj9e|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
+{| class="wikitable" style="width: 40%; text-align:center;"
-!style="width: 33%"|Study
+!style="width: 25%"|Study
-!style="width: 33%"|Years of enrollment
+!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2793032/ Damon et al. 2009 (CALGB 59909)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6450431/ Stock et al. 2019 (CALGB 10403)]
-|2001-2004
+| style="background-color:#91cf61" |Non-randomized
-|style="background-color:#91cf61"|Phase 2
 |-
 |}
-''Note: this is the transplant portion ("Treatment 4") of CALGB 59909.''
+''Note: the instructions for dose escalation of MTX in the manuscript are confusing; the authors have been contacted for clarification.''
 <div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*[[#AALL0232_consolidation|AALL0232 consolidation ("Course II")]]
 </div>
 <div class="toccolours" style="background-color:#b3e2cd">
-====Preceding treatment====
+====Chemotherapy====
-*[[Stem_cell_mobilization#EAR_.26_G-CSF|EAR & stem cell mobilization]]
+*[[Methotrexate (MTX)]] 100 mg/m<sup>2</sup> IV once on day 1, then 150 mg/m<sup>2</sup> IV once on day 11, then 200 mg/m<sup>2</sup> IV once on day 21, then 250 mg/m<sup>2</sup> IV once on day 31, then 300 mg/m<sup>2</sup> IV once on day 41
-{{#lst:Autologous HSCT conditioning regimens|35a696}}
+*[[Pegaspargase (Oncaspar)]] 2500 units IM or IV once per day on days 2 & 22
+====CNS therapy, prophylaxis====
+*[[Methotrexate (MTX)]] 15 mg IT once per day on days 1 & 31
+'''42-day course'''
 </div>
 <div class="toccolours" style="background-color:#cbd5e7">
-</div>
-<div class="toccolours" style="background-color:#b3e2cd">
 ====Subsequent treatment====
-*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once per day on days +42 and +49
+*[[#Cyclophosphamide.2C_Cytarabine.2C_Pegaspargase.2C_Thioguanine.2C_Vincristine.2C_Dexamethasone|Delayed intensification ("Course IV")]]
 </div></div>
 ===References===
-# '''CALGB 59909:''' Damon LE, Johnson JL, Niedzwiecki D, Cheson BD, Hurd DD, Bartlett NL, Lacasce AS, Blum KA, Byrd JC, Kelly M, Stock W, Linker CA, Canellos GP. Immunochemotherapy and autologous stem-cell transplantation for untreated patients with mantle-cell lymphoma: CALGB 59909. J Clin Oncol. 2009 Dec 20;27(36):6101-8. Epub 2009 Nov 16. [https://doi.org/10.1200/jco.2009.22.2554 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2793032/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19917845 PubMed] NCT00020943
+# '''CALGB 10403:''' Stock W, Luger SM, Advani AS, Yin J, Harvey RC, Mullighan CG, Willman CL, Fulton N, Laumann KM, Malnassy G, Paietta E, Parker E, Geyer S, Mrózek K, Bloomfield CD, Sanford B, Marcucci G, Liedtke M, Claxton DF, Foster MC, Bogart JA, Grecula JC, Appelbaum FR, Erba H, Litzow MR, Tallman MS, Stone RM, Larson RA. A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403. Blood. 2019 Apr 4;133(14):1548-1559. Epub 2019 Jan 18. [http://www.bloodjournal.org/content/133/14/1548.long link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6450431/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30658992 PubMed] NCT00558519
-# '''SWOG S1106:''' Chen RW, Li H, Bernstein SH, Kahwash S, Rimsza LM, Forman SJ, Constine L, Shea TC, Cashen AF, Blum KA, Fenske TS, Barr PM, Phillips T, Leblanc M, Fisher RI, Cheson BD, Smith SM, Faham M, Wilkins J, Leonard JP, Kahl BS, Friedberg JW. RB but not R-HCVAD is a feasible induction regimen prior to auto-HCT in frontline MCL: results of SWOG Study S1106. Br J Haematol. 2017 Mar;176(5):759-769. Epub 2016 Dec 19. [https://doi.org/full/10.1111/bjh.14480 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5318240/ link to PMC article] '''does not contain dosing details''' [https://pubmed.ncbi.nlm.nih.gov/27992063 PubMed] NCT01412879
+=Late intensification=
-## '''Update:''' Kamdar M, Li H, Chen RW, Rimsza LM, Leblanc ML, Fenske TS, Shea TC, Barr PM, Phillips TJ, Leonard JP, Kahl BS, Friedberg JW, Smith SM. Five-year outcomes of the S1106 study of R-hyper-CVAD vs R-bendamustine in transplant-eligible patients with mantle cell lymphoma. Blood Adv. 2019 Oct 22;3(20):3132-3135. [https://ashpublications.org/bloodadvances/article/3/20/3132/422496/Fiveyear-outcomes-of-the-S1106-study-of-RhyperCVAD link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849956/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31648328 PubMed]
+==Cyclophosphamide, Cytarabine, Pegaspargase, Thioguanine, Vincristine, Dexamethasone {{#subobject:5176nxe|Regimen=1}}==
-==Cyclophosphamide & TBI, then auto HSCT {{#subobject:0a4915|Regimen=1}}==
-CY/TBI: '''<u>CY</u>'''clophosphamide & '''<u>T</u>'''otal '''<u>B</u>'''ody '''<u>I</u>'''rradiation
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:a2b2d3|Variant=1}}===
+===Regimen {{#subobject:2acb245|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
+{| class="wikitable" style="width: 40%; text-align:center;"
-!style="width: 20%"|Study
+!style="width: 25%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[http://www.bloodjournal.org/content/105/7/2677.long Dreyling et al. 2004]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6450431/ Stock et al. 2019 (CALGB 10403)]
-|1996-2004
+|style="background-color:#91cf61"|Non-randomized
-| style="background-color:#1a9851" |Phase 3 (E-esc)
-|[[Mantle_cell_lymphoma_-_historical#Interferon_alfa_monotherapy|Interferon alfa]]
-| style="background-color:#91cf60" |Seems to have superior OS<sup>1</sup><br>Median OS: 7.5 vs 4.8 yrs<br>(HR 0.66, 95% CI 0.46-0.95)
 |-
 |}
-''<sup>1</sup>Reported efficacy is based on the 2021 update; note that this study was conducted in the pre-rituximab era.''
+''Note: also known as delayed intensification "Course IV".''
 <div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
-*[[Regimen_classes#CHOP-like_therapy|CHOP-like chemotherapy]] x 4 to 6, then [[Stem_cell_mobilization#DexaBEAM_.26_G-CSF|Dexa-BEAM & G-CSF mobilization]]
+*[[#Methotrexate_.26_Pegaspargase|MTX & Pegaspargase interim]] maintenance
-{{#lst:Autologous HSCT conditioning regimens|a2b2d3}}
+</div>
-'''Stem cells re-infused on day 0'''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV once on day 29
+*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> IV or SC once per day on days 29 to 32, 36 to 39
+*[[Pegaspargase (Oncaspar)]] 2500 units/m<sup>2</sup> IM or IV once per day on days 4 +/-1 day & 43
+*[[Thioguanine (Tabloid)]] 60 mg/m<sup>2</sup> PO once per day on days 29 to 42
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 43, 50
+====Glucocorticoid therapy====
+*[[Dexamethasone (Decadron)]] 5 mg/m<sup>2</sup> PO or IV twice per day on days 1 to 7, 15 to 21
+====CNS therapy, prophylaxis====
+*[[Methotrexate (MTX)]] 15 mg IT once per day on days 1, 29, 36
+'''50-day course'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*[[#Mercaptopurine.2C_Methotrexate.2C_Vincristine.2C_Dexamethasone|Mercaptopurine, Methotrexate, Vincristine, Dexamethasone]] maintenance
 </div></div>
 ===References===
-# Dreyling M, Lenz G, Hoster E, Van Hoof A, Gisselbrecht C, Schmits R, Metzner B, Truemper L, Reiser M, Steinhauer H, Boiron JM, Boogaerts MA, Aldaoud A, Silingardi V, Kluin-Nelemans HC, Hasford J, Parwaresch R, Unterhalt M, Hiddemann W. Early consolidation by myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission significantly prolongs progression-free survival in mantle-cell lymphoma: results of a prospective randomized trial of the European MCL Network. Blood. 2005 Apr 1;105(7):2677-84. Epub 2004 Dec 9. [http://www.bloodjournal.org/content/105/7/2677.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15591112 PubMed]
+# '''CALGB 10403:''' Stock W, Luger SM, Advani AS, Yin J, Harvey RC, Mullighan CG, Willman CL, Fulton N, Laumann KM, Malnassy G, Paietta E, Parker E, Geyer S, Mrózek K, Bloomfield CD, Sanford B, Marcucci G, Liedtke M, Claxton DF, Foster MC, Bogart JA, Grecula JC, Appelbaum FR, Erba H, Litzow MR, Tallman MS, Stone RM, Larson RA. A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403. Blood. 2019 Apr 4;133(14):1548-1559. Epub 2019 Jan 18. [http://www.bloodjournal.org/content/133/14/1548.long link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6450431/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30658992 PubMed] NCT00558519
-## '''Update:''' Zoellner AK, Unterhalt M, Stilgenbauer S, Hübel K, Thieblemont C, Metzner B, Topp M, Truemper L, Schmidt C, Bouabdallah K, Krauter J, Lenz G, Dürig J, Vergote V, Schäfer-Eckart K, André M, Kluin-Nelemans HC, van Hoof A, Klapper W, Hiddemann W, Dreyling M, Hoster E; European Mantle Cell Lymphoma Network. Long-term survival of patients with mantle cell lymphoma after autologous haematopoietic stem-cell transplantation in first remission: a post-hoc analysis of an open-label, multicentre, randomised, phase 3 trial. Lancet Haematol. 2021 Sep;8(9):e648-e657. [https://doi.org/10.1016/s2352-3026(21)00195-2 link to original article] [https://pubmed.ncbi.nlm.nih.gov/34450102/ PubMed]
+==Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone {{#subobject:51eb0e|Regimen=1}}==
-==Ibritumomab tiuxetan protocol {{#subobject:165cb4|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:f0c3d9|Variant=1}}===
+===Regimen {{#subobject:2b7045|Variant=1}}===
 {| class="wikitable sortable" style="width: 60%; text-align:center;"
 !style="width: 33%"|Study
@@ Line 1,501: / Line 1,470: @@
 !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3732008/ Smith et al. 2012 (ECOG E1499)]
+|[https://doi.org/10.1200/JCO.2008.18.6916 Huguet et al. 2009 (GRAALL-2003)]
 |2003-2005
 |style="background-color:#91cf61"|Phase 2
 |-
 |}
+''Note: the original article Table 1 has several errors which were corrected in the erratum and the online Table 1. These corrected doses are replicated here.''
 <div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
-*[[#R-CHOP|R-CHOP]] x 4
+*[[#Pediatric-like_GRAALL_consolidation|Pediatric-like GRAALL]] consolidation cycle 6, if patients achieved CR1 after cyclophosphamide, daunorubicin, L-asparaginase, vincristine, prednisone induction
 </div>
 <div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
+====Chemotherapy====
-*[[Rituximab (Rituxan)]] 250 mg/m<sup>2</sup> IV once per day on days 1 & 8, '''given first on day 8'''
+*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV every 12 hours on day 15
-====Radioconjugate therapy====
+*[[Daunorubicin (Cerubidine)]] 30 mg/m<sup>2</sup> IV once per day on days 1 to 3
-*[[Ibritumomab tiuxetan (Zevalin)|Ibritumomab tiuxetan & Yttrium-90 (Zevalin) ]] by the following criteria:
+*[[Asparaginase (Elspar)]] 6000 units/m<sup>2</sup>/day (route not specified) on days 8, 10, 12, 18, 20, 22
-**Platelets at least 150 x 10<sup>9</sup>/L: 0.4 mCi/kg (maximum dose of 32 mCi) IV once on day 8, '''given second'''
+*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 1, 8, 15
-**Platelets between 100 and 149 x 10<sup>9</sup>/L: 0.3 mCi/kg (maximum dose of 32 mCi) IV once on day 8, '''given second'''
+====Glucocorticoid therapy====
-'''8-day course'''
+*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup>/day PO on days 1 to 14
+====Supportive therapy====
+*[[Lenograstim (Granocyte)]] 150 mcg/m<sup>2</sup> SC once per day if ANC less than 500/uL until myeloid recovery
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*[[#Pediatric-like_GRAALL_consolidation|Pediatric-like GRAALL]] consolidation
 </div></div>
 ===References===
-<!-- Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, June 2-6, 2006; the 47th Annual Meeting of the American Society of Hematology, Atlanta, GA, December 8-11, 2007; and the 11th International Conference on Malignant Lymphoma, Lugano, Switzerland, June 15-18, 2011. -->
+# '''GRAALL-2003:''' Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. [https://doi.org/10.1200/JCO.2008.18.6916 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19124805 PubMed] NCT00222027
-# '''ECOG E1499:''' Smith MR, Li H, Gordon L, Gascoyne RD, Paietta E, Forero-Torres A, Kahl BS, Advani R, Hong F, Horning SJ. Phase II study of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone immunochemotherapy followed by yttrium-90-ibritumomab tiuxetan in untreated mantle-cell lymphoma: Eastern Cooperative Oncology Group Study E1499. J Clin Oncol. 2012 Sep 1;30(25):3119-26. Epub 2012 Jul 30. [https://doi.org/10.1200/jco.2012.42.2444 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3732008/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22851557 PubMed] NCT00070447
+==Cytarabine & Idarubicin {{#subobject:284aff|Regimen=1}}==
-## '''Update:''' Smith MR, Hong F, Li H, Gordon LI, Gascoyne RD, Paietta EM, Advani RH, Forero-Torres A, Horning SJ, Kahl BS. Mantle cell lymphoma initial therapy with abbreviated R-CHOP followed by (90)Y-ibritumomab tiuxetan: 10-year follow-up of the phase 2 ECOG-ACRIN study E1499. Leukemia. 2017 Feb;31(2):517-519. Epub 2016 Oct 26. [https://doi.org/10.1038/leu.2016.305 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5288271/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27780968 PubMed]
-==Melphalan & TBI, then auto HSCT {{#subobject:94f995|Regimen=1}}==
-Melphalan & TBI: Melphalan & '''<u>T</u>'''otal '''<u>B</u>'''ody '''<u>I</u>'''rradiation
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:ad4db8|Variant=1}}===
+===Regimen {{#subobject:3d4896|Variant=1}}===
 {| class="wikitable sortable" style="width: 60%; text-align:center;"
 !style="width: 33%"|Study
@@ Line 1,533: / Line 1,505: @@
 !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[http://www.haematologica.org/content/95/8/1350.full Gressin et al. 2010 (GOELAMS LM1996)]
+|[https://doi.org/10.1200/JCO.2008.18.6916 Huguet et al. 2009 (GRAALL-2003)]
-|1996-2000
-| style="background-color:#91cf61" |Phase 2
-|-
-|[http://www.haematologica.org/content/95/8/1350.full Gressin et al. 2010 (GOELAMS LM2001)]
 |2003-2005
-| style="background-color:#91cf61" |Phase 2
+|style="background-color:#91cf61"|Phase 2
 |-
 |}
+''Note: the original article Table 1 has several errors which were corrected in the erratum and the online Table 1. These corrected doses are replicated here.
 <div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
-*GOELAMS LM1996: [[Mantle_cell_lymphoma_-_historical#VAD.2BC|VAD+C]] x 6
+*[[#Pediatric-like_GRAALL_consolidation|Pediatric-like GRAALL]] consolidation cycle 6, if patients achieved CR1 after cytarabine & idarubicin salvage
-*GOELAMS LM2001: [[#R-VAD.2BC|R-VAD+C]] x 6
-{{#lst:Autologous HSCT conditioning regimens|ad4db8}}
-'''Stem cells reinfused after chemoradiotherapy, unclear exactly which day'''
-</div></div>
-===References===
-# '''GOELAMS LM1996:''' Gressin R, Caulet-Maugendre S, Deconinck E, Tournilhac O, Gyan E, Moles MP, El Yamani A, Cornillon J, Rossi JF, Le Gouill S, Lepeu G, Damaj G, Celigny PS, Maisonneuve H, Corront B, Vilque JP, Casassus P, Lamy T, Colonna M, Colombat P; GOELAMS. Evaluation of the (R)VAD+C regimen for the treatment of newly diagnosed mantle cell lymphoma: combined results of two prospective phase II trials from the French GOELAMS Group. Haematologica. 2010 Aug;95(8):1350-7. Epub 2010 Mar 10. [http://www.haematologica.org/content/95/8/1350.full link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2913084/ link to PMC article] '''contains partial protocol''' [https://pubmed.ncbi.nlm.nih.gov/20220059 PubMed]
-# '''GOELAMS LM2001:''' Gressin R, Caulet-Maugendre S, Deconinck E, Tournilhac O, Gyan E, Moles MP, El Yamani A, Cornillon J, Rossi JF, Le Gouill S, Lepeu G, Damaj G, Celigny PS, Maisonneuve H, Corront B, Vilque JP, Casassus P, Lamy T, Colonna M, Colombat P; GOELAMS. Evaluation of the (R)VAD+C regimen for the treatment of newly diagnosed mantle cell lymphoma: combined results of two prospective phase II trials from the French GOELAMS Group. Haematologica. 2010 Aug;95(8):1350-7. Epub 2010 Mar 10. [http://www.haematologica.org/content/95/8/1350.full link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2913084/ link to PMC article] '''contains partial protocol''' [https://pubmed.ncbi.nlm.nih.gov/20220059 PubMed] NCT00285389
-==R-BEAM, then auto HSCT {{#subobject:87ade5|Regimen=1}}==
-R-BEAM: '''<u>R</u>'''ituximab, '''<u>B</u>'''iCNU (Carmustine), '''<u>E</u>'''toposide, '''<u>A</u>'''ra-C (Cytarabine), '''<u>M</u>'''elphalan
-<div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:c0248f|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
-!style="width: 33%"|Study
-!style="width: 33%"|Years of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://doi.org/10.1056/NEJMoa1701769 Le Gouill et al. 2017 (LyMa)]
-|2008-2012
-|style="background-color:#91cf61"|Non-randomized portion of RCT
-|-
-|}
-<div class="toccolours" style="background-color:#cbd5e8">
 </div>
 <div class="toccolours" style="background-color:#b3e2cd">
-====Preceding treatment====
+====Chemotherapy====
-*CR: [[#R-DHAC|R-DHAC]] x 4 or [[#R-DHAOx|R-DHAOx]] x 4 or [[#R-DHAP|R-DHAP]] x 4
+*[[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV every 12 hours on days 1 to 4
-*PR: [[#R-DHAC|R-DHAC]] x 4 or [[#R-DHAOx|R-DHAOx]] x 4 or [[#R-DHAP|R-DHAP]] x 4, then [[#R-CHOP-14_.28Prednisolone.29|R-CHOP-14]] x 4
+*[[Idarubicin (Idamycin)]] 9 mg/m<sup>2</sup> IV once per day on days 1 to 3
-{{#lst:Autologous HSCT conditioning regimens|db487f}}
+====Supportive therapy====
-'''Stem cells re-infused on day 0'''
+*[[Lenograstim (Granocyte)]] 150 mcg/m<sup>2</sup> SC once per day from day 9 until myeloid recovery
 </div>
 <div class="toccolours" style="background-color:#cbd5e7">
-</div>
-<div class="toccolours" style="background-color:#b3e2cd">
 ====Subsequent treatment====
-*[[Mantle_cell_lymphoma_-_null_regimens#Observation|Observation]] versus [[#Rituximab_monotherapy|Rituximab]] maintenance
+*[[#Pediatric-like_GRAALL_consolidation|Pediatric-like GRAALL]] consolidation
 </div></div>
 ===References===
-<!-- # '''Abstract:''' Steven Le Gouill, MD, PhD, Catherine Thieblemont, MD, PhD, Lucie Oberic, Krimo Bouabdallah, MD, Emmanuel Gyan, MD, PhD, Gandhi Damaj, MD, Vincent Ribrag, MD, Serge Bologna, MD, Remy Gressin, MD, Olivier Casasnovas, MD, Corinne Haioun, MD, PhD, Philippe Solal-Celigny, MD, Herve Maisonneuve, MD, Eric Van Den Neste, MD, PhD, Anne Moreau, MD, Marie C Bene, Gilles Salles, MD PhD, Hervé Tilly, MD, PhD, Thierry Lamy, MD, PhD and Olivier Hermine, MD, PhD. Rituximab Maintenance Versus Wait and Watch after Four Courses of R-DHAP Followed By Autologous Stem Cell transplantation in Previously Untreated Young Patients with Mantle Cell Lymphoma: First Interim Analysis of the Phase III Prospective Lyma Trial, a Lysa Study. Blood 2014 124:146. [http://www.bloodjournal.org/content/124/21/146 link to abstract] -->
+# '''GRAALL-2003:''' Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. [https://doi.org/10.1200/JCO.2008.18.6916 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19124805 PubMed] NCT00222027
-# '''LyMa:''' Le Gouill S, Thieblemont C, Oberic L, Moreau A, Bouabdallah K, Dartigeas C, Damaj G, Gastinne T, Ribrag V, Feugier P, Casasnovas O, Zerazhi H, Haioun C, Maisonneuve H, Houot R, Jardin F, Van Den Neste E, Tournilhac O, Le Dû K, Morschhauser F, Cartron G, Fornecker LM, Canioni D, Callanan M, Béné MC, Salles G, Tilly H, Lamy T, Gressin R, Hermine O; LYSA. Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma. N Engl J Med. 2017 Sep 28;377(13):1250-1260. [https://doi.org/10.1056/NEJMoa1701769 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28953447 PubMed] NCT00921414
+==CALGB 8811 late intensification {{#subobject:712de6|Regimen=1}}==
-==TAM6, then auto HSCT {{#subobject:c810fd|Regimen=1}}==
-TAM: '''<u>T</u>'''otal-body irradiation, '''<u>A</u>'''ra-C (Cytarabine), '''<u>M</u>'''elphalan
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:4aee7c|Variant=1}}===
+===Regimen {{#subobject:2ea5b7|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
+{| class="wikitable" style="width: 40%; text-align:center;"
-!style="width: 33%"|Study
+!style="width: 25%"|Study
-!style="width: 33%"|Years of enrollment
+!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[http://www.bloodjournal.org/content/121/1/48.full Delarue et al. 2012]
-|2000-2003
-| style="background-color:#91cf61" |Phase 2
-|-
-|}
-<div class="toccolours" style="background-color:#cbd5e8">
-====Preceding treatment====
-*[[#R-DHAP|R-DHAP]] x 3
-{{#lst:Autologous HSCT conditioning regimens|4aee7c}}
-</div></div>
-===References===
-# Delarue R, Haioun C, Ribrag V, Brice P, Delmer A, Tilly H, Salles G, Van Hoof A, Casasnovas O, Brousse N, Lefrere F, Hermine O; Groupe d'Etude des Lymphomes de l'Adulte. CHOP and DHAP plus rituximab followed by autologous stem cell transplantation in mantle cell lymphoma: a phase 2 study from the Groupe d'Etude des Lymphomes de l'Adulte. Blood. 2013 Jan 3;121(1):48-53. Epub 2012 Jun 20. [http://www.bloodjournal.org/content/121/1/48.full link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22718839 PubMed]
-=Maintenance after first-line therapy=
-==Bortezomib monotherapy {{#subobject:018719|Regimen=1}}==
-<div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:1099af|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
-!style="width: 33%"|Study
-!style="width: 33%"|Years of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4710555/ Till et al. 2015 (SWOG S0601)]
+|[http://www.bloodjournal.org/content/85/8/2025.full Larson et al. 1995 (CALGB 8811)]
-|2006-2008
 |style="background-color:#91cf61"|Phase 2
 |-
@@ Line 1,621: / Line 1,541: @@
 <div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
-*[[#VR-CHOP|VR-CHOP]] x 6
+*[[#Mercaptopurine.2C_Methotrexate.2C_WB-XRT|Mercaptopurine, Methotrexate, WB-XRT interim maintenance ("Course III")]]
 </div>
 <div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
+====Chemotherapy, "Course IV"====
-*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
+*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
-'''3-month cycle for 8 cycles (2 years)'''
+*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 1, 8, 15
+*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV once on day 29
+*[[Thioguanine (Tabloid)]] 60 mg/m<sup>2</sup> PO once per day on days 29 to 42
+*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> SC once per day on days 29 to 32, 36 to 39
+====Glucocorticoid therapy====
+*[[Dexamethasone (Decadron)]] 10 mg/m<sup>2</sup> PO once per day on days 1 to 14
+'''8-week course'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*[[#POMP|POMP]] maintenance ("Course V")
 </div></div>
 ===References===
-# '''SWOG S0601:''' Till BG, Li H, Bernstein SH, Fisher RI, Burack WR, Rimsza LM, Floyd JD, DaSilva MA, Moore DF Jr, Pozdnyakova O, Smith SM, LeBlanc M, Friedberg JW. Phase II trial of R-CHOP plus bortezomib induction therapy followed by bortezomib maintenance for newly diagnosed mantle cell lymphoma: SWOG S0601. Br J Haematol. 2016 Jan;172(2):208-18. Epub 2015 Oct 22. [https://doi.org/10.1111/bjh.13818 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4710555/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26492567 PubMed] NCT00376961
+# '''CALGB 8811:''' Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR, Hooberman AL, Westbrook CA, Arthur DC, George SL, Bloomfield CD, Schiffer CA. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: Cancer and Leukemia Group B study 8811. Blood. 1995 Apr 15;85(8):2025-37. [http://www.bloodjournal.org/content/85/8/2025.full.pdf+html link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/7718875 PubMed]
+=Maintenance after upfront therapy=
-==Lenalidomide monotherapy {{#subobject:fahnzb|Regimen=1}}==
+==Mercaptopurine, Methotrexate, Vincristine, Dexamethasone {{#subobject:51acxe|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #1, 10 mg/day {{#subobject:1gio96|Variant=1}}===
+===Regimen variant #1, 2 years {{#subobject:253v245|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
+{| class="wikitable" style="width: 40%; text-align:center;"
-!style="width: 20%"|Study
+!style="width: 25%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1016/s2352-3026(20)30358-6 Ladetto et al. 2020 (MCL0208)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6450431/ Stock et al. 2019 (CALGB 10403)]
-|2010-2015
+|style="background-color:#91cf61"|Non-randomized
-| style="background-color:#1a9851" |Phase 3 (E-esc)
-|[[Mantle_cell_lymphoma_-_null_regimens#Observation|Observation]]
-| style="background-color:#91cf60" |Seems to have superior PFS<br>PFS36: 80% vs 64%<br>(HR 0.51, 95% CI 0.30-0.87)
 |-
 |}
-''Note: this dosing was intended for patients with platelet count between 60 and 100 x 10<sup>9</sup>/L.''
+''Note: also known as maintenance "Course V". This duration was intended for female patients.''
 <div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
-*[[#BEAM.2C_then_auto_HSCT|BEAM, then auto HSCT]]
+*[[#Cyclophosphamide.2C_Cytarabine.2C_Pegaspargase.2C_Thioguanine.2C_Vincristine.2C_Dexamethasone|Delayed intensification "Course IV"]]
 </div>
 <div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
+====Chemotherapy====
-*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21
+*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup> PO once per day
-'''28-day cycle for 24 cycles'''
+*[[Methotrexate (MTX)]] as follows:
+**Cycles 1 to 4: 20 mg/m<sup>2</sup> PO once per day on days 8, 15, 22, 36, 43, 50, 57, 64, 71, 78
+**Cycles 5 to 8: 20 mg/m<sup>2</sup> PO once per day on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78
+*[[Vincristine (Oncovin)]] 1.5 mg (maximum dose of 2 mg) IV once per day on days 1, 29, 57
+====Glucocorticoid therapy====
+*[[Dexamethasone (Decadron)]] 3 mg/m<sup>2</sup> PO or IV twice per day on days 1 to 5, 29 to 33, 57 to 61
+====CNS therapy, prophylaxis====
+*[[Methotrexate (MTX)]] as follows:
+**Cycles 1 to 4: 15 mg IT once per day on days 1 & 29
+**Cycles 5 to 8: 15 mg IT once on day 1
+'''12-week cycle for 8 cycles (2 years)'''
 </div></div><br>
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #2, 15 mg/day {{#subobject:1ghs36|Variant=1}}===
+===Regimen variant #2, 3 years {{#subobject:25acb1|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
+{| class="wikitable" style="width: 40%; text-align:center;"
-!style="width: 20%"|Study
+!style="width: 25%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1016/s2352-3026(20)30358-6 Ladetto et al. 2020 (MCL0208)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6450431/ Stock et al. 2019 (CALGB 10403)]
-|2010-2015
+|style="background-color:#91cf61"|Non-randomized
-| style="background-color:#1a9851" |Phase 3 (E-esc)
-|[[Mantle_cell_lymphoma_-_null_regimens#Observation|Observation]]
-| style="background-color:#91cf60" |Seems to have superior PFS<br>PFS36: 80% vs 64%<br>(HR 0.51, 95% CI 0.30-0.87)
 |-
 |}
-''Note: this dosing was intended for patients with platelet count greater than 100 x 10<sup>9</sup>/L.''
+''Note: also known as maintenance "Course V". This duration was intended for male patients.''
 <div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
-*[[#BEAM.2C_then_auto_HSCT|BEAM, then auto HSCT]]
+*[[#Cyclophosphamide.2C_Cytarabine.2C_Pegaspargase.2C_Thioguanine.2C_Vincristine.2C_Dexamethasone|Delayed intensification "Course IV"]]
 </div>
 <div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
+====Chemotherapy====
-*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21
+*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup> PO once per day
-'''28-day cycle for 24 cycles'''
+*[[Methotrexate (MTX)]] as follows:
+**Cycles 1 to 4: 20 mg/m<sup>2</sup> PO once per day on days 8, 15, 22, 36, 43, 50, 57, 64, 71, 78
+**Cycles 5 to 12: 20 mg/m<sup>2</sup> PO once per day on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78
+*[[Vincristine (Oncovin)]] 1.5 mg (maximum dose of 2 mg) IV once per day on days 1, 29, 57
+====Glucocorticoid therapy====
+*[[Dexamethasone (Decadron)]] 3 mg/m<sup>2</sup> PO or IV twice per day on days 1 to 5, 29 to 33, 57 to 61
+====CNS therapy, prophylaxis====
+*[[Methotrexate (MTX)]] as follows:
+**Cycles 1 to 4: 15 mg IT once per day on days 1 & 29
+**Cycles 5 to 12: 15 mg IT once on day 1
+'''12-week cycle for 12 cycles (3 years)'''
 </div></div>
 ===References===
-#'''MCL0208:''' Ladetto M, Cortelazzo S, Ferrero S, Evangelista A, Mian M, Tavarozzi R, Zanni M, Cavallo F, Di Rocco A, Stefoni V, Pagani C, Re A, Chiappella A, Balzarotti M, Zilioli VR, Gomes da Silva M, Arcaini L, Molinari AL, Ballerini F, Ferreri AJM, Puccini B, Benedetti F, Stefani PM, Narni F, Casaroli I, Stelitano C, Ciccone G, Vitolo U, Martelli M; Fondazione Italiana Linfomi. Lenalidomide maintenance after autologous haematopoietic stem-cell transplantation in mantle cell lymphoma: results of a Fondazione Italiana Linfomi (FIL) multicentre, randomised, phase 3 trial. Lancet Haematol. 2021 Jan;8(1):e34-e44. Epub 2020 Dec 22. [https://doi.org/10.1016/s2352-3026(20)30358-6 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/33357480 PubMed] NCT02354313
+# '''CALGB 10403:''' Stock W, Luger SM, Advani AS, Yin J, Harvey RC, Mullighan CG, Willman CL, Fulton N, Laumann KM, Malnassy G, Paietta E, Parker E, Geyer S, Mrózek K, Bloomfield CD, Sanford B, Marcucci G, Liedtke M, Claxton DF, Foster MC, Bogart JA, Grecula JC, Appelbaum FR, Erba H, Litzow MR, Tallman MS, Stone RM, Larson RA. A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403. Blood. 2019 Apr 4;133(14):1548-1559. Epub 2019 Jan 18. [http://www.bloodjournal.org/content/133/14/1548.long link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6450431/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30658992 PubMed] NCT00558519
-==Lenalidomide & Rituximab (R<sup>2</sup>) {{#subobject:6bd100|Regimen=1}}==
+==Mercaptopurine & Methotrexate {{#subobject:6366a6|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:d64401|Variant=1}}===
+===Regimen {{#subobject:1fc958|Variant=1}}===
 {| class="wikitable sortable" style="width: 60%; text-align:center;"
 !style="width: 33%"|Study
@@ Line 1,694: / Line 1,632: @@
 !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4710541/ Ruan et al. 2015 (Cornell 1103011566)]
+|[https://doi.org/10.1182/blood.V69.4.1242.1242 Linker et al. 1987]
-|2011-2014
+|1980-1986
 |style="background-color:#91cf61"|Phase 2
 |-
@@ Line 1,701: / Line 1,639: @@
 <div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
-*[[#Lenalidomide_.26_Rituximab_.28R2.29|Lenalidomide & Rituximab]] induction
+*[[#Linker_regimen_.28consolidation.29|Linker regimen]] consolidation
 </div>
 <div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
+====Chemotherapy====
-*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21
+*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup> PO once per day
-*[[Rituximab (Rituxan)]] as follows:
+*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> PO once on day 1
-**Odd cycles: 375 mg/m<sup>2</sup> IV once on day 1
+'''7-day cycle for 130 cycles (30 months)'''
-**Even cycles: no treatment
-'''28-day cycles'''
 </div></div>
 ===References===
-<!-- # '''Abstract:''' Jia Ruan, Peter Martin, Bijal D. Shah, Stephen J. Schuster, Sonali M. Smith, Richard R. Furman, Paul Christos, Amelyn Rodriguez, Paige Wolstencroft, Jakub Svoboda, Alison Bender, Jessica Lewis, Morton Coleman, John P. Leonard. Combination Biologic Therapy Without Chemotherapy As Initial Treatment For Mantle Cell Lymphoma: Multi-Center Phase II Study Of Lenalidomide Plus Rituximab. Blood Nov 2013,122(21)247 [http://www.bloodjournal.org/content/122/21/247 link to abstract]
+# Linker CA, Levitt LJ, O'Donnell M, Ries CA, Link MP, Forman SJ, Farbstein MJ. Improved results of treatment of adult acute lymphoblastic leukemia. Blood. 1987 Apr;69(4):1242-8. [https://doi.org/10.1182/blood.V69.4.1242.1242 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/3470055 PubMed]
-## '''Update Abstract:''' Jia Ruan, MD, PhD, Peter Martin, MD, Bijal D. Shah, MD, Stephen J. Schuster, MD, Sonali M. Smith, MD, Richard R Furman, MD, Paul Christos, DrPH, Amelyn Rodriguez, RN, Louisa Drake, Jakub Svoboda, MD, Jessica Lewis, PA-C, Orel Katz, PA-C, Morton Coleman, MD and John P. Leonard, MD. Sustained Remission with the Combination Biologic Doublet of Lenalidomide Plus Rituximab As Initial Treatment for Mantle Cell Lymphoma: A Multi-Center Phase II Study Report. ASH Annual Meeting 2014 Abstract 625 [https://ash.confex.com/ash/2014/webprogram/Paper73280.html link to abstract] -->
+## '''Update:''' Linker CA, Levitt LJ, O'Donnell M, Forman SJ, Ries CA. Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report. Blood. 1991 Dec 1;78(11):2814-22. [http://www.bloodjournal.org/content/78/11/2814.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/1835410 PubMed]
-# '''Cornell 1103011566:''' Ruan J, Martin P, Shah B, Schuster SJ, Smith SM, Furman RR, Christos P, Rodriguez A, Svoboda J, Lewis J, Katz O, Coleman M, Leonard JP. Lenalidomide plus rituximab as initial treatment for mantle-cell lymphoma. N Engl J Med. 2015 Nov 5;373(19):1835-44. [https://doi.org/10.1056/NEJMoa1505237 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4710541/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26535512 PubMed] NCT01472562
+==POMP {{#subobject:31219|Regimen=1}}==
-## '''Update:''' Ruan J, Martin P, Christos P, Cerchietti L, Tam W, Shah B, Schuster SJ, Rodriguez A, Hyman D, Calvo-Vidal MN, Smith SM, Svoboda J, Furman RR, Coleman M, Leonard JP. Five-year follow-up of lenalidomide plus rituximab as initial treatment of mantle cell lymphoma. Blood. 2018 Nov 8;132(19):2016-2025. Epub 2018 Sep 4. [http://www.bloodjournal.org/content/132/19/2016.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/30181173 PubMed]
+POMP: '''<u>P</u>'''urinethol (Mercaptopurine), '''<u>O</u>'''ncovin (Vincristine), '''<u>M</u>'''ethotrexate, '''<u>P</u>'''rednisone
-==Rituximab monotherapy {{#subobject:712b01|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #1, 6 doses {{#subobject:7b2206|Variant=1}}===
+===Regimen variant #1 {{#subobject:93b1b3|Variant=1}}===
 {| class="wikitable sortable" style="width: 60%; text-align:center;"
 !style="width: 33%"|Study
@@ Line 1,724: / Line 1,659: @@
 !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://doi.org/10.3109/10428194.2010.534518 Sachanas et al. 2011]
+|[https://doi.org/10.1200/JCO.2008.18.6916 Huguet et al. 2009 (GRAALL-2003)]
-|NR in abstract
+|2003-2005
 |style="background-color:#91cf61"|Phase 2
 |-
@@ Line 1,731: / Line 1,666: @@
 <div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
-*[[#Chlorambucil_.26_Rituximab_.28RClb.29|Chlorambucil & Rituximab]] x 12
+*[[#Pediatric-like_GRAALL_consolidation|Pediatric-like GRAALL]] consolidation
 </div>
 <div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
+====Chemotherapy====
-*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1
+*[[Mercaptopurine (6-MP)]] 60 mg/m<sup>2</sup> PO once per day
-'''2-month cycle for 6 cycles (1 year)'''
+*[[Vincristine (Oncovin)]] as follows:
-</div></div><br>
+**Months 1 to 12: 2 mg IV once on day 1
-<div class="toccolours" style="background-color:#eeeeee">
+*[[Methotrexate (MTX)]] 25 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22
-===Regimen variant #2, 12 doses {{#subobject:c9438a|Variant=1}}===
+====Glucocorticoid therapy====
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
+*[[Prednisone (Sterapred)]] as follows:
-!style="width: 33%"|Study
+**Months 1 to 12: 40 mg/m<sup>2</sup>/day PO on days 1 to 7
-!style="width: 33%"|Years of enrollment
+'''1-month cycle for 24 cycles (2 years)'''
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://doi.org/10.3109/10428194.2012.672736 Räty et al. 2012]
-|NR in abstract
-|style="background-color:#91cf61"|Phase 2
-|-
-|}
-<div class="toccolours" style="background-color:#cbd5e8">
-====Preceding treatment====
-*Induction chemotherapy x 10, with CR/PR
-</div>
-<div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
-*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1
-'''2-month cycle for 12 cycles (2 years)'''
 </div></div><br>
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #3, 16 doses {{#subobject:ab3766|Variant=1}}===
+===Regimen variant #2 {{#subobject:7e9f28|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
-!style="width: 33%"|Study
-!style="width: 33%"|Years of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3954048/ Chang et al. 2014 (ECOG E1405)]
-|2007-NR
-|style="background-color:#91cf61"|Phase 2
-|-
-|}
-<div class="toccolours" style="background-color:#cbd5e8">
-====Preceding treatment====
-*[[#VcR-CVAD|VcR-CVAD]] x 6
-</div>
-<div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
-*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
-'''6-month cycle for 4 cycles (2 years)'''
-</div></div><br>
-<div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #4, 18 doses {{#subobject:572f85|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
@@ Line 1,789: / Line 1,688: @@
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1056/NEJMoa1701769 Le Gouill et al. 2017 (LyMa)]
+|[http://www.bloodjournal.org/content/106/12/3760.long Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)]
-|2008-2012
+|1993-2003
-|style="background-color:#1a9851"|Phase 3 (E-esc)
+|style="background-color:#1a9851"|Phase 3 (C)
-|[[Mantle_cell_lymphoma_-_null_regimens#Observation|Observation]]
+|[[Transplant_conditioning_regimens#Etoposide_.26_TBI|Etoposide & TBI, then auto HSCT]]
-|style="background-color:#91cf60"|Seems to have superior OS<br>OS48: 89% vs 80%<br>(HR 0.50, 95% CI 0.26-0.99)
+|style="background-color:#91cf60"|Seems to have superior OS
 |-
 |}
 <div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
-*[[#BEAM.2C_then_auto_HSCT|R-BEAM with autologous HSCT]]
+*[[#International_ALL_Trial|International ALL Trial]] consolidation
 </div>
 <div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
+====Chemotherapy====
-*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1
+*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup> PO once per day
-'''2-month cycle for 18 cycles (3 years)'''
+*[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> IV once on day 1
+*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> IV or PO once per week
+====Glucocorticoid therapy====
+*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 5
+'''3-month cycle for 10 cycles (2.5 years from the start of phase III)'''
 </div></div><br>
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #5, 24 doses {{#subobject:4ad905|Variant=1}}===
+===Regimen variant #3 {{#subobject:9374ec|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
+{| class="wikitable" style="width: 40%; text-align:center;"
-!style="width: 33%"|Study
+!style="width: 25%"|Study
-!style="width: 33%"|Years of enrollment
+!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[http://www.tandfonline.com/doi/full/10.3109/10428190903518345 Lossos et al. 2010 (UM-MCL2)]
+|[https://doi.org/10.1200/jco.2000.18.3.547 Kantarjian et al. 2000]
-|NR in abstract
 |style="background-color:#91cf61"|Phase 2
 |-
 |}
+''Note: this is the IV POMP used from 1995 onwards. Exact timing of drugs is not given, for example, that certain drugs are taken on days 1 to 5 of the cycle.''
 <div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
-*[[#R-MACLO.2FR-IVAM|R-MACLO/R-IVAM]] x 4
+*[[#Hyper-CVAD.2FMA|Hyper-CVAD/MA]] x 8
 </div>
 <div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
+====Chemotherapy====
-*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
+*[[Mercaptopurine (6-MP)]] 1000 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5
-'''6-month cycle for 6 cycles (3 years)'''
+*[[Vincristine (Oncovin)]] 2 mg IV once on day 1
+*[[Methotrexate (MTX)]] 10 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5
+====Glucocorticoid therapy====
+*[[Prednisone (Sterapred)]] 200 mg PO once per day on days 1 to 5
+====Supportive therapy====
+*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)|Trimethoprim/Sulfamethoxazole]] (dose not specified) PO twice per day on Saturday and Sunday for the first 6 months
+*ONE of the following antivirals, for the first 6 months:
+**[[Acyclovir (Zovirax)]] 200 mg PO once per day or 3 times per week
+**[[Valacyclovir (Valtrex)]] 500 mg PO once per day or 3 times per week
+'''1-month cycle for 24 cycles (2 years)'''
 </div></div><br>
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #6, indefinite {{#subobject:f46cd3|Variant=1}}===
+===Regimen variant #4 {{#subobject:91c8d4|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
+{| class="wikitable" style="width: 40%; text-align:center;"
-!style="width: 20%"|Study
+!style="width: 25%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1056/NEJMoa1200920 Kluin-Nelemans et al. 2012 (MCLelderly)]
+|[http://www.bloodjournal.org/content/85/8/2025.full Larson et al. 1995 (CALGB 8811)]
-|2004-2010
+|style="background-color:#91cf61"|Phase 2
-|style="background-color:#1a9851"|Phase 3 (E-switch-ooc)
-|[[Mantle_cell_lymphoma_-_historical#Interferon_alfa_monotherapy|Interferon alfa]]
-|style="background-color:#1a9850"|Superior combined OS<sup>1</sup>
 |-
 |}
-''<sup>1</sup>Superiority was only demonstrated in the group of patients who got R-CHOP first; overall, there was no statistically significant survival difference between the two maintenance groups.''
 <div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
-*[[#R-CHOP|R-CHOP]] x 8 versus [[Mantle_cell_lymphoma_-_historical#FCR|R-FC]] x 6
+*[[#CALGB_8811_late_intensification|Larson regimen (CALGB 8811) late intensification ("Course IV")]]
 </div>
 <div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
+====Chemotherapy, "Course V"====
-*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1
+*[[Mercaptopurine (6-MP)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 28
-'''2-month cycles'''
+*[[Vincristine (Oncovin)]] 2 mg IV once on day 1
-</div></div>
+*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22
-===References===
-# '''UM-MCL2:''' Lossos IS, Hosein PJ, Morgensztern D, Coleman F, Escalón MP, Byrne GE Jr, Rosenblatt JD, Walker GR. High rate and prolonged duration of complete remissions induced by rituximab, methotrexate, doxorubicin, cyclophosphamide, vincristine, ifosfamide, etoposide, cytarabine, and thalidomide (R-MACLO-IVAM-T), a modification of the National Cancer Institute 89-C-41 regimen, in patients with newly diagnosed mantle cell lymphoma. Leuk Lymphoma. 2010 Mar;51(3):406-14. [http://www.tandfonline.com/doi/full/10.3109/10428190903518345 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20038221 PubMed] NCT00878254
-## '''Update:''' Hosein PJ, Sandoval-Sus JD, Goodman D, Arteaga AG, Reis I, Hoffman J, Stefanovic A, Rosenblatt JD, Lossos IS. Updated survival analysis of two sequential prospective trials of R-MACLO-IVAM followed by maintenance for newly diagnosed mantle cell lymphoma. Am J Hematol. 2015 Jun;90(6):E111-6. Epub 2015 Apr 2. [https://doi.org/10.1002/ajh.23996 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4439262/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25737247 PubMed]
-# Sachanas S, Pangalis GA, Vassilakopoulos TP, Korkolopoulou P, Kontopidou FN, Athanasoulia M, Yiakoumis X, Kalpadakis C, Georgiou G, Masouridis S, Moschogiannis M, Tsirkinidis P, Pappis V, Kokoris SI, Siakantaris MP, Panayiotidis P, Angelopoulou MK. Combination of rituximab with chlorambucil as first line treatment in patients with mantle cell lymphoma: a highly effective regimen. Leuk Lymphoma. 2011 Mar;52(3):387-93. Epub 2010 Dec 6. [https://doi.org/10.3109/10428194.2010.534518 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21133713 PubMed]
-# '''MCLelderly:''' Kluin-Nelemans HC, Hoster E, Hermine O, Walewski J, Trneny M, Geisler CH, Stilgenbauer S, Thieblemont C, Vehling-Kaiser U, Doorduijn JK, Coiffier B, Forstpointner R, Tilly H, Kanz L, Feugier P, Szymczyk M, Hallek M, Kremers S, Lepeu G, Sanhes L, Zijlstra JM, Bouabdallah R, Lugtenburg PJ, Macro M, Pfreundschuh M, Procházka V, Di Raimondo F, Ribrag V, Uppenkamp M, André M, Klapper W, Hiddemann W, Unterhalt M, Dreyling MH. Treatment of older patients with mantle-cell lymphoma. N Engl J Med. 2012 Aug 9;367(6):520-31. [https://doi.org/10.1056/NEJMoa1200920 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22873532 PubMed] NCT00209209
-## '''Update:''' Kluin-Nelemans HC, Hoster E, Hermine O, Walewski J, Geisler CH, Trneny M, Stilgenbauer S, Kaiser F, Doorduijn JK, Salles G, Szymczyk M, Tilly H, Kanz L, Schmidt C, Feugier P, Thieblemont C, Zijlstra JM, Ribrag V, Klapper W, Pott C, Unterhalt M, Dreyling MH. Treatment of Older Patients With Mantle Cell Lymphoma (MCL): Long-Term Follow-Up of the Randomized European MCL Elderly Trial. J Clin Oncol. 2020 Jan 20;38(3):248-256. Epub 2019 Dec 5. [https://doi.org/10.1200/jco.19.01294 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31804876 PubMed]
-# Räty R, Honkanen T, Jantunen E, Jyrkkiö S, Karjalainen-Lindsberg ML, Kuittinen O, Lehto M, Mikkola M, Poikonen E, Rauhala A, Rimpiläinen J, Räsänen A, Siitonen S, Suominen M, Vapaatalo M, Elonen E; Finnish Lymphoma Group. Prolonged immunochemotherapy with rituximab, cytarabine and fludarabine added to cyclophosphamide, doxorubicin, vincristine and prednisolone and followed by rituximab maintenance in untreated elderly patients with mantle cell lymphoma: a prospective study by the Finnish Lymphoma Group. Leuk Lymphoma. 2012 Oct;53(10):1920-8. Epub 2012 Apr 23. [https://doi.org/10.3109/10428194.2012.672736 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22397313 PubMed]
-## '''Update: Abstract:''' Riikka Räty, Tuomo Honkanen, Esa Jantunen, MD, PhD, Sirkku Jyrkkiö, Marja-Liisa Karjalainen-Lindsberg, MD, PhD, Outi Kuittinen, Minna Lehto, Maija Mikkola, Eira Poikonen, Auvo Rauhala, Johanna Rimpiläinen, Anu Räsänen, MD, Sanna Siitonen, Merja Suominen, MD, Mirja Vapaatalo and Erkki Elonen. Rituximab Maintenance Bimonthly for Two Years after Prolonged Immunochemotherapy in Elderly Patients with Mantle Cell Lymphoma (MCL) Results in Long Remissions: Update with Six-Year Follow-up of a Prospective Study By the Finnish Lymphoma Group. Blood 2014 124:1749. [http://www.bloodjournal.org/content/124/21/1749 link to abstract]
-# '''ECOG E1405:''' Chang JE, Li H, Smith MR, Gascoyne RD, Paietta EM, Yang DT, Advani RH, Horning SJ, Kahl BS. Phase 2 study of VcR-CVAD with maintenance rituximab for untreated mantle cell lymphoma: an Eastern Cooperative Oncology Group study (E1405). Blood. 2014 Mar 13;123(11):1665-73. Epub 2014 Jan 23. [http://www.bloodjournal.org/content/123/11/1665.full link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3954048/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24458437 PubMed] NCT00433537
-<!-- # '''Abstract:''' Steven Le Gouill, MD, PhD, Catherine Thieblemont, MD, PhD, Lucie Oberic, Krimo Bouabdallah, MD, Emmanuel Gyan, MD, PhD, Gandhi Damaj, MD, Vincent Ribrag, MD, Serge Bologna, MD, Remy Gressin, MD, Olivier Casasnovas, MD, Corinne Haioun, MD, PhD, Philippe Solal-Celigny, MD, Herve Maisonneuve, MD, Eric Van Den Neste, MD, PhD, Anne Moreau, MD, Marie C Bene, Gilles Salles, MD PhD, Hervé Tilly, MD, PhD, Thierry Lamy, MD, PhD and Olivier Hermine, MD, PhD. Rituximab Maintenance Versus Wait and Watch after Four Courses of R-DHAP Followed By Autologous Stem Cell transplantation in Previously Untreated Young Patients with Mantle Cell Lymphoma: First Interim Analysis of the Phase III Prospective Lyma Trial, a Lysa Study. Blood 2014 124:146. [http://www.bloodjournal.org/content/124/21/146 link to abstract] -->
-# '''LyMa:''' Le Gouill S, Thieblemont C, Oberic L, Moreau A, Bouabdallah K, Dartigeas C, Damaj G, Gastinne T, Ribrag V, Feugier P, Casasnovas O, Zerazhi H, Haioun C, Maisonneuve H, Houot R, Jardin F, Van Den Neste E, Tournilhac O, Le Dû K, Morschhauser F, Cartron G, Fornecker LM, Canioni D, Callanan M, Béné MC, Salles G, Tilly H, Lamy T, Gressin R, Hermine O; LYSA. Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma. N Engl J Med. 2017 Sep 28;377(13):1250-1260. [https://doi.org/10.1056/NEJMoa1701769 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28953447 PubMed] NCT00921414
-#'''ECOG-ACRIN EA4151:''' NCT03267433
-=Relapsed or refractory, randomized data=
-==Acalabrutinib monotherapy {{#subobject:548dbb|Regimen=1}}==
-<div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:32f303|Variant=1}}===
-{| class="wikitable" style="color:white; background-color:#404040"
-|<small>'''FDA-recommended dose'''</small>
-|-
-|}
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7864374/ Wang et al. 2017 (ACE-LY-004)]
-|2015-2016
-|style="background-color:#91cf61"|Phase 2 (RT)
-|style="background-color:#d3d3d3"|
-| style="background-color:#e0ecf4" |ORR: 81% (95% CI: 73-87)
-|-
-|Awaiting publication (BRUIN MCL-321)
-|2021-2025
-| style="background-color:#1a9851" |Phase 3 (C)
-|[[#Pirtobrutinib_monotherapy_77|Pirtobrutinib]]
-| style="background-color:#d3d3d3" |TBD
-|-
-|}
-<div class="toccolours" style="background-color:#fdcdac">
-====Prior treatment criteria====
-*BRUIN MCL-321: 1 or more lines of therapy and are BTK inhibitor naïve
-</div>
-<div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
-*[[Acalabrutinib (Calquence)]] 100 mg PO twice per day
-'''Continued indefinitely'''
-</div></div>
-===References===
-# '''ACE-LY-004:''' Wang M, Rule S, Zinzani PL, Goy A, Casasnovas O, Smith SD, Damaj G, Doorduijn J, Lamy T, Morschhauser F, Panizo C, Shah B, Davies A, Eek R, Dupuis J, Jacobsen E, Kater AP, Le Gouill S, Oberic L, Robak T, Covey T, Dua R, Hamdy A, Huang X, Izumi R, Patel P, Rothbaum W, Slatter JG, Jurczak W. Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial. Lancet. 2018 Feb 17;391(10121):659-667. Epub 2017 Dec 11. [https://doi.org/10.1016/S0140-6736(17)33108-2 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7864374/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29241979 PubMed] NCT02213926
-# '''BRUIN MCL-321:''' NCT04662255
-==BCHOP {{#subobject:3dbcd7|Regimen=1}}==
-BCHOP: '''<u>B</u>'''ortezomib, '''<u>C</u>'''yclophosphamide, '''<u>H</u>'''ydroxydaunorubicin (Doxorubicin), '''<u>O</u>'''ncovin (Vincristine), '''<u>P</u>'''rednisolone
-<div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:a32960|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1111/bjh.13101 Furtado et al. 2014 (NCRN-Ply-26s)]
-|2007-2011
-|style="background-color:#1a9851"|Randomized Phase 2 (E-esc)
-|[[Mantle_cell_lymphoma_-_historical#CHOP_.28Prednisolone.29|CHOP]]
-| style="background-color:#1a9850" |Superior OS<br>Median OS: 35.6 vs 11.8 mo<br>(HR 0.37, 95% CI 0.16-0.83)
-|-
-|}
-<div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
-*[[Bortezomib (Velcade)]] 1.6 mg/m<sup>2</sup> IV once per day on days 1 & 8
-====Chemotherapy====
-*[[Cyclophosphamide (Cytoxan)]] 750 mg/m<sup>2</sup> IV once on day 1
-*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV once on day 1
-*[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1
 ====Glucocorticoid therapy====
-*[[Prednisolone (Millipred)]] 100 mg PO once per day on days 1 to 5
+*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 5
-====Supportive therapy====
+'''28-day cycles, continue until 24 months from diagnosis'''
-*[[Acyclovir (Zovirax)]] 400 mg PO twice per day
-'''21-day cycle for up to 8 cycles'''
 </div></div>
 ===References===
-<!-- Previously presented in part (in poster form) at the 17th Congress of the European Haematology Association, June 2012 and orally at the BSH annual scientific meeting 2013. -->
+# '''CALGB 8811:''' Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR, Hooberman AL, Westbrook CA, Arthur DC, George SL, Bloomfield CD, Schiffer CA. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: Cancer and Leukemia Group B study 8811. Blood. 1995 Apr 15;85(8):2025-37. [http://www.bloodjournal.org/content/85/8/2025.full.pdf+html link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/7718875 PubMed]
-# '''NCRN-Ply-26s:''' Furtado M, Johnson R, Kruger A, Turner D, Rule S. Addition of bortezomib to standard dose chop chemotherapy improves response and survival in relapsed mantle cell lymphoma. Br J Haematol. 2015 Jan;168(1):55-62. Epub 2014 Aug 22. [https://doi.org/10.1111/bjh.13101 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25146720 PubMed] NCT00513955
+# Kantarjian HM, O'Brien S, Smith TL, Cortes J, Giles FJ, Beran M, Pierce S, Huh Y, Andreeff M, Koller C, Ha CS, Keating MJ, Murphy S, Freireich EJ. Results of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia. J Clin Oncol. 2000 Feb;18(3):547-61. [https://doi.org/10.1200/jco.2000.18.3.547 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/10653870 PubMed]
-==Bendamustine & Rituximab (BR) {{#subobject:3a2a8c|Regimen=1}}==
+## '''Update:''' Kantarjian H, Thomas D, O'Brien S, Cortes J, Giles F, Jeha S, Bueso-Ramos CE, Pierce S, Shan J, Koller C, Beran M, Keating M, Freireich EJ. Long-term follow-up results of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD), a dose-intensive regimen, in adult acute lymphocytic leukemia. Cancer. 2004 Dec 15;101(12):2788-801. [https://doi.org/10.1002/cncr.20668 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15481055 PubMed]
-BR: '''<u>B</u>'''endamustine, '''<u>R</u>'''ituximab
+# '''MRC UKALL XII/ECOG E2993:''' Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. [http://www.bloodjournal.org/content/106/12/3760.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16105981 PubMed] NCT00002514
+## '''Update:''' Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, Burnett AK, Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J, McMillan A, Franklin IM, Luger S, Ciobanu N, Rowe JM. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008 Feb 15;111(4):1827-33. Epub 2007 Nov 29. [http://www.bloodjournal.org/content/111/4/1827.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/18048644 PubMed]
+## '''Update:''' Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, Marks DI, McMillan AK, Litzow MR, Lazarus HM, Foroni L, Dewald G, Franklin IM, Luger SM, Paietta E, Wiernik PH, Tallman MS, Goldstone AH. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009 May 7;113(19):4489-96. Epub 2009 Feb 24. [http://www.bloodjournal.org/content/113/19/4489.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4188540/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19244158 PubMed]
+## '''Update:''' Fielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow MR, Lazarus H, Luger SM, Marks DI, McMillan AK, Moorman AV, Patel B, Paietta E, Tallman MS, Goldstone AH. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014 Feb 6;123(6):843-50. Epub 2013 Nov 25. [http://www.bloodjournal.org/content/123/6/843.full link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3916877/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24277073 PubMed]
+# '''GRAALL-2003:''' Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. [https://doi.org/10.1200/JCO.2008.18.6916 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19124805 PubMed] NCT00222027
+=Relapsed or refractory=
+==Augmented Hyper-CVAD & Asparaginase {{#subobject:aab460|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #1 {{#subobject:ad6e9d|Variant=1}}===
+===Regimen {{#subobject:d89fd9|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
+{| class="wikitable" style="width: 40%; text-align:center;"
-!style="width: 20%"|Study
+!style="width: 25%"|Study
-!style="width: 20%"|Years of enrollment
+!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[http://link.springer.com/article/10.1007/s00277-015-2478-9 Czuczman et al. 2015]
+|[http://www.clinical-lymphoma-myeloma-leukemia.com/article/S2152-2650(11)70128-8 Faderl et al. 2011]
-|NR
 |style="background-color:#91cf61"|Phase 2
-|style="background-color:#d3d3d3"|
-|style="background-color:#d3d3d3"|
-|-
-|[https://doi.org/10.1016/S1470-2045(15)00447-7 Rummel et al. 2015 (StiL NHL 2-2003)]
-|2003-2010
-|style="background-color:#1a9851"|Phase 3 (E-switch-ic)
-|[[Mantle_cell_lymphoma_-_historical#Fludarabine_.26_Rituximab_.28FR.29|FR]]
-|style="background-color:#91cf60"|Seems to have superior OS
 |-
 |}
-<div class="toccolours" style="background-color:#b3e2cd">
+To be completed
 ====Chemotherapy====
-*[[Bendamustine]] 90 mg/m<sup>2</sup> IV once per day on days 1 & 2
+*[[Cyclophosphamide (Cytoxan)]]
-====Targeted therapy====
+*[[Vincristine (Oncovin)]]
-*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1
+*[[Doxorubicin (Adriamycin)]]
-====Supportive therapy====
+*[[Pegaspargase (Oncaspar)]]
-*Analgesics and antipyretics prior to each dose of [[Rituximab (Rituxan)]]
+====Glucocorticoid therapy====
-'''28-day cycle for 6 to 8 cycles'''
+*[[Dexamethasone (Decadron)]]
-</div></div><br>
-<div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #2 {{#subobject:3f43c5|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
-!style="width: 33%"|Study
-!style="width: 33%"|Years of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://doi.org/10.1200/jco.2005.08.100 Rummel et al. 2005]
-|2000-2003
-|style="background-color:#ffffbe"|Phase 2, <20 pts in subgroup
-|-
-|[https://doi.org/10.1200/jco.2008.17.0001 Robinson et al. 2008 (SDX-105-01)]
-|2004-2005
-|style="background-color:#ffffbe"|Phase 2, <20 pts in subgroup
-|-
-|}
-''Note: Robinson et al. 2008 said that patients "could receive up to six cycles if disease regression was evident between the second and fourth cycles".''
-<div class="toccolours" style="background-color:#b3e2cd">
-====Chemotherapy====
-*[[Bendamustine]] 90 mg/m<sup>2</sup> IV once per day on days 2 & 3
-====Targeted therapy====
-*[[Rituximab (Rituxan)]] as follows:
-**One week prior to start of cycle 1: 375 mg/m<sup>2</sup> IV once
-**Cycles 1 to 4: 375 mg/m<sup>2</sup> IV once on day 1
-**4 weeks after cycle 4: 375 mg/m<sup>2</sup> IV once
-'''28-day cycle for 4 cycles (Rummel et al. 2005) or up to 6 cycles (SDX-105-01; see note)'''
-</div></div>
-===References===
-<!-- No prepublication disclosed -->
-# Rummel MJ, Al-Batran SE, Kim SZ, Welslau M, Hecker R, Kofahl-Krause D, Josten KM, Dürk H, Rost A, Neise M, von Grünhagen U, Chow KU, Hansmann ML, Hoelzer D, Mitrou PS. Bendamustine plus rituximab is effective and has a favorable toxicity profile in the treatment of mantle cell and low-grade non-Hodgkin's lymphoma. J Clin Oncol. 2005 May 20;23(15):3383-9. [https://doi.org/10.1200/jco.2005.08.100 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15908650 PubMed]
-<!-- Preliminary results were presented at the 48th Annual Meeting of the American Society of Hematology, December 9-12, 2006, Orlando, FL. -->
-# '''SDX-105-01:''' Robinson KS, Williams ME, van der Jagt RH, Cohen P, Herst JA, Tulpule A, Schwartzberg LS, Lemieux B, Cheson BD. Phase II multicenter study of bendamustine plus rituximab in patients with relapsed indolent B-cell and mantle cell non-Hodgkin's lymphoma. J Clin Oncol. 2008 Sep 20;26(27):4473-9. Epub 2008 Jul 14. [https://doi.org/10.1200/jco.2008.17.0001 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18626004 PubMed] NCT00069758
-# Czuczman MS, Goy A, Lamonica D, Graf DA, Munteanu MC, van der Jagt RH. Phase II study of bendamustine combined with rituximab in relapsed/refractory mantle cell lymphoma: efficacy, tolerability, and safety findings. Ann Hematol. 2015 Dec;94(12):2025-32. Epub 2015 Sep 28. [http://link.springer.com/article/10.1007/s00277-015-2478-9 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26411584 PubMed]
-<!-- # '''Abstract:''' Mathias J. Rummel, MD, PhD, Ulrich Kaiser, MD, Christina Balser, Martina Beate Stauch, Wolfram Brugger, MD, PhD, Manfred Welslau, Norbert Niederle, Christoph Losem, Harald Ballo, Eckhart Weidmann, Ulrich von Gruenhagen, Lothar Mueller, Michael Sandherr, MD, Julia Vereschagina, Axel Hinke and Juergen Barth. Bendamustine Plus Rituximab Versus Fludarabine Plus Rituximab In Patients with Relapsed Follicular, Indolent and Mantle Cell Lymphomas – Final Results of the Randomized Phase III Study NHL 2-2003 on Behalf of the StiL (Study Group Indolent Lymphomas, Germany). ASH Annual Meeting 2010, Abstract 856 [https://ash.confex.com/ash/2010/webprogram/Paper26917.html link to abstract]
-## '''Update:''' '''Abstract:''' Mathias J. Rummel, MD, Christina Balser, MD, Ulrich Kaiser, MD, Hans Peter Böck, Martina Beate Stauch, MD, Andrea Heider, PhD, Manfred Welslau, Christoph Losem, Eckhart Weidmann, Wolfgang Blau, MD, Alexander Burchardt, MD, Jürgen Barth, Frank Kauff, PhD, Axel Hinke, PhD and Wolfram Brugger, MD. Bendamustine Plus Rituximab Versus Fludarabine Plus Rituximab in Patients with Relapsed Follicular, Indolent, or Mantle Cell Lymphomas – 8-Year Follow-up Results of the Randomized Phase III Study NHL 2-2003 on Behalf of the StiL (Study Group Indolent Lymphomas, Germany). ASH Annual Meeting 2014, Abstract 145 [https://ash.confex.com/ash/2014/webprogram/Paper69154.html link to abstract] -->
-# '''StiL NHL 2-2003:''' Rummel M, Kaiser U, Balser C, Stauch M, Brugger W, Welslau M, Niederle N, Losem C, Boeck HP, Weidmann E, von Gruenhagen U, Mueller L, Sandherr M, Hahn L, Vereshchagina J, Kauff F, Blau W, Hinke A, Barth J; StiL. Bendamustine plus rituximab versus fludarabine plus rituximab for patients with relapsed indolent and mantle-cell lymphomas: a multicentre, randomised, open-label, non-inferiority phase 3 trial. Lancet Oncol. 2016 Jan;17(1):57-66. Epub 2015 Dec 5. [https://doi.org/10.1016/S1470-2045(15)00447-7 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/26655425 PubMed] NCT01456351
-==Cladribine monotherapy {{#subobject:340f61|Regimen=1}}==
-<div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:50be81|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3465670/ Inwards et al. 2008 (NCCTG 95-80-53)]
-|2003-2005
-|style="background-color:#ffffbe"|Phase 2, <20 pts
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|-
-|rowspan=2|[https://doi.org/10.1200/jco.2008.20.7977 Hess et al. 2009 (OPTIMAL<sub>MCL</sub>)]
-|rowspan=2|2005-2007
-|rowspan=2 style="background-color:#1a9851"|Phase 3 (C)
-|1. [[#Temsirolimus_monotherapy|Temsirolimus]]; 175/25
-| style="background-color:#fee08b" |Might have inferior PFS
-|-
-|2. [[#Temsirolimus_monotherapy|Temsirolimus]]; 175 -> 75
-| style="background-color:#d73027" |Inferior PFS
-|-
-|}
-<div class="toccolours" style="background-color:#b3e2cd">
-====Chemotherapy====
-*[[Cladribine (Leustatin)]] 5 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 to 5
-'''28-day cycle for up to 6 cycles'''
-</div></div>
-===References===
-# '''NCCTG 95-80-53:''' Inwards DJ, Fishkin PA, Hillman DW, Brown DW, Ansell SM, Kurtin PJ, Fonseca R, Morton RF, Veeder MH, Witzig TE. Long-term results of the treatment of patients with mantle cell lymphoma with cladribine (2-CDA) alone (95-80-53) or 2-CDA and rituximab (N0189) in the North Central Cancer Treatment Group. Cancer. 2008 Jul 1;113(1):108-16. [https://doi.org/10.1002/cncr.23537 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3465670/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18470909 PubMed]
-# '''OPTIMAL:''' Hess G, Herbrecht R, Romaguera J, Verhoef G, Crump M, Gisselbrecht C, Laurell A, Offner F, Strahs A, Berkenblit A, Hanushevsky O, Clancy J, Hewes B, Moore L, Coiffier B. Phase III study to evaluate temsirolimus compared with investigator's choice therapy for the treatment of relapsed or refractory mantle cell lymphoma. J Clin Oncol. 2009 Aug 10;27(23):3822-9. Epub 2009 Jul 6. [https://doi.org/10.1200/jco.2008.20.7977 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19581539 PubMed] NCT00117598
-==Ibrutinib monotherapy {{#subobject:1e0d5c|Regimen=1}}==
-<div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:529650|Variant=1}}===
-{| class="wikitable" style="color:white; background-color:#404040"
-|<small>'''FDA-recommended dose'''</small>
-|-
-|}
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 17%"|Study
-!style="width: 15%"|Years of enrollment
-!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 17%"|Comparator
-!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4513941/ Wang et al. 2013 (PCYC-1104-CA)]
-|2011-2012
-|style="background-color:#91cf61"|Phase 2 (RT)
-|style="background-color:#d3d3d3"|
-|style="background-color:#d3d3d3"|
-|style="background-color:#d3d3d3"|
-|-
-|[https://doi.org/10.1016/S0140-6736(15)00667-4 Dreyling et al. 2015 (RAY)]
-|2012-2013
-|style="background-color:#1a9851"|Phase 3 (E-switch-ic)
-|[[#Temsirolimus_monotherapy|Temsirolimus]]
-| style="background-color:#d9ef8b" |Might have superior OS<sup>1</sup><br>Median OS: 30.3 vs 23.5 mo<br>(HR 0.74, 95% CI 0.54-1.02)
-|style="background-color:#1a9850"|Improved HRQoL
-|-
-|Awaiting publication (BRUIN MCL-321)
-|2021-2025
-| style="background-color:#1a9851" |Phase 3 (C)
-|[[#Pirtobrutinib_monotherapy_77|Pirtobrutinib]]
-| style="background-color:#d3d3d3" |TBD
-|style="background-color:#d3d3d3"|TBD
-|-
-|}
-''<sup>1</sup>Reported efficacy is based on the 2018 update.''
-<div class="toccolours" style="background-color:#fdcdac">
-====Prior treatment criteria====
-*BRUIN MCL-321: 1 or more lines of therapy and are BTK inhibitor naïve
-</div>
-<div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
-*[[Ibrutinib (Imbruvica)]] 560 mg PO once per day
-'''Continued indefinitely'''
 </div></div>
 ===References===
-# '''PCYC-1104-CA:''' Wang ML, Rule S, Martin P, Goy A, Auer R, Kahl BS, Jurczak W, Advani RH, Romaguera JE, Williams ME, Barrientos JC, Chmielowska E, Radford J, Stilgenbauer S, Dreyling M, Jedrzejczak WW, Johnson P, Spurgeon SE, Li L, Zhang L, Newberry K, Ou Z, Cheng N, Fang B, McGreivy J, Clow F, Buggy JJ, Chang BY, Beaupre DM, Kunkel LA, Blum KA. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013 Aug 8;369(6):507-16. Epub 2013 Jun 19. [https://doi.org/10.1056/NEJMoa1306220 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4513941/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23782157 PubMed] NCT01236391
+# Faderl S, Thomas DA, O'Brien S, Ravandi F, Garcia-Manero G, Borthakur G, Ferrajoli A, Verstovsek S, Ayoubi M, Rytting M, Feliu J, Kantarjian HM. Augmented hyper-CVAD based on dose-intensified vincristine, dexamethasone, and asparaginase in adult acute lymphoblastic leukemia salvage therapy. Clin Lymphoma Myeloma Leuk. 2011 Feb;11(1):54-9. [http://www.clinical-lymphoma-myeloma-leukemia.com/article/S2152-2650(11)70128-8 link to original article] [https://pubmed.ncbi.nlm.nih.gov/21454191 PubMed]
-<!-- ## '''Update: Abstract:''' Michael Wang, MD, Simon Rule, MD, Peter Martin, MD, Andre Goy, MD, Rebecca Auer, MD, PhD, Brad S. Kahl, MD, Wojciech Jurczak, Ranjana Advani, MD, Jorge E. Romaguera, MD, Michael E. Williams, MD, Jacqueline C. Barrientos, M.D., Ewa Chmielowska, MD, John Radford, Stephan Stilgenbauer, MD, Martin Dreyling, Wieslaw Wiktor Jedrzejczak, MD, Peter W Johnson, MD, Stephen E. Spurgeon, MD, Liang Zhang, MD, PhD, Linda Baher, Mei Cheng, PhD, Darrin M. Beaupre, MD and Kristie A. Blum, MD. Single-Agent Ibrutinib Demonstrates Safety and Durability of Response at 2 Years Follow-up in Patients with Relapsed or Refractory Mantle Cell Lymphoma: Updated Results of an International, Multicenter, Open-Label Phase 2 Study. Blood 2014 124:4453. [http://www.bloodjournal.org/content/124/21/4453 link to abstract] -->
+==Blinatumomab monotherapy {{#subobject:e7b2c6|Regimen=1}}==
-## '''Update:''' Wang ML, Blum KA, Martin P, Goy A, Auer R, Kahl BS, Jurczak W, Advani RH, Romaguera JE, Williams ME, Barrientos JC, Chmielowska E, Radford J, Stilgenbauer S, Dreyling M, Jedrzejczak WW, Johnson P, Spurgeon SE, Zhang L, Baher L, Cheng M, Lee D, Beaupre DM, Rule S. Long-term follow-up of MCL patients treated with single-agent ibrutinib: updated safety and efficacy results. Blood. 2015 Aug 6;126(6):739-45. Epub 2015 Jun 9. [http://www.bloodjournal.org/content/126/6/739 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4528064/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26059948 PubMed]
-# '''RAY:''' Dreyling M, Jurczak W, Jerkeman M, Silva RS, Rusconi C, Trneny M, Offner F, Caballero D, Joao C, Witzens-Harig M, Hess G, Bence-Bruckler I, Cho SG, Bothos J, Goldberg JD, Enny C, Traina S, Balasubramanian S, Bandyopadhyay N, Sun S, Vermeulen J, Rizo A, Rule S. Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an international, randomised, open-label, phase 3 study. Lancet. 2016 Feb 20;387(10020):770-8. Epub 2015 Dec 4. Erratum in: Lancet. 2016 Feb 20;387(10020):750.[https://doi.org/10.1016/S0140-6736(15)00667-4 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26673811 PubMed] NCT01646021
-## '''HRQoL analysis:''' Hess G, Rule S, Jurczak W, Jerkeman M, Santucci Silva R, Rusconi C, Caballero D, Joao C, Witzens-Harig M, Bence-Bruckler I, Cho SG, Zhou W, Goldberg JD, Trambitas C, Enny C, Vermeulen J, Traina S, Chiou CF, Diels J, Dreyling M. Health-related quality of life data from a phase 3, international, randomized, open-label, multicenter study in patients with previously treated mantle cell lymphoma treated with ibrutinib versus temsirolimus. Leuk Lymphoma. 2017 Dec;58(12):2824-2832. Epub 2017 May 30. [https://doi.org/10.1080/10428194.2017.1326034 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28556689 PubMed]
-## '''Update:''' Rule S, Jurczak W, Jerkeman M, Rusconi C, Trneny M, Offner F, Caballero D, Joao C, Witzens-Harig M, Hess G, Bence-Bruckler I, Cho SG, Thieblemont C, Zhou W, Henninger T, Goldberg J, Vermeulen J, Dreyling M. Ibrutinib versus temsirolimus: 3-year follow-up of patients with previously treated mantle cell lymphoma from the phase 3, international, randomized, open-label RAY study. Leukemia. 2018 Aug;32(8):1799-1803. Epub 2018 Feb 2. [https://www.nature.com/articles/s41375-018-0023-2 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6087720/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29572505 PubMed]
-# '''BRUIN MCL-321:''' NCT04662255
-==Lenalidomide monotherapy {{#subobject:b5de78|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:2d2b4a|Variant=1}}===
+===Regimen variant #1 {{#subobject:2db105|Variant=1}}===
 {| class="wikitable" style="color:white; background-color:#404040"
 |<small>'''FDA-recommended dose'''</small>
@@ Line 2,110: / Line 1,806: @@
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1200/jco.2007.15.3429 Wiernik et al. 2008 (CC-5013-NHL-002)]
+|[https://doi.org/10.1016/S1470-2045(14)71170-2 Topp et al. 2014 (MT103-211)]
-|2005-2006
+|2012-2013
-|style="background-color:#ffffbe"|Phase 2, <20 pts in subgroup
-|style="background-color:#d3d3d3"|
-|style="background-color:#d3d3d3"|
-|-
-|[https://doi.org/10.1093/annonc/mdq626 Witzig et al. 2011 (NHL-003)]
-|2006-2008
-|style="background-color:#91cf61"|Phase 2
-|style="background-color:#d3d3d3"|
-|style="background-color:#d3d3d3"|
-|-
-|[https://doi.org/10.1111/bjh.12008 Eve et al. 2012]
-|2008-2010
-|style="background-color:#91cf61"|Phase 2
-|style="background-color:#d3d3d3"|
-|style="background-color:#d3d3d3"|
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879693/ Goy et al. 2013 (EMERGE)]
-|2009-2012
 |style="background-color:#91cf61"|Phase 2 (RT)
 |style="background-color:#d3d3d3"|
 |style="background-color:#d3d3d3"|
 |-
-|[https://doi.org/10.1016/S1470-2045(15)00559-8 Trněný et al. 2016 (SPRINT)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5881572/ Kantarjian et al. 2017 (TOWER)]
-|2009-2013
+|2014-2015
-|style="background-color:#1a9851"|Randomized Phase 2 (E-switch-ooc)
+|style="background-color:#1a9851"|Phase 3 (E-RT-switch-ooc)
-|Investigator's choice of:<br>1. [[#Chlorambucil_monotherapy_88|Chlorambucil]]<br>2. [[#Cytarabine_monotherapy_88|Cytarabine]]<br>3. [[#Fludarabine_monotherapy_88|Fludarabine]]<br>4. [[#Gemcitabine_monotherapy_88|Gemcitabine]]<br>5. [[#Rituximab_monotherapy_88|Rituximab]]
+|Standard re-induction chemotherapy
-|style="background-color:#1a9850"|Superior PFS<br>Median PFS: 8.7 vs 5.2 mo<br>(HR 0.61, 95% CI 0.44-0.84)
-|-
-|}
-''Note: Participants in EMERGE "were required to have had prior treatment with rituximab, cyclophosphamide and anthracycline (or mitoxantrone), and to have relapsed or progressed (less than 12 months) after or were refractory to bortezomib." Investigator's choice in the SPRINT trial was restricted to single-agent therapy with cytarabine, rituximab, gemcitabine, fludarabine, or chlorambucil.''
-<div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
-*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21
-'''28-day cycles'''
-</div>
-<div class="toccolours" style="background-color:#cbd5e7">
-====Subsequent treatment====
-*Eve et al. 2012: [[#Lenalidomide_monotherapy_3|Lenalidomide]] maintenance after 6 cycles
-</div></div>
-===References===
-<!-- Presented in part as oral presentations at the 48th Annual Meeting of the American Society of Hematology, December 9-12, 2006, Orlando, FL, and the 3rd International Conference of Innovative Therapies for Lymphoid Malignancies, September 28, 2006, Palermo, Italy; and as poster presentations at the 48th Annual Meeting of the American Society of Hematology, December 9-12, 2006, Orlando, FL, the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL; and the Pan Pacific Lymphoma Conference, June 11-15, 2007, Maui, HI. -->
-# '''CC-5013-NHL-002:''' Wiernik PH, Lossos IS, Tuscano JM, Justice G, Vose JM, Cole CE, Lam W, McBride K, Wride K, Pietronigro D, Takeshita K, Ervin-Haynes A, Zeldis JB, Habermann TM. Lenalidomide monotherapy in relapsed or refractory aggressive non-Hodgkin's lymphoma. J Clin Oncol. 2008 Oct 20;26(30):4952-7. Epub 2008 Jul 7. [https://doi.org/10.1200/jco.2007.15.3429 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18606983 PubMed] NCT00179660
-## '''Update:''' Habermann TM, Lossos IS, Justice G, Vose JM, Wiernik PH, McBride K, Wride K, Ervin-Haynes A, Takeshita K, Pietronigro D, Zeldis JB, Tuscano JM. Lenalidomide oral monotherapy produces a high response rate in patients with relapsed or refractory mantle cell lymphoma. Br J Haematol. 2009 May;145(3):344-9. Epub 2009 Feb 24. [https://doi.org/10.1111/j.1365-2141.2009.07626.x link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19245430 PubMed]
-## '''Pooled update:''' Witzig TE, Zinzani PL, Habermann TM, Tuscano JM, Drach J, Ramchandren R, Kalayoglu Besisik S, Takeshita K, Casadebaig Bravo ML, Zhang L, Fu T, Goy A. Long-term analysis of phase II studies of single-agent lenalidomide in relapsed/refractory mantle cell lymphoma. Am J Hematol. 2017 Oct;92(10):E575-E583. Epub 2017 Aug 28. [https://doi.org/10.1002/ajh.24854 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28699256 PubMed]
-# '''NHL-003:''' Witzig TE, Vose JM, Zinzani PL, Reeder CB, Buckstein R, Polikoff JA, Bouabdallah R, Haioun C, Tilly H, Guo P, Pietronigro D, Ervin-Haynes AL, Czuczman MS. An international phase II trial of single-agent lenalidomide for relapsed or refractory aggressive B-cell non-Hodgkin's lymphoma. Ann Oncol. 2011 Jul;22(7):1622-7. Epub 2011 Jan 12. [https://doi.org/10.1093/annonc/mdq626 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21228334 PubMed] NCT00413036
-## '''Update:''' Zinzani PL, Vose JM, Czuczman MS, Reeder CB, Haioun C, Polikoff J, Tilly H, Zhang L, Prandi K, Li J, Witzig TE. Long-term follow-up of lenalidomide in relapsed/refractory mantle cell lymphoma: subset analysis of the NHL-003 study. Ann Oncol. 2013 Nov;24(11):2892-7. Epub 2013 Sep 12. [https://doi.org/10.1093/annonc/mdt366 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3811905/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24030098 PubMed]
-## '''Pooled update:''' Witzig TE, Zinzani PL, Habermann TM, Tuscano JM, Drach J, Ramchandren R, Kalayoglu Besisik S, Takeshita K, Casadebaig Bravo ML, Zhang L, Fu T, Goy A. Long-term analysis of phase II studies of single-agent lenalidomide in relapsed/refractory mantle cell lymphoma. Am J Hematol. 2017 Oct;92(10):E575-E583. Epub 2017 Aug 28. [https://doi.org/10.1002/ajh.24854 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28699256 PubMed]
-# Eve HE, Carey S, Richardson SJ, Heise CC, Mamidipudi V, Shi T, Radford JA, Auer RL, Bullard SH, Rule SA. Single-agent lenalidomide in relapsed/refractory mantle cell lymphoma: results from a UK phase II study suggest activity and possible gender differences. Br J Haematol. 2012 Oct;159(2):154-63. Epub 2012 Aug 9. [https://doi.org/10.1111/bjh.12008 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22881386 PubMed]
-<!-- Presented in part at the 54th American Society of Hematology Meeting and Exposition, Atlanta, GA, December 8-11, 2012. -->
-# '''EMERGE:''' Goy A, Sinha R, Williams ME, Kalayoglu Besisik S, Drach J, Ramchandren R, Zhang L, Cicero S, Fu T, Witzig TE. Single-agent lenalidomide in patients with mantle-cell lymphoma who relapsed or progressed after or were refractory to bortezomib: Phase II MCL-001 (EMERGE) study. J Clin Oncol. 2013 Oct 10;31(29):3688-95. Epub 2013 Sep 3. [https://doi.org/10.1200/jco.2013.49.2835 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879693/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24002500 PubMed] NCT00737529
-## '''Update:''' Goy A, Kalayoglu Besisik S, Drach J, Ramchandren R, Robertson MJ, Avivi I, Rowe JM, Herbrecht R, Van Hoof A, Zhang L, Cicero S, Fu T, Witzig T. Longer-term follow-up and outcome by tumour cell proliferation rate (Ki-67) in patients with relapsed/refractory mantle cell lymphoma treated with lenalidomide on MCL-001(EMERGE) pivotal trial. Br J Haematol. 2015 Aug;170(4):496-503. Epub 2015 Apr 28. [https://doi.org/10.1111/bjh.13456 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5029780/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25921098 PubMed]
-## '''Pooled update:''' Witzig TE, Zinzani PL, Habermann TM, Tuscano JM, Drach J, Ramchandren R, Kalayoglu Besisik S, Takeshita K, Casadebaig Bravo ML, Zhang L, Fu T, Goy A. Long-term analysis of phase II studies of single-agent lenalidomide in relapsed/refractory mantle cell lymphoma. Am J Hematol. 2017 Oct;92(10):E575-E583. Epub 2017 Aug 28. [https://doi.org/10.1002/ajh.24854 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28699256 PubMed]
-<!-- # '''Abstract:''' Marek Trneny, Thierry Lamy, Jan Walewski, Wojciech Jurczak, David Belada, MD, Jiri Mayer, Prof., MD, Ph.D., John Radford, Julia Alexeeva, Dzhelil Osmanov, Tsvetan Biyukov, Meera Patturajan, Marie-Laure Casadebaig Bravo and Luca Arcaini. Phase II Randomized, Multicenter Study of Lenalidomide Vs Best Investigator’s Choice in Relapsed/Refractory Mantle Cell Lymphoma: Results of the MCL-002 (SPRINT) Study. ASH Annual Meeting 2014 Abstract 627 [https://ash.confex.com/ash/2014/webprogram/Paper69212.html link to abstract] -->
-# '''SPRINT:''' Trněný M, Lamy T, Walewski J, Belada D, Mayer J, Radford J, Jurczak W, Morschhauser F, Alexeeva J, Rule S, Afanasyev B, Kaplanov K, Thyss A, Kuzmin A, Voloshin S, Kuliczkowski K, Giza A, Milpied N, Stelitano C, Marks R, Trümper L, Biyukov T, Patturajan M, Bravo MC, Arcaini L; SPRINT trial investigators and in collaboration with the European Mantle Cell Lymphoma Network. Lenalidomide versus investigator's choice in relapsed or refractory mantle cell lymphoma (MCL-002; SPRINT): a phase 2, randomised, multicentre trial. Lancet Oncol. 2016 Mar;17(3):319-31. Epub 2016 Feb 15. [https://doi.org/10.1016/S1470-2045(15)00559-8 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26899778 PubMed] NCT00875667
-==R-FCM {{#subobject:4f239|Regimen=1}}==
-R-FCM: '''<u>R</u>'''ituximab, '''<u>F</u>'''ludarabine, '''<u>C</u>'''yclophosphamide, '''<u>M</u>'''itoxantrone
-<div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:b06ce3|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[http://www.bloodjournal.org/content/104/10/3064.long Forstpointner et al. 2004]
-|1998-2001
-|style="background-color:#1a9851"|Phase 3 (E-esc)
-|[[Mantle_cell_lymphoma_-_historical#FCM|FCM]]
 |style="background-color:#1a9850"|Superior OS
 |-
 |}
-<div class="toccolours" style="background-color:#b3e2cd">
+''The most common comparator in TOWER was FLAG +/- anthracycline.''
-====Targeted therapy====
+====Immunotherapy====
-*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day -1
+*[[Blinatumomab (Blincyto)]] as follows:
-====Chemotherapy====
+**Cycle 1: 9 mcg/day IV continuous infusion over 7 days, started on day 1, then 28 mcg/day IV continuous infusion over 21 days, started on day 8 (total dose: 651 mcg)
-*[[Fludarabine (Fludara)]] 25 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 3
+**Cycles 2 to 5: 28 mcg/day IV continuous infusion over 28 days, started on day 1 (total dose per cycle: 784 mcg)
-*[[Cyclophosphamide (Cytoxan)]] 200 mg/m<sup>2</sup> IV over 4 hours once per day on days 1 to 3
+'''42-day cycle for up to 5 cycles''' (2 cycles for induction and 3 additional cycles for consolidation)
-*[[Mitoxantrone (Novantrone)]] 8 mg/m<sup>2</sup> IV over 30 minutes once on day 1
-'''28-day cycle for 4 cycles'''
 </div>
 <div class="toccolours" style="background-color:#cbd5e7">
 ====Subsequent treatment====
-*PR/CR: [[#Rituximab_monotherapy_2|Rituximab]] maintenance versus [[Mantle_cell_lymphoma_-_null_regimens#Observation_2|no further treatment]]
+*TOWER: Optional [[#Blinatumomab_monotherapy_3|blinatumomab]] maintenance
-</div></div>
-===References===
-# Forstpointner R, Dreyling M, Repp R, Hermann S, Hänel A, Metzner B, Pott C, Hartmann F, Rothmann F, Rohrberg R, Böck HP, Wandt H, Unterhalt M, Hiddemann W; German Low-Grade Lymphoma Study Group. The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. 2004 Nov 15;104(10):3064-71. Epub 2004 Jul 29. [http://www.bloodjournal.org/content/104/10/3064.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15284112 PubMed]
-## '''Update:''' Forstpointner R, Unterhalt M, Dreyling M, Böck HP, Repp R, Wandt H, Pott C, Seymour JF, Metzner B, Hänel A, Lehmann T, Hartmann F, Einsele H, Hiddemann W; German Low Grade Lymphoma Study Group. Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell lymphomas: Results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG). Blood. 2006 Dec 15;108(13):4003-8. Epub 2006 Aug 31. [http://www.bloodjournal.org/content/108/13/4003.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16946304 PubMed]
-==Temsirolimus monotherapy {{#subobject:575bde|Regimen=1}}==
-<div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #1, 25 mg {{#subobject:503d5|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
-!style="width: 33%"|Study
-!style="width: 33%"|Years of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3627208/ Ansell et al. 2008]
-|2004-2005
-|style="background-color:#91cf61"|Phase 2
-|-
-|}
-<div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
-*[[Temsirolimus (Torisel)]] 25 mg IV over 30 minutes once per day on days 1, 8, 15, 22
-====Supportive therapy====
-*[[Diphenhydramine (Benadryl)]] 25 to 50 mg IV once per day on days 1, 8, 15, 22, given prior to [[Temsirolimus (Torisel)]]
-'''28-day cycle for up to 13 cycles, stopped at various timepoints (see paper for details)'''
 </div></div><br>
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #2, 175 -> 75 {{#subobject:273d39|Variant=1}}===
+===Regimen variant #2 {{#subobject:aadee8|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
+{| class="wikitable" style="width: 40%; text-align:center;"
-!style="width: 17%"|Study
-!style="width: 15%"|Years of enrollment
-!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 17%"|Comparator
-!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
-|-
-|rowspan=2|[https://doi.org/10.1200/jco.2008.20.7977 Hess et al. 2009 (OPTIMAL<sub>MCL</sub>)]
-|rowspan=2|2005-2007
-|rowspan=2 style="background-color:#1a9851"|Phase 3 (E-switch-ooc)
-|Investigator's choice:<br>1. [[#Alemtuzumab_monotherapy|Alemtuzumab]]<br>2. [[#Chlorambucil_monotherapy|Chlorambucil]]<br>3. [[#Cladribine_monotherapy_2|Cladribine]]<br>4. [[#Etoposide_monotherapy|Etoposide]]<br>5. [[#Fludarabine_monotherapy|Fludarabine]]<br>6. [[#Gemcitabine_monotherapy|Gemcitabine]]<br>7. [[#Thalidomide_monotherapy|Thalidomide]]<br>8. [[#Vinblastine_monotherapy|Vinblastine]]
-|style="background-color:#1a9850"|Superior PFS<br>Median PFS: 4.8 vs 1.9 mo<br>(HR 0.44, 97.5% CI 0.25-0.78)
-|
-|-
-|9. [[#Temsirolimus_monotherapy|Temsirolimus]]; 175/25
-|style="background-color:#d3d3d3"|Not reported
-|
-|-
-|[https://doi.org/10.1016/S0140-6736(15)00667-4 Dreyling et al. 2015 (RAY)]
-|2012-2013
-|style="background-color:#1a9851"|Phase 3 (C)
-|[[#Ibrutinib_monotherapy|Ibrutinib]]
-| style="background-color:#fee08b" |Might have inferior OS<sup>1</sup>
-|style="background-color:#d73027"|Worse HRQoL
-|-
-|}
-''<sup>1</sup>Reported efficacy is based on the 2018 update.''<br>
-''Note: The most commonly compared regimens in OPTIMAL were single agent gemcitabine and single agent fludarabine. Note that OPTIMAL should not be confused with the trial by the same name in NSCLC.''
-<div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
-*[[Temsirolimus (Torisel)]] as follows:
-**Cycle 1: 175 mg IV over 30 to 60 minutes once per day on days 1, 8, 15
-**Cycle 2 onwards: 75 mg IV over 30 to 60 minutes once per day on days 1, 8, 15
-====Supportive therapy====
-*[[:Category:Antihistamines|Antihistamine]] once per day on days 1, 8, 15; 30 minutes prior to [[Temsirolimus (Torisel)]]
-*Corticosteroid use was not allowed in OPTIMAL.
-'''21-day cycles'''
-</div></div><br>
-<div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #3, 250 mg {{#subobject:ec06c7|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
-!style="width: 33%"|Study
-!style="width: 33%"|Years of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://doi.org/10.1200/jco.2005.13.466 Witzig et al. 2005]
-|2002-2003
-|style="background-color:#91cf61"|Phase 2
-|-
-|}
-<div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
-*[[Temsirolimus (Torisel)]] 250 mg IV over 30 minutes once per day on days 1, 8, 15, 22
-====Supportive therapy====
-*Use of white blood cell growth factors at physician discretion if neutropenia occurred.
-*Use of erythropoietin for anemia was allowed.
-'''28-day cycle for up to 13 cycles or 2 cycles past CR'''
-</div></div>
-===References===
-# Witzig TE, Geyer SM, Ghobrial I, Inwards DJ, Fonseca R, Kurtin P, Ansell SM, Luyun R, Flynn PJ, Morton RF, Dakhil SR, Gross H, Kaufmann SH. Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J Clin Oncol. 2005 Aug 10;23(23):5347-56. Epub 2005 Jun 27. [https://doi.org/10.1200/jco.2005.13.466 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15983389 PubMed]
-# Ansell SM, Inwards DJ, Rowland KM Jr, Flynn PJ, Morton RF, Moore DF Jr, Kaufmann SH, Ghobrial I, Kurtin PJ, Maurer M, Allmer C, Witzig TE; North Central Cancer Treatment Group. Low-dose, single-agent temsirolimus for relapsed mantle cell lymphoma: a phase 2 trial in the North Central Cancer Treatment Group. Cancer. 2008 Aug 1;113(3):508-14. [https://doi.org/10.1002/cncr.23580 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3627208/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18543327 PubMed]
-# '''OPTIMAL:''' Hess G, Herbrecht R, Romaguera J, Verhoef G, Crump M, Gisselbrecht C, Laurell A, Offner F, Strahs A, Berkenblit A, Hanushevsky O, Clancy J, Hewes B, Moore L, Coiffier B. Phase III study to evaluate temsirolimus compared with investigator's choice therapy for the treatment of relapsed or refractory mantle cell lymphoma. J Clin Oncol. 2009 Aug 10;27(23):3822-9. Epub 2009 Jul 6. [https://doi.org/10.1200/jco.2008.20.7977 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19581539 PubMed] NCT00117598
-# '''RAY:''' Dreyling M, Jurczak W, Jerkeman M, Silva RS, Rusconi C, Trneny M, Offner F, Caballero D, Joao C, Witzens-Harig M, Hess G, Bence-Bruckler I, Cho SG, Bothos J, Goldberg JD, Enny C, Traina S, Balasubramanian S, Bandyopadhyay N, Sun S, Vermeulen J, Rizo A, Rule S. Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an international, randomised, open-label, phase 3 study. Lancet. 2016 Feb 20;387(10020):770-8. Epub 2015 Dec 4. Erratum in: Lancet. 2016 Feb 20;387(10020):750.[https://doi.org/10.1016/S0140-6736(15)00667-4 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26673811 PubMed] NCT01646021
-## '''HRQoL analysis:''' Hess G, Rule S, Jurczak W, Jerkeman M, Santucci Silva R, Rusconi C, Caballero D, Joao C, Witzens-Harig M, Bence-Bruckler I, Cho SG, Zhou W, Goldberg JD, Trambitas C, Enny C, Vermeulen J, Traina S, Chiou CF, Diels J, Dreyling M. Health-related quality of life data from a phase 3, international, randomized, open-label, multicenter study in patients with previously treated mantle cell lymphoma treated with ibrutinib versus temsirolimus. Leuk Lymphoma. 2017 Dec;58(12):2824-2832. Epub 2017 May 30. [https://doi.org/10.1080/10428194.2017.1326034 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28556689 PubMed]
-## '''Update:''' Rule S, Jurczak W, Jerkeman M, Rusconi C, Trneny M, Offner F, Caballero D, Joao C, Witzens-Harig M, Hess G, Bence-Bruckler I, Cho SG, Thieblemont C, Zhou W, Henninger T, Goldberg J, Vermeulen J, Dreyling M. Ibrutinib versus temsirolimus: 3-year follow-up of patients with previously treated mantle cell lymphoma from the phase 3, international, randomized, open-label RAY study. Leukemia. 2018 Aug;32(8):1799-1803. Epub 2018 Feb 2. [https://www.nature.com/articles/s41375-018-0023-2 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6087720/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29572505 PubMed]
-==Zanubrutinib monotherapy {{#subobject:ea485a|Regimen=1}}==
-<div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:44abc0|Variant=1}}===
-{| class="wikitable" style="color:white; background-color:#404040"
-|<small>'''FDA-recommended dose'''</small>
-|-
-|}
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 20%"|Study
-!style="width: 20%"|Years of enrollment
-!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 20%"|Comparator
-!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6742923/ Tam et al. 2019 (BGB-3111-AU-003)]
-|2014-2018
-| style="background-color:#91cf61" |Phase 2 (RT)
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|-
-|[https://doi.org/10.1158/1078-0432.ccr-19-3703 Song et al. 2020 (BGB-3111-206)]
-|2017
-| style="background-color:#91cf61" |Phase 2 (RT)
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|-
-|Awaiting publication (BRUIN MCL-321)
-|2021-2025
-| style="background-color:#1a9851" |Phase 3 (C)
-|[[#Pirtobrutinib_monotherapy_77|Pirtobrutinib]]
-| style="background-color:#d3d3d3" |TBD
-|-
-|}
-<div class="toccolours" style="background-color:#fdcdac">
-====Prior treatment criteria====
-*BRUIN MCL-321: 1 or more lines of therapy and are BTK inhibitor naïve
-</div>
-<div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
-*[[Zanubrutinib (Brukinsa)]] 160 mg PO twice per day
-'''28-day cycle for up to 39 cycles (3 years)'''
-</div></div>
-===References===
-# '''BGB-3111-AU-003:''' Tam CS, Trotman J, Opat S, Burger JA, Cull G, Gottlieb D, Harrup R, Johnston PB, Marlton P, Munoz J, Seymour JF, Simpson D, Tedeschi A, Elstrom R, Yu Y, Tang Z, Han L, Huang J, Novotny W, Wang L, Roberts AW. Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL. Blood. 2019 Sep 12;134(11):851-859. Epub 2019 Jul 24. [https://doi.org/10.1182/blood.2019001160 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6742923/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31340982/ PubMed] NCT02343120
-## '''Update:''' Tam CS, Opat S, Simpson D, Cull G, Munoz J, Phillips TJ, Kim WS, Rule S, Atwal SK, Wei R, Novotny W, Huang J, Wang M, Trotman J. Zanubrutinib for the treatment of relapsed or refractory mantle cell lymphoma. Blood Adv. 2021 Jun 22;5(12):2577-2585. [https://doi.org/10.1182/bloodadvances.2020004074 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8270663/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/34152395/ PubMed]
-# '''BGB-3111-206:''' Song Y, Zhou K, Zou D, Zhou J, Hu J, Yang H, Zhang H, Ji J, Xu W, Jin J, Lv F, Feng R, Gao S, Guo H, Zhou L, Elstrom R, Huang J, Novotny W, Wei R, Zhu J. Treatment of Patients with Relapsed or Refractory Mantle-Cell Lymphoma with Zanubrutinib, a Selective Inhibitor of Bruton's Tyrosine Kinase. Clin Cancer Res. 2020 Aug 15;26(16):4216-4224. Epub 2020 May 27. [https://doi.org/10.1158/1078-0432.ccr-19-3703 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/32461234/ PubMed] NCT03206970
-## '''Update:''' Song Y, Zhou K, Zou D, Zhou J, Hu J, Yang H, Zhang H, Ji J, Xu W, Jin J, Lv F, Feng R, Gao S, Guo H, Zhou L, Huang J, Novotny W, Kim P, Yu Y, Wu B, Zhu J. Zanubrutinib in relapsed/refractory mantle cell lymphoma: long-term efficacy and safety results from a phase 2 study. Blood. 2022 May 26;139(21):3148-3158. [https://doi.org/10.1182/blood.2021014162 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9136878/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35303070/ PubMed]
-# '''BRUIN MCL-321:''' NCT04662255
-=Relapsed or refractory, non-randomized or retrospective data=
-==Arsenic trioxide & Chlorambucil {{#subobject:1edb5c|Regimen=1}}==
-<div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:c6220a|Variant=1}}===
-{| class="wikitable sortable" style="width: 80%; text-align:center;"
 !style="width: 25%"|Study
-!style="width: 25%"|Years of enrollment
 !style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[https://doi.org/10.1093/annonc/mdu142 Gill et al. 2014]
+|[https://doi.org/10.1200/jco.2010.32.7270 Topp et al. 2011 (MT103-202)]
-|2003-2011
 |style="background-color:#91cf61"|Phase 2
-|ORR: 49%
 |-
-|}
+|[https://doi.org/10.1200/JCO.2014.56.3247 Topp et al. 2014 (MT103-206)]
-''Note: patients with SD or better after cycle 1 proceed onwards.''
+|style="background-color:#91cf61"|Phase 2
-<div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
-*[[Arsenic trioxide (Trisenox)]] as follows:
-**Cycle 1: 10 mg PO once per day on days 1 to 28, then 5 mg PO once per day on days 29 to 42
-**Cycle 2 onwards: 3 mg PO once per day
-====Chemotherapy====
-*[[Chlorambucil (Leukeran)]] as follows:
-**Cycle 1: 4 mg PO once per day, increased to 8 mg PO once per day if leukocyte count allowed
-**Cycle 2 onwards: 2 mg PO once per day
-====Supportive therapy====
-*[[Ascorbic acid (Vitamin C)]] as follows:
-**Cycle 1: 1000 mg PO once per day
-**Cycle 2 onwards: 300 mg PO once per day
-'''42-day cycle for 1 cycle, then 28-day cycles'''
-</div></div>
-===References===
-# Gill H, Au WY, Cheung WW, Lee EY, Kwong YL. Oral arsenic trioxide-based regimen as salvage treatment for relapsed or refractory mantle cell lymphoma. Ann Oncol. 2014 Jul;25(7):1391-7. Epub 2014 Apr 12. [https://doi.org/10.1093/annonc/mdu142 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/24728036 PubMed]
-==BeRT {{#subobject:37c30e|Regimen=1}}==
-BeRT: '''<u>Be</u>'''ndamustine, '''<u>R</u>'''ituximab, '''<u>T</u>'''emsirolimus
-<div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:f424c7|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
-!style="width: 33%"|Study
-!style="width: 33%"|Years of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://doi.org/10.1038/leu.2015.60 Hess et al. 2015 (Mz-341)]
-|2010-NR
-|style="background-color:#ffffbe"|Phase 1/2, <20 pts reported
 |-
 |}
-''Note: The temsirolimus dose was the maximum dose used in the phase 1 portion of the trial; no DLT were observed.''
 <div class="toccolours" style="background-color:#b3e2cd">
-====Chemotherapy====
+====Immunotherapy====
-*[[Bendamustine]] 90 mg/m<sup>2</sup> IV once per day on days 1 & 2
+*[[Blinatumomab (Blincyto)]] 15 mcg/m<sup>2</sup>/day IV continuous infusion over 28 days, started on day 1 (total dose per cycle: 420 mcg/m<sup>2</sup>)
-====Targeted therapy====
+'''42-day course'''
-*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1
-*[[Temsirolimus (Torisel)]] 75 mg IV once per day on days 1, 8, 15
-'''28-day cycle for up to 4 cycles'''
-</div></div>
-===References===
-# '''Mz-341:''' Hess G, Keller U, Scholz CW, Witzens-Harig M, Atta J, Buske C, Kirschey S, Ruckes C, Medler C, van Oordt C, Klapper W, Theobald M, Dreyling M. Safety and efficacy of Temsirolimus in combination with Bendamustine and Rituximab in relapsed mantle cell and follicular lymphoma. Leukemia. 2015 Aug;29(8):1695-701. Epub 2015 Mar 13. [https://doi.org/10.1038/leu.2015.60 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25765545 PubMed] NCT01078142
-==BDR {{#subobject:d29ebe|Regimen=1}}==
-BDR: '''<u>B</u>'''ortezomib, '''<u>D</u>'''examethasone, '''<u>R</u>'''ituximab
-<br>BORID: '''<u>BO</u>'''rtezomib, '''<u>RI</u>'''tuximab, '''<u>D</u>'''examethasone
-<div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:36635a|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
-!style="width: 33%"|Study
-!style="width: 33%"|Years of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3128220/ Lamm et al. 2011 (MCL 03)]
-|2005-NR
-|style="background-color:#ffffbe"|Phase 2, <20 pts reported
-|-
-|}
-<div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
-*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV over 3 to 5 seconds once per day on days 1, 4, 8, 11
-*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1
-====Glucocorticoid therapy====
-*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4
-'''21-day cycle for 6 cycles'''
 </div>
 <div class="toccolours" style="background-color:#cbd5e7">
 ====Subsequent treatment====
-*Responding patients: [[#Rituximab_monotherapy_2|Rituximab]] consolidation
+*Patients who had an allogeneic donor could receive an allogeneic hematopoietic stem cell transplant any time after cycle 1. Patients who had response could receive up to an additional 3 cycles of consolidation therapy--same as above.
 </div></div>
 ===References===
-# '''MCL 03:''' Lamm W, Kaufmann H, Raderer M, Hoffmann M, Chott A, Zielinski C, Drach J. Bortezomib combined with rituximab and dexamethasone is an active regimen for patients with relapsed and chemotherapy-refractory mantle cell lymphoma. Haematologica. 2011 Jul;96(7):1008-14. Epub 2011 Apr 12. [http://www.haematologica.org/content/96/7/1008.long link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3128220/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21486866 PubMed] NCT00261612
+<!-- # '''Abstract:''' Max S. Topp, Nicola Goekbuget, Anthony Selwyn Stein, Ralf C. Bargou, Hervé Dombret, Adele K. Fielding, Josep M. Ribera, Robin Foà, Gerhard Zugmaier, Chris Holland, Tapan Maniar, Birgit Huber, Dirk Nagorsen, Hagop M. Kantarjian. Confirmatory open-label, single-arm, multicenter phase 2 study of the BiTE antibody blinatumomab in patients (pts) with relapsed/refractory B-precursor acute lymphoblastic leukemia (r/r ALL). J Clin Oncol 32:5s, 2014 (suppl; abstr 7005^). [http://meetinglibrary.asco.org/content/129500-144 link to abstract] -->
-==Bortezomib monotherapy {{#subobject:3bc0e1|Regimen=1}}==
+# '''MT103-202:''' Topp MS, Kufer P, Gökbuget N, Goebeler M, Klinger M, Neumann S, Horst HA, Raff T, Viardot A, Schmid M, Stelljes M, Schaich M, Degenhard E, Köhne-Volland R, Brüggemann M, Ottmann O, Pfeifer H, Burmeister T, Nagorsen D, Schmidt M, Lutterbuese R, Reinhardt C, Baeuerle PA, Kneba M, Einsele H, Riethmüller G, Hoelzer D, Zugmaier G, Bargou RC. Targeted therapy with the T-cell-engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival. J Clin Oncol. 2011 Jun 20;29(18):2493-8. Epub 2011 May 16. [https://doi.org/10.1200/jco.2010.32.7270 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21576633 PubMed] NCT00560794
+## '''Update:''' Topp MS, Gökbuget N, Zugmaier G, Degenhard E, Goebeler ME, Klinger M, Neumann SA, Horst HA, Raff T, Viardot A, Stelljes M, Schaich M, Köhne-Volland R, Brüggemann M, Ottmann OG, Burmeister T, Baeuerle PA, Nagorsen D, Schmidt M, Einsele H, Riethmüller G, Kneba M, Hoelzer D, Kufer P, Bargou RC. Long-term follow-up of hematologic relapse-free survival in a phase 2 study of blinatumomab in patients with MRD in B-lineage ALL. Blood. 2012 Dec 20;120(26):5185-7. [http://www.bloodjournal.org/content/120/26/5185.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/23024237 PubMed]
+## '''Update:''' Gökbuget N, Zugmaier G, Klinger M, Kufer P, Stelljes M, Viardot A, Horst HA, Neumann S, Brüggemann M, Ottmann OG, Burmeister T, Wessiepe D, Topp MS, Bargou R. Long-term relapse-free survival in a phase 2 study of blinatumomab for the treatment of patients with minimal residual disease in B-lineage acute lymphoblastic leukemia. Haematologica. 2017 Apr;102(4):e132-e135. Epub 2017 Jan 12. [http://www.haematologica.org/content/102/4/e132.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5395124/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28082340 PubMed]
+# '''MT103-206:''' Topp MS, Gökbuget N, Zugmaier G, Klappers P, Stelljes M, Neumann S, Viardot A, Marks R, Diedrich H, Faul C, Reichle A, Horst HA, Brüggemann M, Wessiepe D, Holland C, Alekar S, Mergen N, Einsele H, Hoelzer D, Bargou RC. Phase II trial of the anti-CD19 bispecific T cell-engager blinatumomab shows hematologic and molecular remissions in patients with relapsed or refractory B-precursor acute lymphoblastic leukemia. J Clin Oncol. 2014 Dec 20;32(36):4134-40. Epub 2014 Nov 10. [https://doi.org/10.1200/JCO.2014.56.3247 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25385737 PubMed] NCT01209286
+## '''Update:''' Zugmaier G, Gökbuget N, Klinger M, Viardot A, Stelljes M, Neumann S, Horst HA, Marks R, Faul C, Diedrich H, Reichle A, Brüggemann M, Holland C, Schmidt M, Einsele H, Bargou RC, Topp MS. Long-term survival and T-cell kinetics in relapsed/refractory ALL patients who achieved MRD response after blinatumomab treatment. Blood. 2015 Dec 10;126(24):2578-84. Epub 2015 Oct 19. [http://www.bloodjournal.org/content/126/24/2578.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4671107/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26480933 PubMed]
+# '''MT103-211:''' Topp MS, Gökbuget N, Stein AS, Zugmaier G, O'Brien S, Bargou RC, Dombret H, Fielding AK, Heffner L, Larson RA, Neumann S, Foà R, Litzow M, Ribera JM, Rambaldi A, Schiller G, Brüggemann M, Horst HA, Holland C, Jia C, Maniar T, Huber B, Nagorsen D, Forman SJ, Kantarjian HM. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol. 2015 Jan;16(1):57-66. Epub 2014 Dec 16. Erratum in: Lancet Oncol. 2015 Apr;16(4):e158. [https://doi.org/10.1016/S1470-2045(14)71170-2 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25524800 PubMed] NCT01466179
+# '''TOWER:''' Kantarjian H, Stein A, Gökbuget N, Fielding AK, Schuh AC, Ribera JM, Wei A, Dombret H, Foà R, Bassan R, Arslan Ö, Sanz MA, Bergeron J, Demirkan F, Lech-Maranda E, Rambaldi A, Thomas X, Horst HA, Brüggemann M, Klapper W, Wood BL, Fleishman A, Nagorsen D, Holland C, Zimmerman Z, Topp MS. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017 Mar 2;376(9):836-847. [https://doi.org/10.1056/NEJMoa1609783 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5881572/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28249141 PubMed] NCT02013167
+## '''HRQoL analysis:''' Topp MS, Zimmerman Z, Cannell P, Dombret H, Maertens J, Stein A, Franklin J, Tran Q, Cong Z, Schuh AC. Health-related quality of life in adults with relapsed/refractory acute lymphoblastic leukemia treated with blinatumomab. Blood. 2018 Jun 28;131(26):2906-2914. Epub 2018 May 8. [https://doi.org/10.1182/blood-2017-09-804658 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6024638/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29739753 PubMed]
+==Brexucabtagene autoleucel monotherapy {{#subobject:4z3u14|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #1, 1.3 mg/m<sup>2</sup> {{#subobject:c484ca|Variant=1}}===
+===Regimen {{#subobject:6np0a6|Variant=1}}===
-{| class="wikitable" style="width: 60%; text-align:center;"
+{| class="wikitable" style="color:white; background-color:#404040"
-!style="width: 33%"|Study
+|<small>'''FDA-recommended dose'''</small>
-!style="width: 33%"|Years of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://doi.org/10.1200/jco.2006.07.9665 Fisher et al. 2006 (PINNACLE)]
-|2003-NR
-|style="background-color:#91cf61"|Phase 2 (RT)
 |-
 |}
-<div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
-*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
-'''21-day cycles''' "up to 17 cycles or four cycles beyond initial reporting of CR/CRu, discontinuing for progressive disease (PD) or unacceptable toxicity, or by patient/investigator decision."
-</div></div><br>
-<div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #2, 1.5 mg/m<sup>2</sup> {{#subobject:9dff83|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
-!style="width: 33%"|Study
-!style="width: 33%"|Years of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://doi.org/10.1200/jco.2005.02.050 O'Connor et al. 2005]
-|2001-2003
-|style="background-color:#ffffbe"|Phase 2, <20 pts reported
-|-
-|}
-<div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
-*[[Bortezomib (Velcade)]] 1.5 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
-====Supportive therapy====
-*"Use of antiemetics, erythropoietin, and [[Filgrastim (Neupogen)]] was allowed if deemed necessary by the treating physician."
-'''21-day cycles'''
-</div></div>
-===References===
-# O'Connor OA, Wright J, Moskowitz C, Muzzy J, MacGregor-Cortelli B, Stubblefield M, Straus D, Portlock C, Hamlin P, Choi E, Dumetrescu O, Esseltine D, Trehu E, Adams J, Schenkein D, Zelenetz AD. Phase II clinical experience with the novel proteasome inhibitor bortezomib in patients with indolent non-Hodgkin's lymphoma and mantle cell lymphoma. J Clin Oncol. 2005 Feb 1;23(4):676-84. Epub 2004 Dec 21. [https://doi.org/10.1200/jco.2005.02.050 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15613699 PubMed]
-# '''PINNACLE:''' Fisher RI, Bernstein SH, Kahl BS, Djulbegovic B, Robertson MJ, de Vos S, Epner E, Krishnan A, Leonard JP, Lonial S, Stadtmauer EA, O'Connor OA, Shi H, Boral AL, Goy A. Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. J Clin Oncol. 2006 Oct 20;24(30):4867-74. Epub 2006 Sep 25. [https://doi.org/10.1200/jco.2006.07.9665 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17001068 PubMed]
-## '''Update:''' Goy A, Bernstein SH, Kahl BS, Djulbegovic B, Robertson MJ, de Vos S, Epner E, Krishnan A, Leonard JP, Lonial S, Nasta S, O'Connor OA, Shi H, Boral AL, Fisher RI. Bortezomib in patients with relapsed or refractory mantle cell lymphoma: updated time-to-event analyses of the multicenter phase 2 PINNACLE study. Ann Oncol. 2009 Mar;20(3):520-5. Epub 2008 Dec 12. [https://doi.org/10.1093/annonc/mdn656 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4592328/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19074748 PubMed]
-==Brexucabtagene autoleucel monotherapy {{#subobject:4z3u14|Regimen=1}}==
-<div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:6np0a6|Variant=1}}===
 {| class="wikitable sortable" style="width: 60%; text-align:center;"
 !style="width: 33%"|Study
@@ Line 2,473: / Line 1,874: @@
 !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7731441/ Wang et al. 2020 (ZUMA-2)]
+|[https://doi.org/10.1016/s0140-6736(21)01222-8 Shah et al. 2021 (ZUMA-3)]
-|2016-2019
+|2018-2019
 | style="background-color:#91cf61" |Phase 2 (RT)
 |-
@@ Line 2,484: / Line 1,885: @@
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Immunotherapy====
-*[[Brexucabtagene autoleucel (Tecartus)]] 2 x 10<sup>6</sup> CAR T cells/kg IV once on day 0
+*[[Brexucabtagene autoleucel (Tecartus)]] 1 x 10<sup>6</sup> CAR T cells/kg IV once on day 0
 </div></div>
 ===References===
-#'''ZUMA-2:''' Wang M, Munoz J, Goy A, Locke FL, Jacobson CA, Hill BT, Timmerman JM, Holmes H, Jaglowski S, Flinn IW, McSweeney PA, Miklos DB, Pagel JM, Kersten MJ, Milpied N, Fung H, Topp MS, Houot R, Beitinjaneh A, Peng W, Zheng L, Rossi JM, Jain RK, Rao AV, Reagan PM. KTE-X19 CAR T-Cell Therapy in Relapsed or Refractory Mantle-Cell Lymphoma. N Engl J Med. 2020 Apr 2;382(14):1331-1342. [https://doi.org/10.1056/nejmoa1914347 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7731441/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32242358/ PubMed] NCT02601313
+#'''ZUMA-3:''' Shah BD, Ghobadi A, Oluwole OO, Logan AC, Boissel N, Cassaday RD, Leguay T, Bishop MR, Topp MS, Tzachanis D, O'Dwyer KM, Arellano ML, Lin Y, Baer MR, Schiller GJ, Park JH, Subklewe M, Abedi M, Minnema MC, Wierda WG, DeAngelo DJ, Stiff P, Jeyakumar D, Feng C, Dong J, Shen T, Milletti F, Rossi JM, Vezan R, Masouleh BK, Houot R. KTE-X19 for relapsed or refractory adult B-cell acute lymphoblastic leukaemia: phase 2 results of the single-arm, open-label, multicentre ZUMA-3 study. Lancet. 2021 Aug 7;398(10299):491-502. Epub 2021 Jun 4. [https://doi.org/10.1016/s0140-6736(21)01222-8 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/34097852/ PubMed] NCT02614066
-==Everolimus monotherapy {{#subobject:ae5164|Regimen=1}}==
+==Clofarabine monotherapy {{#subobject:6befdc|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:de05a7|Variant=1}}===
+===Regimen {{#subobject:9e7379|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
+{| class="wikitable" style="width: 40%; text-align:center;"
-!style="width: 33%"|Study
-!style="width: 33%"|Years of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3396682/ Renner et al. 2012 (SAKK 36/06)]
-|2007-2010
-|style="background-color:#91cf61"|Phase 2
-|-
-|[https://doi.org/10.1111/bjh.12780 Wang et al. 2014 (PILLAR-1)]
-|2008-2011
-|style="background-color:#91cf61"|Phase 2
-|-
-|}
-''Note: to be taken in a fasting state or with a light fat-free meal.''
-<div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
-*[[Everolimus (Afinitor)]] 10 mg PO once per day
-'''28-day cycles'''
-</div></div>
-===References===
-# '''SAKK 36/06:''' Renner C, Zinzani PL, Gressin R, Klingbiel D, Dietrich PY, Hitz F, Bargetzi M, Mingrone W, Martinelli G, Trojan A, Bouabdallah K, Lohri A, Gyan E, Biaggi C, Cogliatti S, Bertoni F, Ghielmini M, Brauchli P, Ketterer N; SAKK; GOELAMS; European Mantle Cell Lymphoma Network. A multicenter phase II trial (SAKK 36/06) of single-agent everolimus (RAD001) in patients with relapsed or refractory mantle cell lymphoma. Haematologica. 2012 Jul;97(7):1085-91. Epub 2012 Feb 7. [http://www.haematologica.org/content/97/7/1085.long link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3396682/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22315486 PubMed] NCT00516412
-# '''PILLAR-1:''' Wang M, Popplewell LL, Collins RH Jr, Winter JN, Goy A, Kaminski MS, Bartlett NL, Johnston PB, Lister J, Fanning SR, Tuscano JM, Beck JT, Kaya H, Robeva A, Fan J, Klimovsky J, Cheung W, Cherfi A, O'Connor OA. Everolimus for patients with mantle cell lymphoma refractory to or intolerant of bortezomib: multicentre, single-arm, phase 2 study. Br J Haematol. 2014 May;165(4):510-8. Epub 2014 Mar 2. [https://doi.org/10.1111/bjh.12780 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/24579926 PubMed] NCT00702052
-==Ibrutinib & Rituximab {{#subobject:5c125a|Regimen=1}}==
-<div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:2b53b7|Variant=1}}===
-{| class="wikitable sortable" style="width: 80%; text-align:center;"
 !style="width: 25%"|Study
-!style="width: 25%"|Years of enrollment
 !style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[https://doi.org/10.1016/S1470-2045(15)00438-6 Wang et al. 2015 (MDACC 2013-0090)]
+|[http://www.bloodjournal.org/content/102/7/2379.long Kantarjian et al. 2003]
-|2013-2014
+|style="background-color:#ffffbe"|Phase 2, <20 patients in this arm
-|style="background-color:#91cf61"|Phase 2
-| style="background-color:#f7fcfd" |ORR: 88% (95% CI 76-95.5)
 |-
 |}
 <div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
+====Chemotherapy====
-*[[Ibrutinib (Imbruvica)]] 560 mg PO once per day
+*[[Clofarabine (Clolar)]] 40 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5
-*[[Rituximab (Rituxan)]] as follows:
+'''3- to 6-week cycles, depending on response count recovery'''
-**Cycle 1: 375 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
-**Cycle 2: no rituximab
-**Cycles 3 to 7: 375 mg/m<sup>2</sup> IV once on day 1
-**Cycle 8 onwards: 375 mg/m<sup>2</sup> IV once on day 1
-'''28-day cycle for 7 cycles, then 8-week cycles (up to 2 years for rituximab)'''
 </div></div>
 ===References===
-<!-- # '''Abstract:''' Michael (Luhua) Wang, MD, Fredrick Hagemeister, MD, Jason R. Westin, MD, Luis Fayad, MD, Felipe Samaniego, MD, Francesco Turturro, MD, Wendy Chen, Liang Zhang, MD, PhD, Maria Badillo, BS, Maria DeLa Rosa, Alicia Addison, Larry W. Kwak, MD, PhD and Jorge E. Romaguera, MD. Ibrutinib and Rituximab Are an Efficacious and Safe Combination in Relapsed Mantle Cell Lymphoma: Preliminary Results from a Phase II Clinical Trial. ASH Annual Meeting 2014 Abstract 627 [https://ash.confex.com/ash/2014/webprogram/Paper69685.html link to abstract] -->
+# Kantarjian H, Gandhi V, Cortes J, Verstovsek S, Du M, Garcia-Manero G, Giles F, Faderl S, O'Brien S, Jeha S, Davis J, Shaked Z, Craig A, Keating M, Plunkett W, Freireich EJ. Phase 2 clinical and pharmacologic study of clofarabine in patients with refractory or relapsed acute leukemia. Blood. 2003 Oct 1;102(7):2379-86. Epub 2003 Jun 5. [http://www.bloodjournal.org/content/102/7/2379.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12791647 PubMed]
-# '''MDACC 2013-0090:''' Wang ML, Lee H, Chuang H, Wagner-Bartak N, Hagemeister F, Westin J, Fayad L, Samaniego F, Turturro F, Oki Y, Chen W, Badillo M, Nomie K, DeLa Rosa M, Zhao D, Lam L, Addison A, Zhang H, Young KH, Li S, Santos D, Medeiros LJ, Champlin R, Romaguera J, Zhang L. Ibrutinib in combination with rituximab in relapsed or refractory mantle cell lymphoma: a single-centre, open-label, phase 2 trial. Lancet Oncol. 2016 Jan;17(1):48-56. Epub 2015 Nov 28. [https://doi.org/10.1016/S1470-2045(15)00438-6 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26640039 PubMed] NCT01880567
+==Cytarabine monotherapy {{#subobject:4dcf05|Regimen=1}}==
-==Ibrutinib & Venetoclax {{#subobject:b479ff|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:1aa538|Variant=1}}===
+===Regimen {{#subobject:045c1c|Variant=1}}===
-{| class="wikitable sortable" style="width: 80%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+!style="width: 20%"|Study
-!style="width: 25%"|Years of enrollment
+!style="width: 20%"|Years of enrollment
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1056/NEJMoa1715519 Tam et al. 2018 (AIM)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5594743/ Kantarjian et al. 2016 (INO-VATE ALL)]
-|2015-2016
+|2012-2014
-|style="background-color:#91cf61"|Phase 2
+|style="background-color:#1a9851"|Phase 3 (C)
-| style="background-color:#bfd3e6" |ORR: 71% (95% CI 49-87)
+|[[#Inotuzumab_ozogamicin_monotherapy|Inotuzumab ozogamicin]]
+|style="background-color:#fc8d59"|Seems to have inferior OS
 |-
 |}
-''Note: the venetoclax dosing is based on a mid-protocol amendment.''
 <div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
+====Chemotherapy====
-*[[Ibrutinib (Imbruvica)]] 560 mg PO once per day
+*[[Cytarabine (Ara-C)]] by the following criteria:
-*[[Venetoclax (Venclexta)]] as follows:
+**Younger than 55: 3000 mg/m<sup>2</sup> IV every 12 hours on days 1 to 6 (total dose: 36,000 mg/m<sup>2</sup>)
-**Week 5: 50 mg PO once per day
+**55 or older: 1500 mg/m<sup>2</sup> IV every 12 hours on days 1 to 6 (total dose: 18,000 mg/m<sup>2</sup>)
-**Week 6: 100 mg PO once per day
+'''6-day course'''
-**Week 7: 200 mg PO once per day
-**Weeks 8 to 15: 400 mg PO once per day
-**Week 16 onwards:
-***CR achieved: 400 mg PO once per day
-***CR not achieved: 800 mg PO once per day
-'''Continued indefinitely'''
 </div></div>
 ===References===
-# '''AIM:''' Tam CS, Anderson MA, Pott C, Agarwal R, Handunnetti S, Hicks RJ, Burbury K, Turner G, Di Iulio J, Bressel M, Westerman D, Lade S, Dreyling M, Dawson SJ, Dawson MA, Seymour JF, Roberts AW. Ibrutinib plus venetoclax for the treatment of mantle-cell lymphoma. N Engl J Med. 2018 Mar 29;378(13):1211-1223. [https://doi.org/10.1056/NEJMoa1715519 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/29590547 PubMed] NCT02471391
+<!-- no pre-pub disclosed -->
-==Lenalidomide & Rituximab (R<sup>2</sup>) {{#subobject:c6d2a9|Regimen=1}}==
+# '''INO-VATE ALL:''' Kantarjian HM, DeAngelo DJ, Stelljes M, Martinelli G, Liedtke M, Stock W, Gökbuget N, O'Brien S, Wang K, Wang T, Paccagnella ML, Sleight B, Vandendries E, Advani AS. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016 Aug 25;375(8):740-53. Epub 2016 Jun 12. [https://doi.org/10.1056/NEJMoa1509277 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5594743/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27292104 PubMed] NCT01564784
+## '''Update:''' Kantarjian HM, DeAngelo DJ, Stelljes M, Liedtke M, Stock W, Gökbuget N, O'Brien SM, Jabbour E, Wang T, Liang White J, Sleight B, Vandendries E, Advani AS. Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia: Final report and long-term survival follow-up from the randomized, phase 3 INO-VATE study. Cancer. 2019 Jul 15;125(14):2474-2487. Epub 2019 Mar 28. [https://doi.org/10.1002/cncr.32116 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6618133/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30920645 PubMed]
+==Cytarabine & Idarubicin {{#subobject:d6d882|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #1, 10/375 {{#subobject:1c4391|Variant=1}}===
+===Regimen {{#subobject:9cfc92|Variant=1}}===
 {| class="wikitable sortable" style="width: 60%; text-align:center;"
 !style="width: 33%"|Study
@@ Line 2,581: / Line 1,943: @@
 !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[http://clincancerres.aacrjournals.org/content/21/8/1835.full Chong et al. 2015 (UPCC 02408)]
+|[https://doi.org/10.1200/JCO.2008.18.6916 Huguet et al. 2009 (GRAALL-2003)]
-|2008-2012
+|2003-2005
-|style="background-color:#ffffbe"|Phase 2, <20 pts in subgroup
+|style="background-color:#91cf61"|Phase 2
 |-
-|}
+|[https://doi.org/10.1056/NEJMoa1605085 Maury et al. 2016 (GRAALL-2005/R)]
-<div class="toccolours" style="background-color:#b3e2cd">
+|2006-2014
-====Targeted therapy====
+|style="background-color:#91cf61"|Non-randomized portion of phase 3 RCT
-*[[Lenalidomide (Revlimid)]] 10 mg PO once per day
-*[[Rituximab (Rituxan)]] as follows:
-**Cycle 3 only: 375 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
-'''28-day cycles'''
-</div></div><br>
-<div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #2, 25/375 {{#subobject:cd071c|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
-!style="width: 33%"|Study
-!style="width: 33%"|Years of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://doi.org/10.1016/S1470-2045(12)70200-0 Wang et al. 2012 (MDACC 2005-0461)]
-|2006-2009
-|style="background-color:#91cf61"|Phase 1/2
 |-
 |}
+''Note: the original '''GRAALL-2003''' article Table 1 has several errors which were corrected in the erratum and the online Table 1. These corrected doses are replicated here. This regimen is for patients not achieving CR1 with induction.''
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*[[#Cyclophosphamide.2C_Daunorubicin.2C_L-Asparaginase.2C_Vincristine.2C_Prednisone|Cyclophosphamide, Daunorubicin, L-aspariginase, Vincristine, Prednisone]] induction
+</div>
 <div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
+====Chemotherapy====
-*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21
+*[[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV over 3 hours every 12 hours on days 1 to 4 (total dose: 16,000 mg/m<sup>2</sup>)
-*[[Rituximab (Rituxan)]] as follows:
+*[[Idarubicin (Idamycin)]] 12 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 3
-**Cycle 1 only: 375 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
+====Supportive therapy====
-'''28-day cycles'''
+*[[Lenograstim (Granocyte)]] by the following study-specific criteria:
+**GRAALL-2003: 150 mcg/m<sup>2</sup> SC once per day from day 9 until myeloid recovery
+**GRAALL-2005: 263 mcg IV or SC once per day from day 9 until first day with ANC greater than 1000/uL
+'''One course'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*Patients achieving CR1 after salvage: [[#Pediatric-like_GRAALL_consolidation|Pediatric-like GRAALL]] consolidation
 </div></div>
 ===References===
-# '''MDACC 2005-0461:''' Wang M, Fayad L, Wagner-Bartak N, Zhang L, Hagemeister F, Neelapu SS, Samaniego F, McLaughlin P, Fanale M, Younes A, Cabanillas F, Fowler N, Newberry KJ, Sun L, Young KH, Champlin R, Kwak L, Feng L, Badillo M, Bejarano M, Hartig K, Chen W, Chen Y, Byrne C, Bell N, Zeldis J, Romaguera J. Lenalidomide in combination with rituximab for patients with relapsed or refractory mantle-cell lymphoma: a phase 1/2 clinical trial. Lancet Oncol. 2012 Jul;13(7):716-23. Epub 2012 Jun 6. [https://doi.org/10.1016/S1470-2045(12)70200-0 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/22677155 PubMed] NCT00294632
+# '''GRAALL-2003:''' Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. [https://doi.org/10.1200/JCO.2008.18.6916 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19124805 PubMed] NCT00222027
-# '''UPCC 02408:''' Chong EA, Ahmadi T, Aqui NA, Svoboda J, Nasta SD, Mato AR, Walsh KM, Schuster SJ. Combination of lenalidomide and rituximab overcomes rituximab resistance in patients with indolent B-cell and mantle cell lymphomas. Clin Cancer Res. 2015 Apr 15;21(8):1835-42. Epub 2015 Jan 28. [http://clincancerres.aacrjournals.org/content/21/8/1835.full link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25632047 PubMed] NCT00783367
+# '''GRAALL-2005/R:''' Maury S, Chevret S, Thomas X, Heim D, Leguay T, Huguet F, Chevallier P, Hunault M, Boissel N, Escoffre-Barbe M, Hess U, Vey N, Pignon JM, Braun T, Marolleau JP, Cahn JY, Chalandon Y, Lhéritier V, Beldjord K, Béné MC, Ifrah N, Dombret H; GRAALL. Rituximab in B-lineage adult acute lymphoblastic leukemia. N Engl J Med. 2016 Sep 15;375(11):1044-53. [https://doi.org/10.1056/NEJMoa1605085 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1605085/suppl_file/nejmoa1605085_protocol.pdf link to supplement] '''contains dosing details in supplement''' [https://pubmed.ncbi.nlm.nih.gov/27626518 PubMed] NCT00327678
-==Obinutuzumab monotherapy {{#subobject:7f1090|Regimen=1}}==
+==Cytarabine, Idarubicin, Rituximab {{#subobject:7ae2cb|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:d640e0|Variant=1}}===
+===Regimen {{#subobject:748401|Variant=1}}===
 {| class="wikitable sortable" style="width: 60%; text-align:center;"
 !style="width: 33%"|Study
@@ Line 2,623: / Line 1,982: @@
 !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[http://www.bloodjournal.org/content/119/22/5126.long Salles et al. 2012 (GAUGUIN)]
+|[https://doi.org/10.1056/NEJMoa1605085 Maury et al. 2016 (GRAALL-2005/R)]
-|2008-2009
+|2006-2014
-|style="background-color:#91cf61"|Phase 1/2
+|style="background-color:#91cf61"|Non-randomized portion of RCT
 |-
 |}
-''Note: this is the phase 2 dosing used in the subgroup analysis by Morschhauser et al. 2013.''
+''This regimen is for patients not achieving CR1 with induction.''
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*[[#Cyclophosphamide.2C_Daunorubicin.2C_L-Asparaginase.2C_Vincristine.2C_Prednisone.2C_Rituximab|Cyclophosphamide, Daunorubicin, L-aspariginase, Vincristine, Prednisone, Rituximab]] induction
+</div>
 <div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV over 3 hours every 12 hours on days 1 to 4 (total dose: 16,000 mg/m<sup>2</sup>)
+*[[Idarubicin (Idamycin)]] 12 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 3
 ====Targeted therapy====
-*[[Obinutuzumab (Gazyva)]] as follows:
+*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once per day on days 1 & 7
-**Cycle 1: 1600 mg (diluted to 10 mg/mL) IV once per day on days 1 & 8
-**Cycles 2 to 8: 800 mg IV once on day 1
-**Initial infusion rate is 50 mg/hour. In the absence of infusion-related reactions (IRRs), the rate is then increased by 50 mg/hour every 30 minutes, up to a maximum of 400 mg/hour.
 ====Supportive therapy====
-*[[Acetaminophen (Tylenol)]] or paracetamol 650 to 1000 mg PO once per infusion, 30 minutes prior to [[Obinutuzumab (Gazyva)]]
+*[[Lenograstim (Granocyte)]] 263 mcg IV or SC once per day, starting on day 9, continuing until first day with ANC greater than 1000/uL
-*[[:Category:Antihistamines|An antihistamine]] once per infusion, 30 minutes prior to [[Obinutuzumab (Gazyva)]]
+'''One course'''
-**If there were no infusion-related reactions (IRRs) requiring medication or infusion interruption, antihistamine could be omitted for subsequent infusions
-*Premedication with [[:Category:Steroids|corticosteroids]] recommended for patients at high risk of infusion-related reactions (IRRs)
-*Use of [[:Category:Granulocyte_colony-stimulating_factors|G-CSF]] allowed for severe neutropenia
-*Antibiotic prophylaxis allowed
-'''21-day cycle for 8 cycles'''
-</div></div>
-===References===
-# '''GAUGUIN:''' Salles G, Morschhauser F, Lamy T, Milpied N, Thieblemont C, Tilly H, Bieska G, Asikanius E, Carlile D, Birkett J, Pisa P, Cartron G. Phase 1 study results of the type II glycoengineered humanized anti-CD20 monoclonal antibody obinutuzumab (GA101) in B-cell lymphoma patients. Blood. 2012 May 31;119(22):5126-32. Epub 2012 Mar 19. [http://www.bloodjournal.org/content/119/22/5126.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/22431570 PubMed] NCT00517530
-## '''Subgroup analysis:''' Morschhauser FA, Cartron G, Thieblemont C, Solal-Céligny P, Haioun C, Bouabdallah R, Feugier P, Bouabdallah K, Asikanius E, Lei G, Wenger M, Wassner-Fritsch E, Salles GA. Obinutuzumab (GA101) monotherapy in relapsed/refractory diffuse large B-cell lymphoma or mantle-cell lymphoma: results from the phase II GAUGUIN study. J Clin Oncol. 2013 Aug 10;31(23):2912-9. Epub 2013 Jul 8. [https://doi.org/10.1200/jco.2012.46.9585 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23835718 PubMed]
-## '''Subgroup analysis:''' Salles GA, Morschhauser F, Solal-Céligny P, Thieblemont C, Lamy T, Tilly H, Gyan E, Lei G, Wenger M, Wassner-Fritsch E, Cartron G. Obinutuzumab (GA101) in patients with relapsed/refractory indolent non-Hodgkin lymphoma: results from the phase II GAUGUIN study. J Clin Oncol. 2013 Aug 10;31(23):2920-6. Epub 2013 Jul 8. [https://doi.org/10.1200/jco.2012.46.9718 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23835715 PubMed]
-## '''Subgroup analysis:''' Cartron G, de Guibert S, Dilhuydy MS, Morschhauser F, Leblond V, Dupuis J, Mahe B, Bouabdallah R, Lei G, Wenger M, Wassner-Fritsch E, Hallek M. Obinutuzumab (GA101) in relapsed/refractory chronic lymphocytic leukemia: final data from the phase 1/2 GAUGUIN study. Blood. 2014 Oct 2;124(14):2196-202. Epub 2014 Aug 20. [http://www.bloodjournal.org/content/124/14/2196 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25143487 PubMed]
-==PEP-C {{#subobject:e8f271|Regimen=1}}==
-PEP-C: '''<u>P</u>'''rednisone, '''<u>E</u>'''toposide, '''<u>P</u>'''rocarbazine, '''<u>C</u>'''yclophosphamide
-<div class="toccolours" style="background-color:#eeeeee">
-===Protocol {{#subobject:3bb8f7|Variant=1}}===
-{| class="wikitable" style="width: 40%; text-align:center;"
-!style="width: 25%"|Study
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://doi.org/10.1080/10428190701837330 Coleman et al. 2008<sub>MCL</sub>]
-| style="background-color:#ffffbe" |Retrospective
-|-
-|}
-<div class="toccolours" style="background-color:#b3e2cd">
-====Glucocorticoid therapy, induction phase====
-*[[Prednisone (Sterapred)]] 20 mg PO once per day after breakfast
-====Chemotherapy, induction phase====
-*[[Etoposide (Vepesid)]] 50 mg PO once per day after dinner
-*[[Procarbazine (Matulane)]] 50 mg PO once per day at bedtime
-*[[Cyclophosphamide (Cytoxan)]] 50 mg PO once per day after lunch
-====Supportive therapy====
-*[[Ondansetron (Zofran)]] (dose not specified) with each [[Procarbazine (Matulane)]] dose
-'''Continue until WBC count less than 3 x 10<sup>9</sup>/L, hold until WBC count recovery, then titrate in maintenance phase per paper (see publication for details)'''
-====Chemotherapy, maintenance phase====
-*Same medications and doses given per day as used in the induction phase, but the number of days per week they are used is titrated to maintain a WBC count of at least 3; for example, 5 out of 7 days, every other day, once per week, etc.
-</div></div>
-===References===
-# '''Retrospective:''' Coleman M, Martin P, Ruan J, Furman R, Niesvizky R, Elstrom R, George P, Leonard J, Kaufmann T. Low-dose metronomic, multidrug therapy with the PEP-C oral combination chemotherapy regimen for mantle cell lymphoma. Leuk Lymphoma. 2008 Mar;49(3):447-50. [https://doi.org/10.1080/10428190701837330 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18297520 PubMed]
-==R-BL {{#subobject:82e685|Regimen=1}}==
-R-BL: '''<u>R</u>'''ituximab, '''<u>B</u>'''endamustine, '''<u>L</u>'''enalidomide
-<br>R2B: '''<u>R</u>'''evlimid (Lenalidomide), '''<u>R</u>'''ituximab, '''<u>B</u>'''endamustine
-<div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:1c30ec|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
-!style="width: 33%"|Study
-!style="width: 33%"|Years of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5477625/ Zaja et al. 2017]
-|2012-2013
-|style="background-color:#91cf61"|Phase 2
-|-
-|}
-<div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
-*[[Rituximab (Rituxan)]] as follows:
-**Cycle 1: 375 mg/m<sup>2</sup> IV once on day 8
-**Cycles 2 to 4: 375 mg/m<sup>2</sup> IV once on day 1
-*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 14
-====Chemotherapy====
-*[[Bendamustine]] 70 mg/m<sup>2</sup> IV once per day on days 2 & 3
-'''28-day cycle for 4 cycles'''
 </div>
 <div class="toccolours" style="background-color:#cbd5e7">
 ====Subsequent treatment====
-*Patients with PR/CR: [[#Lenalidomide_.26_Rituximab_.28R2.29_4|Lenalidomide & rituximab]] consolidation
+*Patients achieving CR1 after salvage: Pediatric-like GRAALL consolidation with rituximab
 </div></div>
 ===References===
-# Zaja F, Ferrero S, Stelitano C, Ferrari A, Salvi F, Arcari A, Musuraca G, Botto B, Spina M, Cellini C, Patti C, Liberati AM, Minotto C, Pileri SA, Ceccarelli M, Volpetti S, Ferranti A, Drandi D, Montechiarello E, Ladetto M, Carmichael J, Fanin R. Second-line rituximab, lenalidomide, and bendamustine in mantle cell lymphoma: a phase II clinical trial of the Fondazione Italiana Linfomi. Haematologica. 2017 May;102(5):e203-e206. Epub 2017 Jan 12. [http://www.haematologica.org/content/102/5/e203.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5477625/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28082342 PubMed]
+# '''GRAALL-2005/R:''' Maury S, Chevret S, Thomas X, Heim D, Leguay T, Huguet F, Chevallier P, Hunault M, Boissel N, Escoffre-Barbe M, Hess U, Vey N, Pignon JM, Braun T, Marolleau JP, Cahn JY, Chalandon Y, Lhéritier V, Beldjord K, Béné MC, Ifrah N, Dombret H; GRAALL. Rituximab in B-lineage adult acute lymphoblastic leukemia. N Engl J Med. 2016 Sep 15;375(11):1044-53. [https://doi.org/10.1056/NEJMoa1605085 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1605085/suppl_file/nejmoa1605085_protocol.pdf link to supplement] '''contains dosing details in supplement''' [https://pubmed.ncbi.nlm.nih.gov/27626518 PubMed] NCT00327678
-==RT-PEPC {{#subobject:bc6d27|Regimen=1}}==
+==Cytarabine & Mitoxantrone (MC) {{#subobject:6237f0|Regimen=1}}==
-RT-PEPC: '''<u>R</u>'''ituximab, '''<u>T</u>'''halidomide, '''<u>P</u>'''rednisone, '''<u>E</u>'''toposide, '''<u>P</u>'''rocarbazine, '''<u>C</u>'''yclophosphamide
+MC: '''<u>M</u>'''itoxantrone & '''<u>C</u>'''ytarabine
 <div class="toccolours" style="background-color:#eeeeee">
-===Protocol {{#subobject:ed397d|Variant=1}}===
+===Regimen {{#subobject:395e92|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 33%"|Study
+!style="width: 20%"|Study
-!style="width: 33%"|Years of enrollment
+!style="width: 20%"|Years of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3004744/ Ruan et al. 2010a]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5594743/ Kantarjian et al. 2016 (INO-VATE ALL)]
-|NR
+|2012-2014
-|style="background-color:#91cf61"|Non-randomized
+|style="background-color:#1a9851"|Phase 3 (C)
+|[[#Inotuzumab_ozogamicin_monotherapy|Inotuzumab ozogamicin]]
+|style="background-color:#fc8d59"|Seems to have inferior OS
 |-
 |}
 <div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy, induction phase====
+====Chemotherapy====
-*[[Rituximab (Rituxan)]] (dose not specified) IV once per day on days 1, 8, 15, 22
+*[[Cytarabine (Ara-C)]] 200 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose per cycle: 1400 mg/m<sup>2</sup>)
-*[[Thalidomide (Thalomid)]] 50 mg PO once per day during months 1 & 2, then 100 mg PO once per day for month 3
+*[[Mitoxantrone (Novantrone)]] 12 mg/m<sup>2</sup> IV over 20 minutes once per day on days 1 to 3
-====Glucocorticoid therapy, induction phase====
+'''15- to 20-day cycle for up to 4 cycles'''
-*[[Prednisone (Sterapred)]] 20 mg PO once per day after breakfast
+====Dose modifications====
-====Chemotherapy, induction phase====
+*[[Mitoxantrone (Novantrone)]] dose reduction to 8 mg/m<sup>2</sup> allowed on the basis of age, coexisting conditions, and previous anthracycline use
-*[[Etoposide (Vepesid)]] 50 mg PO once per day after dinner
-*[[Procarbazine (Matulane)]] 50 mg PO once per day at bedtime
-*[[Cyclophosphamide (Cytoxan)]] 50 mg PO once per day after lunch
-====Supportive therapy, induction phase====
-*[[Aspirin]] 81 mg PO once per day "after 2 episodes of DVT occurred."
-'''3-month course, followed by:'''
-====Targeted therapy, maintenance phase====
-*[[Rituximab (Rituxan)]] (dose not specified) IV once per day on days 1, 8, 15, 22
-*[[Thalidomide (Thalomid)]] 100 mg PO once per day
-====Chemotherapy, maintenance phase====
-*PEPC: Same medications and doses given per day as used in the induction phase, but titrated to maintain ANC of at least 2000/uL.
-====Supportive therapy, maintenance phase====
-*[[Aspirin]] 81 mg PO once per day "after 2 episodes of DVT occurred."
-'''4-month cycles'''
 </div></div>
 ===References===
-# Ruan J, Martin P, Coleman M, Furman RR, Cheung K, Faye A, Elstrom R, Lachs M, Hajjar KA, Leonard JP. Durable responses with the metronomic rituximab and thalidomide plus prednisone, etoposide, procarbazine, and cyclophosphamide regimen in elderly patients with recurrent mantle cell lymphoma. Cancer. 2010 Jun 1;116(11):2655-64. [https://doi.org/10.1002/cncr.25055 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3004744/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20235190 PubMed]
+# '''INO-VATE ALL:''' Kantarjian HM, DeAngelo DJ, Stelljes M, Martinelli G, Liedtke M, Stock W, Gökbuget N, O'Brien S, Wang K, Wang T, Paccagnella ML, Sleight B, Vandendries E, Advani AS. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016 Aug 25;375(8):740-53. Epub 2016 Jun 12. [https://doi.org/10.1056/NEJMoa1509277 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1509277/suppl_file/nejmoa1509277_protocol.pdf link to original protocol] '''contains dosing details in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5594743/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27292104 PubMed] NCT01564784
-==Temsirolimus & Rituximab {{#subobject:8a89c9|Regimen=1}}==
+## '''Update:''' Kantarjian HM, DeAngelo DJ, Stelljes M, Liedtke M, Stock W, Gökbuget N, O'Brien SM, Jabbour E, Wang T, Liang White J, Sleight B, Vandendries E, Advani AS. Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia: Final report and long-term survival follow-up from the randomized, phase 3 INO-VATE study. Cancer. 2019 Jul 15;125(14):2474-2487. Epub 2019 Mar 28. [https://doi.org/10.1002/cncr.32116 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6618133/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30920645 PubMed]
+==FLAG {{#subobject:600e85|Regimen=1}}==
+FLAG: '''<u>FL</u>'''udarabine, '''<u>A</u>'''ra-C (Cytarabine), '''<u>G</u>'''-CSF
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:8fb4aa|Variant=1}}===
+===Regimen {{#subobject:e2c900|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 33%"|Study
+!style="width: 20%"|Study
-!style="width: 33%"|Years of enrollment
+!style="width: 20%"|Years of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1016/S1470-2045(11)70062-6 Ansell et al. 2011 (NCCTG N038H)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5594743/ Kantarjian et al. 2016 (INO-VATE ALL)]
-|2005-2009
+|2012-2014
-|style="background-color:#91cf61"|Phase 2
+|style="background-color:#1a9851"|Phase 3 (C)
+|[[#Inotuzumab_ozogamicin_monotherapy|Inotuzumab ozogamicin]]
+|style="background-color:#fc8d59"|Seems to have inferior OS
 |-
 |}
 <div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
+====Chemotherapy====
-*[[Temsirolimus (Torisel)]] 25 mg IV once per day on days 1, 8, 15, 22
+*[[Fludarabine (Fludara)]] 30 mg/m<sup>2</sup> IV over 30 minutes once per day on days 2 to 6
-*[[Rituximab (Rituxan)]] as follows:
+*[[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV once per day on days 1 to 6
-**Cycle 1: 375 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
+====Growth factor therapy====
-**Cycles 3, 5, 7, 9, 11: 375 mg/m<sup>2</sup> IV once on day 1
+*[[:Category:Granulocyte_colony-stimulating_factors|G-CSF]] 5 mcg/kg or at the institutional standard dose once per day (interval not specified)
-'''28-day cycle up to 12 cycles'''
+'''28-day cycle for up to 4 cycles'''
 </div></div>
 ===References===
-# '''NCCTG N038H:''' Ansell SM, Tang H, Kurtin PJ, Koenig PA, Inwards DJ, Shah K, Ziesmer SC, Feldman AL, Rao R, Gupta M, Erlichman C, Witzig TE. Temsirolimus and rituximab in patients with relapsed or refractory mantle cell lymphoma: a phase 2 study. Lancet Oncol. 2011 Apr;12(4):361-8. [https://doi.org/10.1016/S1470-2045(11)70062-6 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3106222/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21440503 PubMed] NCT00109967
+# '''INO-VATE ALL:''' Kantarjian HM, DeAngelo DJ, Stelljes M, Martinelli G, Liedtke M, Stock W, Gökbuget N, O'Brien S, Wang K, Wang T, Paccagnella ML, Sleight B, Vandendries E, Advani AS. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016 Aug 25;375(8):740-53. Epub 2016 Jun 12. [https://doi.org/10.1056/NEJMoa1509277 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5594743/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27292104 PubMed] NCT01564784
-==Bortezomib & Rituximab (VR) {{#subobject:ea40ed|Regimen=1}}==
+## '''Update:''' Kantarjian HM, DeAngelo DJ, Stelljes M, Liedtke M, Stock W, Gökbuget N, O'Brien SM, Jabbour E, Wang T, Liang White J, Sleight B, Vandendries E, Advani AS. Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia: Final report and long-term survival follow-up from the randomized, phase 3 INO-VATE study. Cancer. 2019 Jul 15;125(14):2474-2487. Epub 2019 Mar 28. [https://doi.org/10.1002/cncr.32116 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6618133/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30920645 PubMed]
-VR: '''<u>V</u>'''elcade (Bortezomib), '''<u>R</u>'''ituximab
+==Hyper-CVAD/MA & Everolimus {{#subobject:71a41c|Regimen=1}}==
+Hyper-CVAD/MA & Everolimus: '''<u>Hyper</u>'''fractionated '''<u>C</u>'''yclophosphamide, '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>D</u>'''examethasone alternating with '''<u>M</u>'''ethotrexate, '''<u>A</u>'''ra-C (Cytarabine), with Everolimus
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:4421a0|Variant=1}}===
+===Protocol {{#subobject:2efb7e|Variant=1}}===
 {| class="wikitable sortable" style="width: 60%; text-align:center;"
 !style="width: 33%"|Study
@@ Line 2,777: / Line 2,075: @@
 !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3116936/ Baiocchi et al. 2011 (OSU-0430)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4470787/ Daver et al. 2015 (MDACC 2009-0100)]
-|2005-2009
+|2010-2014
-|style="background-color:#ffffbe"|Phase 2, <20 pts
+|style="background-color:#91cf61"|Phase 1/2
 |-
 |}
-''Note: Bortezomib dose was initially 1.5 mg/m<sup>2</sup> but was reduced due to excess grade 3 neurotoxicity.''
+''Note: there are some difference between this protocol and other published Hyper-CVAD protocols, including flexibility in the timing of vincristine and dexamethasone. Some details were missing, in particular the supportive medications for the B cycles. The everolimus dose is the MTD.''
 <div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
+====Targeted therapy, all cycles====
-*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
+*[[Everolimus (Afinitor)]] 5 mg PO once per day
-*[[Rituximab (Rituxan)]] as follows:
+====Chemotherapy, Part A (cycles 1, 3, 5, 7)====
-**Cycles 2 to 5: 375 mg/m<sup>2</sup> IV once per day on days 1 & 8
+*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> IV over 3 hours every 12 hours on days 1 to 3 (total dose per cycle: 1800 mg/m<sup>2</sup>)
-'''21-day cycle for up to 5 cycles'''
+*[[Vincristine (Oncovin)]] by the following age-based criteria:
-</div>
+**Younger than 18: 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 4 & 11 (+/- 2 days)
-<div class="toccolours" style="background-color:#cbd5e7">
+**18 and older: 2 mg IV once per day on days 4 & 11 (+/- 2 days)
-====Subsequent treatment====
+*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 4
-*SD or better: Optional [[#Bortezomib_.26_Rituximab_.28VR.29_2|VR]] maintenance
+====Glucocorticoid therapy, Part A (cycles 1, 3, 5, 7)====
+*[[Dexamethasone (Decadron)]] by the following age-based criteria:
+**Younger than 18: 20 mg/m<sup>2</sup> (maximum dose of 40 mg) IV or PO once per day on days 1 to 4, 11 to 14 (+/- 2 days)
+**18 and older: 40 mg IV or PO once per day on days 1 to 4, 11 to 14 (+/- 2 days)
+====Supportive therapy, Part A (cycles 1, 3, 5, 7)====
+*[[Mesna (Mesnex)]] 600 mg/m<sup>2</sup>/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 1800 mg/m<sup>2</sup>)
+*[[Pegfilgrastim (Neulasta)]] 6 mg SC once, approximately 24 hours after completion of chemotherapy
+====Chemotherapy, Part A (cycles 1, 3, 5, 7)====
+*[[Methotrexate (MTX)]] 200 mg/m<sup>2</sup> IV over 2 hours once on day 1, then 800 mg/m<sup>2</sup> IV over 22 hours (total dose per cycle: 1000 mg/m<sup>2</sup>)
+*[[Cytarabine (Ara-C)]] by the following age-based criteria:
+**Younger than 60: 3000 mg/m<sup>2</sup> IV over 2 hours every 12 hours on days 2 & 3 (total dose per cycle: 12,000 mg/m<sup>2</sup>)
+**60 and older, or with creatinine at least 1.5 x the upper limit of normal: 1000 mg/m<sup>2</sup> IV over 2 hours every 12 hours on days 2 & 3 (total dose per cycle: 4000 mg/m<sup>2</sup>)
+====Glucocorticoid therapy, Part A (cycles 1, 3, 5, 7)====
+*[[Methylprednisolone (Solumedrol)]] by the following age-based criteria:
+**Younger than 18: 25 mg/m<sup>2</sup> (maximum dose of 50 mg) IV over 2 hours every 12 hours on days 1 to 3 (total dose per cycle: 150 mg/m<sup>2</sup>)
+**18 and older: 50 mg IV over 2 hours every 12 hours on days 1 to 3 (total dose per cycle: 300 mg/m<sup>2</sup>)
+***''It isn't clear if this is meant to be a supportive or antineoplastic medication.''
 </div></div>
 ===References===
-# '''OSU-0430:''' Baiocchi RA, Alinari L, Lustberg ME, Lin TS, Porcu P, Li X, Johnston JS, Byrd JC, Blum KA. Phase 2 trial of rituximab and bortezomib in patients with relapsed or refractory mantle cell and follicular lymphoma. Cancer. 2011 Jun 1;117(11):2442-51. Epub 2010 Dec 14. [https://doi.org/10.1002/cncr.25792 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3116936/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24048792 PubMed] NCT00201877
+# '''MDACC 2009-0100:''' Daver N, Boumber Y, Kantarjian H, Ravandi F, Cortes J, Rytting ME, Kawedia JD, Basnett J, Culotta KS, Zeng Z, Lu H, Richie MA, Garris R, Xiao L, Liu W, Baggerly KA, Jabbour E, O'Brien S, Burger J, Bendall LJ, Thomas D, Konopleva M. A Phase I/II study of the mTOR inhibitor everolimus in combination with HyperCVAD chemotherapy in patients with relapsed/refractory acute lymphoblastic leukemia. Clin Cancer Res. 2015 Jun 15;21(12):2704-14. Epub 2015 Feb 27. [http://clincancerres.aacrjournals.org/content/21/12/2704.full link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4470787/ link to PMC article] '''contains partial protocol in supplement''' [https://pubmed.ncbi.nlm.nih.gov/25724525 PubMed] NCT00968253
-=Consolidation after second-line therapy=
+==Inotuzumab ozogamicin monotherapy {{#subobject:d90806|Regimen=1}}==
-==BFR, then allo HSCT {{#subobject:c2659b|Regimen=1}}==
-BFR: '''<u>B</u>'''endamustine, '''<u>F</u>'''ludarabine, '''<u>R</u>'''ituximab
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:41fd04|Variant=1}}===
+===Regimen {{#subobject:8be9f9|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
+{| class="wikitable" style="color:white; background-color:#404040"
-!style="width: 33%"|Study
+|<small>'''FDA-recommended dose'''</small>
-!style="width: 33%"|Years of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4260365/ Khouri et al. 2014 (MDACC 2008-0246)]
-|2009-2013
-| style="background-color:#ffffbe" |Phase 2, <20 pts in this subgroup
 |-
 |}
-{{#lst:Allogeneic HSCT|41fd04}}
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-====Immunotherapy====
+!style="width: 20%"|Study
-*[[Allogeneic stem cells]]
+!style="width: 20%"|Years of enrollment
-'''Stem cells transfused on day 0'''
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-</div></div>
+!style="width: 20%"|Comparator
-===References===
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-# '''MDACC 2008-0246:''' Khouri IF, Wei W, Korbling M, Turturro F, Ahmed S, Alousi A, Anderlini P, Ciurea S, Jabbour E, Oran B, Popat UR, Rondon G, Bassett RL Jr, Gulbis A. BFR (bendamustine, fludarabine, and rituximab) allogeneic conditioning for chronic lymphocytic leukemia/lymphoma: reduced myelosuppression and GVHD. Blood. 2014 Oct 2;124(14):2306-12. Epub 2014 Aug 21. [http://www.bloodjournal.org/content/124/14/2306.long link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4260365/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25145344 PubMed] NCT00880815
-==FluBuCy, then allo HSCT {{#subobject:84acb0|Regimen=1}}==
-FluBuCy: '''<u>Flu</u>'''darabine, '''<u>Bu</u>'''sulfan, '''<u>Cy</u>'''clophosphamide
-<div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:bfe434|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
-!style="width: 33%"|Study
-!style="width: 33%"|Years of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://doi.org/10.1016/S1470-2045(14)70161-5 Glass et al. 2014 (DSHNHL R3)]
+|[https://doi.org/10.1016/S1470-2045(11)70386-2 Kantarjian et al. 2012 (MDACC 2009-0872)]
-|2004-2009
+|2010-2011
 | style="background-color:#91cf61" |Phase 2
+| style="background-color:#d3d3d3" |
+| style="background-color:#d3d3d3" |
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5594743/ Kantarjian et al. 2016 (INO-VATE ALL)]
+|2012-2014
+|style="background-color:#1a9851"|Phase 3 (E-RT-switch-ooc)
+|Investigator's choice of:<br> 1. [[#Cytarabine_monotherapy|Cytarabine]]<br> 2. [[#Cytarabine_.26_Mitoxantrone_.28MC.29|MC]]<br> 3. [[#FLAG|FLAG]]
+|style="background-color:#91cf60"|Seems to have superior OS
 |-
 |}
-{{#lst:Allogeneic HSCT|bfe434}}
+''Note: the protocol in the text of Kantarjian et al. 2016 is confusing, as it does not specify BSA-based dosing; the original protocol is clear on this, as is the FDA package insert.''
-====Immunotherapy====
+<div class="toccolours" style="background-color:#b3e2cd">
-*[[Allogeneic stem cells]]
+====Antibody-drug conjugate therapy====
-'''Stem cells transfused on day 0'''
+*[[Inotuzumab ozogamicin (Besponsa)]] as follows:
+**Cycle 1: 0.8 mg/m<sup>2</sup> IV once on day 1, then 0.5 mg/m<sup>2</sup> IV once per day on days 8 & 15
+**Cycles 2 to 6, patients achieving CR or CRi: 0.5 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
+**Cycles 2 to 6, less than CR: 0.8 mg/m<sup>2</sup> IV once on day 1, then 0.5 mg/m<sup>2</sup> IV once per day on days 8 & 15
+'''21-day cycle for 1 cycle, then 28-day cycle for up to 5 cycles'''
 </div></div>
 ===References===
-<!-- # Glass B, rabbits Kamp J, Wulf G, Dreger P, Pfreundschuh M, Gramatzki M Silling G, Wilhelm C, Zeis M, Görlitz A, Pfeiffer S, Hilgers R, Truemper L, Schmitz N. High-dose chemotherapy Followed by allogeneic stem cell transplantation in relapsed and refractory high-risk aggressive non-Hodgkin's lymphoma: Results of a prospective study of the German high-grade non-Hodgkin's lymphoma study group. J Clin Oncol 30, 2012 (suppl; abstr 8004) -->
+# '''MDACC 2009-0872:''' Kantarjian H, Thomas D, Jorgensen J, Jabbour E, Kebriaei P, Rytting M, York S, Ravandi F, Kwari M, Faderl S, Rios MB, Cortes J, Fayad L, Tarnai R, Wang SA, Champlin R, Advani A, O'Brien S. Inotuzumab ozogamicin, an anti-CD22-calecheamicin conjugate, for refractory and relapsed acute lymphocytic leukaemia: a phase 2 study. Lancet Oncol. 2012 Apr;13(4):403-11. Epub 2012 Feb 21. [https://doi.org/10.1016/S1470-2045(11)70386-2 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/22357140 PubMed] NCT01134575
-# '''DSHNHL R3:''' Glass B, Hasenkamp J, Wulf G, Dreger P, Pfreundschuh M, Gramatzki M, Silling G, Wilhelm C, Zeis M, Görlitz A, Pfeiffer S, Hilgers R, Truemper L, Schmitz N; German High-Grade Lymphoma Study Group. Rituximab after lymphoma-directed conditioning and allogeneic stem-cell transplantation for relapsed and refractory aggressive non-Hodgkin lymphoma (DSHNHL R3): an open-label, randomised, phase 2 trial. Lancet Oncol. 2014 Jun;15(7):757-66. Epub 2014 May 11. [https://doi.org/10.1016/S1470-2045(14)70161-5 link to original article] [http://www.dshnhl.org/app/download/9495510598/Studienprotokoll+DSHNHL+alloFBC+final+vollst.pdf link to original protocol (in German)] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/24827808 PubMed] NCT00785330
+# '''INO-VATE ALL:''' Kantarjian HM, DeAngelo DJ, Stelljes M, Martinelli G, Liedtke M, Stock W, Gökbuget N, O'Brien S, Wang K, Wang T, Paccagnella ML, Sleight B, Vandendries E, Advani AS. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016 Aug 25;375(8):740-53. Epub 2016 Jun 12. [https://doi.org/10.1056/NEJMoa1509277 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1509277/suppl_file/nejmoa1509277_protocol.pdf link to original protocol] '''contains dosing details in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5594743/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27292104 PubMed] NCT01564784
-==Lenalidomide & Rituximab (R<sup>2</sup>) {{#subobject:3d8123|Regimen=1}}==
+## '''Update:''' Kantarjian HM, DeAngelo DJ, Stelljes M, Liedtke M, Stock W, Gökbuget N, O'Brien SM, Jabbour E, Wang T, Liang White J, Sleight B, Vandendries E, Advani AS. Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia: Final report and long-term survival follow-up from the randomized, phase 3 INO-VATE study. Cancer. 2019 Jul 15;125(14):2474-2487. Epub 2019 Mar 28. [https://doi.org/10.1002/cncr.32116 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6618133/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30920645 PubMed]
+==Tisagenlecleucel monotherapy {{#subobject:d68f14|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:b59073|Variant=1}}===
+===Regimen {{#subobject:60fc19|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
+{| class="wikitable sortable" style="width: 80%; text-align:center;"
-!style="width: 33%"|Study
+!style="width: 25%"|Study
-!style="width: 33%"|Years of enrollment
+!style="width: 25%"|Years of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4267531/ Maude et al. 2014 (UPCC04409)]
+|2012-2014
+|style="background-color:#91cf61"|Phase 1/2a
+|
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5477625/ Zaja et al. 2017]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5996391/ Maude et al. 2018 (ELIANA)]
-|2012-2013
+|2015-2017
-|style="background-color:#91cf61"|Phase 2
+|style="background-color:#91cf61"|Phase 2 (RT)
+|ORR: 81%
 |-
 |}
+''Note: dosing instructions are based on ELIANA.''
 <div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
-*[[#R-BL|R2B]] x 4
+*Lymphodepleting therapy with [[Autologous_HSCT#FC|FC]] or [[Autologous_HSCT#CYVE|CYVE]]
 </div>
 <div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
+====Immunotherapy====
-*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21
+*[[Tisagenlecleucel (Kymriah)]] by the following criteria:
-*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1
+**Up to 50 kg: 2 to 5 x 10<sup>6</sup> CTL019 transduced viable T-cells per kg body weight IV once on day 0
-'''28-day cycle for 2 cycles'''
+**Greater than 50 kg: 1.0 to 2.5 x 10<sup>8</sup> CTL019 transduced viable T-cells IV once on day 0
-</div>
+'''One course'''
-<div class="toccolours" style="background-color:#cbd5e7">
-====Subsequent treatment====
-*Patients with a continued PR/CR: [[#Lenalidomide_monotherapy_3|Lenalidomide]] maintenance
 </div></div>
 ===References===
-# Zaja F, Ferrero S, Stelitano C, Ferrari A, Salvi F, Arcari A, Musuraca G, Botto B, Spina M, Cellini C, Patti C, Liberati AM, Minotto C, Pileri SA, Ceccarelli M, Volpetti S, Ferranti A, Drandi D, Montechiarello E, Ladetto M, Carmichael J, Fanin R. Second-line rituximab, lenalidomide, and bendamustine in mantle cell lymphoma: a phase II clinical trial of the Fondazione Italiana Linfomi. Haematologica. 2017 May;102(5):e203-e206. Epub 2017 Jan 12. [http://www.haematologica.org/content/102/5/e203.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5477625/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28082342 PubMed]
+# '''UPCC04409:''' Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, Chew A, Gonzalez VE, Zheng Z, Lacey SF, Mahnke YD, Melenhorst JJ, Rheingold SR, Shen A, Teachey DT, Levine BL, June CH, Porter DL, Grupp SA. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014 Oct 16;371(16):1507-17. Erratum in: N Engl J Med. 2016 Mar 10;374(10):998. [https://doi.org/10.1056/NEJMoa1407222 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4267531/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25317870 PubMed] NCT01029366
-=Maintenance after second-line therapy=
+# '''ELIANA:''' Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, Bader P, Verneris MR, Stefanski HE, Myers GD, Qayed M, De Moerloose B, Hiramatsu H, Schlis K, Davis KL, Martin PL, Nemecek ER, Yanik GA, Peters C, Baruchel A, Boissel N, Mechinaud F, Balduzzi A, Krueger J, June CH, Levine BL, Wood P, Taran T, Leung M, Mueller KT, Zhang Y, Sen K, Lebwohl D, Pulsipher MA, Grupp SA. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018 Feb 1;378(5):439-448. [https://doi.org/10.1056/NEJMoa1709866 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1709866/suppl_file/nejmoa1709866_protocol.pdf link to supplementary protocol] '''contains dosing details in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5996391/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29385370 PubMed] NCT02435849
-==Lenalidomide monotherapy {{#subobject:f4a26c|Regimen=1}}==
+=Consolidation after salvage therapy=
+==Blinatumomab monotherapy {{#subobject:e7bh86|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #1, 15 mg 21/28, 18 months {{#subobject:f90ac2|Variant=1}}===
+===Regimen {{#subobject:2db2g7|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 33%"|Study
+!style="width: 20%"|Study
-!style="width: 33%"|Years of enrollment
+!style="width: 20%"|Years of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5477625/ Zaja et al. 2017]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7926290/ Brown et al. 2021 (COG AALL1331)]
-|2012-2013
+|2014-2019
-|style="background-color:#91cf61"|Phase 2
+|style="background-color:#1a9851"|Phase 3 (E-switch-ooc)
+|Standard salvage consolidation chemotherapy
+| style="background-color:#d9ef8b" |Might have superior DFS
 |-
 |}
-<div class="toccolours" style="background-color:#cbd5e8">
-====Preceding treatment====
-*[[#Lenalidomide_.26_Rituximab_.28R2.29_4|Lenalidomide & Rituximab]] x 2
-</div>
 <div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
+====Immunotherapy====
-*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21
+*[[Blinatumomab (Blincyto)]] 15 mcg/m<sup>2</sup>/day IV continuous infusion over 28 days, started on day 1 (total dose per cycle: 420 mcg/m<sup>2</sup>)
-'''28-day cycle for up to 20 cycles (18 months)'''
+'''35-day cycle for 2 cycles'''
-</div></div><br>
-<div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #2, 15 mg 21/28, indefinite {{#subobject:7c3cfe|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
-!style="width: 33%"|Study
-!style="width: 33%"|Years of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://doi.org/10.1111/bjh.12008 Eve et al. 2012]
-|2008-2010
-|style="background-color:#91cf61"|Phase 2
-|-
-|}
-<div class="toccolours" style="background-color:#cbd5e8">
-====Preceding treatment====
-*[[#Lenalidomide_monotherapy_2|Lenalidomide]] x 6
 </div>
-<div class="toccolours" style="background-color:#b3e2cd">
+<div class="toccolours" style="background-color:#cbd5e7">
-====Targeted therapy====
+====Subsequent treatment====
-*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21
+*Allogeneic hematopoietic stem cell transplant
-'''28-day cycles'''
 </div></div>
 ===References===
-# Eve HE, Carey S, Richardson SJ, Heise CC, Mamidipudi V, Shi T, Radford JA, Auer RL, Bullard SH, Rule SA. Single-agent lenalidomide in relapsed/refractory mantle cell lymphoma: results from a UK phase II study suggest activity and possible gender differences. Br J Haematol. 2012 Oct;159(2):154-63. Epub 2012 Aug 9. [https://doi.org/10.1111/bjh.12008 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22881386 PubMed]
+# '''COG AALL1331:''' Brown PA, Ji L, Xu X, Devidas M, Hogan LE, Borowitz MJ, Raetz EA, Zugmaier G, Sharon E, Bernhardt MB, Terezakis SA, Gore L, Whitlock JA, Pulsipher MA, Hunger SP, Loh ML. Effect of Postreinduction Therapy Consolidation With Blinatumomab vs Chemotherapy on Disease-Free Survival in Children, Adolescents, and Young Adults With First Relapse of B-Cell Acute Lymphoblastic Leukemia: A Randomized Clinical Trial. JAMA. 2021 Mar 2;325(9):833-842. [https://doi.org/10.1001/jama.2021.0669 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7926290/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33651090/ PubMed] NCT02101853
-# Zaja F, Ferrero S, Stelitano C, Ferrari A, Salvi F, Arcari A, Musuraca G, Botto B, Spina M, Cellini C, Patti C, Liberati AM, Minotto C, Pileri SA, Ceccarelli M, Volpetti S, Ferranti A, Drandi D, Montechiarello E, Ladetto M, Carmichael J, Fanin R. Second-line rituximab, lenalidomide, and bendamustine in mantle cell lymphoma: a phase II clinical trial of the Fondazione Italiana Linfomi. Haematologica. 2017 May;102(5):e203-e206. Epub 2017 Jan 12. [http://www.haematologica.org/content/102/5/e203.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5477625/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28082342 PubMed]
+==Cyclophosphamide & TBI, then allo HSCT {{#subobject:a9e6e8|Regimen=1}}==
-==Rituximab monotherapy {{#subobject:ea4966|Regimen=1}}==
+Cy/TBI: '''<u>Cy</u>'''clophosphamide & '''<u>T</u>'''otal '''<u>B</u>'''ody '''<u>I</u>'''rradiation
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #1 {{#subobject:6875f6|Variant=1}}===
+===Regimen {{#subobject:1ba28d|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 !style="width: 20%"|Study
@@ Line 2,926: / Line 2,225: @@
 !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[http://www.bloodjournal.org/content/104/10/3064.long Forstpointner et al. 2004]
+|[https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/581686 Rudolph et al. 1973]
-|1998-2001
+|1968-1970
-|style="background-color:#1a9851"|Phase 3 (E-esc)
+| style="background-color:#ffffbe" |Non-randomized, <20 pts in subgroup
-|[[Mantle_cell_lymphoma_-_null_regimens#Observation_2|Observation]]
+| style="background-color:#d3d3d3" |
-|style="background-color:#91cf60"|Seems to have superior response duration
+| style="background-color:#d3d3d3" |
 |-
-|}
+|[https://doi.org/10.1056/NEJM198708203170801 Kersey et al. 1987]
-<div class="toccolours" style="background-color:#cbd5e8">
+|1982-1985
-====Preceding treatment====
+|style="background-color:#1a9851"|Quasi-randomized
-*[[Mantle_cell_lymphoma_-_historical#FCM|FCM]] x 4 versus [[#R-FCM|R-FCM]] x 4, followed in 3 months by:
+|Auto HSCT
-</div>
+| style="background-color:#1a9850" |Superior RFS
-<div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
-*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
-'''3-month cycle for 2 cycles'''
-</div></div><br>
-<div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #2 {{#subobject:607ae6|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
-!style="width: 33%"|Study
-!style="width: 33%"|Years of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3128220/ Lamm et al. 2011 (MCL 03)]
-|2005-NR
-|style="background-color:#ffffbe"|Phase 2, <20 pts
 |-
 |}
-<div class="toccolours" style="background-color:#cbd5e8">
+{{#lst:Allogeneic HSCT|6ca28d}}
-====Preceding treatment====
+====Immunotherapy====
-*[[#BDR|BORID]] x 6
+*[[Allogeneic stem cells]]
-</div>
+'''Stem cells transfused on day 0'''
-<div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
-*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1
-'''8-week cycle for 4 cycles'''
 </div></div>
 ===References===
-# Forstpointner R, Dreyling M, Repp R, Hermann S, Hänel A, Metzner B, Pott C, Hartmann F, Rothmann F, Rohrberg R, Böck HP, Wandt H, Unterhalt M, Hiddemann W; German Low-Grade Lymphoma Study Group. The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. 2004 Nov 15;104(10):3064-71. Epub 2004 Jul 29. [http://www.bloodjournal.org/content/104/10/3064.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15284112 PubMed]
+# Rudolph RH, Fefer A, Thomas ED, Buckner CD, Clift RA, Storb R. Isogeneic marrow grafts for hematologic malignancy in man. Arch Intern Med. 1973 Aug;132(2):279-85. [https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/581686 link to original article] [https://pubmed.ncbi.nlm.nih.gov/4268940 PubMed]
-## '''Update:''' Forstpointner R, Unterhalt M, Dreyling M, Böck HP, Repp R, Wandt H, Pott C, Seymour JF, Metzner B, Hänel A, Lehmann T, Hartmann F, Einsele H, Hiddemann W; German Low Grade Lymphoma Study Group. Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell lymphomas: Results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG). Blood. 2006 Dec 15;108(13):4003-8. Epub 2006 Aug 31. [http://www.bloodjournal.org/content/108/13/4003.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16946304 PubMed]
+## '''Update:''' Fefer A, Einstein AB, Thomas ED, Buckner CD, Clift RA, Glucksberg H, Neiman PE, Storb R. Bone-marrow transplantation for hematologic neoplasia in 16 patients with identical twins. N Engl J Med. 1974 Jun 20;290(25):1389-93. [https://doi.org/10.1056/NEJM197406202902501 link to original article] [https://pubmed.ncbi.nlm.nih.gov/4597885 PubMed]
-# '''MCL 03:''' Lamm W, Kaufmann H, Raderer M, Hoffmann M, Chott A, Zielinski C, Drach J. Bortezomib combined with rituximab and dexamethasone is an active regimen for patients with relapsed and chemotherapy-refractory mantle cell lymphoma. Haematologica. 2011 Jul;96(7):1008-14. Epub 2011 Apr 12. [http://www.haematologica.org/content/96/7/1008.long link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3128220/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21486866 PubMed] NCT00261612
+# Kersey JH, Weisdorf D, Nesbit ME, LeBien TW, Woods WG, McGlave PB, Kim T, Vallera DA, Goldman AI, Bostrom B, Hurd D, Ramsay NKC. Comparison of autologous and allogeneic bone marrow transplantation for treatment of high-risk refractory acute lymphoblastic leukemia. N Engl J Med. 1987 Aug 20;317(8):461-7. [https://doi.org/10.1056/NEJM198708203170801 link to original article] [https://pubmed.ncbi.nlm.nih.gov/3302708 PubMed]
-==Bortezomib & Rituximab (VR) {{#subobject:465914|Regimen=1}}==
+=Maintenance after subsequent lines of therapy=
-VR: '''<u>V</u>'''elcade (Bortezomib), '''<u>R</u>'''ituximab
+==Blinatumomab monotherapy {{#subobject:94aea7|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:67cd8d|Variant=1}}===
+===Regimen {{#subobject:1e4bff|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!style="width: 33%"|Study
+!style="width: 20%"|Study
-!style="width: 33%"|Years of enrollment
+!style="width: 20%"|Years of enrollment
-!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3116936/ Baiocchi et al. 2011 (OSU-0430)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5881572/ Kantarjian et al. 2017 (TOWER)]
-|2005-2009
+|2014-2015
-|style="background-color:#ffffbe"|Phase 2, <20 pts
+|style="background-color:#1a9851"|Phase 3 (E-RT-switch-ooc)
+|Standard maintenance chemotherapy
+|style="background-color:#1a9850"|Superior OS
 |-
 |}
+''The most common comparator was not specified but is presumably POMP.''
 <div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
-*[[#Bortezomib_.26_Rituximab_.28VR.29|VR]] x 5
+*[[#Blinatumomab_monotherapy_2|Blinatumomab induction and]] consolidation
 </div>
 <div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
+====Immunotherapy====
-*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1 & 8
+*[[Blinatumomab (Blincyto)]] 28 mcg/day IV continuous infusion over 28 days, started on day 1 (total dose per cycle: 784 mcg)
-*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once per day on days 1 & 8
+'''12-week cycle for up to 5 cycles (1 year)'''
-'''6-month cycle for up to 4 cycles (2 years)'''
 </div></div>
 ===References===
-# '''OSU-0430:''' Baiocchi RA, Alinari L, Lustberg ME, Lin TS, Porcu P, Li X, Johnston JS, Byrd JC, Blum KA. Phase 2 trial of rituximab and bortezomib in patients with relapsed or refractory mantle cell and follicular lymphoma. Cancer. 2011 Jun 1;117(11):2442-51. Epub 2010 Dec 14. [https://doi.org/10.1002/cncr.25792 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3116936/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24048792 PubMed] NCT00201877
+# '''TOWER:''' Kantarjian H, Stein A, Gökbuget N, Fielding AK, Schuh AC, Ribera JM, Wei A, Dombret H, Foà R, Bassan R, Arslan Ö, Sanz MA, Bergeron J, Demirkan F, Lech-Maranda E, Rambaldi A, Thomas X, Horst HA, Brüggemann M, Klapper W, Wood BL, Fleishman A, Nagorsen D, Holland C, Zimmerman Z, Topp MS. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017 Mar 2;376(9):836-847. [https://doi.org/10.1056/NEJMoa1609783 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5881572/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28249141 PubMed] NCT02013167
+## '''HRQoL analysis:''' Topp MS, Zimmerman Z, Cannell P, Dombret H, Maertens J, Stein A, Franklin J, Tran Q, Cong Z, Schuh AC. Health-related quality of life in adults with relapsed/refractory acute lymphoblastic leukemia treated with blinatumomab. Blood. 2018 Jun 28;131(26):2906-2914. Epub 2018 May 8. [https://doi.org/10.1182/blood-2017-09-804658 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6024638/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29739753 PubMed]
 =Investigational agents=
 ''These are drugs under study with at least some promising results for this disease.''
-*[[Abexinostat (PCI-24781)]]
+*[[Epratuzumab (humanised anti-CD22 antibody)]]
-*[[Alisertib (MLN8237)]]
+[[Category:B-cell acute lymphoblastic leukemia regimens]]
-=Prognosis=
-==Mantle cell lymphoma international prognostic index (MIPI)==
-Calculation generally require a calculator. The MIPI is calculated using the following formula: [0.03535 × age (in years)] + 0.6978 (if ECOG PS greater than 1) + [1.367 × log<sub>10</sub>(LDH/ULN)] + [0.9393 × log<sub>10</sub>(white cells per uL blood)]. Risk factors include:
-*Age
-*[[#ECOG_performance_status_.28WHO.2FZubrod_score.29|ECOG Performance Status]]
-*Serum LDH level (''note that reference ranges can vary widely!'')
-*Number of nodal sites
-*WBC count
-Risk stratification:
-*'''Less than 5.7 points''': Low risk
-*'''5.7 to less than 6.2 points''': Intermediate risk
-*'''Greater than or equal to 6.2 points''': High risk
-</div></div>
-===References===
-# Hoster E, Dreyling M, Klapper W, Gisselbrecht C, van Hoof A, Kluin-Nelemans HC, Pfreundschuh M, Reiser M, Metzner B, Einsele H, Peter N, Jung W, Wörmann B, Ludwig WD, Dührsen U, Eimermacher H, Wandt H, Hasford J, Hiddemann W, Unterhalt M; German Low Grade Lymphoma Study Group; European Mantle Cell Lymphoma Network. A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma. Blood. 2008 Jan 15;111(2):558-65. Epub 2007 Oct 25. Erratum in: Blood. 2008 Jun 15;111(12):5761. [http://www.bloodjournal.org/content/111/2/558.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/17962512 PubMed]
-# Hoster E, Klapper W, Hermine O, Kluin-Nelemans HC, Walewski J, van Hoof A, Trneny M, Geisler CH, Di Raimondo F, Szymczyk M, Stilgenbauer S, Thieblemont C, Hallek M, Forstpointner R, Pott C, Ribrag V, Doorduijn J, Hiddemann W, Dreyling MH, Unterhalt M. Confirmation of the mantle-cell lymphoma International Prognostic Index in randomized trials of the European Mantle-Cell Lymphoma Network. J Clin Oncol. 2014 May 1;32(13):1338-46. Epub 2014 Mar 31. [https://doi.org/10.1200/jco.2013.52.2466 link to original article] [https://pubmed.ncbi.nlm.nih.gov/24687837 PubMed]
-=Response criteria=
-*[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4979083/ Lugano Classification criteria (2014)] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4979083/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25113753 PubMed]
-*[https://doi.org/10.1200/jco.1999.17.4.1244 NCI Sponsored International Working Group criteria (1999)] [https://pubmed.ncbi.nlm.nih.gov/10561185 PubMed]
-[[Category:Mantle cell lymphoma regimens]]
 [[Category:Disease-specific pages]]
-[[Category:Aggressive lymphomas]]
+[[Category:Acute lymphoblastic leukemias]]
-[[Category:Non-Hodgkin lymphomas]]

Difference between revisions of "Staging page"

Revision as of 11:31, 17 October 2022

Guidelines

ESMO

EWALL/EBMT

"How I Treat"

NCCN

Prephase

Prednisone monotherapy

Regimen

Glucocorticoid therapy

CNS therapy, prophylaxis

Subsequent treatment

References

Vincristine & Prednisone

Regimen

Chemotherapy

Glucocorticoid therapy

References

Upfront induction therapy

Cyclophosphamide, Cytarabine, Mercaptopurine

Regimen

Preceding treatment

Chemotherapy

CNS therapy, prophylaxis

Subsequent treatment

References

Cyclophosphamide, Daunorubicin, Vincristine, Prednisone

Regimen

Chemotherapy

Glucocorticoid therapy

Subsequent treatment

References

Cyclophosphamide, Daunorubicin, Vincristine, Prednisolone

Regimen

Chemotherapy

Glucocorticoid therapy

CNS therapy, prophylaxis

Subsequent treatment

References

Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone

Regimen variant #1

Preceding treatment

Chemotherapy

Glucocorticoid therapy

CNS therapy, prophylaxis

Supportive therapy

Subsequent treatment

Regimen variant #2, "HyperC"

Preceding treatment

Chemotherapy

Glucocorticoid therapy

CNS therapy, prophylaxis

Supportive therapy

Subsequent treatment

Regimen variant #3

Chemotherapy, "Induction phase I"

Glucocorticoid therapy

Subsequent treatment

Regimen variant #4, "Larson regimen"

Chemotherapy, "Course I"

Glucocorticoid therapy

Subsequent treatment

References

Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone, Rituximab

Regimen variant #1

Preceding treatment

Chemotherapy

Glucocorticoid therapy

Targeted therapy

CNS therapy, prophylaxis

Supportive therapy

Subsequent treatment

References

Cyclophosphamide, Idarubicin, Vincristine, Prednisone

Regimen

Chemotherapy

Glucocorticoid therapy

Subsequent treatment

References