B-cell acute lymphoblastic leukemia

Section editor
	Ashwin Kishtagari, MD Vanderbilt University Nashville, TN, USA LinkedIn

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 are to be found on dedicated pages:

• B-cell ALL, Ph-positive
• CNS leukemia
• T-cell acute lymphoblastic leukemia
• Pediatric B-cell ALL
  • Pediatric B-cell ALL, Ph-positive
• Infant ALL

• We have moved How I Treat articles to a dedicated page.

50 regimens on this page 64 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

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

ESMO

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

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) PubMed

NCCN

• NCCN does not currently have guidelines at this granular level; please see NCCN Guidelines - Acute Lymphoblastic Leukemia.

SITC

• 2020: Boyiadzis et al. The Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of acute leukemia PubMed

Pre-phase

Prednisone monotherapy

Regimen

Study	Dates 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

1. 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	Dates of enrollment	Evidence
McCredie et al. 1983 (SWOG-7416)	1975-1977	Non-randomized part 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

1. 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

Blinatumomab monotherapy

Regimen

Study	Dates of enrollment	Evidence
Advani et al. 2022 (SWOG S1318)	2015-NR	Phase 2

Immunotherapy

• Blinatumomab (Blincyto) as follows:
  • Cycle 1: 9 mcg/m²/day IV continuous infusion over 7 days, started on day 1, then 28 mcg/m²/day IV continuous infusion over 21 days, started on day 1 (total dose per cycle: 651 mcg/m²)
  • Cycle 2: 28 mcg/m²/day IV continuous infusion over 28 days, started on day 1 (total dose per cycle: 784 mcg/m²)

2 cycles

Subsequent treatment

• SWOG S1318, CR or CRi: Blinatumomab consolidation, then POMP maintenance

References

1. SWOG S1318: Advani AS, Moseley A, O'Dwyer KM, Wood BL, Fang M, Wieduwilt MJ, Aldoss I, Park JH, Klisovic RB, Baer MR, Stock W, Bhave RR, Othus M, Harvey RC, Willman CL, Litzow MR, Stone RM, Sharon E, Erba HP. SWOG 1318: A Phase II Trial of Blinatumomab Followed by POMP Maintenance in Older Patients With Newly Diagnosed Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia. J Clin Oncol. 2022 May 10;40(14):1574-1582. Epub 2022 Feb 14. link to original article link to PMC article contains dosing details in manuscript PubMed NCT02143414

Cyclophosphamide, Cytarabine, Mercaptopurine

Regimen

Study	Dates of enrollment	Evidence
Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)	1993-2003	Non-randomized part of phase 3 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

1. 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	Dates 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

1. 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	Dates 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

1. 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	Dates 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 pre-phase

Chemotherapy

• Cyclophosphamide (Cytoxan) by the following study-specific criteria:
  • GRAALL-2003, good early responders: 750 mg/m² IV over 3 hours once per day on days 1 & 15
  • GRAALL-2005: 750 mg/m² IV over 3 hours once per day on days 1 & 15
  • GRAALL-2003, poor early responders: 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/μL

Subsequent treatment

• GRAALL-2005/R, patients with resistant disease: Cytarabine & idarubicin salvage prior to further consolidation
• GRAALL-2005/R, responders: Pediatric-like GRAALL consolidation

Regimen variant #2, "HyperC"

Historic variant

Study	Dates 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 pre-phase

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/μL

28-day course

Subsequent treatment

• GRAALL-2005/R, patients with resistant disease: Cytarabine & idarubicin salvage prior to further consolidation
• GRAALL-2005/R, responders: Pediatric-like GRAALL consolidation

Regimen variant #3

Study	Dates 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

• GIMEMA ALL 0288, responders: Induction phase II, see paper for details
• GIMEMA ALL 0288, non-responders: Salvage, see paper for details

Regimen variant #4, "Larson regimen"

Study	Dates of enrollment	Evidence
Larson et al. 1995 (CALGB 8811)	1988-1991	Phase 2

Chemotherapy, "Course I"

• Cyclophosphamide (Cytoxan) by the following age-based criteria:
  • Younger than 60 years old: 1200 mg/m² IV once on day 1
  • 60 years old or older: 800 mg/m² IV once on day 1
• Daunorubicin (Cerubidine) by the following age-based criteria:
  • Younger than 60 years old: 45 mg/m² IV once per day on days 1 to 3
  • 60 years old 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 years old: 60 mg/m² PO once per day on days 1 to 21
  • 60 years old 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

1. 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
2. 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
3. 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
4. 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
5. 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

Study	Dates 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 (primary endpoint) EFS24: 65% vs 52% (HR 0.66, 95% CI 0.45-0.98)

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 pre-phase

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/μL

One course

Subsequent treatment

• GRAALL-2005/R, patients with resistant disease: Cytarabine, idarubicin, rituximab salvage prior to further consolidation
• GRAALL-2005/R, PR or better: Pediatric-like GRAALL consolidation with rituximab

References

1. 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	Dates 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 (primary endpoint)

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

1. 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

Historic variant

Study	Dates of enrollment	Evidence
Hoelzer et al. 1984	1978-1981	Non-randomized

Note: This variant is 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	Dates 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	Dates 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	Dates of enrollment	Evidence
Linker et al. 1987	1980-1986	Phase 2

Chemotherapy

• Daunorubicin (Cerubidine) by the following response-based 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 response-based 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 response-based 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 response-based 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, 1800 cGy 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, 2800 cGy 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

4- to 6-week course

Subsequent treatment

• Linker regimen consolidation therapy

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

Study	Dates of enrollment	Evidence
Pullarkat et al. 2008 (SWOG S9400)	1995-2000	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	Dates of enrollment	Evidence
Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)	1993-2003	Non-randomized part of phase 3 RCT

Note: 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

1. 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
2. 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
3. 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
4. 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
5. 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
6. 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	Dates 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:
  • 40 years old or younger: 1000 units/m² IV once per day on days 4 & 18
  • 41 years old 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

28-day course

Subsequent treatment

• See paper for protocol details

References

1. 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	Dates of enrollment	Evidence
Rytting et al. 2014	2006-2012	Non-randomized
Stock et al. 2019 (CALGB 10403)	2007-2012	Non-randomized

Note: ABFM stands for 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:
  • 1 to 1.99 years old: 30 mg IT once on day 1
  • 2 to 2.99 years old: 50 mg IT once on day 1
  • 3 years old or older: 70 mg IT once on day 1
• Methotrexate (MTX) by the following age-based criteria:
  • 1 to 1.99 years old: 8 mg IT once per day on days 8 & 29
  • 2 to 2.99 years old: 10 mg IT once per day on days 8 & 29
  • 3 to 8.99 years old: 12 mg IT once per day on days 8 & 29
  • 9 years old or 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	Dates of enrollment	Evidence
Pullarkat et al. 2008 (SWOG S9400)	1995-2000	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.

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
• Pegaspargase (Oncaspar) by the following response-based criteria:
  • All patients: 2000 units/m² IV once on day 15
  • Persistent leukemia on day 21: 2000 units/m² IV once on day 38
• 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

Glucocorticoid therapy

• Prednisone (Sterapred) by the following response-based criteria:
  • All patients: 60 mg/m²/day PO on days 1 to 28
  • CR on day 21: tapered from day 29 to 42
  • Persistent leukemia on day 21: 60 mg/m²/day PO on days 29 to 42

42-day course

Subsequent treatment

• See protocol for details of treatment beyond induction

References

1. 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
2. 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 Jun 30. link to original article link to PMC article PubMed
3. 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)

Regimen

Study	Dates of enrollment	Evidence
Koller et al. 1997	1992-1995	Non-randomized
Thomas et al. 1999	1992-1997	Phase 2
Kantarjian et al. 2000	1992-1998	Phase 2
Thomas et al. 2004	1992-2001	Non-randomized

Chemotherapy, Hyper-CVAD portion (cycles 1, 3, 5, 7; "Part A")

• 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 imaging-based criteria:
  • Normal LVEF: 50 mg/m² IV continuous infusion over 24 hours, started on day 4
  • LVEF 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, Hyper-CVAD portion (cycles 1, 3, 5, 7; "Part A")

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

Supportive therapy, Hyper-CVAD portion (cycles 1, 3, 5, 7; "Part A")

• Mesna (Mesnex) 600 mg/m²/day IV continuous infusion over 72 hours, started on day 1, starting 1 hour prior to cyclophosphamide and completed 12 hours after the last dose of cyclophosphamide
• 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/μL

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

Chemotherapy, MA portion (cycles 2, 4, 6, 8; "Part B")

• 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 years old: 3000 mg/m² IV over 2 hours every 12 hours on days 2 & 3 (total dose per cycle: 12,000 mg/m²)
  • 60 years old 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, MA portion (cycles 2, 4, 6, 8; "Part B")

• 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, MA portion (cycles 2, 4, 6, 8; "Part B")

• Leucovorin (Folinic acid) 50 mg IV once on day 3, 12 hours after methotrexate 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/μL

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

CNS prophylaxis, both portions

• Methotrexate (MTX) by the following route-based 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 treatment, both portions

• 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

1. 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
2. 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
3. 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
4. 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
5. 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

Regimen

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

Note: please see the paper for details about intrathecal dosing.

Chemotherapy, Mini-Hyper-CVD portion (cycles 1, 3, 5, 7; "Part A")

• Cyclophosphamide (Cytoxan) 150 mg/m² IV every 12 hours on days 1 to 3 (total dose per cycle: 900 mg/m²)
• Vincristine (Oncovin) 2 mg IV once per day on days 1 & 8

Glucocorticoid therapy, Mini-Hyper-CVD portion (cycles 1, 3, 5, 7; "Part A")

• Dexamethasone (Decadron) 20 mg IV or PO once per day on days 1 to 4, 11 to 14

Antibody-drug conjugate therapy, Mini-Hyper-CVD portion ("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, MA portion (cycles 2, 4, 6, 8; "Part B")

• Methotrexate (MTX) 250 mg/m² IV once on day 1
• Cytarabine (Ara-C) 500 mg/m² IV every 12 hours on days 2 & 3 (total dose per cycle: 2000 mg/m²)

Antibody-drug conjugate therapy, MA portion ("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 maintenance x 3 y

References

1. 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)

Regimen

Study	Dates of enrollment	Evidence
Thomas et al. 2010 (MDACC ID02-230)	1992-2009	Non-randomized
Thomas et al. 2006	2000-02 to 2005-01	Pilot, fewer than 20 patients reported

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

Targeted therapy, both portions

• Rituximab (Rituxan) as follows:
  • Cycles 1 & 3: 375 mg/m² IV over 2 to 6 hours once per day on days 1 & 11
  • Cycles 2 & 4: 375 mg/m² IV over 2 to 6 hours once per day on days 2 & 8

Chemotherapy, Hyper-CVAD portion (cycles 1, 3, 5, 7; "Part A")

• 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, Hyper-CVAD portion (cycles 1, 3, 5, 7; "Part A")

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

Supportive therapy, Hyper-CVAD portion (cycles 1, 3, 5, 7; "Part A")

• Mesna (Mesnex) 600 mg/m²/day IV continuous infusion over 72 hours, started on day 1, starting 1 hour prior to cyclophosphamide and completed 12 hours after the last dose of cyclophosphamide (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

Chemotherapy, MA portion (cycles 2, 4, 6, 8; "Part B")

• 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, MA portion (cycles 2, 4, 6, 8; "Part B")

• Leucovorin (Folinic acid) 50 mg IV once on day 3, 12 hours after methotrexate 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

8 cycles; 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 prophylaxis, both portions

• 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.

Dose and schedule 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

1. 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
2. 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	Dates of enrollment	Evidence
Stock et al. 2019 (CALGB 10403)	2007-2012	Non-randomized

Note: ABFM stands for 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

1. 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	Dates of enrollment	Evidence
Larson et al. 1995 (CALGB 8811)	1988-1991	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

1. 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

Regimen

Study	Dates of enrollment	Evidence
Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)	1993-2003	Non-randomized part of phase 3 RCT

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).

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

• Leucovorin (Folinic acid) at "standard" doses

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

Subsequent treatment

• MRC UKALL XII/ECOG E2993, 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 consolidation
• MRC UKALL XII/ECOG E2993, all others: Etoposide & TBI, then auto HSCT versus International ALL Trial consolidation

References

1. 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	Dates of enrollment	Evidence
Stock et al. 2019 (CALGB 10403)	2007-2012	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

1. 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	Dates 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

• BLAST, patients who had an allogeneic donor: proceed to allogeneic hematopoietic stem cell transplant any time after cycle 1

References

1. 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
2. ECOG-ACRIN E1910: NCT02003222

Cyclophosphamide & TBI, then allo HSCT

Cy/TBI: Cyclophosphamide & Total Body Irradiation

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Non-relapse mortality
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 part 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

References

1. 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
2. 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
3. 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	Dates of enrollment	Evidence
Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)	1993-2003	Non-randomized part of phase 3 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

References

1. 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 consolidation

Regimen

Study	Dates 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 (primary endpoint)

Preceding treatment

• L-asparaginase & Methotrexate intensification

Chemotherapy, first portion (course 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, first portion (course 1)

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

Chemotherapy, second portion (course 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

Chemotherapy, third portion (course 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

Chemotherapy, fourth portion (course 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

4-week course, then 4-week course, then 8-week course, then one course

CNS 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

1. 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	Dates 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

• Leucovorin (Folinic acid) 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 infusion

References

1. 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)

Regimen

Study	Dates 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/μL and platelet count to greater than 100 x 10⁹/L.

Preceding treatment

• DOLP induction

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

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

Chemotherapy, B portion (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

Chemotherapy, C portion (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, C portion (cycle 9)

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

Supportive therapy, C portion (cycle 9)

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

Approximately one-month cycle for 9 cycles

Subsequent treatment

• 6-MP & MTX maintenance

References

1. 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

Regimen

Study	Dates 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; the total length of each 3-portion block is not specified and is dependent on count recovery.

Preceding treatment

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

Chemotherapy, A portion (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, A portion (cycles 1, 4, 7)

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

Supportive therapy, A portion (cycles 1, 4, 7)

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

Chemotherapy, B portion (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, B portion (cycles 2, 5, 8)

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

Chemotherapy, C portion (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, C portion (cycles 3, 6, 9)

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

9 cycles

Subsequent treatment

• GRAALL-2003, CR after induction: Cyclophosphamide, daunorubicin, L-asparaginase, vincristine, prednisone late intensification between cycles 6 and 7
• GRAALL-2003, CR after salvage: Cytarabine & idarubicin late intensification between cycles 6 and 7
• GRAALL-2003, all patients: POMP maintenance after completion of consolidation

References

1. 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 ["Course III"]

Regimen

Study	Dates of enrollment	Evidence
Larson et al. 1995 (CALGB 8811)	1988-1991	Phase 2

Preceding treatment

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

Chemotherapy

• 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, 2400 cGy total given in 10 fractions from days 1 to 12

CNS 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

1. 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	Dates of enrollment	Evidence
Stock et al. 2019 (CALGB 10403)	2007-2012	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

• AALL0232 delayed intensification ("Course IV")

References

1. 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	Dates of enrollment	Evidence
Stock et al. 2019 (CALGB 10403)	2007-2012	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

1. 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	Dates 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/μL until myeloid recovery

Subsequent treatment

• Pediatric-like GRAALL consolidation

References

1. 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	Dates 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

1. 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	Dates of enrollment	Evidence
Larson et al. 1995 (CALGB 8811)	1988-1991	Phase 2

Preceding treatment

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

Chemotherapy

• 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

1. 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	Dates of enrollment	Evidence
Stock et al. 2019 (CALGB 10403)	2007-2012	Non-randomized

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

Preceding treatment

• CALGB 10403 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	Dates of enrollment	Evidence
Stock et al. 2019 (CALGB 10403)	2007-2012	Non-randomized

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

Preceding treatment

• CALGB 10403 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

1. 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	Dates 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

1. 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	Dates 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	Dates 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 (secondary endpoint)

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	Dates of enrollment	Evidence
Kantarjian et al. 2000	1992-1998	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

• Induction 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, CALGB 8811 "Course V"

Study	Dates of enrollment	Evidence
Larson et al. 1995 (CALGB 8811)	1988-1991	Phase 2

Preceding treatment

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

Chemotherapy

• 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

1. 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
2. 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
3. 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
4. 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

7+3m

MC: Mitoxantrone & Cytarabine

Regimen

Study	Dates 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 and schedule modifications

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

References

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. 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

Augmented Hyper-CVAD/MA & Asparaginase

Regimen

Study	Dates of enrollment	Evidence
Faderl et al. 2011	NR	Phase 2

Note: it is not clear from the manuscript whether vincristine and dexamethasone were given in all cycle or just the A cycles, as is typical in most Hyper-CVAD regimens.

Chemotherapy, Hyper-CVAD portion (cycles 1, 3, 5, 7; "Part A")

• 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 1, 8, 15
• Doxorubicin (Adriamycin) 50 mg/m² IV continuous infusion over 24 hours, started on day 4
• Pegaspargase (Oncaspar) 2500 units/m² IV once on day 1

Glucocorticoid therapy, Hyper-CVAD portion (cycles 1, 3, 5, 7; "Part A")

• Dexamethasone (Decadron) 80 mg IV or PO once per day on days 1 to 4, 15 to 18

Supportive therapy, Hyper-CVAD portion (cycles 1, 3, 5, 7; "Part A")

• Mesna (Mesnex) 600 mg/m²/day IV continuous infusion over 72 hours, started on day 1, starting 1 hour prior to cyclophosphamide and completed 12 hours after the last dose of cyclophosphamide
• Filgrastim (Neupogen) 10 mcg/kg SC once per day, starting 24 hours after completion chemotherapy, given until post-nadir ANC greater than 1000/μL

Chemotherapy, MA portion (cycles 2, 4, 6, 8; "Part B")

• Methotrexate (MTX) 1000 mg/m² IV continuous infusion over 24 hours, started on day 1
• Cytarabine (Ara-C) 3000 mg/m² IV every 12 hours on days 2 & 3 (total dose per cycle: 12,000 mg/m²)
• Pegaspargase (Oncaspar) 2500 units/m² IV once on day 5

Supportive therapy, MA portion (cycles 2, 4, 6, 8; "Part B")

• Leucovorin (Folinic acid) 50 mg IV once on day 3, 12 hours after methotrexate 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 24 hours after completion chemotherapy, given until post-nadir ANC greater than 1000/μL

21- to 35-day cycle for 8 cycles

References

1. 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 contains dosing details in manuscript PubMed

Blinatumomab monotherapy

Regimen variant #1

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Topp et al. 2014 (MT103-211)	2012-2013	Phase 2 (RT)
Kantarjian et al. 2017 (TOWER)	2014-01 to 2015-09	Phase 3 (E-RT-switch-ooc)	Standard re-induction chemotherapy	Superior OS (primary endpoint) Median OS: 7.7 vs 4 mo (HR 0.71, 95% CI 0.55-0.93)

Note: The most common comparator in TOWER was FLAG +/- anthracycline. The first 2 cycles were considered induction and the next 3 consolidation.

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 2 to 5 cycles

Subsequent treatment

• TOWER: Optional blinatumomab maintenance

Regimen variant #2

Study	Dates of enrollment	Evidence
Topp et al. 2011 (MT103-202)	2008-2009	Phase 2
Topp et al. 2014 (MT103-206)	2010-2012	Phase 2

Prior treatment criteria

• MT103-202: Chemotherapy exposure

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

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. 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. Epub 2012 Sep 28. 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
2. 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
3. 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
4. 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	Dates of enrollment	Evidence
Shah et al. 2021 (ZUMA-3)	2018-2019	Phase 2 (RT)

Preceding treatment

• FC lymphodepletion

Immunotherapy

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

One course

References

1. 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	Dates of enrollment	Evidence
Kantarjian et al. 2003	NR	Phase 2, fewer than 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

1. 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	Dates 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 age-based criteria:
  • Younger than 55 years old: 3000 mg/m² IV every 12 hours on days 1 to 6 (total dose: 36,000 mg/m²)
  • 55 years old or older: 1500 mg/m² IV every 12 hours on days 1 to 6 (total dose: 18,000 mg/m²)

6-day course

References

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. 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	Dates of enrollment	Evidence
Huguet et al. 2009 (GRAALL-2003)	2003-2005	Phase 2
Maury et al. 2016 (GRAALL-2005/R)	2006-2014	Non-randomized part 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/μL

One course

Subsequent treatment

• GRAALL-2005/R, CR1 after salvage: Pediatric-like GRAALL consolidation

References

1. 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
2. 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	Dates of enrollment	Evidence
Maury et al. 2016 (GRAALL-2005/R)	2006-2014	Non-randomized part of phase 3 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/μL

One course

Subsequent treatment

• GRAALL-2005/R, CR1 after salvage: Pediatric-like GRAALL consolidation with rituximab

References

1. 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

FLAG

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

Regimen

Study	Dates 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

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. 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

Regimen

Study	Dates 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, Hyper-CVAD portion (cycles 1, 3, 5, 7; "Part A")

• 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 years old: 1.5 mg/m² (maximum dose of 2 mg) IV once per day on days 4 & 11 (+/- 2 days)
  • 18 years old or 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, Hyper-CVAD portion (cycles 1, 3, 5, 7; "Part A")

• Dexamethasone (Decadron) by the following age-based criteria:
  • Younger than 18 years old: 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 years old or older: 40 mg IV or PO once per day on days 1 to 4, 11 to 14 (+/- 2 days)

Supportive therapy, Hyper-CVAD portion (cycles 1, 3, 5, 7; "Part A")

• 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, MA portion (cycles 2, 4, 6, 8; "Part B")

• 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- and renal function-based criteria:
  • Younger than 60 years old: 3000 mg/m² IV over 2 hours every 12 hours on days 2 & 3 (total dose per cycle: 12,000 mg/m²)
  • 60 years old or older OR creatinine 1.5 x the upper limit of normal or more: 1000 mg/m² IV over 2 hours every 12 hours on days 2 & 3 (total dose per cycle: 4000 mg/m²)

Glucocorticoid therapy, MA portion (cycles 2, 4, 6, 8; "Part B")

• Methylprednisolone (Solumedrol) by the following age-based criteria:
  • Younger than 18 years old: 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 years old or 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.

8 cycles

References

1. 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	Dates 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: 1a. Cytarabine 1b. MC 1c. FLAG	Seems to have superior OS (co-primary endpoint) Median OS: 7.7 vs 6.7 mo (HR 0.77, 97.5% CI 0.58-1.03)

Antibody-drug conjugate therapy

• Inotuzumab ozogamicin (Besponsa) 0.8 mg/m² IV once on day 1, then 0.5 mg/m² IV once per day on days 8 & 15

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

Dose and schedule modifications

• If patients achieved a CR or CRi, the day 1 dose was reduced to 0.5 mg/m² for all subsequent cycles.

References

1. 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
2. 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	Dates 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 weight-based criteria:
  • Up to 50 kg: 2 to 5 x 10⁶ CTL019 transduced viable T-cells per kg body weight IV once on day 0
  • More than 50 kg: 1.0 to 2.5 x 10⁸ CTL019 transduced viable T-cells IV once on day 0

One course

References

1. 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
2. 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	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Brown et al. 2021 (COG AALL1331)	2014-2019	Phase 3 (E-RT-switch-ooc)	Standard salvage consolidation chemotherapy	Might have superior DFS (primary endpoint) DFS24: 54.4% vs 39% (HR 0.70, 95% CI 0.47-1.03)

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

1. 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	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Non-relapse mortality
Rudolph et al. 1973	1968-1970	Non-randomized, fewer than 20 pts in subgroup
Kersey et al. 1987	1982-1985	Quasi-randomized	Auto HSCT	Superior RFS
Zhang et al. 2023	2016-01 to 2020-02	Phase 3 (C)	BuCy	Non-inferior OS24	Similar NRM

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

References

1. 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
2. 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
3. Zhang H, Fan Z, Huang F, Han L, Xu Y, Xu N, Deng L, Wang S, Lin D, Luo X, Zhang Q, Liu X, Li X, Liang X, Xie S, Qu H, Yu S, Zhou H, Shi P, Xuan L, Lin R, Liu H, Jin H, Sun J, Liu Q. Busulfan Plus Cyclophosphamide Versus Total Body Irradiation Plus Cyclophosphamide for Adults Acute B Lymphoblastic Leukemia: An Open-Label, Multicenter, Phase III Trial. J Clin Oncol. 2023 Jan 10;41(2):343-353. Epub 2022 Sep 9. link to original article link to PMC article contains dosing details in manuscript PubMed NCT02670252

Maintenance after subsequent lines of therapy

Blinatumomab monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kantarjian et al. 2017 (TOWER)	2014-01 to 2015-09	Phase 3 (E-RT-switch-ooc)	Standard maintenance chemotherapy	Superior OS (primary endpoint) Median OS: 7.7 vs 4 mo (HR 0.71, 95% CI 0.55-0.93)

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

Preceding treatment

• Blinatumomab induction, then Blinatumomab 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

1. 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