Revision as of 00:13, 14 September 2016

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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

Prephase

Prednisone (Sterapred)

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Regimen

Study	Evidence
Huguet et al. 2009 (GRAALL-2003)	Phase II

Note: 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.

Chemotherapy

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

CNS treatment

Methotrexate (MTX) 15 mg IT once at some point between days -7 and -4

Patients then proceeded to cyclophosphamide, daunorubicin, L-asparaginase, vincristine, prednisone induction.

References

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 early article contains verified protocol PubMed

Induction therapy, Ph-negative

ABFM

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ABFM: Augmented Berlin-Frankfurt-Münster regimen

Regimen

To be completed

References

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 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 May 14. [Epub ahead of print] PubMed

Cyclophosphamide, Cytarabine, Mercaptopurine

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Regimen

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

Treatment preceded by "Phase 1" induction: daunorubicin, L-asparaginase, vincristine, prednisone.

Chemotherapy

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

CNS prophylaxis

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

Treatment followed by L-asparaginase & methotrexate intensification.

References

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 verified protocol PubMed
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 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 verified protocol PubMed

Cyclophosphamide, Daunorubicin, Vincristine, Prednisone

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Regimen

Study	Evidence	Comparator
Thomas et al. 2004 (LALA-94)	Phase III	Cyclophosphamide, Idarubicin, Vincristine, Prednisone

Unlikely to be completed, here for historic context only.

Chemotherapy

References

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 PubMed

Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone

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

Regimen #1

Study	Evidence	Comparator
Huguet et al. 2009 (GRAALL-2003)	Phase II
Maury et al. 2015 (GRAALL-R 2005)	Phase III	Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone, Rituximab

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 prophylaxis and treatment. Treatment preceded by prednisone prephase.

Chemotherapy

Cyclophosphamide (Cytoxan) as follows:
- 750 mg/m² IV once per day on days 1 & 15 in "good early responders"
- 750 mg/m² IV once on day 1, then 500 mg/m² IV q12h on days 15 & 16 in "poor early responders"
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/day (route not specified) on days 8, 10, 12, 20, 22, 24, 26, 28
Vincristine (Oncovin) 2 mg IV once per day on days 1, 8, 15, 22
Prednisone (Sterapred) 60 mg/m²/day on days 1 to 14

Supportive medications

Lenograstim (Granocyte) 150 μg/m² SC once per day from day 17 until myeloid recovery

Patients with resistant disease received cytarabine & idarubicin salvage prior to further consolidation. All others proceeded to pediatric-like GRAALL consolidation.

Regimen #2, "Larson regimen"

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

Chemotherapy ("Course I")

Cyclophosphamide (Cytoxan) as follows:
- For patients <60 years old: 1200 mg/m² IV once on day 1
- For patients ≥60 years old: 800 mg/m² IV once on day 1
Daunorubicin (Cerubidine) as follows:
- For patients <60 years old: 45 mg/m² IV once per day on days 1 to 3
- For patients ≥60 years old: 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
Prednisone (Sterapred) as follows:
- For patients <60 years old: 60 mg/m² PO once per day on days 1 to 21
- For patients ≥60 years old: 60 mg/m² PO once per day on days 1 to 7

To be followed by Larson/CALGB 8811 regimen courses II to IV (consolidation & intensification).

Regimen #3

Study	Evidence	Comparator
Annino et al. 2002 (GIMEMA ALL 0288)	Phase III	Daunorubicin, L-Asparaginase, Vincristine, Prednisone

Unlikely to be completed, here for historic context only.

Chemotherapy

References

Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR et al. 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 verified protocol PubMed
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 Group. 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 PubMed
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 early article contains verified protocol PubMed
Abstract: Maury et al. Addition of Rituximab Improves the Outcome of Adult Patients with CD20-Positive, Ph-Negative, B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL): Results of the Randomized Graall-R 2005 Study. ASH 2015 Annual Meeting Abstract 1.link to abstract

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

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Regimen

Study	Evidence	Comparator
Maury et al. 2015 (GRAALL-R 2005)	Phase III	Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone

Note: this regimen was meant for CD20+ patients less than 60 years old. Details were scant in the abstract but a total of 16 to 18 Rituximab (Rituxan) 375 mg/m² infusions were given during the course of therapy. This will be fleshed out when the manuscript is published.

References

Abstract: Maury et al. Addition of Rituximab Improves the Outcome of Adult Patients with CD20-Positive, Ph-Negative, B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL): Results of the Randomized Graall-R 2005 Study. ASH 2015 Annual Meeting Abstract 1.link to abstract

Cyclophosphamide, Doxorubicin, L-Asparaginase, Vincristine, Prednisolone

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Regimen

Study	Evidence
Takeuchi et al. 2002 (JALSG-ALL93)	Non-randomized

Unlikely to be completed, here for historic context only.

Chemotherapy

References

Takeuchi J, Kyo T, Naito K, Sao H, Takahashi M, Miyawaki S, Kuriyama K, Ohtake S, Yagasaki F, Murakami H, Asou N, Ino T, Okamoto T, Usui N, Nishimura M, Shinagawa K, Fukushima T, Taguchi H, Morii T, Mizuta S, Akiyama H, Nakamura Y, Ohshima T, Ohno R. Induction therapy by frequent administration of doxorubicin with four other drugs, followed by intensive consolidation and maintenance therapy for adult acute lymphoblastic leukemia: the JALSG-ALL93 study. Leukemia. 2002 Jul;16(7):1259-66. link to original article PubMed

Cyclophosphamide, Idarubicin, Vincristine, Prednisone

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Regimen

Study	Evidence	Comparator
Thomas et al. 2004 (LALA-94)	Phase III	Cyclophosphamide, Daunorubicin, Vincristine, Prednisone

Unlikely to be completed, here for historic context only.

Chemotherapy

References

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 PubMed

Daunorubicin, L-Asparaginase, Vincristine, Prednisone +/- Imatinib

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

Regimen #1

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

To our knowledge, this is the largest induction trial in adult ALL, N=1,646. CR rate was 91%. There are many local variants of this protocol, which begins with "Phase I":

Chemotherapy

Daunorubicin (Cerubidine) 65 mg/m² IV once per day on days 1, 8, 15, 22
Asparaginase (Elspar) 10,000 units IV or IM once per day on days 17 to 28
Vincristine (Oncovin) 1.4 mg/m² IV once per day on days 1, 8, 15, 22
Prednisone (Sterapred) 60 mg/m² PO once per day on days 1 to 28

Ph+ patients

Imatinib (Gleevec) 400 mg PO once per day, increased to 600 mg PO once per day "wherever possible"
- Note: Two variants have been tested: from 2003 to 2005, imatinib was added after induction; from 2005 onward, imatinib was added during induction. Various durations are proposed, see Fielding et al. 2013 for more details.

CNS prophylaxis

Methotrexate (MTX) 12 mg IT once on day 15

4-week course

Treatment followed by "Phase 2" induction: cyclophosphamide, cytarabine, mercaptopurine.

Regimen #2

Study	Evidence	Comparator
Annino et al. 2002 (GIMEMA ALL 0288)	Phase III	Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone

Unlikely to be completed, here for historic context only.

Chemotherapy

Regimen #3, "Linker regimen"

Study	Evidence
Linker et al. 1987	Phase II

Chemotherapy, part 1

Daunorubicin (Cerubidine) 50 mg/m² IV once per day on days 1 to 3
Asparaginase (Elspar) 6000 units/m² IM once per day on days 17 to 28
Vincristine (Oncovin) 2 mg IV once per day on days 1, 8, 15, 22
Prednisone (Sterapred) 60 mg/m² PO once per day on days 1 to 28

If bone marrow on day 14 has residual leukemia:

Chemotherapy, part 2

Daunorubicin (Cerubidine) 50 mg/m² IV once on day 15

If bone marrow on day 28 has residual leukemia:

Chemotherapy, part 3

Daunorubicin (Cerubidine) 50 mg/m² IV once per day on days 29 & 30
Vincristine (Oncovin) 2 mg IV once per day on days 29 & 36
Prednisone (Sterapred) 60 mg/m² PO once per day on days 29 to 42
Asparaginase (Elspar) 6000 units/m² IM once per day on days 29 to 35

CNS prophylaxis

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

CNS treatment

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

To be followed by Linker regimen consolidation therapy.

References

Linker CA, Levitt LJ, O'Donnell M, Ries CA, Link MP, Forman SJ, Farbstein MJ. Improved results of treatment of adult acute lymphoblastic leukemia. Blood. 1987 Apr;69(4):1242-8. link to original article contains verified protocol 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 verified protocol PubMed
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 Group. 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 PubMed
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 verified protocol PubMed
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 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 verified protocol PubMed

Hyper-CVAD/MA

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

Regimen

Study	Evidence
Thomas et al. 1999	Phase II

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

Cyclophosphamide (Cytoxan) 300 mg/m² IV over 2 hours Q12H on days 1 to 3 (6 total doses)
Vincristine (Oncovin) 2 mg IV once per day on days 4 & 11
Doxorubicin (Adriamycin) 50 mg/m² IV over 24 hours (over 48 hours in patients with ejection fractions (EF) <50%) on day 4
Dexamethasone (Decadron) 40 mg PO/IV once per day on days 1 to 4, 11 to 14

Supportive medications

Mesna (Mesnex) 600 mg/m²/day IV continuous infusion on days 1 to 3, starting 1 hour before Cyclophosphamide (Cytoxan) and completed 12 hours after the last dose of Cyclophosphamide (Cytoxan)
One of the following antibiotics:
- EITHER Ciprofloxacin (Cipro) 500 mg PO BID
- OR Levofloxacin (Levaquin) 500 mg PO once per day
- OR Trimethoprim/Sulfamethoxazole (Bactrim DS) (160/800 mg) PO BID
Fluconazole (Diflucan) 200 mg PO once per day
One of the following antivirals:
- EITHER Acyclovir (Zovirax) 200 mg PO BID
- OR Valacyclovir (Valtrex) 500 mg PO once per day
Filgrastim (Neupogen) 10 μg/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 >1 x 10⁹/L

Next cycle to start as soon as absolute neutrophil count is > 1 x 10⁹/L at least 24 hours off of G-CSF and platelet count > 60 x 10⁹/L

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

Methotrexate (MTX) 200 mg/m² IV over 2 hours, then 800 mg/m² IV over 22 hours on day 1
Cytarabine (Cytosar) 3000 mg/m² IV over 2 hours Q12H on days 2 & 3 (4 total doses)
- Dose-reduced to 1000 mg/m² for patients older than 60 years old
Methylprednisolone (Solumedrol) 50 mg IV Q12H on days 1 to 3 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 medications

Folinic acid (Leucovorin) 50 mg IV once 12 hours after Methotrexate (MTX) is complete, then 15 mg IV Q6H x 8 doses until serum methotrexate level <0.1 µM
One of the following antibiotics:
- EITHER Ciprofloxacin (Cipro) 500 mg PO BID
- OR Levofloxacin (Levaquin) 500 mg PO once per day
- OR Trimethoprim/Sulfamethoxazole (Bactrim DS) (160/800 mg) PO BID
Fluconazole (Diflucan) 200 mg PO once per day
One of the following antivirals:
- EITHER Acyclovir (Zovirax) 200 mg PO BID
- OR Valacyclovir (Valtrex) 500 mg PO once per day
Filgrastim (Neupogen) 10 μg/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 >1 x 10⁹/L

Next cycle to start as soon as absolute neutrophil count is > 1 x 10⁹/L at least 24 hours off of G-CSF and platelet count > 60 x 10⁹/L

CNS prophylaxis

Methotrexate (MTX) 12 mg (6 mg if given via Ommaya reservoir) IT on day 2
Cytarabine (Cytosar) 100 mg IT on 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) >1400 IU/L and/or proliferative index percentage of S + G2M >=14%

For known CNS disease

Methotrexate (MTX) 12 mg (6 mg if given via Ommaya reservoir) IT alternating with Cytarabine (Cytosar) 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 (Cytosar) 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 (Cytosar) 100 mg IT once on day 7 OR 8

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

References

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
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 verified protocol PubMed
Kantarjian HM, O'Brien S, Smith TL, Cortes J, Giles FJ, Beran M, Pierce S, Huh Y, Andreeff M, Koller C, Ha CS, Keating MJ, Murphy S, Freireich EJ. Results of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia. J Clin Oncol. 2000 Feb;18(3):547-61. link to original article contains verified protocol 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 verified protocol PubMed
Thomas DA, O'Brien S, Cortes J, Giles FJ, Faderl S, Verstovsek S, Ferrajoli A, Koller C, Beran M, Pierce S, Ha CS, Cabanillas F, Keating MJ, Kantarjian H. Outcome with the hyper-CVAD regimens in lymphoblastic lymphoma. Blood. 2004 Sep 15;104(6):1624-30. Epub 2004 Jun 3. link to original article contains verified protocol PubMed

R-Hyper-CVAD/R-MA

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

Regimen #1, modified hyper-CVAD

Study	Evidence
Thomas et al. 2010	Non-randomized

To be completed

Regimen #2

Study	Evidence
Thomas et al. 2006	Pilot, <20 patients reported

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

Rituximab (Rituxan) as follows:
- Cycles 1 & 3: 375 mg/m² IV over 2 to 6 hours once per day on days 1 & 11
- Cycles 5 & 7: no rituximab
Cyclophosphamide (Cytoxan) 300 mg/m² IV over 2 hours Q12H on days 1 to 3 (6 total doses)
Vincristine (Oncovin) 2 mg IV once per day on days 4 & 11
Doxorubicin (Adriamycin) 50 mg/m² IV continuous infusion over 24 hours on day 4
Dexamethasone (Decadron) 40 mg PO/IV once per day on days 1 to 4, 11 to 14

Supportive medications

Mesna (Mesnex) 600 mg/m²/day IV continuous infusion on days 1 to 3, starting 1 hour before Cyclophosphamide (Cytoxan) and completed 12 hours after the last dose of Cyclophosphamide (Cytoxan)
Filgrastim (Neupogen) 10 μg/kg SC once per day starting 24 hours after completion of chemotherapy, given until WBC >3 x 10⁹/L or bone pain present
One of the following antibiotics:
- EITHER Quinolone
- OR Trimethoprim/Sulfamethoxazole (Bactrim DS) (160/800 mg) dose/route not specified
Fluconazole (Diflucan) dose/route not specified
One of the following antivirals:
- EITHER Acyclovir (Zovirax) dose/route not specified
- OR Valacyclovir (Valtrex) dose/route not specified

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

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

Rituximab (Rituxan) as follows:
- Cycles 2 & 4: 375 mg/m² IV over 2 to 6 hours once per day on days 2 & 8
- Cycles 6 & 8: no rituximab
Methotrexate (MTX) 1000 mg/m² IV over 24 hours on day 1
Cytarabine (Cytosar) 3000 mg/m² IV over 2 hours Q12H on days 2 & 3 (4 total doses)

Supportive medications

Folinic acid (Leucovorin) 50 mg IV once 12 hours after Methotrexate (MTX) is complete, then 15 mg IV Q6H x 8 doses until serum methotrexate level <0.1 µM
Filgrastim (Neupogen) 10 μg/kg SC once per day starting 24 hours after completion of chemotherapy, given until WBC >3 x 10⁹/L or bone pain present
One of the following antibiotics:
- EITHER Quinolone
- OR Trimethoprim/Sulfamethoxazole (Bactrim DS) (160/800 mg) dose/route not specified
Fluconazole (Diflucan) dose/route not specified
One of the following antivirals:
- EITHER Acyclovir (Zovirax) dose/route not specified
- OR Valacyclovir (Valtrex) dose/route not specified

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

CNS prophylaxis

Methotrexate (MTX) 12 mg (6 mg if given via Ommaya reservoir) IT on day 2
Cytarabine (Cytosar) 100 mg IT 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 modifications

Cytarabine (Cytosar) reduced to 1000 mg/m² for patients ≥60 years old, creatinine ≥1.5 mg/dL or 0 hour MTX level ≥20 µmol/L
Vincristine (Oncovin) reduced to 1 mg for bilirubin > 2 mg/dL or NCI common toxicity criteria Grade 2+ peripheral neuropathy, omitted for bilirubin > 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 > 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 creatinine clearance 10 to 50 mL/min (eliminated for < 10 mL/min), by 25% to 75% for delayed excretion and/or nephrotoxicity with prior course (dependent on severity) or by 50% for pleural effusions/ascites with drainage of fluid as feasible.

References

Thomas DA, Faderl S, O'Brien S, Bueso-Ramos C, Cortes J, Garcia-Manero G, Giles FJ, Verstovsek S, Wierda WG, Pierce SA, Shan J, Brandt M, Hagemeister FB, Keating MJ, Cabanillas F, Kantarjian H. Chemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia. Cancer. 2006 Apr 1;106(7):1569-80. link to original article contains verified protocol PubMed
1. Update: Fayad L, Thomas D, Romaguera J. Update of the M. D. 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. PubMed
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

Induction therapy, Ph-positive

Daunorubicin, Vincristine, Prednisolone, Nilotinib

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Regimen

Study	Evidence
Kim et al. 2015	Phase II

Chemotherapy

Daunorubicin (Cerubidine) 90 mg/m²/day IV continuous infusion on days 1 to 3 (total dose: 270 mg/m²)
Vincristine (Oncovin) 2 mg IV once per day on days 1 & 8
Prednisolone (Millipred) 60 mg/m² PO or 48 mg/m² IV once per day on days 1 to 14
Nilotinib (Tasigna) 400 mg PO BID starting on day 8

CNS Prophylaxis

Methotrexate (MTX) 15 mg mixed with Hydrocortisone (Cortef) 50 mg IT

Up to 10 doses given during or after induction

Treatment followed by nilotinib-based consolidation or allogeneic hematopoetic cell transplant. Transplant regimen left to the discretion of the investigator.

References

Kim DY, Joo YD, Lim SN, Kim SD, Lee JH, Lee JH, Kim DH, Kim K, Jung CW, Kim I, Yoon SS, Park S, Ahn JS, Yang DH, Lee JJ, Lee HS, Kim YS, Mun YC, Kim H, Park JH, Moon JH, Sohn SK, Lee SM, Lee WS, Kim KH, Won JH, Hyun MS, Park J, Lee JH, Shin HJ, Chung JS, Lee H, Eom HS, Lee GW, Cho YU, Jang S, Park CJ, Chi HS, Lee KH; Adult Acute Lymphoblastic Leukemia Working Party of the Korean Society of Hematology. Nilotinib combined with multiagent chemotherapy for newly diagnosed Philadelphia-positive acute lymphoblastic leukemia. Blood. 2015 Aug 6;126(6):746-56. Epub 2015 Jun 11. link to original article contains verified protocol PubMed

Hyper-CVAD & Dasatinib

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Hyper-CVAD: Hyperfractionated Cyclophosphamide, Vincristine, Adriamycin (Doxorubicin), Dexamethasone

Regimen

Study	Evidence
Ravandi et al. 2010	Phase II

Note: the dosing of dasatinib has changed three times for this protocol. The initial protocol was 50 mg PO BID, which was then changed to 100 mg PO once per day after these were shown to be equivalent in a separate trial. Starting with patient #43, the protocol was further amended to 100 mg of dasatinib once per day in the first 14 days of the first cycle only, followed by 70 mg once per day continuously from the second cycle through completion of induction. These details are described in the update referenced below.

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

Cyclophosphamide (Cytoxan) 300 mg/m² IV over 2 hours Q12H on days 1 to 3 (6 total doses)
Vincristine (Oncovin) 2 mg IV once per day on days 4 & 11
Doxorubicin (Adriamycin) 50 mg/m² IV continuous infusion over 24 hours on day 4
- Infusion given over 48 hours in patients with ejection fractions (EF) <50%
Dexamethasone (Decadron) 40 mg PO/IV once per day on days 1 to 4, 11 to 14
Dasatinib (Sprycel) as follows:
- Cycle 1 days 1 to 14: 100 mg PO once per day
- Remainder of course: 70 mg PO once per day

Supportive medications

Mesna (Mesnex) 600 mg/m²/day IV continuous infusion on days 1 to 3, starting 1 hour before Cyclophosphamide (Cytoxan) and completed 12 hours after the last dose of Cyclophosphamide (Cytoxan)
One of the following antibiotics:
- EITHER Ciprofloxacin (Cipro) 500 mg PO BID
- OR Levofloxacin (Levaquin) 500 mg PO once per day
- OR Trimethoprim/Sulfamethoxazole (Bactrim DS) (160/800 mg) PO BID
Fluconazole (Diflucan) 200 mg PO once per day
One of the following antivirals:
- EITHER Acyclovir (Zovirax) 200 mg PO BID
- OR Valacyclovir (Valtrex) 500 mg PO once per day
Filgrastim (Neupogen) 10 μg/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 >1 x 10⁹/L
Cycle 1 also involved:
- Hydration options included D5 water or 1/2 NS with 75 to 100 mEq sodium acetate per liter at 50 to 100 mL/H
- Allopurinol (Zyloprim) to decrease likelihood of tumor lysis syndrome; Rasburicase (Elitek) could be used instead for patients with high white blood cell counts at initial presentation
- Oral sodium bicarbonate (no dosage or frequency listed) on days 1 to 3

Next cycle to start after count recovery. No definite criteria listed by the reference, but other Hyper-CVAD regimens used absolute neutrophil count > 1 x 10⁹/L at least 24 hours off of G-CSF and platelet count > 60 x 10⁹/L

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

Methotrexate (MTX) 1000 mg/m² IV continuous infusion over 24 hours on day 1
Cytarabine (Cytosar) 3000 mg/m² (1000 mg/m² for patients at least 60 years old) IV over 2 hours Q12H on days 2 & 3 (4 total doses)
Dasatinib (Sprycel) 70 mg PO once per day

Supportive medications

Folinic acid (Leucovorin) 50 mg IV x1 12 hours after Methotrexate (MTX) is complete, then 15 mg IV Q6H x 8 doses until serum methotrexate level <0.1 µM
- Leucovorin rescue with Folinic acid (Leucovorin) 50 mg IV Q6H if serum methotrexate levels were greater than 20 uM at 0 hours after completion of Methotrexate (MTX); >1 uM at 24 hours; >0.1 uM at 48 hours
One of the following antibiotics:
- EITHER Ciprofloxacin (Cipro) 500 mg PO BID
- OR Levofloxacin (Levaquin) 500 mg PO once per day
- OR Trimethoprim/Sulfamethoxazole (Bactrim DS) (160/800 mg) PO BID
Fluconazole (Diflucan) 200 mg PO once per day
One of the following antivirals:
- EITHER Acyclovir (Zovirax) 200 mg PO BID
- OR Valacyclovir (Valtrex) 500 mg PO once per day
D5W or 1/2 NS with 75 to 100 mEq sodium acetate per liter at 100 to 125 mL/H
Filgrastim (Neupogen) 10 μg/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 >1 x 10⁹/L
Acetazolamide (Diamox) (no dosage/schedule listed) used if urine pH <7 to promote excretion

Next cycle to start after count recovery. No definite criteria listed by the reference, but other Hyper-CVAD regimens used absolute neutrophil count > 1 x 10⁹/L at least 24 hours off of G-CSF and platelet count > 60 x 10⁹/L

CNS prophylaxis

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

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) >1400 IU/L and/or proliferative index percentage of S + G2M of at least 14%

For known CNS disease

Methotrexate (MTX) 12 mg (6 mg if given via Ommaya reservoir) IT alternating with Cytarabine (Cytosar) 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 (Cytosar) 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 (Cytosar) 100 mg IT once on day 7
Therapeutic external radiation is given to patients with CNS disease at presentation

Patients achieving a CR proceeded to maintenance dasatinib, vincristine, and prednisone.

References

Ravandi F, O'Brien S, Thomas D, Faderl S, Jones D, Garris R, Dara S, Jorgensen J, Kebriaei P, Champlin R, Borthakur G, Burger J, Ferrajoli A, Garcia-Manero G, Wierda W, Cortes J, Kantarjian H. First report of phase 2 study of dasatinib with hyper-CVAD for the frontline treatment of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia. Blood. 2010 Sep 23;116(12):2070-7. Epub 2010 May 13. link to original article contains verified protocol--parts of the protocol were not explicitly listed in this reference, which instead referred to Thomas et al. 2004 and Kantarjian et al. 2004 PubMed
1. Update: Ravandi F, O'Brien SM, Cortes JE, Thomas DM, Garris R, Faderl S, Burger JA, Rytting ME, Ferrajoli A, Wierda WG, Verstovsek S, Champlin R, Kebriaei P, McCue DA, Huang X, Jabbour E, Garcia-Manero G, Estrov Z, Kantarjian HM. Long-term follow-up of a phase 2 study of chemotherapy plus dasatinib for the initial treatment of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Cancer. 2015 Dec 1;121(23):4158-64. Epub 2015 Aug 26. link to original article PubMed

Hyper-CVAD & Imatinib

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Hyper-CVAD: Hyperfractionated Cyclophosphamide, Vincristine, Adriamycin (Doxorubicin), Dexamethasone

Regimen

Study	Evidence
Thomas et al. 2003	Phase II

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

Cyclophosphamide (Cytoxan) 300 mg/m² IV over 2 hours Q12H on days 1 to 3 (6 total doses)
Vincristine (Oncovin) 2 mg IV once per day on days 4 & 11
Doxorubicin (Adriamycin) 50 mg/m² IV over 24 hours (over 48 hours in patients with ejection fractions (EF) <50%) on day 4
Dexamethasone (Decadron) 40 mg PO/IV once per day on days 1 to 4, 11 to 14
Imatinib (Gleevec) 400 mg PO once per day on days 1 to 14

Supportive medications

Mesna (Mesnex) 600 mg/m²/day IV continuous infusion on days 1 to 3, starting 1 hour before Cyclophosphamide (Cytoxan) and completed 12 hours after the last dose of Cyclophosphamide (Cytoxan)
One of the following antibiotics:
- EITHER Ciprofloxacin (Cipro) 500 mg PO BID
- OR Levofloxacin (Levaquin) 500 mg PO once per day
- OR Trimethoprim/Sulfamethoxazole (Bactrim DS) (160/800 mg) PO BID
Fluconazole (Diflucan) 200 mg PO once per day
One of the following antivirals:
- EITHER Acyclovir (Zovirax) 200 mg PO BID
- OR Valacyclovir (Valtrex) 500 mg PO once per day
Filgrastim (Neupogen) 10 μg/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 >1 x 10⁹/L
Cycle 1 also involved:
- Hydration options included D5 water or 1/2 NS with 75 to 100 mEq sodium acetate per liter at 50 to 100 mL/H
- Allopurinol (Zyloprim) to decrease likelihood of tumor lysis syndrome; Rasburicase (Elitek) could be used instead for patients with high white blood cell counts at initial presentation
- Oral sodium bicarbonate (no dosage or frequency listed) on days 1 to 3

Next cycle to start after count recovery. No definite criteria listed by the reference, but other Hyper-CVAD regimens used absolute neutrophil count > 1 x 10⁹/L at least 24 hours off of G-CSF and platelet count > 60 x 10⁹/L

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

Methotrexate (MTX) 1000 mg/m² IV over 24 hours on day 1
Cytarabine (Cytosar) 3000 mg/m² (1000 mg/m² for patients at least 60 years old) IV over 2 hours Q12H on days 2 & 3 (4 total doses)
Imatinib (Gleevec) 400 mg PO once per day on days 1 to 14

Supportive medications

Folinic acid (Leucovorin) 50 mg IV x1 12 hours after Methotrexate (MTX) is complete, then 15 mg IV Q6H x 8 doses until serum methotrexate level <0.1 µM
- Leucovorin rescue with Folinic acid (Leucovorin) 50 mg IV Q6H if serum methotrexate levels were greater than 20 uM at 0 hours after completion of Methotrexate (MTX); >1 uM at 24 hours; >0.1 uM at 48 hours
One of the following antibiotics:
- EITHER Ciprofloxacin (Cipro) 500 mg PO BID
- OR Levofloxacin (Levaquin) 500 mg PO once per day
- OR Trimethoprim/Sulfamethoxazole (Bactrim DS) (160/800 mg) PO BID
Fluconazole (Diflucan) 200 mg PO once per day
One of the following antivirals:
- EITHER Acyclovir (Zovirax) 200 mg PO BID
- OR Valacyclovir (Valtrex) 500 mg PO once per day
D5W or 1/2 NS with 75 to 100 mEq sodium acetate per liter at 100 to 125 mL/H
Filgrastim (Neupogen) 10 μg/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 >1 x 10⁹/L
Acetazolamide (Diamox) (no dosage/schedule listed) used if urine pH <7 to promote excretion

Next cycle to start after count recovery. No definite criteria listed by the reference, but other Hyper-CVAD regimens used absolute neutrophil count > 1 x 10⁹/L at least 24 hours off of G-CSF and platelet count > 60 x 10⁹/L

CNS prophylaxis

Methotrexate (MTX) 12 mg (6 mg if given via Ommaya reservoir) IT on day 2
Cytarabine (Cytosar) 100 mg IT on 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) >1400 IU/L and/or proliferative index percentage of S + G2M of at least 14%

For known CNS disease

Methotrexate (MTX) 12 mg (6 mg if given via Ommaya reservoir) IT alternating with Cytarabine (Cytosar) 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 (Cytosar) 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 on day 2
- Cytarabine (Cytosar) 100 mg IT on day 7 OR 8
Therapeutic external radiation is given to patients with CNS disease at presentation

Maintenance therapy after completing 8 cycles of the intensive Part A and Part B chemotherapy

Imatinib (Gleevec) 600 mg PO once per day on days 1 to 28
Vincristine (Oncovin) 2 mg IV once on day 1
Prednisone (Sterapred) 200 mg PO once per day on days 1 to 5

28-day cycle for 5 cycles; then, in month 6, Hyper-CVAD Part A x 1 cycle as described above; then resume maintenance therapy, 28-day cycle for 6 cycles; then, in month 13, Hyper-CVAD Part A x 1 cycle as described above

References

Thomas DA, Faderl S, Cortes J, O'Brien S, Giles FJ, Kornblau SM, Garcia-Manero G, Keating MJ, Andreeff M, Jeha S, Beran M, Verstovsek S, Pierce S, Letvak L, Salvado A, Champlin R, Talpaz M, Kantarjian H. Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood. 2004 Jun 15;103(12):4396-407. Epub 2003 Oct 9. link to original article contains verified protocol PubMed
1. Update: Daver N, Thomas D, Ravandi F, Cortes J, Garris R, Jabbour E, Garcia-Manero G, Borthakur G, Kadia T, Rytting M, Konopleva M, Kantarjian H, O' Brien S. Final report of a phase II study of imatinib mesylate with hyper-CVAD for the frontline treatment of adult patients with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia. Haematologica. 2015 May;100(5):653-61. Epub 2015 Feb 14. link to original article PubMed

Hyper-CVAD & Ponatinib

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Hyper-CVAD: Hyperfractionated Cyclophosphamide, Vincristine, Adriamycin (Doxorubicin), Dexamethasone

Regimen

Study	Evidence
Jabbour et al. 2015	Phase II

To be completed

References

Jabbour E, Kantarjian H, Ravandi F, Thomas D, Huang X, Faderl S, Pemmaraju N, Daver N, Garcia-Manero G, Sasaki K, Cortes J, Garris R, Yin CC, Khoury JD, Jorgensen J, Estrov Z, Bohannan Z, Konopleva M, Kadia T, Jain N, DiNardo C, Wierda W, Jeanis V, O'Brien S. Combination of hyper-CVAD with ponatinib as first-line therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia: a single-centre, phase 2 study. Lancet Oncol. 2015 Nov;16(15):1547-55. Epub 2015 Sep 30. link to SD article PubMed

Early intensification therapy

Larson regimen (CALGB 8811)

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

Regimen

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

Treatment preceded by cyclophosphamide, daunorubicin, L-asparaginase, vincristine, prednisone induction ("Course I").

Chemotherapy ("Course II")

Methotrexate (MTX) 15 mg IT once on day 1
Cyclophosphamide (Cytoxan) 1000 mg/m² IV once on day 1
Mercaptopurine (Purinethol) 60 mg/m² PO once per day on days 1 to 14
Cytarabine (Cytosar) 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

28-day cycle for 2 cycles

Treatment followed by Larson regime (CALGB 8811) interim maintenance ("Course III").

References

Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR et al. 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 verified protocol PubMed

L-Asparaginase & Methotrexate

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

Regimen

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

Treatment preceded by "Phase 2" induction: cyclophosphamide, cytarabine, mercaptopurine.

Chemotherapy

Methotrexate (MTX) 3 g/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 medications

Folinic acid (Leucovorin) at "standard" doses

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

Patients who were younger than 50 years of age and had an HLA-matched sibling donor, as well as Ph+ patients with any donor, proceeded to etoposide & TBI -> alloHCT. All others were randomized to etoposide & TBI -> autoHCT versus International ALL Trial consolidation.

References

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 verified protocol PubMed
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 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 verified protocol PubMed

Consolidation therapy

International ALL Trial (MRC UKALL XII/ECOG E2993)

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Regimen

Study	Evidence	Comparator
Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)	Phase III	Etoposide & TBI -> autoHCT

Treatment preceded by L-asparaginase & methotrexate intensification.

Cycle 1

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

Cycle 2

To start 4 weeks after Cycle 1

Cytarabine (Cytosar) 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

Cycle 3

To start 4 weeks after Cycle 2

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 (Cytosar) 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

Cycle 4

To start 8 weeks after Cycle 3

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

CNS Prophylaxis

Cytarabine (Cytosar) 50 mg IT once per week for 4 weeks, then once per quarter for 4 doses (8 doses, total)
Cranial irradiation to 2400 cGy

Treatment followed by POMP maintenance.

References

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 verified protocol PubMed
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 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 verified protocol PubMed

Mercaptopurine, Methotrexate, WB-XRT

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Regimen

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

Treatment preceded by Larson regimen (CALGB 8811) early intensification ("Course II").

Chemoradiotherapy ("Course III")

Methotrexate (MTX) 15 mg IT once per day on days 1, 8, 15, 22, 29
Mercaptopurine (Purinethol) 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
Cranial radiation, 24 Gy total given in 10 fractions from days 1 to 12

12-week course

Treatment followed by Larson regimen (CALGB 8811) late intensification ("Course IV").

References

Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR et al. 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 verified protocol PubMed

Linker regimen (consolidation)

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

Regimen

Study	Evidence
Linker et al. 1987	Phase II

Treatment preceded by daunorubicin, L-asparaginase, vincristine, prednisone induction. Each cycle is approximately one month, based on recovery of ANC to >1000 and platelet count to >100,000.

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

Daunorubicin (Cerubidine) 50 mg/m² IV once per day on days 1 & 2
Vincristine (Oncovin) 2 mg IV once per day on days 1 & 8
Prednisone (Sterapred) 60 mg/m² PO once per day on days 1 to 14
Asparaginase (Elspar) 12000 units/m² IM once per day on days 2, 4, 7, 9, 11, 14

Approximately one-month cycle

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

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

Approximately one-month cycle

Treatment C (cycle 9)

Methotrexate (MTX) 690 mg/m² IV over 42 hours on day 1
Prednisone (Sterapred) 60 mg/m² PO once per day on days 1 to 14
Asparaginase (Elspar) 12000 units/m² IM once per day on days 2, 4, 7, 9, 11, 14

Approximately one-month cycle

Supportive medications

Folinic acid (Leucovorin) 15 mg/m² IV every 6 hours x 12 doses, starting after Methotrexate (MTX) is complete (at 42 hours)

Treatment followed by mercaptopurine & methotrexate maintenance.

References

Linker CA, Levitt LJ, O'Donnell M, Ries CA, Link MP, Forman SJ, Farbstein MJ. Improved results of treatment of adult acute lymphoblastic leukemia. Blood. 1987 Apr;69(4):1242-8. link to original article contains verified protocol 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 verified protocol PubMed

Nilotinib-based consolidation

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Regimen

Study	Evidence
Kim et al. 2015	Phase II

Treatment preceded by daunorubicin, vincristine, prednisolone, nilotinib induction. Duration of each cycle of consolidation is not specified but is presumably based on toxicities and count recovery. Nilotinib is taken continuously during consolidation.

Consolidation A (Cycle 1)

Daunorubicin (Cerubidine) 45 mg/m²/day IV continuous infusion on days 1 & 2 (total dose 90 mg/m²)
Vincristine (Oncovin) 2 mg IV once per day on days 1 & 8
Prednisolone (Millipred) 60 mg/m² PO once per day on days 1 to 14
Nilotinib (Tasigna) 400 mg PO BID

Consolidation B (Cycles 2 & 4)

Cytarabine (Cytosar) 2000 mg/m² IV over 2 hours once per day on days 1 to 4
Etoposide (Vepesid) 150 mg/m² IV over 3 hours once per day on days 1 to 4
Nilotinib (Tasigna) 400 mg PO BID

Consolidation C (Cycles 3 & 5)

Methotrexate (MTX) 220 mg/m² IV bolus, then 60 mg/m²/hr IV continuous infusion for 36 hours twice per cycle (days 1 & 2, 15 & 16)
Nilotinib (Tasigna) 400 mg PO BID

Supportive medications

Folinic acid (Leucovorin) 50 mg/m² IV every 6 hours x 3 doses, then PO (dose not specified) until serum methotrexate level <0.05

Treatment followed by nilotinib maintenance.

References

Kim DY, Joo YD, Lim SN, Kim SD, Lee JH, Lee JH, Kim DH, Kim K, Jung CW, Kim I, Yoon SS, Park S, Ahn JS, Yang DH, Lee JJ, Lee HS, Kim YS, Mun YC, Kim H, Park JH, Moon JH, Sohn SK, Lee SM, Lee WS, Kim KH, Won JH, Hyun MS, Park J, Lee JH, Shin HJ, Chung JS, Lee H, Eom HS, Lee GW, Cho YU, Jang S, Park CJ, Chi HS, Lee KH; Adult Acute Lymphoblastic Leukemia Working Party of the Korean Society of Hematology. Nilotinib combined with multiagent chemotherapy for newly diagnosed Philadelphia-positive acute lymphoblastic leukemia. Blood. 2015 Aug 6;126(6):746-56. Epub 2015 Jun 11. link to original article contains verified protocol PubMed

Pediatric-like GRAALL consolidation

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Regimen

Study	Evidence
Huguet et al. 2009 (GRAALL-2003)	Phase II

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. Treatment preceded by cyclophosphamide, daunorubicin, L-asparaginase, vincristine, prednisone induction or cytarabine & idarubicin salvage.

Consolidation A (Cycles 1, 4, 7)

Cytarabine (Cytosar) 2000 mg/m² IV q12h on days 1 & 2
Dexamethasone (Decadron) 10 mg (route not specified) q12h on days 1 & 2
Asparaginase (Elspar) 10,000 units/m² (route not specified) once on day 3

Supportive medications

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

Consolidation B (Cycles 2, 5, 8)

Methotrexate (MTX) 3000 mg/m² IV continuous infusion 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 (Purinethol) 60 mg/m² PO once per day on days 15 to 21

Supportive medications

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

Consolidation C (Cycles 3, 6, 9)

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

Supportive medications

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

Patients with CR after cyclophosphamide, daunorubicin, L-asparaginase, vincristine, prednisone induction received cyclophosphamide, daunorubicin, L-asparaginase, vincristine, prednisone late intensification between cycles 6 and 7. Patients with CR after cytarabine & idarubicin salvage received cytarabine & idarubicin late intensification between cycles 6 and 7. All patients proceeded to POMP maintenance after completion of consolidation.

References

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 early article contains verified protocol PubMed

Late intensification

Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone

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Regimen

Study	Evidence
Huguet et al. 2009 (GRAALL-2003)	Phase II

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. Treatment preceded by pediatric-like GRAALL consolidation cycle 6, and is for patients achieving CR after cyclophosphamide, daunorubicin, L-asparaginase, vincristine, prednisone induction.

Chemotherapy

Cyclophosphamide (Cytoxan) 500 mg/m² IV q12h on days 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
Prednisone (Sterapred) 60 mg/m²/day on days 1 to 14

Supportive medications

Lenograstim (Granocyte) 150 μg/m² SC once per day "if ANC < 500" until myeloid recovery

Patients then proceeded back to pediatric-like GRAALL consolidation.

References

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 early article contains verified protocol PubMed

Cytarabine & Idarubicin

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Regimen

Study	Evidence
Huguet et al. 2009 (GRAALL-2003)	Phase II

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. Treatment preceded by pediatric-like GRAALL consolidation cycle 6, and is for patients achieving CR after cytarabine & idarubicin salvage.

Chemotherapy

Cytarabine (Cytosar) 2000 mg/m² IV q12h on days 1 to 4
Idarubicin (Idamycin) 9 mg/m² IV once per day on days 1 to 3

Supportive medications

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

Patients then proceeded back to pediatric-like GRAALL consolidation.

References

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 early article contains verified protocol PubMed

Larson regimen (CALGB 8811)

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Regimen

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

Treatment preceded by mercaptopurine, methotrexate, WB-XRT ("Course III").

Chemotherapy ("Course IV")

Doxorubicin (Adriamycin) 30 mg/m² IV once per day on days 1, 8, 15
Vincristine (Oncovin) 2 mg IV once per day on days 1, 8, 15
Dexamethasone (Decadron) 10 mg/m² PO once per day on days 1 to 14
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 (Cytosar) 75 mg/m² SC once per day on days 29 to 32, 36 to 39

8-week course

To be followed by POMP maintenance ("Course V").

References

Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR et al. 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 verified protocol PubMed

Maintenance therapy

Dasatinib, Vincristine, Prednisone

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Regimen

Study	Evidence
Ravandi et al. 2010	Phase II

Treatment preceded by HyperCVAD & Dasatinib x 8, and only offered to patients who achieved a CR.

Chemotherapy

Dasatinib (Sprycel) 100 mg PO once per day on days 1 to 28
Vincristine (Oncovin) 2 mg IV once on day 1
Prednisone (Sterapred) 200 mg PO once per day on days 1 to 5

28-day cycles for 2 years

Maintenance therapy could be interrupted by provider's choice--typically only given to people with at least minimal residual disease (MRD) or more--in month 6 and 13 to give Hyper-CVAD Part A x 1 cycle. Then, after 2 years of maintenance therapy, patients proceed to dasatinib monotherapy:

Dasatinib (Sprycel) 100 mg PO once per day, continued indefinitely

References

Ravandi F, O'Brien S, Thomas D, Faderl S, Jones D, Garris R, Dara S, Jorgensen J, Kebriaei P, Champlin R, Borthakur G, Burger J, Ferrajoli A, Garcia-Manero G, Wierda W, Cortes J, Kantarjian H. First report of phase 2 study of dasatinib with hyper-CVAD for the frontline treatment of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia. Blood. 2010 Sep 23;116(12):2070-7. Epub 2010 May 13. link to original article contains verified protocol--parts of the protocol were not explicitly listed in this reference, which instead referred to Thomas et al. 2004 and Kantarjian et al. 2004 PubMed
1. Update: Ravandi F, O'Brien SM, Cortes JE, Thomas DM, Garris R, Faderl S, Burger JA, Rytting ME, Ferrajoli A, Wierda WG, Verstovsek S, Champlin R, Kebriaei P, McCue DA, Huang X, Jabbour E, Garcia-Manero G, Estrov Z, Kantarjian HM. Long-term follow-up of a phase 2 study of chemotherapy plus dasatinib for the initial treatment of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Cancer. 2015 Dec 1;121(23):4158-64. Epub 2015 Aug 26. link to original article PubMed

Mercaptopurine & Methotrexate

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Regimen

Study	Evidence
Linker et al. 1987	Phase II

Treatment preceded by Linker regimen consolidation therapy.

Chemotherapy

Mercaptopurine (Purinethol) 75 mg/m² PO once per day
Methotrexate (MTX) 20 mg/m² PO once per week

30-month course

References

Linker CA, Levitt LJ, O'Donnell M, Ries CA, Link MP, Forman SJ, Farbstein MJ. Improved results of treatment of adult acute lymphoblastic leukemia. Blood. 1987 Apr;69(4):1242-8. link to original article contains verified protocol 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 verified protocol PubMed

Nilotinib (Tasigna)

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Regimen

Study	Evidence
Kim et al. 2015	Phase II

Treatment preceded by nilotinib-based consolidation.

Chemotherapy

Nilotinib (Tasigna) 400 mg PO BID

2-year course

References

Kim DY, Joo YD, Lim SN, Kim SD, Lee JH, Lee JH, Kim DH, Kim K, Jung CW, Kim I, Yoon SS, Park S, Ahn JS, Yang DH, Lee JJ, Lee HS, Kim YS, Mun YC, Kim H, Park JH, Moon JH, Sohn SK, Lee SM, Lee WS, Kim KH, Won JH, Hyun MS, Park J, Lee JH, Shin HJ, Chung JS, Lee H, Eom HS, Lee GW, Cho YU, Jang S, Park CJ, Chi HS, Lee KH; Adult Acute Lymphoblastic Leukemia Working Party of the Korean Society of Hematology. Nilotinib combined with multiagent chemotherapy for newly diagnosed Philadelphia-positive acute lymphoblastic leukemia. Blood. 2015 Aug 6;126(6):746-56. Epub 2015 Jun 11. link to original article contains verified protocol PubMed

POMP

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

Regimen #1

Study	Evidence
Huguet et al. 2009 (GRAALL-2003)	Phase II

Treatment preceded by pediatric-like GRAALL consolidation.

Chemotherapy

Prednisone (Sterapred) 40 mg/m²/day PO on days 1 to 7 of each month x 12 months
Vincristine (Oncovin) 2 mg IV once on day 1 of each month x 12 months
Methotrexate (MTX) 25 mg/m² PO once per week x 24 months
Mercaptopurine (Purinethol) 60 mg/m² PO once per day x 24 months

24-month course

Regimen #2

Study	Evidence	Comparator
Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)	Phase III	Etoposide & TBI -> autoHCT

Treatment preceded by International ALL Trial consolidation.

Chemotherapy

Prednisone (Sterapred) 60 mg/m² PO once per day for 5 days every 3 months
Vincristine (Oncovin) 1.4 mg/m² IV once every 3 months
Methotrexate (MTX) 20 mg/m² PO or IV once per week
Mercaptopurine (Purinethol) 75 mg/m² PO once per day

Continue for a total of 2.5 years from the start of phase III

Regimen #3

Study	Evidence
Kantarjian et al. 2004	Phase II

Treatment preceded by Hyper-CVAD (induction). Kantarjian et al. 2004 said how many days each drug is given per month, but did not specifically say, for example, that certain drugs are taken on days 1 to 5 of the cycle.

Chemotherapy

Prednisone (Sterapred) 200 mg PO once per day for 5 days, given with Vincristine (Oncovin)
Vincristine (Oncovin) 2 mg IV once per month
Methotrexate (MTX) 10 mg/m² IV over 1 hour once per day for 5 days
Mercaptopurine (Purinethol) 1000 mg/m² IV over 1 hour once per day for 5 days

Supportive medications

Trimethoprim/Sulfamethoxazole (dosage not listed) PO BID on Saturday and Sunday for the first 6 months
One of the following antivirals:
- EITHER Acyclovir (Zovirax) 200 mg PO once per day or 3 times per week for the first 6 months
- OR Valacyclovir (Valtrex) 500 mg PO once per day or 3 times per week for the first 6 months

1-month cycles for 2 years

Regimen #4

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

Treatment preceded by Larson regimen (CALGB 8811) late intensification ("Course IV").

Chemotherapy ("Course V")

Prednisone (Sterapred) 60 mg/m² PO once per day on days 1 to 5
Vincristine (Oncovin) 2 mg IV once on day 1
Methotrexate (MTX) 20 mg/m² PO once per day on days 1, 8, 15, 22
Mercaptopurine (Purinethol) 60 mg/m² PO once per day on days 1 to 28

28-day cycles, continue until 24 months from diagnosis

References

Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR et al. 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 verified protocol PubMed
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 verified protocol PubMed
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 verified protocol PubMed
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 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 verified protocol PubMed
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 early article contains verified protocol PubMed

Relapsed/refractory, Ph-negative

Augmented Hyper-CVAD & Asparaginase

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Regimen

Study	Evidence
Faderl et al. 2011	Phase II

To be completed

References

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

Blinatumomab (Blincyto)

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Regimen #1

Study	Evidence
Topp et al. 2014 (MT103-211)	Phase II

This is the FDA-approved dose & schedule.

Chemotherapy

Blinatumomab (Blincyto) given as follows:
- Cycle 1: 9 μg/day IV continuous infusion on days 1 to 7, then 28 μg/day on days 8 to 28
- Subsequent cycles: 28 μg/day IV continuous infusion on days 1 to 28

6-week cycle for up to 5 cycles (2 cycles for induction and 3 additional cycles for consolidation)

Regimen #2

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

This is not the FDA-approved dose & schedule.

Chemotherapy

Blinatumomab (Blincyto) 15 μg/m²/day IV continuous infusion for days 1 to 28

6-week cycle; 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

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 verified protocol PubMed
1. Update: Topp MS, Gökbuget N, Zugmaier G, Degenhard E, Goebeler ME, Klinger M, Neumann SA, Horst HA, Raff T, Viardot A, Stelljes M, Schaich M, Köhne-Volland R, Brüggemann M, Ottmann OG, Burmeister T, Baeuerle PA, Nagorsen D, Schmidt M, Einsele H, Riethmüller G, Kneba M, Hoelzer D, Kufer P, Bargou RC. Long-term follow-up of hematologic relapse-free survival in a phase 2 study of blinatumomab in patients with MRD in B-lineage ALL. Blood. 2012 Dec 20;120(26):5185-7. link to original article PubMed
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
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 PubMed
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

CCE

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CCE: Clofarabine, Cyclophosphamide, Etoposide

Regimen

Study	Evidence
Locatelli et al. 2009	Non-randomized

Patients in this study were pediatric: ≤ 15 years old at diagnosis and ≤ 21 years old at time of treatment. No patients had CNS disease at time of treatment, and no patients received CNS prophylaxis.

Chemotherapy

Clofarabine (Clolar) 40 mg/m² IV over 2 hours once per day on days 1 to 5, given first
Cyclophosphamide (Cytoxan) 400 mg/m² IV over 1 hour once per day on days 1 to 5
Etoposide (Vepesid) 150 mg/m² IV over 2 hours once per day on days 1 to 5

Supportive medications

Prophylactic steroids used for patients with >30 x 10⁹ blasts/L in the peripheral blood prior to treatment

5-day course

2 out of 25 patients received a second course of CCE as consolidation therapy. Responding patients were given allogeneic HSCT if a suitable donor was immediately available or were given consolidation courses of chemotherapy including multiple agents active against ALL cells, chosen according to the treating physician's preference."

References

Locatelli F, Testi AM, Bernardo ME, Rizzari C, Bertaina A, Merli P, Pession A, Giraldi E, Parasole R, Barberi W, Zecca M. Clofarabine, cyclophosphamide and etoposide as single-course re-induction therapy for children with refractory/multiple relapsed acute lymphoblastic leukaemia. Br J Haematol. 2009 Nov;147(3):371-8. Epub 2009 Aug 29. link to original article contains verified protocol PubMed

Clofarabine (Clolar)

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Regimen

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

Chemotherapy

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

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

References

Kantarjian H, Gandhi V, Cortes J, Verstovsek S, Du M, Garcia-Manero G, Giles F, Faderl S, O'Brien S, Jeha S, Davis J, Shaked Z, Craig A, Keating M, Plunkett W, Freireich EJ. Phase 2 clinical and pharmacologic study of clofarabine in patients with refractory or relapsed acute leukemia. Blood. 2003 Oct 1;102(7):2379-86. Epub 2003 Jun 5. link to original article contains verified protocol PubMed
Retrospective: Barba P, Sampol A, Calbacho M, Gonzalez J, Serrano J, Martínez-Sánchez P, Fernández P, García-Boyero R, Bueno J, Ribera JM. Clofarabine-based chemotherapy for relapsed/refractory adult acute lymphoblastic leukemia and lymphoblastic lymphoma. The Spanish experience. Am J Hematol. 2012 Jun;87(6):631-4. Epub 2012 Mar 19. link to original article PubMed

Cytarabine (Cytosar)

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Regimen

Study	Evidence	Comparator
Kantarjian et al. 2016	Phase III	Inotuzumab ozogamicin

Chemotherapy

Cytarabine (Cytosar) 3000 mg/m² IV q12h
- Dose reduced to 1500 mg/m² IV q12h for patients ≥55 years

One course of up to 12 doses

References

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 PubMed

Cytarabine & Idarubicin

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Regimen

Study	Evidence
Huguet et al. 2009 (GRAALL-2003)	Phase II

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. Treatment preceded by cyclophosphamide, daunorubicin, L-aspariginase, vincristine, prednisone induction.

Chemotherapy

Cytarabine (Cytosar) 2000 mg/m² IV q12h on days 1 to 4
Idarubicin (Idamycin) 12 mg/m² IV once per day on days 1 to 3

Supportive medications

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

Patients achieving CR after salvage proceeded to pediatric-like GRAALL consolidation.

References

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 early article contains verified protocol PubMed

Cytarabine & Mitoxantrone

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Regimen

Study	Evidence	Comparator
Kantarjian et al. 2016	Phase III	Inotuzumab ozogamicin

This regimen as reported resembles 7+3m; it is not clear whether the cytarabine is given as bolus or continuous infusion from the manuscript.

Chemotherapy

Cytarabine (Cytosar) 200 mg/m²/day IV on days 1 to 7
Mitoxantrone (Novantrone) 12 mg/m² IV once per day on days 1 to 3
- Dose reduction to 8 mg/m² allowed on the basis of age, coexisting conditions, and previous anthracycline use

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

References

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 protocol PubMed

FLAG

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

Regimen

Study	Evidence	Comparator
Kantarjian et al. 2016	Phase III	Inotuzumab ozogamicin

Chemotherapy

Fludarabine (Fludara) 30 mg/m² IV over 30 minutes once per day on days 2 to 6
Cytarabine (Cytosar) 2000 mg/m² IV once per day on days 1 to 6
G-CSF 5 μg/kg or at the institutional standard dose once per day (interval not specified)

28-day cycle for up to 4 cycles

References

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 PubMed

Hyper-CVAD & Everolimus

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Hyper-CVAD: Hyperfractionated Cyclophosphamide, Vincristine, Adriamycin (Doxorubicin), Dexamethasone

Regimen

Study	Evidence
Daver et al. 2015	Phase II

To be completed

References

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 PubMed

Vincristine liposomal (Marqibo)

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Regimen

Study	Evidence
O'Brien et al. 2012 (RALLY)	Phase II

Chemotherapy

Vincristine liposomal (Marqibo) 2.25 mg/m² IV over 1 hour on days 1, 8, 15, 22

28-day cycles, continued until "response achievement, leukemia progression, toxicity, or decision to pursue other therapy"

References

O'Brien S, Schiller G, Lister J, Damon L, Goldberg S, Aulitzky W, Ben-Yehuda D, Stock W, Coutre S, Douer D, Heffner LT, Larson M, Seiter K, Smith S, Assouline S, Kuriakose P, Maness L, Nagler A, Rowe J, Schaich M, Shpilberg O, Yee K, Schmieder G, Silverman JA, Thomas D, Deitcher SR, Kantarjian H. High-dose vincristine sulfate liposome injection for advanced, relapsed, and refractory adult Philadelphia chromosome-negative acute lymphoblastic leukemia. J Clin Oncol. 2013 Feb 20;31(6):676-83. Epub 2012 Nov 19. link to original article contains verified protocol PubMed

Relapsed/refractory, Ph-positive

Bosutinib (Bosulif)

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Regimen

Study	Evidence
Kantarjian et al. 2013	Phase I/II

Note: the dosing described is that reported for the phase 2 portion of the phase 1/2 study.

Chemotherapy

Bosutinib (Bosulif) 500 mg PO once per day, take with food
- If no grade 3 or higher drug-related toxicity occurs, dose of Bosutinib (Bosulif) can be escalated to 600 mg PO once per day if response is suboptimal. Suboptimal response defined as no complete hematologic response (CHR) by week 8 or complete cytogenetic response (CCyR) by week 12.

Given until progression of disease or unacceptable toxicity

References

Kantarjian HM, Cortes JE, Kim DW, Khoury HJ, Brümmendorf TH, Porkka K, Martinelli G, Durrant S, Leip E, Kelly V, Turnbull K, Besson N, Gambacorti-Passerini C. Bosutinib safety and management of toxicity in leukemia patients with resistance or intolerance to imatinib and other tyrosine kinase inhibitors. Blood. 2014 Feb 27;123(9):1309-18. Epub 2013 Dec 17. link to original article contains verified protocol PubMed

Dasatinib (Sprycel)

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Regimen #1

Study	Evidence	Comparator
Ottmann et al. 2007 (START-L)	Phase II
Lilly et al. 2010	Phase III	Dasatinib 140 mg once per day

Chemotherapy

Dasatinib (Sprycel) 70 mg PO twice per day

Given until progression of disease or unacceptable toxicity

Regimen #2

Study	Evidence	Comparator
Lilly et al. 2010	Phase III	Dasatinib 70 mg BID

Chemotherapy

Dasatinib (Sprycel) 140 mg PO once per day

Given until progression of disease or unacceptable toxicity

References

Ottmann O, Dombret H, Martinelli G, Simonsson B, Guilhot F, Larson RA, Rege-Cambrin G, Radich J, Hochhaus A, Apanovitch AM, Gollerkeri A, Coutre S. Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study. Blood. 2007 Oct 1;110(7):2309-15. Epub 2007 May 11. link to original article contains verified protocol PubMed
Lilly MB, Ottmann OG, Shah NP, Larson RA, Reiffers JJ, Ehninger G, Müller MC, Charbonnier A, Bullorsky E, Dombret H, Brigid Bradley-Garelik M, Zhu C, Martinelli G. Dasatinib 140 mg once daily versus 70 mg twice daily in patients with Ph-positive acute lymphoblastic leukemia who failed imatinib: Results from a phase 3 study. Am J Hematol. 2010 Mar;85(3):164-70. link to original article contains verified protocol PubMed

Nilotinib (Tasigna)

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Regimen

Study	Evidence
Kantarjian et al. 2006	Phase II

Chemotherapy

Nilotinib (Tasigna) 300 to 400 mg PO BID

References

Kantarjian H, Giles F, Wunderle L, Bhalla K, O'Brien S, Wassmann B, Tanaka C, Manley P, Rae P, Mietlowski W, Bochinski K, Hochhaus A, Griffin JD, Hoelzer D, Albitar M, Dugan M, Cortes J, Alland L, Ottmann OG. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med. 2006 Jun 15;354(24):2542-51. link to original article PubMed

Ponatinib (Iclusig)

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Regimen

Study	Evidence
Cortes et al. 2013 (PACE)	Phase II

Chemotherapy

Ponatinib (Iclusig) 45 mg PO once per day; may be taken either with or without food

Given until progression of disease or unacceptable toxicity

References

Cortes JE, Kim DW, Pinilla-Ibarz J, le Coutre P, Paquette R, Chuah C, Nicolini FE, Apperley JF, Khoury HJ, Talpaz M, Dipersio J, Deangelo DJ, Abruzzese E, Rea D, Baccarani M, Müller MC, Gambacorti-Passerini C, Wong S, Lustgarten S, Rivera VM, Clackson T, Turner CD, Haluska FG, Guilhot F, Deininger MW, Hochhaus A, Hughes T, Goldman JM, Shah NP, Kantarjian H; the PACE Investigators. A Phase 2 Trial of Ponatinib in Philadelphia Chromosome-Positive Leukemias. N Engl J Med. 2013 Nov 7;369(19):1783-96. Epub 2013 Nov 1. link to original article PubMed
1. Update: Abstract: Dong-Wook Kim, Javier Pinilla-Ibarz, Philipp D le Coutre, Ronald Paquette, Charles Chuah, Franck E. Nicolini, Jane F Apperley, H. Jean Khoury, Moshe Talpaz, John F. DiPersio, Daniel J DeAngelo, Elisabetta Abruzzese, Delphine Rea, Michele Baccarani, Martin C. Müller, Carlo Gambacorti-Passerini, Stephanie Lustgarten, Victor M. Rivera, Tim Clackson, Christopher D Turner, Frank G Haluska, François Guilhot, Michael W. Deininger, Andreas Hochhaus, Timothy P. Hughes, John M Goldman, Neil P. Shah, Hagop M. Kantarjian. Ponatinib In Patients (pts) With Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL) Resistant Or Intolerant To Dasatinib Or Nilotinib, Or With The T315I BCR-ABL Mutation: 2-Year Follow-Up Of The PACE Trial. Blood Nov 2013,122(21)650 link to original abstract

Pediatric ALL

Pediatric ALL regimens tend to be very complex. This list on ped-onc.org appears to be fairly comprehensive and includes regimen details for some of the common regimens e.g. COG-AALL0232. For now we will try to include a list of references here and potentially build these regimens here, over time.

References

Domenech C, Suciu S, De Moerloose B, Mazingue F, Plat G, Ferster A, Uyttebroeck A, Sirvent N, Lutz P, Yakouben K, Munzer M, Röhrlich P, Plantaz D, Millot F, Philippet P, Dastugue N, Girard S, Cavé H, Benoit Y, Bertrandfor Y; Children's Leukemia Group (CLG) of European Organisation for Research and Treatment of Cancer (EORTC). Dexamethasone (6 mg/m²/day) and prednisolone (60 mg/m²/day) were equally effective as induction therapy for childhood acute lymphoblastic leukemia in the EORTC CLG 58951 randomized trial. Haematologica. 2014 Jul;99(7):1220-7. Epub 2014 Apr 11. link to PMC full text PubMed

Investigational agents

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

@@ Line 1: / Line 1: @@
 '''Use of this site is subject to you reading and agreeing with the terms set forth in the [[HemOnc.org_-_A_Hematology_Oncology_Wiki:General_disclaimer|disclaimer]].'''
-Is there a regimen missing from this list?  Would you like to share a different dosage/schedule or an additional reference for a regimen?  Have you noticed an error?  Do you have an idea that will help the site grow to better meet your needs and the needs of many others?  You are [[How_to_contribute|invited to contribute to the site]].
+Is there a regimen missing from this list? Would you like to share a different dosage/schedule or an additional reference for a regimen? Have you noticed an error? Do you have an idea that will help the site grow to better meet your needs and the needs of many others? You are [[How_to_contribute|invited to contribute to the site]].
 {| class="wikitable" style="float:right; margin-right: 5px;"
 |-
-|<div style="background-color: #66FF66; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]]  |?Regimen |limit=10000|format=sum}} regimens on this page</b></font></div>
+|<div style="background-color: #66FF66; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} regimens on this page</b></font></div>
-<div style="background-color: #66CCFF; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]]  |?Variant |limit=10000|format=sum}} variants on this page</b></font></div>
+<div style="background-color: #66CCFF; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} variants on this page</b></font></div>
 |}
 {{TOC limit|limit=3}}
@@ Line 33: / Line 33: @@
 |-
 |}
 ''Note: 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.''
 ====Chemotherapy====
@@ Line 41: / Line 40: @@
 *[[Methotrexate (MTX)]] 15 mg IT once at some point between days -7 and -4
-''Patients then proceeded to [[#Pediatric-like_GRAALL_induction|pediatric-like GRAALL induction]].''
+''Patients then proceeded to [[#Cyclophosphamide.2C_Daunorubicin.2C_L-Asparaginase.2C_Vincristine.2C_Prednisone|cyclophosphamide, daunorubicin, L-asparaginase, vincristine, prednisone induction]].''
 ===References===
@@ Line 61: / Line 60: @@
 ## '''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 May 14. [Epub ahead of print] [http://www.ncbi.nlm.nih.gov/pubmed/27178680 PubMed]
-==Cyclophosphamide, Daunorubicin, Prednisone, Vincristine {{#subobject:29d427|Regimen=1}}==
+==Cyclophosphamide, Cytarabine, Mercaptopurine {{#subobject:317919|Regimen=1}}==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#toc|back to top]]
 |}
-===Regimen {{#subobject:7ff1ac|Variant=1}}===
+===Regimen {{#subobject:d69105|Variant=1}}===
 {| border="1" style="text-align:center;" !align="left"
 |'''Study'''
 |[[Levels_of_Evidence#Evidence|'''Evidence''']]
-|'''Comparator'''
 |-
-|[http://jco.ascopubs.org/content/22/20/4075.long Thomas et al. 2004 (LALA-94)]
+|[http://bloodjournal.hematologylibrary.org/content/106/12/3760.long Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)]
 |<span
-style="background:#00cd00;
+style="background:#EEEE00;
 padding:3px 6px 3px 6px;
 border-color:black;
 border-width:2px;
-border-style:solid;">Phase III</span>
+border-style:solid;">Non-randomized portion of RCT</span>
-|[[#Cyclophosphamide.2C_Idarubicin.2C_Prednisone.2C_Vincristine|Cyclophosphamide, Idarubicin, Prednisone, Vincristine]]
 |-
 |}
-''Unlikely to be completed, here for historic context only.''
+''Treatment preceded by "Phase 1" induction: [[#Daunorubicin.2C_L-Asparaginase.2C_Vincristine.2C_Prednisone|daunorubicin, L-asparaginase, vincristine, prednisone]].''
 ====Chemotherapy====
-*[[Cyclophosphamide (Cytoxan)]]
+*[[Cyclophosphamide (Cytoxan)]] 650 mg/m<sup>2</sup> IV once per day on days 1, 15, 29
-*[[Daunorubicin (Cerubidine)]]
+*[[Cytarabine (Cytosar)]] 75 mg/m<sup>2</sup> IV once per day on days 1 to 4, 8 to 11, 15 to 18, 22 to 25
-*[[Prednisone (Sterapred)]]
+*[[Mercaptopurine (Purinethol)]] 6 mg/m<sup>2</sup> PO once per day on days 1 to 28
-*[[Vincristine (Oncovin)]]
+====CNS prophylaxis====
+*[[Methotrexate (MTX)]] 12 mg IT once per day on days 1, 8, 15, 22
+''Treatment followed by [[L-asparaginase & methotrexate intensification]].''
 ===References===
-# 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. [http://jco.ascopubs.org/content/22/20/4075.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/15353542 PubMed]
+# Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. [http://bloodjournal.hematologylibrary.org/content/106/12/3760.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/16105981 PubMed]
+## '''Update:''' Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, Burnett AK, Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J, McMillan A, Franklin IM, Luger S, Ciobanu N, Rowe JM. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008 Feb 15;111(4):1827-33. Epub 2007 Nov 29. [http://bloodjournal.hematologylibrary.org/content/111/4/1827.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/18048644 PubMed]
+## '''Update:''' Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, Marks DI, McMillan AK, Litzow MR, Lazarus HM, Foroni L, Dewald G, Franklin IM, Luger SM, Paietta E, Wiernik PH, Tallman MS, Goldstone AH. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009 May 7;113(19):4489-96. Epub 2009 Feb 24. [http://bloodjournal.hematologylibrary.org/content/113/19/4489.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/19244158 PubMed]
+## '''Update:''' Fielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow MR, Lazarus H, Luger SM, Marks DI, McMillan AK, Moorman AV, Patel B, Paietta E, Tallman MS, Goldstone AH. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014 Feb 6;123(6):843-50. Epub 2013 Nov 25. [http://bloodjournal.hematologylibrary.org/content/123/6/843.full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/24277073 PubMed]
-==Cyclophosphamide, Daunorubicin, L-Asparaginase, Prednisone, Vincristine {{#subobject:0cee78|Regimen=1}}==
+==Cyclophosphamide, Daunorubicin, Vincristine, Prednisone {{#subobject:29d427|Regimen=1}}==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#toc|back to top]]
 |}
-===Regimen {{#subobject:1bf42b|Variant=1}}===
+===Regimen {{#subobject:7ff1ac|Variant=1}}===
 {| border="1" style="text-align:center;" !align="left"
 |'''Study'''
@@ Line 103: / Line 108: @@
 |'''Comparator'''
 |-
-|[http://www.bloodjournal.org/content/99/3/863.long Annino et al. 2002 (GIMEMA ALL 0288)]
+|[http://jco.ascopubs.org/content/22/20/4075.long Thomas et al. 2004 (LALA-94)]
 |<span
 style="background:#00cd00;
@@ Line 110: / Line 115: @@
 border-width:2px;
 border-style:solid;">Phase III</span>
-|[[#Daunorubicin.2C_L-Asparaginase.2C_Prednisone.2C_Vincristine|Daunorubicin, L-Asparaginase, Prednisone, Vincristine]]
+|[[#Cyclophosphamide.2C_Idarubicin.2C_Vincristine.2C_Prednisone|Cyclophosphamide, Idarubicin, Vincristine, Prednisone]]
 |-
 |}
@@ Line 117: / Line 122: @@
 *[[Cyclophosphamide (Cytoxan)]]
 *[[Daunorubicin (Cerubidine)]]
-*[[Asparaginase (Elspar)|L-Asparaginase]]
+*[[Vincristine (Oncovin)]]
 *[[Prednisone (Sterapred)]]
-*[[Vincristine (Oncovin)]]
 ===References===
-# 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 Group. Treatment of adult acute lymphoblastic leukemia (ALL): long-term follow-up of the GIMEMA ALL 0288 randomized study. Blood. 2002 Feb 1;99(3):863-71. [http://www.bloodjournal.org/content/99/3/863.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/11806988 PubMed]
+# 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. [http://jco.ascopubs.org/content/22/20/4075.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/15353542 PubMed]
-==Cyclophosphamide, Doxorubicin, L-Asparaginase, Prednisolone, Vincristine {{#subobject:6edd1f|Regimen=1}}==
+==Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone {{#subobject:0cee78|Regimen=1}}==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#toc|back to top]]
 |}
-===Regimen {{#subobject:0f2246|Variant=1}}===
+'''[[Asparaginase (Elspar)]] was discontinued by the manufacturer in December 2012, and is now essentially out of stock. Alternatives include [[Pegaspargase (Oncaspar)]] or [[Asparaginase Erwinia chrysanthemi (Erwinaze)]].'''
+===Regimen #1 {{#subobject:2aaaf3|Variant=1}}===
 {| border="1" style="text-align:center;" !align="left"
 |'''Study'''
 |[[Levels_of_Evidence#Evidence|'''Evidence''']]
+|'''Comparator'''
+|-
+|[http://jco.ascopubs.org/content/27/6/911.long Huguet et al. 2009 (GRAALL-2003)]
+|<span
+style="background:#EEEE00;
+padding:3px 6px 3px 6px;
+border-color:black;
+border-width:2px;
+border-style:solid;">Phase II</span>
+|
 |-
-|[http://www.nature.com/leu/journal/v16/n7/full/2402526a.html Takeuchi et al. 2002 (JALSG-ALL93)]
+|[https://ash.confex.com/ash/2015/webprogram/Paper82882.html Maury et al. 2015 (GRAALL-R 2005)]
 |<span
-style="background:#eeee00;
+style="background:#00CD00;
 padding:3px 6px 3px 6px;
 border-color:black;
 border-width:2px;
-border-style:solid;">Non-randomized</span>
+border-style:solid;">Phase III</span>
+|[[#Cyclophosphamide.2C_Daunorubicin.2C_L-Asparaginase.2C_Vincristine.2C_Prednisone.2C_Rituximab|Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone, Rituximab]]
 |-
 |}
-''Unlikely to be completed, here for historic context only.''
+''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 prophylaxis and treatment. Treatment preceded by [[#Prednisone_.28Sterapred.29|prednisone prephase]].''
 ====Chemotherapy====
-*[[Cyclophosphamide (Cytoxan)]]
+*[[Cyclophosphamide (Cytoxan)]] as follows:
-*[[Doxorubicin (Adriamycin)]]
+**750 mg/m<sup>2</sup> IV once per day on days 1 & 15 in "good early responders"
-*[[Asparaginase (Elspar)|L-Asparaginase]]
+**750 mg/m<sup>2</sup> IV once on day 1, then 500 mg/m<sup>2</sup> IV q12h on days 15 & 16 in "poor early responders"
-*[[Prednisolone (Millipred)]]
+*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV once per day on days 1 to 3, then 30 mg/m<sup>2</sup> IV once per day on days 15 & 16
-*[[Vincristine (Oncovin)]]
+*[[Asparaginase (Elspar)]] 6000 units/m<sup>2</sup>/day (route not specified) on days 8, 10, 12, 20, 22, 24, 26, 28
+*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 1, 8, 15, 22
+*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup>/day on days 1 to 14
+====Supportive medications====
+*[[Lenograstim (Granocyte)]] 150 μg/m<sup>2</sup> SC once per day from day 17 until myeloid recovery
-===References===
+''Patients with resistant disease received [[#Cytarabine_.26_Idarubicin|cytarabine & idarubicin salvage]] prior to further consolidation. All others proceeded to [[#Pediatric-like_GRAALL_consolidation|pediatric-like GRAALL consolidation]].''
-# Takeuchi J, Kyo T, Naito K, Sao H, Takahashi M, Miyawaki S, Kuriyama K, Ohtake S, Yagasaki F, Murakami H, Asou N, Ino T, Okamoto T, Usui N, Nishimura M, Shinagawa K, Fukushima T, Taguchi H, Morii T, Mizuta S, Akiyama H, Nakamura Y, Ohshima T, Ohno R. Induction therapy by frequent administration of doxorubicin with four other drugs, followed by intensive consolidation and maintenance therapy for adult acute lymphoblastic leukemia: the JALSG-ALL93 study. Leukemia. 2002 Jul;16(7):1259-66. [http://www.nature.com/leu/journal/v16/n7/full/2402526a.html link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/12094249 PubMed]
-==Cyclophosphamide, Idarubicin, Prednisone, Vincristine {{#subobject:4c1f91|Regimen=1}}==
+===Regimen #2, "Larson regimen" {{#subobject:e460e0|Variant=1}}===
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#toc|back to top]]
-|}
-===Regimen {{#subobject:435069|Variant=1}}===
 {| border="1" style="text-align:center;" !align="left"
 |'''Study'''
 |[[Levels_of_Evidence#Evidence|'''Evidence''']]
-|'''Comparator'''
 |-
-|[http://jco.ascopubs.org/content/22/20/4075.long Thomas et al. 2004 (LALA-94)]
+|[http://bloodjournal.hematologylibrary.org/content/85/8/2025.full Larson et al. 1995 (CALGB 8811)]
 |<span
-style="background:#00cd00;
+style="background:#EEEE00;
 padding:3px 6px 3px 6px;
 border-color:black;
 border-width:2px;
-border-style:solid;">Phase III</span>
+border-style:solid;">Phase II</span>
-|[[#Cyclophosphamide.2C_Daunorubicin.2C_Prednisone.2C_Vincristine|Cyclophosphamide, Daunorubicin, Prednisone, Vincristine]]
 |-
 |}
-''Unlikely to be completed, here for historic context only.''
+====Chemotherapy ("Course I")====
-====Chemotherapy====
+*[[Cyclophosphamide (Cytoxan)]] as follows:
-*[[Cyclophosphamide (Cytoxan)]]
+**For patients <60 years old: 1200 mg/m<sup>2</sup> IV once on day 1
-*[[Idarubicin (Idamycin)]]
+**For patients ≥60 years old: 800 mg/m<sup>2</sup> IV once on day 1
-*[[Prednisone (Sterapred)]]
+*[[Daunorubicin (Cerubidine)]] as follows:
-*[[Vincristine (Oncovin)]]
+**For patients <60 years old: 45 mg/m<sup>2</sup> IV once per day on days 1 to 3
+**For patients ≥60 years old: 30 mg/m<sup>2</sup> IV once per day on days 1 to 3
+*[[Asparaginase (Elspar)]] 6000 units/m<sup>2</sup> SC once per day on days 5, 8, 11, 15, 18, 22
+*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 1, 8, 15, 22
+*[[Prednisone (Sterapred)]] as follows:
+**For patients <60 years old: 60 mg/m<sup>2</sup> PO once per day on days 1 to 21
+**For patients ≥60 years old: 60 mg/m<sup>2</sup> PO once per day on days 1 to 7
-===References===
+''To be followed by [[#Larson.2FCALGB_8811_regimen_.28consolidation.29|Larson/CALGB 8811 regimen courses II to IV (consolidation & intensification)]].''
-# 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. [http://jco.ascopubs.org/content/22/20/4075.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/15353542 PubMed]
-==Daunorubicin, L-Asparaginase, Prednisone, Vincristine {{#subobject:3c9897|Regimen=1}}==
+===Regimen #3 {{#subobject:1bf42b|Variant=1}}===
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#toc|back to top]]
-|}
-===Regimen {{#subobject:6da40d|Variant=1}}===
 {| border="1" style="text-align:center;" !align="left"
 |'''Study'''
@@ Line 203: / Line 217: @@
 border-width:2px;
 border-style:solid;">Phase III</span>
-|[[#Cyclophosphamide.2C_Daunorubicin.2C_L-Asparaginase.2C_Prednisone.2C_Vincristine|Cyclophosphamide, Daunorubicin, L-Asparaginase, Prednisone, Vincristine]]
+|[[#Daunorubicin.2C_L-Asparaginase.2C_Vincristine.2C_Prednisone|Daunorubicin, L-Asparaginase, Vincristine, Prednisone]]
 |-
 |}
@@ Line 210: / Line 224: @@
 *[[Cyclophosphamide (Cytoxan)]]
 *[[Daunorubicin (Cerubidine)]]
+*[[Asparaginase (Elspar)|L-Asparaginase]]
+*[[Vincristine (Oncovin)]]
 *[[Prednisone (Sterapred)]]
-*[[Vincristine (Oncovin)]]
 ===References===
+# Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR et al. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study 8811. Blood. 1995 Apr 15;85(8):2025-37. [http://bloodjournal.hematologylibrary.org/content/85/8/2025.full.pdf+html link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/7718875 PubMed]
 # 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 Group. Treatment of adult acute lymphoblastic leukemia (ALL): long-term follow-up of the GIMEMA ALL 0288 randomized study. Blood. 2002 Feb 1;99(3):863-71. [http://www.bloodjournal.org/content/99/3/863.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/11806988 PubMed]
+# 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. [http://jco.ascopubs.org/content/27/6/911.long link to early article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19124805 PubMed]
+# '''Abstract:''' Maury et al. Addition of Rituximab Improves the Outcome of Adult Patients with CD20-Positive, Ph-Negative, B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL): Results of the Randomized Graall-R 2005 Study. ASH 2015 Annual Meeting Abstract 1.[https://ash.confex.com/ash/2015/webprogram/Paper82882.html link to abstract]
-==Hyper-CVAD/MA {{#subobject:8e1d75|Regimen=1}}==
+==Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone, Rituximab {{#subobject:18fec2|Regimen=1}}==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#toc|back to top]]
 |}
-Hyper-CVAD/MA: '''<u>Hyper</u>'''fractionated '''<u>C</u>'''yclophosphamide, '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>D</u>'''examethasone alternating with '''<u>M</u>'''ethotrexate, '''<u>A</u>'''ra-C (Cytarabine)
+===Regimen {{#subobject:aa59d3|Variant=1}}===
-===Regimen {{#subobject:70e9ec|Variant=1}}===
 {| border="1" style="text-align:center;" !align="left"
 |'''Study'''
 |[[Levels_of_Evidence#Evidence|'''Evidence''']]
+|'''Comparator'''
 |-
-|[http://jco.ascopubs.org/content/17/8/2461.long Thomas et al. 1999]
+|[https://ash.confex.com/ash/2015/webprogram/Paper82882.html Maury et al. 2015 (GRAALL-R 2005)]
 |<span
-style="background:#EEEE00;
+style="background:#00CD00;
 padding:3px 6px 3px 6px;
 border-color:black;
 border-width:2px;
-border-style:solid;">Phase II</span>
+border-style:solid;">Phase III</span>
+|[[#Cyclophosphamide.2C_Daunorubicin.2C_L-Asparaginase.2C_Vincristine.2C_Prednisone|Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone]]
 |-
 |}
+''Note: this regimen was meant for CD20+ patients less than 60 years old. Details were scant in the abstract but a total of 16 to 18 [[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> infusions were given during the course of therapy. This will be fleshed out when the manuscript is published.''
-====Part A (cycles 1, 3, 5, 7):====
+===References===
-*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> IV over 2 hours Q12H on days 1 to 3 (6 total doses)
+# '''Abstract:''' Maury et al. Addition of Rituximab Improves the Outcome of Adult Patients with CD20-Positive, Ph-Negative, B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL): Results of the Randomized Graall-R 2005 Study. ASH 2015 Annual Meeting Abstract 1.[https://ash.confex.com/ash/2015/webprogram/Paper82882.html link to abstract]
-*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 4 & 11
-*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV over 24 hours (over 48 hours in patients with ejection fractions (EF) <50%) on day 4
-*[[Dexamethasone (Decadron)]] 40 mg PO/IV once per day on days 1 to 4, 11 to 14
-====Supportive medications====
+==Cyclophosphamide, Doxorubicin, L-Asparaginase, Vincristine, Prednisolone {{#subobject:6edd1f|Regimen=1}}==
-*[[Mesna (Mesnex)]] 600 mg/m<sup>2</sup>/day IV continuous infusion on days 1 to 3, starting 1 hour before [[Cyclophosphamide (Cytoxan)]] and completed 12 hours after the last dose of [[Cyclophosphamide (Cytoxan)]]
+{| class="wikitable" style="float:right; margin-left: 5px;"
-*One of the following antibiotics:
+|-
-**EITHER [[Ciprofloxacin (Cipro)]] 500 mg PO BID
+|[[#toc|back to top]]
-**OR [[Levofloxacin (Levaquin)]] 500 mg PO once per day
+|}
-**OR [[Trimethoprim/Sulfamethoxazole (Bactrim DS)]] (160/800 mg) PO BID
+===Regimen {{#subobject:0f2246|Variant=1}}===
-*[[Fluconazole (Diflucan)]] 200 mg PO once per day
+{| border="1" style="text-align:center;" !align="left"
-*One of the following antivirals:
+|'''Study'''
-**EITHER [[Acyclovir (Zovirax)]] 200 mg PO BID
+|[[Levels_of_Evidence#Evidence|'''Evidence''']]
-**OR [[Valacyclovir (Valtrex)]] 500 mg PO once per day
+|-
-*[[Filgrastim (Neupogen)]] 10 μg/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 >1 x 10<sup>9</sup>/L
+|[http://www.nature.com/leu/journal/v16/n7/full/2402526a.html Takeuchi et al. 2002 (JALSG-ALL93)]
+|<span
+style="background:#eeee00;
+padding:3px 6px 3px 6px;
+border-color:black;
+border-width:2px;
+border-style:solid;">Non-randomized</span>
+|-
+|}
+''Unlikely to be completed, here for historic context only.''
+====Chemotherapy====
+*[[Cyclophosphamide (Cytoxan)]]
+*[[Doxorubicin (Adriamycin)]]
+*[[Asparaginase (Elspar)|L-Asparaginase]]
+*[[Vincristine (Oncovin)]]
+*[[Prednisolone (Millipred)]]
-'''Next cycle to start as soon as absolute neutrophil count is > 1 x 10<sup>9</sup>/L at least 24 hours off of G-CSF and platelet count > 60 x 10<sup>9</sup>/L'''
+===References===
+# Takeuchi J, Kyo T, Naito K, Sao H, Takahashi M, Miyawaki S, Kuriyama K, Ohtake S, Yagasaki F, Murakami H, Asou N, Ino T, Okamoto T, Usui N, Nishimura M, Shinagawa K, Fukushima T, Taguchi H, Morii T, Mizuta S, Akiyama H, Nakamura Y, Ohshima T, Ohno R. Induction therapy by frequent administration of doxorubicin with four other drugs, followed by intensive consolidation and maintenance therapy for adult acute lymphoblastic leukemia: the JALSG-ALL93 study. Leukemia. 2002 Jul;16(7):1259-66. [http://www.nature.com/leu/journal/v16/n7/full/2402526a.html link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/12094249 PubMed]
-====Part B (cycles 2, 4, 6, 8):====
+==Cyclophosphamide, Idarubicin, Vincristine, Prednisone {{#subobject:4c1f91|Regimen=1}}==
-*[[Methotrexate (MTX)]] 200 mg/m<sup>2</sup> IV over 2 hours, then 800 mg/m<sup>2</sup> IV over 22 hours on day 1
+{| class="wikitable" style="float:right; margin-left: 5px;"
-*[[Cytarabine (Cytosar)]] 3000 mg/m<sup>2</sup> IV over 2 hours Q12H on days 2 & 3 (4 total doses)
+|-
-**Dose-reduced to 1000 mg/m<sup>2</sup> for patients older than 60 years old
+|[[#toc|back to top]]
-*[[Methylprednisolone (Solumedrol)]] 50 mg IV Q12H on days 1 to 3 ''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.''
+|}
+===Regimen {{#subobject:435069|Variant=1}}===
+{| border="1" style="text-align:center;" !align="left"
+|'''Study'''
+|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+|'''Comparator'''
+|-
+|[http://jco.ascopubs.org/content/22/20/4075.long Thomas et al. 2004 (LALA-94)]
+|<span
+style="background:#00cd00;
+padding:3px 6px 3px 6px;
+border-color:black;
+border-width:2px;
+border-style:solid;">Phase III</span>
+|[[#Cyclophosphamide.2C_Daunorubicin.2C_Vincristine.2C_Prednisone|Cyclophosphamide, Daunorubicin, Vincristine, Prednisone]]
+|-
+|}
+''Unlikely to be completed, here for historic context only.''
+====Chemotherapy====
+*[[Cyclophosphamide (Cytoxan)]]
+*[[Idarubicin (Idamycin)]]
+*[[Vincristine (Oncovin)]]
+*[[Prednisone (Sterapred)]]
-====Supportive medications====
+===References===
-*[[Folinic acid (Leucovorin)]] 50 mg IV once 12 hours after [[Methotrexate (MTX)]] is complete, then 15 mg IV Q6H x 8 doses until serum methotrexate level <0.1 µM
+# 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. [http://jco.ascopubs.org/content/22/20/4075.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/15353542 PubMed]
-*One of the following antibiotics:
-**EITHER [[Ciprofloxacin (Cipro)]] 500 mg PO BID
-**OR [[Levofloxacin (Levaquin)]] 500 mg PO once per day
-**OR [[Trimethoprim/Sulfamethoxazole (Bactrim DS)]] (160/800 mg) PO BID
-*[[Fluconazole (Diflucan)]] 200 mg PO once per day
-*One of the following antivirals:
-**EITHER [[Acyclovir (Zovirax)]] 200 mg PO BID
-**OR [[Valacyclovir (Valtrex)]] 500 mg PO once per day
-*[[Filgrastim (Neupogen)]] 10 μg/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 >1 x 10<sup>9</sup>/L
-'''Next cycle to start as soon as absolute neutrophil count is > 1 x 10<sup>9</sup>/L at least 24 hours off of G-CSF and platelet count > 60 x 10<sup>9</sup>/L'''
+==Daunorubicin, L-Asparaginase, Vincristine, Prednisone +/- Imatinib {{#subobject:3c9897|Regimen=1}}==
+{| class="wikitable" style="float:right; margin-left: 5px;"
-====CNS prophylaxis====
+|-
-*[[Methotrexate (MTX)]] 12 mg (6 mg if given via Ommaya reservoir) IT on day 2
+|[[#toc|back to top]]
-*[[Cytarabine (Cytosar)]] 100 mg IT on day 7 '''OR''' 8
+|}
+'''[[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)]].'''
-'''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) >1400 IU/L and/or proliferative index percentage of S + G2M =14%'''
+===Regimen #1 {{#subobject:6d5745|Variant=1}}===
+{| border="1" style="text-align:center;" !align="left"
-====For known CNS disease====
+|'''Study'''
-*[[Methotrexate (MTX)]] 12 mg (6 mg if given via Ommaya reservoir) IT alternating with [[Cytarabine (Cytosar)]] 100 mg IT, with both given every week until cell count in CSF normalizes and cytology is negative for malignancy
+|[[Levels_of_Evidence#Evidence|'''Evidence''']]
-*Then [[Methotrexate (MTX)]] 12 mg (6 mg if given via Ommaya reservoir) IT given weeks 1 & 3 and [[Cytarabine (Cytosar)]] 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 (Cytosar)]] 100 mg IT once on day 7 '''OR''' 8
-''Certain patient populations (see e.g. Kantarjian et al. 2004) proceed to receive [[Acute_lymphocytic_leukemia#POMP|POMP maintenance therapy]].''
-===References===
-# Cortes J, O'Brien SM, Pierce S, Keating MJ, Freireich EJ, Kantarjian HM. The value of high-dose systemic chemotherapy and intrathecal therapy for central nervous system prophylaxis in different risk groups of adult acute lymphoblastic leukemia. Blood. 1995 Sep 15;86(6):2091-7. [http://bloodjournal.hematologylibrary.org/content/86/6/2091.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/7662956 PubMed]
-# Thomas DA, Cortes J, O'Brien S, Pierce S, Faderl S, Albitar M, Hagemeister FB, Cabanillas FF, Murphy S, Keating MJ, Kantarjian H. Hyper-CVAD program in Burkitt's-type adult acute lymphoblastic leukemia. J Clin Oncol. 1999 Aug;17(8):2461-70. [http://jco.ascopubs.org/content/17/8/2461.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/10561310 PubMed]
-# Kantarjian HM, O'Brien S, Smith TL, Cortes J, Giles FJ, Beran M, Pierce S, Huh Y, Andreeff M, Koller C, Ha CS, Keating MJ, Murphy S, Freireich EJ. Results of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia. J Clin Oncol. 2000 Feb;18(3):547-61. [http://jco.ascopubs.org/content/18/3/547.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/10653870 PubMed]
-## '''Update:''' Kantarjian H, Thomas D, O'Brien S, Cortes J, Giles F, Jeha S, Bueso-Ramos CE, Pierce S, Shan J, Koller C, Beran M, Keating M, Freireich EJ. Long-term follow-up results of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD), a dose-intensive regimen, in adult acute lymphocytic leukemia. Cancer. 2004 Dec 15;101(12):2788-801. [http://onlinelibrary.wiley.com/doi/10.1002/cncr.20668/full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/15481055 PubMed]
-# Thomas DA, O'Brien S, Cortes J, Giles FJ, Faderl S, Verstovsek S, Ferrajoli A, Koller C, Beran M, Pierce S, Ha CS, Cabanillas F, Keating MJ, Kantarjian H. Outcome with the hyper-CVAD regimens in lymphoblastic lymphoma. Blood. 2004 Sep 15;104(6):1624-30. Epub 2004 Jun 3. [http://bloodjournal.hematologylibrary.org/content/104/6/1624.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/15178574 PubMed]
-==International ALL Trial (MRC UKALL XII/ECOG E2993) {{#subobject:317919|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#toc|back to top]]
-|}
-===Regimen {{#subobject:d69105|Variant=1}}===
-{| border="1" style="text-align:center;" !align="left"
-|'''Study'''
-|[[Levels_of_Evidence#Evidence|'''Evidence''']]
-|-
 |[http://bloodjournal.hematologylibrary.org/content/106/12/3760.long Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)]
 |<span
@@ Line 317: / Line 338: @@
 border-color:black;
 border-width:2px;
-border-style:solid;">Phase II</span>
+border-style:solid;">Non-randomized portion of RCT</span>
 |-
 |}
+''To our knowledge, this is the largest induction trial in adult ALL, N=1,646. CR rate was 91%. There are many local variants of this protocol, which begins with "Phase I":''
-''To our knowledge, this is the largest induction trial in adult ALL, N=1,646. CR rate was 90%. There are many local variants of this protocol.''
+====Chemotherapy====
+*[[Daunorubicin (Cerubidine)]] 65 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
-'''[[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)]].'''
+*[[Asparaginase (Elspar)]] 10,000 units IV or IM once per day on days 17 to 28
-====Phase I, weeks 1 to 4====
-*[[Daunorubicin (Cerubidine)]] 65 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
 *[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
-*[[Asparaginase (Elspar)]] 10,000 units IV or IM once per day on days 17 to 28
 *[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 28
+====Ph+ patients====
+*[[Imatinib (Gleevec)]] 400 mg PO once per day, increased to 600 mg PO once per day "wherever possible"
+**Note: Two variants have been tested: from 2003 to 2005, imatinib was added after induction; from 2005 onward, imatinib was added during induction. Various durations are proposed, see Fielding et al. 2013 for more details.
 ====CNS prophylaxis====
 *[[Methotrexate (MTX)]] 12 mg IT once on day 15
-====Phase II, weeks 5 to 8====
+'''4-week course'''
-*[[Cyclophosphamide (Cytoxan)]] 650 mg/m<sup>2</sup> IV once per day on days 1, 15, 29
-*[[Cytarabine (Cytosar)]] 75 mg/m<sup>2</sup> IV once per day on days 1 to 4, 8 to 11, 15 to 18, 22 to 25
-*[[Mercaptopurine (Purinethol)]] 6 mg/m<sup>2</sup> PO once per day on days 1 to 28
-====CNS prophylaxis====
-*[[Methotrexate (MTX)]] 12 mg IT once per day on days 1, 8, 15, 22
-'''To be followed by [[Acute_lymphocytic_leukemia#International_ALL_Trial_.28MRC_UKALL_XII.2FECOG_E2993.29_3|consolidation portion of the protocol]].'''
-===References===
-# Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. [http://bloodjournal.hematologylibrary.org/content/106/12/3760.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/16105981 PubMed]
-## '''Update:''' Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, Burnett AK, Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J, McMillan A, Franklin IM, Luger S, Ciobanu N, Rowe JM. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008 Feb 15;111(4):1827-33. Epub 2007 Nov 29. [http://bloodjournal.hematologylibrary.org/content/111/4/1827.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/18048644 PubMed]
-## '''Update:''' Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, Marks DI, McMillan AK, Litzow MR, Lazarus HM, Foroni L, Dewald G, Franklin IM, Luger SM, Paietta E, Wiernik PH, Tallman MS, Goldstone AH. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009 May 7;113(19):4489-96. Epub 2009 Feb 24. [http://bloodjournal.hematologylibrary.org/content/113/19/4489.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/19244158 PubMed]
-## '''Update:''' Fielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow MR, Lazarus H, Luger SM, Marks DI, McMillan AK, Moorman AV, Patel B, Paietta E, Tallman MS, Goldstone AH. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014 Feb 6;123(6):843-50. Epub 2013 Nov 25. [http://bloodjournal.hematologylibrary.org/content/123/6/843.full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/24277073 PubMed]
-==Larson/CALGB 8811 regimen (induction) {{#subobject:ea8544|Regimen=1}}==
+''Treatment followed by "Phase 2" induction: [[cyclophosphamide, cytarabine, mercaptopurine]].''
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#toc|back to top]]
-|}
-===Regimen {{#subobject:e460e0|Variant=1}}===
+===Regimen #2 {{#subobject:6da40d|Variant=1}}===
 {| border="1" style="text-align:center;" !align="left"
 |'''Study'''
 |[[Levels_of_Evidence#Evidence|'''Evidence''']]
+|'''Comparator'''
 |-
-|[http://bloodjournal.hematologylibrary.org/content/85/8/2025.full Larson et al. 1995 (CALGB 8811)]
+|[http://www.bloodjournal.org/content/99/3/863.long Annino et al. 2002 (GIMEMA ALL 0288)]
 |<span
-style="background:#EEEE00;
+style="background:#00cd00;
 padding:3px 6px 3px 6px;
 border-color:black;
 border-width:2px;
-border-style:solid;">Phase II</span>
+border-style:solid;">Phase III</span>
+|[[#Cyclophosphamide.2C_Daunorubicin.2C_L-Asparaginase.2C_Vincristine.2C_Prednisone|Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone]]
 |-
 |}
+''Unlikely to be completed, here for historic context only.''
+====Chemotherapy====
+*[[Daunorubicin (Cerubidine)]]
+*[[Asparaginase (Elspar)]]
+*[[Vincristine (Oncovin)]]
+*[[Prednisone (Sterapred)]]
-'''[[Asparaginase (Elspar)]] was discontinued by the manufacturer in December 2012, and is now essentially out of stock. Alternatives include [[Pegaspargase (Oncaspar)]] or [[Asparaginase Erwinia chrysanthemi (Erwinaze)]].'''
+===Regimen #3, "Linker regimen" {{#subobject:9ce40a|Variant=1}}===
-====Course I (induction)====
-For patients <60 years old:
-*[[Cyclophosphamide (Cytoxan)]] 1200 mg/m<sup>2</sup> IV once on day 1
-*[[Daunorubicin (Cerubidine)]] 45 mg/m<sup>2</sup> IV once per day on days 1 to 3
-*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 1, 8, 15, 22
-*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 21
-*[[Asparaginase (Elspar)]] 6000 units/m<sup>2</sup> SC once per day on days 5, 8, 11, 15, 18, 22
-For patients ≥60 years old:
-*[[Cyclophosphamide (Cytoxan)]] 800 mg/m<sup>2</sup> IV once on day 1
-*[[Daunorubicin (Cerubidine)]] 30 mg/m<sup>2</sup> IV once per day on days 1 to 3
-*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 1, 8, 15, 22
-*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 7
-*[[Asparaginase (Elspar)]] 6000 units/m<sup>2</sup> SC once per day on days 5, 8, 11, 15, 18, 22
-''To be followed by [[#Larson.2FCALGB_8811_regimen_.28consolidation.29|Larson/CALGB 8811 regimen courses II to IV (consolidation & intensification)]].''
-===References===
-# Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR et al. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study 8811. Blood. 1995 Apr 15;85(8):2025-37. [http://bloodjournal.hematologylibrary.org/content/85/8/2025.full.pdf+html link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/7718875 PubMed]
-==Linker regimen {{#subobject:34c24b|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#toc|back to top]]
-|}
-===Regimen {{#subobject:9ce40a|Variant=1}}===
 {| border="1" style="text-align:center;" !align="left"
 |'''Study'''
@@ Line 412: / Line 396: @@
 |-
 |}
+====Chemotherapy, part 1====
-'''[[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)]].'''
-====Chemotherapy====
 *[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV once per day on days 1 to 3
+*[[Asparaginase (Elspar)]] 6000 units/m<sup>2</sup> IM once per day on days 17 to 28
 *[[Vincristine (Oncovin)]] 2 mg IV once per day on days 1, 8, 15, 22
 *[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 28
-*[[Asparaginase (Elspar)]] 6000 units/m<sup>2</sup> IM once per day on days 17 to 28
-If bone marrow on day 14 has residual leukemia:
+''If bone marrow on day 14 has residual leukemia:''
+====Chemotherapy, part 2====
 *[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV once on day 15
-If bone marrow on day 28 has residual leukemia:
+''If bone marrow on day 28 has residual leukemia:''
+====Chemotherapy, part 3====
 *[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV once per day on days 29 & 30
 *[[Vincristine (Oncovin)]] 2 mg IV once per day on days 29 & 36
@@ Line 429: / Line 413: @@
 *[[Asparaginase (Elspar)]] 6000 units/m<sup>2</sup> IM once per day on days 29 to 35
-Central nervous system (CNS) prophylaxis for patients without CNS involvement at diagnosis is started within 1 week of achieving complete remission:
+====CNS prophylaxis====
+*This is for patients without CNS involvement at diagnosis, and is started within 1 week of achieving complete remission:
 *Cranial radiation, 18 Gy total given in 10 fractions over 12 to 14 days
 *[[Methotrexate (MTX)]] 12 mg IT once per week x 6 doses concurrent with radiation
-Central nervous system (CNS) treatment for patients with CNS involvement at diagnosis:
+====CNS treatment====
+*This is for patients with CNS involvement at diagnosis:
 *Cranial radiation, 28 Gy total given
-*[[Methotrexate (MTX)]] 12 mg IT once per week x 10 doses that starts while they are receiving induction therapy, then given monthly during the first year of therapy
+*[[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
 ''To be followed by [[#Linker_regimen_.28consolidation.29|Linker regimen consolidation therapy]].''
@@ Line 442: / Line 428: @@
 # 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. [http://bloodjournal.hematologylibrary.org/content/69/4/1242.full.pdf+html link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/3470055 PubMed]
 ## '''Update:''' Linker CA, Levitt LJ, O'Donnell M, Forman SJ, Ries CA. Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report. Blood. 1991 Dec 1;78(11):2814-22. [http://bloodjournal.hematologylibrary.org/content/78/11/2814.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/1835410 PubMed]
+# 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 Group. Treatment of adult acute lymphoblastic leukemia (ALL): long-term follow-up of the GIMEMA ALL 0288 randomized study. Blood. 2002 Feb 1;99(3):863-71. [http://www.bloodjournal.org/content/99/3/863.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/11806988 PubMed]
+# Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. [http://bloodjournal.hematologylibrary.org/content/106/12/3760.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/16105981 PubMed]
+## '''Update:''' Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, Burnett AK, Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J, McMillan A, Franklin IM, Luger S, Ciobanu N, Rowe JM. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008 Feb 15;111(4):1827-33. Epub 2007 Nov 29. [http://bloodjournal.hematologylibrary.org/content/111/4/1827.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/18048644 PubMed]
+## '''Update:''' Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, Marks DI, McMillan AK, Litzow MR, Lazarus HM, Foroni L, Dewald G, Franklin IM, Luger SM, Paietta E, Wiernik PH, Tallman MS, Goldstone AH. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009 May 7;113(19):4489-96. Epub 2009 Feb 24. [http://bloodjournal.hematologylibrary.org/content/113/19/4489.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/19244158 PubMed]
+## '''Update:''' Fielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow MR, Lazarus H, Luger SM, Marks DI, McMillan AK, Moorman AV, Patel B, Paietta E, Tallman MS, Goldstone AH. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014 Feb 6;123(6):843-50. Epub 2013 Nov 25. [http://bloodjournal.hematologylibrary.org/content/123/6/843.full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/24277073 PubMed]
-==Pediatric-like GRAALL induction {{#subobject:eeded9|Regimen=1}}==
+==Hyper-CVAD/MA {{#subobject:8e1d75|Regimen=1}}==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#toc|back to top]]
 |}
-===Regimen {{#subobject:2aaaf3|Variant=1}}===
+Hyper-CVAD/MA: '''<u>Hyper</u>'''fractionated '''<u>C</u>'''yclophosphamide, '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>D</u>'''examethasone alternating with '''<u>M</u>'''ethotrexate, '''<u>A</u>'''ra-C (Cytarabine)
+===Regimen {{#subobject:70e9ec|Variant=1}}===
 {| border="1" style="text-align:center;" !align="left"
 |'''Study'''
 |[[Levels_of_Evidence#Evidence|'''Evidence''']]
-|'''Comparator'''
 |-
-|[http://jco.ascopubs.org/content/27/6/911.full Huguet et al. 2009 (GRAALL-2003)]
+|[http://jco.ascopubs.org/content/17/8/2461.long Thomas et al. 1999]
 |<span
 style="background:#EEEE00;
@@ Line 461: / Line 453: @@
 border-width:2px;
 border-style:solid;">Phase II</span>
-|
-|-
-|[https://ash.confex.com/ash/2015/webprogram/Paper82882.html Maury et al. 2015 (GRAALL-R 2005)]
-|<span
-style="background:#00CD00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase III</span>
-|[[#Pediatric-like_GRAALL_induction_with_rituximab|Pediatric-like GRAALL induction with rituximab]]
 |-
 |}
+====Part A (cycles 1, 3, 5, 7):====
-''Note: 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. Treatment preceded by [[#Prednisone_.28Sterapred.29|prednisone prephase]].''
+*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> IV over 2 hours Q12H on days 1 to 3 (6 total doses)
-====Chemotherapy====
+*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 4 & 11
-*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup>/day on days 1 to 14
+*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV over 24 hours (over 48 hours in patients with ejection fractions (EF) <50%) on day 4
-*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV once per day on days 1 to 3, then 30 mg/m<sup>2</sup> IV once per day on days 15 & 16
+*[[Dexamethasone (Decadron)]] 40 mg PO/IV once per day on days 1 to 4, 11 to 14
-*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 1, 8, 15, 22
-*[[Asparaginase (Elspar)]] 6000 units/m<sup>2</sup>/day (route not specified) on days 8, 10, 12, 20, 22, 24, 26, 28
-*[[Cyclophosphamide (Cytoxan)]] as follows:
-**750 mg/m<sup>2</sup> IV once per day on days 1 & 15 in "good early responders"
-**750 mg/m<sup>2</sup> IV once on day 1, then 500 mg/m<sup>2</sup> IV q12h on days 15 & 16 in "poor early responders"
 ====Supportive medications====
-*[[Lenograstim (Granocyte)]] 150 μg/m<sup>2</sup> SC once per day from day 17 until myeloid recovery
+*[[Mesna (Mesnex)]] 600 mg/m<sup>2</sup>/day IV continuous infusion on days 1 to 3, starting 1 hour before [[Cyclophosphamide (Cytoxan)]] and completed 12 hours after the last dose of [[Cyclophosphamide (Cytoxan)]]
+*One of the following antibiotics:
+**EITHER [[Ciprofloxacin (Cipro)]] 500 mg PO BID
+**OR [[Levofloxacin (Levaquin)]] 500 mg PO once per day
+**OR [[Trimethoprim/Sulfamethoxazole (Bactrim DS)]] (160/800 mg) PO BID
+*[[Fluconazole (Diflucan)]] 200 mg PO once per day
+*One of the following antivirals:
+**EITHER [[Acyclovir (Zovirax)]] 200 mg PO BID
+**OR [[Valacyclovir (Valtrex)]] 500 mg PO once per day
+*[[Filgrastim (Neupogen)]] 10 μg/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 >1 x 10<sup>9</sup>/L
-''Patients with resistant disease received [[#Pediatric-like_GRAALL_salvage|pediatric-like GRAALL salvage]] prior to further consolidation. All others proceeded to [[#Pediatric-like_GRAALL_consolidation|pediatric-like GRAALL consolidation]].''
+'''Next cycle to start as soon as absolute neutrophil count is > 1 x 10<sup>9</sup>/L at least 24 hours off of G-CSF and platelet count > 60 x 10<sup>9</sup>/L'''
-===References===
+====Part B (cycles 2, 4, 6, 8):====
-# 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. [http://jco.ascopubs.org/content/early/2015/12/07/JCO.2015.61.5385.long link to early article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19124805 PubMed]
+*[[Methotrexate (MTX)]] 200 mg/m<sup>2</sup> IV over 2 hours, then 800 mg/m<sup>2</sup> IV over 22 hours on day 1
+*[[Cytarabine (Cytosar)]] 3000 mg/m<sup>2</sup> IV over 2 hours Q12H on days 2 & 3 (4 total doses)
+**Dose-reduced to 1000 mg/m<sup>2</sup> for patients older than 60 years old
+*[[Methylprednisolone (Solumedrol)]] 50 mg IV Q12H on days 1 to 3 ''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 medications====
+*[[Folinic acid (Leucovorin)]] 50 mg IV once 12 hours after [[Methotrexate (MTX)]] is complete, then 15 mg IV Q6H x 8 doses until serum methotrexate level <0.1 µM
+*One of the following antibiotics:
+**EITHER [[Ciprofloxacin (Cipro)]] 500 mg PO BID
+**OR [[Levofloxacin (Levaquin)]] 500 mg PO once per day
+**OR [[Trimethoprim/Sulfamethoxazole (Bactrim DS)]] (160/800 mg) PO BID
+*[[Fluconazole (Diflucan)]] 200 mg PO once per day
+*One of the following antivirals:
+**EITHER [[Acyclovir (Zovirax)]] 200 mg PO BID
+**OR [[Valacyclovir (Valtrex)]] 500 mg PO once per day
+*[[Filgrastim (Neupogen)]] 10 μg/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 >1 x 10<sup>9</sup>/L
-==Pediatric-like GRAALL induction with rituximab {{#subobject:18fec2|Regimen=1}}==
+'''Next cycle to start as soon as absolute neutrophil count is > 1 x 10<sup>9</sup>/L at least 24 hours off of G-CSF and platelet count > 60 x 10<sup>9</sup>/L'''
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#toc|back to top]]
-|}
-===Regimen {{#subobject:aa59d3|Variant=1}}===
-{| border="1" style="text-align:center;" !align="left"
-|'''Study'''
-|[[Levels_of_Evidence#Evidence|'''Evidence''']]
-|'''Comparator'''
-|-
-|[https://ash.confex.com/ash/2015/webprogram/Paper82882.html Maury et al. 2015 (GRAALL-R 2005)]
-|<span
-style="background:#00CD00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase III</span>
-|[[#Pediatric-like_GRAALL_induction|Pediatric-like GRAALL induction]]
-|-
-|}
-''Note: this regimen was meant for CD20+ patients less than 60 years old. Details were scant in the abstract but a total of 16 to 18 [[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> infusions were given during the course of therapy. This will be fleshed out when the manuscript is published.''
+====CNS prophylaxis====
+*[[Methotrexate (MTX)]] 12 mg (6 mg if given via Ommaya reservoir) IT on day 2
+*[[Cytarabine (Cytosar)]] 100 mg IT on day 7 '''OR''' 8
-===References===
+'''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) >1400 IU/L and/or proliferative index percentage of S + G2M >=14%'''
-# '''Abstract:''' Maury et al. Addition of Rituximab Improves the Outcome of Adult Patients with CD20-Positive, Ph-Negative, B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL): Results of the Randomized Graall-R 2005 Study. ASH 2015 Annual Meeting Abstract 1.[https://ash.confex.com/ash/2015/webprogram/Paper82882.html link to abstract]
-==R-Hyper-CVAD/R-MA {{#subobject:7daccd|Regimen=1}}==
+====For known CNS disease====
-{| class="wikitable" style="float:right; margin-left: 5px;"
+*[[Methotrexate (MTX)]] 12 mg (6 mg if given via Ommaya reservoir) IT alternating with [[Cytarabine (Cytosar)]] 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 (Cytosar)]] 100 mg IT, given weeks 2 & 4
-|[[#toc|back to top]]
+*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
-R-Hyper-CVAD/R-MA: '''<u>R</u>'''ituximab, '''<u>Hyper</u>'''fractionated '''<u>C</u>'''yclophosphamide, '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>D</u>'''examethasone alternating with '''<u>R</u>'''ituximab, '''<u>M</u>'''ethotrexate, '''<u>A</u>'''ra-C (Cytarabine)
+**[[Cytarabine (Cytosar)]] 100 mg IT once on day 7 '''OR''' 8
+''Certain patient populations (see e.g. Kantarjian et al. 2004) proceed to receive [[Acute_lymphocytic_leukemia#POMP|POMP maintenance therapy]].''
+===References===
+# Cortes J, O'Brien SM, Pierce S, Keating MJ, Freireich EJ, Kantarjian HM. The value of high-dose systemic chemotherapy and intrathecal therapy for central nervous system prophylaxis in different risk groups of adult acute lymphoblastic leukemia. Blood. 1995 Sep 15;86(6):2091-7. [http://bloodjournal.hematologylibrary.org/content/86/6/2091.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/7662956 PubMed]
+# Thomas DA, Cortes J, O'Brien S, Pierce S, Faderl S, Albitar M, Hagemeister FB, Cabanillas FF, Murphy S, Keating MJ, Kantarjian H. Hyper-CVAD program in Burkitt's-type adult acute lymphoblastic leukemia. J Clin Oncol. 1999 Aug;17(8):2461-70. [http://jco.ascopubs.org/content/17/8/2461.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/10561310 PubMed]
+# Kantarjian HM, O'Brien S, Smith TL, Cortes J, Giles FJ, Beran M, Pierce S, Huh Y, Andreeff M, Koller C, Ha CS, Keating MJ, Murphy S, Freireich EJ. Results of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia. J Clin Oncol. 2000 Feb;18(3):547-61. [http://jco.ascopubs.org/content/18/3/547.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/10653870 PubMed]
+## '''Update:''' Kantarjian H, Thomas D, O'Brien S, Cortes J, Giles F, Jeha S, Bueso-Ramos CE, Pierce S, Shan J, Koller C, Beran M, Keating M, Freireich EJ. Long-term follow-up results of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD), a dose-intensive regimen, in adult acute lymphocytic leukemia. Cancer. 2004 Dec 15;101(12):2788-801. [http://onlinelibrary.wiley.com/doi/10.1002/cncr.20668/full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/15481055 PubMed]
+# Thomas DA, O'Brien S, Cortes J, Giles FJ, Faderl S, Verstovsek S, Ferrajoli A, Koller C, Beran M, Pierce S, Ha CS, Cabanillas F, Keating MJ, Kantarjian H. Outcome with the hyper-CVAD regimens in lymphoblastic lymphoma. Blood. 2004 Sep 15;104(6):1624-30. Epub 2004 Jun 3. [http://bloodjournal.hematologylibrary.org/content/104/6/1624.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/15178574 PubMed]
+==R-Hyper-CVAD/R-MA {{#subobject:7daccd|Regimen=1}}==
+{| class="wikitable" style="float:right; margin-left: 5px;"
+|-
+|[[#toc|back to top]]
+|}
+R-Hyper-CVAD/R-MA: '''<u>R</u>'''ituximab, '''<u>Hyper</u>'''fractionated '''<u>C</u>'''yclophosphamide, '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>D</u>'''examethasone alternating with '''<u>R</u>'''ituximab, '''<u>M</u>'''ethotrexate, '''<u>A</u>'''ra-C (Cytarabine)
 ===Regimen #1, modified hyper-CVAD {{#subobject:48fa59|Variant=1}}===
@@ Line 604: / Line 602: @@
 '''Given each cycle for a total of 16 intrathecal treatments.'''
-''If CNS disease present, therapy augmented to twice-weekly alternating (MTX, ara-C) treatments until CSF cell count normalizes and cytology is negative, then continues for 4 more alternating weekly treatments; prophylaxis course then resumes.''
+''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 modifications====
@@ Line 619: / Line 617: @@
 =Induction therapy, Ph-positive=
-==Hyper-CVAD & Dasatinib {{#subobject:7722d2|Regimen=1}}==
+==Daunorubicin, Vincristine, Prednisolone, Nilotinib {{#subobject:2b1389|Regimen=1}}==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#toc|back to top]]
 |}
-Hyper-CVAD: Hyperfractionated '''<u>C</u>'''yclophosphamide, '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>D</u>'''examethasone
+===Regimen {{#subobject:e721b6|Variant=1}}===
-===Regimen {{#subobject:b88b6e|Variant=1}}===
 {| border="1" style="text-align:center;" !align="left"
 |'''Study'''
 |[[Levels_of_Evidence#Evidence|'''Evidence''']]
 |-
-|[http://bloodjournal.hematologylibrary.org/content/116/12/2070.long Ravandi et al. 2010]
+|[http://www.bloodjournal.org/content/126/6/746.long Kim et al. 2015]
 |<span
 style="background:#EEEE00;
@@ Line 640: / Line 636: @@
 |-
 |}
+====Chemotherapy====
+*[[Daunorubicin (Cerubidine)]] 90 mg/m<sup>2</sup>/day IV continuous infusion on days 1 to 3 (total dose: 270 mg/m<sup>2</sup>)
+*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 1 & 8
+*[[Prednisolone (Millipred)]] 60 mg/m<sup>2</sup> PO or 48 mg/m<sup>2</sup> IV once per day on days 1 to 14
+*[[Nilotinib (Tasigna)]] 400 mg PO BID starting on day 8
-''Note: the dosing of dasatinib has changed three times for this protocol. The initial protocol was 50 mg PO BID, which was then changed to 100 mg PO once per day after these were shown to be equivalent in a separate trial. Starting with patient #43, the protocol was further amended to 100 mg of dasatinib once per day in the first 14 days of the first cycle only, followed by 70 mg once per day continuously from the second cycle through completion of induction. These details are described in the update referenced below.''
+====CNS Prophylaxis====
+*[[Methotrexate (MTX)]] 15 mg mixed with [[Hydrocortisone (Cortef)]] 50 mg IT
-====Part A (cycles 1, 3, 5, 7)====
+'''Up to 10 doses given during or after induction'''
-*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> IV over 2 hours Q12H on days 1 to 3 (6 total doses)
-*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 4 & 11
-*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV continuous infusion over 24 hours on day 4
-**Infusion given over 48 hours in patients with ejection fractions (EF) <50%
-*[[Dexamethasone (Decadron)]] 40 mg PO/IV once per day on days 1 to 4, 11 to 14
-*[[Dasatinib (Sprycel)]] as follows:
-**Cycle 1 days 1 to 14: 100 mg PO once per day
-**Remainder of course: 70 mg PO once per day
-Supportive care:
+''Treatment followed by [[Acute_lymphocytic_leukemia#Nilotinib-based_consolidation|nilotinib-based consolidation]] or allogeneic hematopoetic cell transplant. Transplant regimen left to the discretion of the investigator.''
-*[[Mesna (Mesnex)]] 600 mg/m<sup>2</sup>/day IV continuous infusion on days 1 to 3, starting 1 hour before [[Cyclophosphamide (Cytoxan)]] and completed 12 hours after the last dose of [[Cyclophosphamide (Cytoxan)]]
-*One of the following antibiotics:
-**EITHER [[Ciprofloxacin (Cipro)]] 500 mg PO BID
-**OR [[Levofloxacin (Levaquin)]] 500 mg PO once per day
-**OR [[Trimethoprim/Sulfamethoxazole (Bactrim DS)]] (160/800 mg) PO BID
-*[[Fluconazole (Diflucan)]] 200 mg PO once per day
-*One of the following antivirals:
-**EITHER [[Acyclovir (Zovirax)]] 200 mg PO BID
-**OR [[Valacyclovir (Valtrex)]] 500 mg PO once per day
-*[[Filgrastim (Neupogen)]] 10 μg/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 >1 x 10<sup>9</sup>/L
-*Cycle 1 also involved:
-**Hydration options included D5 water or 1/2 NS with 75 to 100 mEq sodium acetate per liter at 50 to 100 mL/H
-**[[Allopurinol (Zyloprim)]] to decrease likelihood of tumor lysis syndrome; [[Rasburicase (Elitek)]] could be used instead for patients with high white blood cell counts at initial presentation
-**Oral sodium bicarbonate (no dosage or frequency listed) on days 1 to 3
-'''Next cycle to start after count recovery. No definite criteria listed by the reference, but other [[#Hyper-CVAD_.28induction.29|Hyper-CVAD regimens]] used absolute neutrophil count > 1 x 10<sup>9</sup>/L at least 24 hours off of G-CSF and platelet count > 60 x 10<sup>9</sup>/L'''
+===References===
+# Kim DY, Joo YD, Lim SN, Kim SD, Lee JH, Lee JH, Kim DH, Kim K, Jung CW, Kim I, Yoon SS, Park S, Ahn JS, Yang DH, Lee JJ, Lee HS, Kim YS, Mun YC, Kim H, Park JH, Moon JH, Sohn SK, Lee SM, Lee WS, Kim KH, Won JH, Hyun MS, Park J, Lee JH, Shin HJ, Chung JS, Lee H, Eom HS, Lee GW, Cho YU, Jang S, Park CJ, Chi HS, Lee KH; Adult Acute Lymphoblastic Leukemia Working Party of the Korean Society of Hematology. Nilotinib combined with multiagent chemotherapy for newly diagnosed Philadelphia-positive acute lymphoblastic leukemia. Blood. 2015 Aug 6;126(6):746-56. Epub 2015 Jun 11. [http://www.bloodjournal.org/content/126/6/746.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/26065651 PubMed]
-====Part B (cycles 2, 4, 6, 8)====
+==Hyper-CVAD & Dasatinib {{#subobject:7722d2|Regimen=1}}==
-*[[Methotrexate (MTX)]] 1000 mg/m<sup>2</sup> IV continuous infusion over 24 hours on day 1
+{| class="wikitable" style="float:right; margin-left: 5px;"
-*[[Cytarabine (Cytosar)]] 3000 mg/m<sup>2</sup> (1000 mg/m<sup>2</sup> for patients at least 60 years old) IV over 2 hours Q12H on days 2 & 3 (4 total doses)
+|-
-*[[Dasatinib (Sprycel)]] 70 mg PO once per day
+|[[#toc|back to top]]
+|}
+Hyper-CVAD: Hyperfractionated '''<u>C</u>'''yclophosphamide, '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>D</u>'''examethasone
-====Supportive medications====
+===Regimen {{#subobject:b88b6e|Variant=1}}===
-*[[Folinic acid (Leucovorin)]] 50 mg IV x1 12 hours after [[Methotrexate (MTX)]] is complete, then 15 mg IV Q6H x 8 doses until serum methotrexate level <0.1 µM
+{| border="1" style="text-align:center;" !align="left"
-**Leucovorin rescue with [[Folinic acid (Leucovorin)]] 50 mg IV Q6H if serum methotrexate levels were greater than 20 uM at 0 hours after completion of [[Methotrexate (MTX)]]; >1 uM at 24 hours; >0.1 uM at 48 hours
+|'''Study'''
-*One of the following antibiotics:
+|[[Levels_of_Evidence#Evidence|'''Evidence''']]
-**EITHER [[Ciprofloxacin (Cipro)]] 500 mg PO BID
+|-
-**OR [[Levofloxacin (Levaquin)]] 500 mg PO once per day
+|[http://bloodjournal.hematologylibrary.org/content/116/12/2070.long Ravandi et al. 2010]
-**OR [[Trimethoprim/Sulfamethoxazole (Bactrim DS)]] (160/800 mg) PO BID
+|<span
-*[[Fluconazole (Diflucan)]] 200 mg PO once per day
+style="background:#EEEE00;
+padding:3px 6px 3px 6px;
+border-color:black;
+border-width:2px;
+border-style:solid;">Phase II</span>
+|-
+|}
+''Note: the dosing of dasatinib has changed three times for this protocol. The initial protocol was 50 mg PO BID, which was then changed to 100 mg PO once per day after these were shown to be equivalent in a separate trial. Starting with patient #43, the protocol was further amended to 100 mg of dasatinib once per day in the first 14 days of the first cycle only, followed by 70 mg once per day continuously from the second cycle through completion of induction. These details are described in the update referenced below.''
+====Part A (cycles 1, 3, 5, 7)====
+*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> IV over 2 hours Q12H on days 1 to 3 (6 total doses)
+*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 4 & 11
+*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV continuous infusion over 24 hours on day 4
+**Infusion given over 48 hours in patients with ejection fractions (EF) <50%
+*[[Dexamethasone (Decadron)]] 40 mg PO/IV once per day on days 1 to 4, 11 to 14
+*[[Dasatinib (Sprycel)]] as follows:
+**Cycle 1 days 1 to 14: 100 mg PO once per day
+**Remainder of course: 70 mg PO once per day
+====Supportive medications====
+*[[Mesna (Mesnex)]] 600 mg/m<sup>2</sup>/day IV continuous infusion on days 1 to 3, starting 1 hour before [[Cyclophosphamide (Cytoxan)]] and completed 12 hours after the last dose of [[Cyclophosphamide (Cytoxan)]]
+*One of the following antibiotics:
+**EITHER [[Ciprofloxacin (Cipro)]] 500 mg PO BID
+**OR [[Levofloxacin (Levaquin)]] 500 mg PO once per day
+**OR [[Trimethoprim/Sulfamethoxazole (Bactrim DS)]] (160/800 mg) PO BID
+*[[Fluconazole (Diflucan)]] 200 mg PO once per day
 *One of the following antivirals:
 **EITHER [[Acyclovir (Zovirax)]] 200 mg PO BID
 **OR [[Valacyclovir (Valtrex)]] 500 mg PO once per day
-*D5W or 1/2 NS with 75 to 100 mEq sodium acetate per liter at 100 to 125 mL/H
+*[[Filgrastim (Neupogen)]] 10 μg/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 >1 x 10<sup>9</sup>/L
+*Cycle 1 also involved:
+**Hydration options included D5 water or 1/2 NS with 75 to 100 mEq sodium acetate per liter at 50 to 100 mL/H
+**[[Allopurinol (Zyloprim)]] to decrease likelihood of tumor lysis syndrome; [[Rasburicase (Elitek)]] could be used instead for patients with high white blood cell counts at initial presentation
+**Oral sodium bicarbonate (no dosage or frequency listed) on days 1 to 3
+'''Next cycle to start after count recovery. No definite criteria listed by the reference, but other [[#Hyper-CVAD_.28induction.29|Hyper-CVAD regimens]] used absolute neutrophil count > 1 x 10<sup>9</sup>/L at least 24 hours off of G-CSF and platelet count > 60 x 10<sup>9</sup>/L'''
+====Part B (cycles 2, 4, 6, 8)====
+*[[Methotrexate (MTX)]] 1000 mg/m<sup>2</sup> IV continuous infusion over 24 hours on day 1
+*[[Cytarabine (Cytosar)]] 3000 mg/m<sup>2</sup> (1000 mg/m<sup>2</sup> for patients at least 60 years old) IV over 2 hours Q12H on days 2 & 3 (4 total doses)
+*[[Dasatinib (Sprycel)]] 70 mg PO once per day
+====Supportive medications====
+*[[Folinic acid (Leucovorin)]] 50 mg IV x1 12 hours after [[Methotrexate (MTX)]] is complete, then 15 mg IV Q6H x 8 doses until serum methotrexate level <0.1 µM
+**Leucovorin rescue with [[Folinic acid (Leucovorin)]] 50 mg IV Q6H if serum methotrexate levels were greater than 20 uM at 0 hours after completion of [[Methotrexate (MTX)]]; >1 uM at 24 hours; >0.1 uM at 48 hours
+*One of the following antibiotics:
+**EITHER [[Ciprofloxacin (Cipro)]] 500 mg PO BID
+**OR [[Levofloxacin (Levaquin)]] 500 mg PO once per day
+**OR [[Trimethoprim/Sulfamethoxazole (Bactrim DS)]] (160/800 mg) PO BID
+*[[Fluconazole (Diflucan)]] 200 mg PO once per day
+*One of the following antivirals:
+**EITHER [[Acyclovir (Zovirax)]] 200 mg PO BID
+**OR [[Valacyclovir (Valtrex)]] 500 mg PO once per day
+*D5W or 1/2 NS with 75 to 100 mEq sodium acetate per liter at 100 to 125 mL/H
 *[[Filgrastim (Neupogen)]] 10 μg/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 >1 x 10<sup>9</sup>/L
 *[[Acetazolamide (Diamox)]] (no dosage/schedule listed) used if urine pH <7 to promote excretion
@@ Line 833: / Line 866: @@
 # Jabbour E, Kantarjian H, Ravandi F, Thomas D, Huang X, Faderl S, Pemmaraju N, Daver N, Garcia-Manero G, Sasaki K, Cortes J, Garris R, Yin CC, Khoury JD, Jorgensen J, Estrov Z, Bohannan Z, Konopleva M, Kadia T, Jain N, DiNardo C, Wierda W, Jeanis V, O'Brien S. Combination of hyper-CVAD with ponatinib as first-line therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia: a single-centre, phase 2 study. Lancet Oncol. 2015 Nov;16(15):1547-55. Epub 2015 Sep 30. [http://www.sciencedirect.com/science/article/pii/S1470204515002077 link to SD article] [http://www.ncbi.nlm.nih.gov/pubmed/26432046 PubMed]
-==International ALL Trial (MRC UKALL XII/ECOG E2993) {{#subobject:bad8be|Regimen=1}}==
+=Early intensification therapy=
+==Larson regimen (CALGB 8811) {{#subobject:225653|Regimen=1}}==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#toc|back to top]]
 |}
+'''[[Asparaginase (Elspar)]] was discontinued by the manufacturer in December 2012, and is now essentially out of stock. Alternatives include [[Pegaspargase (Oncaspar)]] or [[Asparaginase Erwinia chrysanthemi (Erwinaze)]].'''
-===Regimen {{#subobject:d669b0|Variant=1}}===
+===Regimen {{#subobject:b3e19a|Variant=1}}===
 {| border="1" style="text-align:center;" !align="left"
 |'''Study'''
 |[[Levels_of_Evidence#Evidence|'''Evidence''']]
 |-
-|[http://bloodjournal.hematologylibrary.org/content/106/12/3760.long Rowe et al. (MRC UKALL XII/ECOG E2993)]
+|[http://bloodjournal.hematologylibrary.org/content/85/8/2025.full Larson et al. 1995 (CALGB 8811)]
 |<span
 style="background:#EEEE00;
@@ Line 853: / Line 887: @@
 |-
 |}
+''Treatment preceded by [[#Cyclophosphamide.2C_Daunorubicin.2C_L-Asparaginase.2C_Vincristine.2C_Prednisone|cyclophosphamide, daunorubicin, L-asparaginase, vincristine, prednisone induction ("Course I")]].''
+====Chemotherapy ("Course II")====
+*[[Methotrexate (MTX)]] 15 mg IT once on day 1
+*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV once on day 1
+*[[Mercaptopurine (Purinethol)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 14
+*[[Cytarabine (Cytosar)]] 75 mg/m<sup>2</sup> 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/m<sup>2</sup> SC once per day on days 15, 18, 22, 25
-''To our knowledge, this is the largest induction trial in adult ALL, N=1,646. CR rate was 90%. There are many local variants of this protocol.''
+'''28-day cycle for 2 cycles'''
-'''[[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)]].'''
+''Treatment followed by [[Larson regime (CALGB 8811) interim maintenance ("Course III")]].''
-====Phase I, weeks 1 to 4====
+===References===
-*[[Daunorubicin (Cerubidine)]] 65 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
+# Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR et al. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study 8811. Blood. 1995 Apr 15;85(8):2025-37. [http://bloodjournal.hematologylibrary.org/content/85/8/2025.full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/7718875 PubMed]
-*[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
-*[[Asparaginase (Elspar)]] 10,000 units IV or IM once per day on days 17 to 28
-*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 28
-====CNS prophylaxis====
+==L-Asparaginase & Methotrexate {{#subobject:0c63ca|Regimen=1}}==
-*[[Methotrexate (MTX)]] 12 mg IT once on day 15
+{| class="wikitable" style="float:right; margin-left: 5px;"
+|-
-====Phase II, weeks 5 to 8====
+|[[#toc|back to top]]
-*[[Cyclophosphamide (Cytoxan)]] 650 mg/m<sup>2</sup> IV once per day on days 1, 15, 29
+|}
-*[[Cytarabine (Cytosar)]] 75 mg/m<sup>2</sup> IV once per day on days 1 to 4, 8 to 11, 15 to 18, 22 to 25
+'''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)]].'''
-*[[Mercaptopurine (Purinethol)]] 6 mg/m<sup>2</sup> PO once per day on days 1 to 28
+===Regimen {{#subobject:51817e|Variant=1}}===
+{| border="1" style="text-align:center;" !align="left"
-====CNS prophylaxis====
+|'''Study'''
-*[[Methotrexate (MTX)]] 12 mg IT once per day on days 1, 8, 15, 22
+|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+|-
+|[http://bloodjournal.hematologylibrary.org/content/106/12/3760.long Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)]
+|<span
+style="background:#EEEE00;
+padding:3px 6px 3px 6px;
+border-color:black;
+border-width:2px;
+border-style:solid;">Non-randomized portion of RCT</span>
+|-
+|}
+''Treatment preceded by "Phase 2" induction: [[cyclophosphamide, cytarabine, mercaptopurine]].''
+====Chemotherapy====
+*[[Methotrexate (MTX)]] 3 g/m<sup>2</sup> 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 medications====
+*[[Folinic acid (Leucovorin)]] at "standard" doses
-====Ph+ patients====
+'''3 cycles (length of cycle not specified in original reference)'''
-''Two variants have been tested: from 2003 to 2005, imatinib was added after induction; from 2005 onward, imatinib was added during induction. Various durations are proposed, see Fielding et al. 2013 for more details.''
-*[[Imatinib (Gleevec)]] 400 mg PO once per day, increased to 600 mg PO once per day "wherever possible"
-''Treatment followed by [[Acute_lymphocytic_leukemia#International_ALL_Trial_.28MRC_UKALL_XII.2FECOG_E2993.29_3|consolidation portion of the protocol]].''
+''Patients who were younger than 50 years of age and had an HLA-matched sibling donor, as well as Ph+ patients with any donor, proceeded to [[Transplant_conditioning_regimens#Etoposide_.26_TBI_2|etoposide & TBI -> alloHCT]]. All others were randomized to [[Transplant_conditioning_regimens#Etoposide_.26_TBI|etoposide & TBI -> autoHCT]] versus [[#International_ALL_Trial_.28MRC_UKALL_XII.2FECOG_E2993.29_3|International ALL Trial consolidation]].''
 ===References===
@@ Line 887: / Line 941: @@
 ## '''Update:''' Fielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow MR, Lazarus H, Luger SM, Marks DI, McMillan AK, Moorman AV, Patel B, Paietta E, Tallman MS, Goldstone AH. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014 Feb 6;123(6):843-50. Epub 2013 Nov 25. [http://bloodjournal.hematologylibrary.org/content/123/6/843.full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/24277073 PubMed]
-==Nilotinib-based induction {{#subobject:2b1389|Regimen=1}}==
+=Consolidation therapy=
+==International ALL Trial (MRC UKALL XII/ECOG E2993) {{#subobject:a1cf91|Regimen=1}}==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#toc|back to top]]
 |}
+===Regimen {{#subobject:1d1710|Variant=1}}===
-===Regimen {{#subobject:e721b6|Variant=1}}===
 {| border="1" style="text-align:center;" !align="left"
 |'''Study'''
 |[[Levels_of_Evidence#Evidence|'''Evidence''']]
+|'''Comparator'''
 |-
-|[http://www.bloodjournal.org/content/126/6/746.long Kim et al. 2015]
+|[http://bloodjournal.hematologylibrary.org/content/106/12/3760.long Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)]
 |<span
-style="background:#EEEE00;
+style="background:#00cd00;
 padding:3px 6px 3px 6px;
 border-color:black;
 border-width:2px;
-border-style:solid;">Phase II</span>
+border-style:solid;">Phase III</span>
+|[[Transplant_conditioning_regimens#Etoposide_.26_TBI|Etoposide & TBI -> autoHCT]]
 |-
 |}
-====Chemotherapy====
+''Treatment preceded by [[L-asparaginase & methotrexate intensification]].''
-*[[Daunorubicin (Cerubidine)]] 90 mg/m<sup>2</sup>/day IV continuous infusion on days 1 to 3 (total dose: 270 mg/m<sup>2</sup>)
+=====Cycle 1=====
-*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 1 & 8
+*[[Cytarabine (Cytosar)]] 75 mg/m<sup>2</sup> IV once per day on days 1 to 5
-*[[Prednisolone (Millipred)]] 60 mg/m<sup>2</sup> PO or 48 mg/m<sup>2</sup> IV once per day on days 1 to 14
+*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5
-*[[Nilotinib (Tasigna)]] 400 mg PO BID starting on day 8
+*[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
+*[[Dexamethasone (Decadron)]] 10 mg/m<sup>2</sup> PO once per day on days 1 to 28
-====CNS Prophylaxis====
+=====Cycle 2=====
-*[[Methotrexate (MTX)]] 15 mg mixed with [[Hydrocortisone (Cortef)]] 50 mg IT
+''To start 4 weeks after Cycle 1''
+*[[Cytarabine (Cytosar)]] 75 mg/m<sup>2</sup> IV once per day on days 1 to 5
+*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5
-'''Up to 10 doses given during or after induction'''
+=====Cycle 3=====
+''To start 4 weeks after Cycle 2''
+*[[Daunorubicin (Cerubidine)]] 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
+*[[Cyclophosphamide (Cytoxan)]] 650 mg/m<sup>2</sup> IV once on day 29
+*[[Cytarabine (Cytosar)]] 75 mg/m<sup>2</sup> IV once per day on days 31 to 34, 38 to 41
+*[[Thioguanine (Tabloid)]] 60 mg/m<sup>2</sup> PO once per day on days 29 to 42
-''Treatment followed by [[Acute_lymphocytic_leukemia#Nilotinib-based_consolidation|nilotinib-based consolidation]] or allogeneic hematopoetic cell transplant. Transplant regimen left to the discretion of the investigator.''
+=====Cycle 4=====
+''To start 8 weeks after Cycle 3''
+*[[Cytarabine (Cytosar)]] 75 mg/m<sup>2</sup> IV once per day on days 1 to 5
+*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5
+====CNS Prophylaxis====
+*[[Cytarabine (Cytosar)]] 50 mg IT once per week for 4 weeks, then once per quarter for 4 doses (8 doses, total)
+*Cranial irradiation to 2400 cGy
+''Treatment followed by [[#POMP|POMP maintenance]].''
 ===References===
-# Kim DY, Joo YD, Lim SN, Kim SD, Lee JH, Lee JH, Kim DH, Kim K, Jung CW, Kim I, Yoon SS, Park S, Ahn JS, Yang DH, Lee JJ, Lee HS, Kim YS, Mun YC, Kim H, Park JH, Moon JH, Sohn SK, Lee SM, Lee WS, Kim KH, Won JH, Hyun MS, Park J, Lee JH, Shin HJ, Chung JS, Lee H, Eom HS, Lee GW, Cho YU, Jang S, Park CJ, Chi HS, Lee KH; Adult Acute Lymphoblastic Leukemia Working Party of the Korean Society of Hematology. Nilotinib combined with multiagent chemotherapy for newly diagnosed Philadelphia-positive acute lymphoblastic leukemia. Blood. 2015 Aug 6;126(6):746-56. Epub 2015 Jun 11. [http://www.bloodjournal.org/content/126/6/746.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/26065651 PubMed]
+# Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. [http://bloodjournal.hematologylibrary.org/content/106/12/3760.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/16105981 PubMed]
+## '''Update:''' Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, Burnett AK, Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J, McMillan A, Franklin IM, Luger S, Ciobanu N, Rowe JM. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008 Feb 15;111(4):1827-33. Epub 2007 Nov 29. [http://bloodjournal.hematologylibrary.org/content/111/4/1827.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/18048644 PubMed]
+## '''Update:''' Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, Marks DI, McMillan AK, Litzow MR, Lazarus HM, Foroni L, Dewald G, Franklin IM, Luger SM, Paietta E, Wiernik PH, Tallman MS, Goldstone AH. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009 May 7;113(19):4489-96. Epub 2009 Feb 24. [http://bloodjournal.hematologylibrary.org/content/113/19/4489.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/19244158 PubMed]
+## '''Update:''' Fielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow MR, Lazarus H, Luger SM, Marks DI, McMillan AK, Moorman AV, Patel B, Paietta E, Tallman MS, Goldstone AH. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014 Feb 6;123(6):843-50. Epub 2013 Nov 25. [http://bloodjournal.hematologylibrary.org/content/123/6/843.full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/24277073 PubMed]
-=Consolidation therapy=
+==Mercaptopurine, Methotrexate, WB-XRT {{#subobject:64a822|Regimen=1}}==
-==International ALL Trial (MRC UKALL XII/ECOG E2993) {{#subobject:a1cf91|Regimen=1}}==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#toc|back to top]]
 |}
+===Regimen {{#subobject:4011bd|Variant=1}}===
-===Regimen {{#subobject:1d1710|Variant=1}}===
 {| border="1" style="text-align:center;" !align="left"
 |'''Study'''
 |[[Levels_of_Evidence#Evidence|'''Evidence''']]
 |-
-|[http://bloodjournal.hematologylibrary.org/content/106/12/3760.long Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)]
+|[http://bloodjournal.hematologylibrary.org/content/85/8/2025.full Larson et al. 1995 (CALGB 8811)]
 |<span
 style="background:#EEEE00;
@@ Line 944: / Line 1,018: @@
 |-
 |}
+''Treatment preceded by [[Larson regimen (CALGB 8811) early intensification ("Course II")]].''
+====Chemoradiotherapy ("Course III")====
+*[[Methotrexate (MTX)]] 15 mg IT once per day on days 1, 8, 15, 22, 29
+*[[Mercaptopurine (Purinethol)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 70
+*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> PO once per day on days 36, 43, 50, 57, 64
+*Cranial radiation, 24 Gy total given in 10 fractions from days 1 to 12
-'''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)]].'''
+'''12-week course'''
-''Treatment preceded by induction portion of the protocol ([[Acute_lymphocytic_leukemia#International_ALL_Trial_.28MRC_UKALL_XII.2FECOG_E2993.29|Ph-]] or [[Acute_lymphocytic_leukemia#International_ALL_Trial_.28MRC_UKALL_XII.2FECOG_E2993.29_2|Ph+]]).''
+''Treatment followed by [[Larson regimen (CALGB 8811) late intensification ("Course IV")]].''
-====Phase III, "Intensification"====
+===References===
-*[[Methotrexate (MTX)]] 3 g/m<sup>2</sup> IV once per day on days 1, 8, 22
+# Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR et al. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study 8811. Blood. 1995 Apr 15;85(8):2025-37. [http://bloodjournal.hematologylibrary.org/content/85/8/2025.full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/7718875 PubMed]
-*[[Asparaginase (Elspar)]] 10,000 units (route not specified) once per day on days 2, 9, 23
-====Supportive medications====
+==Linker regimen (consolidation) {{#subobject:3a5313|Regimen=1}}==
-*[[Folinic acid (Leucovorin)]] at "standard" doses
+{| class="wikitable" style="float:right; margin-left: 5px;"
+|-
+|[[#toc|back to top]]
+|}
+'''[[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)]].'''
-'''3 cycles (length of cycle not specified in original reference)'''
+===Regimen {{#subobject:33e7c0|Variant=1}}===
+{| border="1" style="text-align:center;" !align="left"
-''For patients randomized to transplantation (autologous or allogeneic), no further therapy was specified, except that Ph+ patients were given interferon for another 15 months.''
+|'''Study'''
+|[[Levels_of_Evidence#Evidence|'''Evidence''']]
-====Phase IV, "Consolidation"====
+|-
+|[http://bloodjournal.hematologylibrary.org/content/69/4/1242.full.pdf+html Linker et al. 1987]
-=====Cycle 1=====
+|<span
-*[[Cytarabine (Cytosar)]] 75 mg/m<sup>2</sup> IV once per day on days 1 to 5
+style="background:#EEEE00;
-*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5
+padding:3px 6px 3px 6px;
-*[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
+border-color:black;
-*[[Dexamethasone (Decadron)]] 10 mg/m<sup>2</sup> PO once per day on days 1 to 28
+border-width:2px;
+border-style:solid;">Phase II</span>
+|-
+|}
+''Treatment preceded by [[daunorubicin, L-asparaginase, vincristine, prednisone induction]]. Each cycle is approximately one month, based on recovery of ANC to >1000 and platelet count to >100,000.''
+====Treatment A (cycles 1, 3, 5, 7)====
+*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV once per day on days 1 & 2
+*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 1 & 8
+*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 14
+*[[Asparaginase (Elspar)]] 12000 units/m<sup>2</sup> IM once per day on days 2, 4, 7, 9, 11, 14
-=====Cycle 2=====
+'''Approximately one-month cycle'''
-''To start 4 weeks after Cycle 1''
-*[[Cytarabine (Cytosar)]] 75 mg/m<sup>2</sup> IV once per day on days 1 to 5
-*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5
-=====Cycle 3=====
+====Treatment B (cycles 2, 4, 6, 8)====
-''To start 4 weeks after Cycle 2''
+*[[Teniposide (Vumon)]] 165 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
-*[[Daunorubicin (Cerubidine)]] 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
+*[[Cytarabine (Cytosar)]] 300 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
-*[[Cyclophosphamide (Cytoxan)]] 650 mg/m<sup>2</sup> IV once on day 29
-*[[Cytarabine (Cytosar)]] 75 mg/m<sup>2</sup> IV once per day on days 31 to 34, 38 to 41
-*[[Thioguanine (Tabloid)]] 60 mg/m<sup>2</sup> PO once per day on days 29 to 42
-=====Cycle 4=====
+'''Approximately one-month cycle'''
-''To start 8 weeks after Cycle 3''
-*[[Cytarabine (Cytosar)]] 75 mg/m<sup>2</sup> IV once per day on days 1 to 5
-*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5
-'''CNS Prophylaxis'''
+====Treatment C (cycle 9)====
-*[[Cytarabine (Cytosar)]] 50 mg IT weekly x 4 weeks, then quarterly x 4 doses (8 doses, total)
+*[[Methotrexate (MTX)]] 690 mg/m<sup>2</sup> IV over 42 hours on day 1
-*Cranial irradiation to 2400 cGy
+*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 14
+*[[Asparaginase (Elspar)]] 12000 units/m<sup>2</sup> IM once per day on days 2, 4, 7, 9, 11, 14
+'''Approximately one-month cycle'''
+====Supportive medications====
+*[[Folinic acid (Leucovorin)]] 15 mg/m<sup>2</sup> IV every 6 hours x 12 doses, starting after [[Methotrexate (MTX)]] is complete (at 42 hours)
-''To be followed by [[#POMP|POMP maintenance]].''
+''Treatment followed by [[mercaptopurine & methotrexate maintenance]].''
 ===References===
-# Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. [http://bloodjournal.hematologylibrary.org/content/106/12/3760.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/16105981 PubMed]
+# Linker CA, Levitt LJ, O'Donnell M, Ries CA, Link MP, Forman SJ, Farbstein MJ. Improved results of treatment of adult acute lymphoblastic leukemia. Blood. 1987 Apr;69(4):1242-8. [http://bloodjournal.hematologylibrary.org/content/69/4/1242.full.pdf+html link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/3470055 PubMed] content property of [http://hemonc.org HemOnc.org]
+## '''Update:''' Linker CA, Levitt LJ, O'Donnell M, Forman SJ, Ries CA. Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report. Blood. 1991 Dec 1;78(11):2814-22. [http://bloodjournal.hematologylibrary.org/content/78/11/2814.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/1835410 PubMed]
-==Larson/CALGB 8811 regimen (consolidation) {{#subobject:64a822|Regimen=1}}==
+==Nilotinib-based consolidation {{#subobject:2b1576|Regimen=1}}==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
@@ Line 1,000: / Line 1,090: @@
 |}
-===Regimen {{#subobject:4011bd|Variant=1}}===
+===Regimen {{#subobject:e153b6|Variant=1}}===
 {| border="1" style="text-align:center;" !align="left"
 |'''Study'''
 |[[Levels_of_Evidence#Evidence|'''Evidence''']]
 |-
-|[http://bloodjournal.hematologylibrary.org/content/85/8/2025.full Larson et al. 1995 (CALGB 8811)]
+|[http://www.bloodjournal.org/content/126/6/746.long Kim et al. 2015]
 |<span
 style="background:#EEEE00;
@@ Line 1,015: / Line 1,105: @@
 |}
-''Treatment preceded by [[#Larson.2FCALGB_8811_regimen_.28induction.29|Larson/CALGB 8811 regimen course I (induction)]].''
+''Treatment preceded by [[daunorubicin, vincristine, prednisolone, nilotinib induction]]. Duration of each cycle of consolidation is not specified but is presumably based on toxicities and count recovery. Nilotinib is taken continuously during consolidation.''
-'''[[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)]].'''
+====Consolidation A (Cycle 1)====
+*[[Daunorubicin (Cerubidine)]] 45 mg/m<sup>2</sup>/day IV continuous infusion on days 1 & 2 (total dose 90 mg/m<sup>2</sup>)
+*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 1 & 8
+*[[Prednisolone (Millipred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 14
+*[[Nilotinib (Tasigna)]] 400 mg PO BID
-====Course II (early intensification)====
+====Consolidation B (Cycles 2 & 4)====
-*[[Methotrexate (MTX)]] 15 mg IT once on day 1
+*[[Cytarabine (Cytosar)]] 2000 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 to 4
-*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV once on day 1
+*[[Etoposide (Vepesid)]] 150 mg/m<sup>2</sup> IV over 3 hours once per day on days 1 to 4
-*[[Mercaptopurine (Purinethol)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 14
+*[[Nilotinib (Tasigna)]] 400 mg PO BID
-*[[Cytarabine (Cytosar)]] 75 mg/m<sup>2</sup> 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/m<sup>2</sup> SC once per day on days 15, 18, 22, 25
-'''28-day cycle for 2 cycles'''
+====Consolidation C (Cycles 3 & 5)====
+*[[Methotrexate (MTX)]] 220 mg/m<sup>2</sup> IV bolus, then 60 mg/m<sup>2</sup>/hr IV continuous infusion for 36 hours twice per cycle (days 1 & 2, 15 & 16)
+*[[Nilotinib (Tasigna)]] 400 mg PO BID
-====Course III (CNS prophylaxis and interim maintenance)====
+====Supportive medications====
-*Cranial radiation, 24 Gy total given in 10 fractions from days 1 to 12
+*[[Folinic acid (Leucovorin)]] 50 mg/m<sup>2</sup> IV every 6 hours x 3 doses, then PO (dose not specified) until serum methotrexate level <0.05
-*[[Methotrexate (MTX)]] 15 mg IT once per day on days 1, 8, 15, 22, 29
-*[[Mercaptopurine (Purinethol)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 70
-*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> PO once per day on days 36, 43, 50, 57, 64
-'''12-week course'''
-====Course IV (late intensification)====
-*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
-*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 1, 8, 15
-*[[Dexamethasone (Decadron)]] 10 mg/m<sup>2</sup> PO once per day on days 1 to 14
-*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV once on day 29
-*[[Thioguanine (Tabloid)]] 60 mg/m<sup>2</sup> PO once per day on days 29 to 42
-*[[Cytarabine (Cytosar)]] 75 mg/m<sup>2</sup> SC once per day on days 29 to 32, 36 to 39
-'''8-week course'''
-''To be followed by [[#Larson.2FCALGB_8811_regimen_.28maintenance.29|Larson/CALGB 8811 regimen course V (maintenance)]].''
+''Treatment followed by [[#Nilotinib_.28Tasigna.29|nilotinib maintenance]].''
 ===References===
-# Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR et al. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study 8811. Blood. 1995 Apr 15;85(8):2025-37. [http://bloodjournal.hematologylibrary.org/content/85/8/2025.full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/7718875 PubMed]
+# Kim DY, Joo YD, Lim SN, Kim SD, Lee JH, Lee JH, Kim DH, Kim K, Jung CW, Kim I, Yoon SS, Park S, Ahn JS, Yang DH, Lee JJ, Lee HS, Kim YS, Mun YC, Kim H, Park JH, Moon JH, Sohn SK, Lee SM, Lee WS, Kim KH, Won JH, Hyun MS, Park J, Lee JH, Shin HJ, Chung JS, Lee H, Eom HS, Lee GW, Cho YU, Jang S, Park CJ, Chi HS, Lee KH; Adult Acute Lymphoblastic Leukemia Working Party of the Korean Society of Hematology. Nilotinib combined with multiagent chemotherapy for newly diagnosed Philadelphia-positive acute lymphoblastic leukemia. Blood. 2015 Aug 6;126(6):746-56. Epub 2015 Jun 11. [http://www.bloodjournal.org/content/126/6/746.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/26065651 PubMed]
-==Linker regimen (consolidation) {{#subobject:3a5313|Regimen=1}}==
+==Pediatric-like GRAALL consolidation {{#subobject:32d4f7|Regimen=1}}==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#toc|back to top]]
 |}
+===Regimen {{#subobject:5fe62b|Variant=1}}===
-===Regimen {{#subobject:33e7c0|Variant=1}}===
 {| border="1" style="text-align:center;" !align="left"
 |'''Study'''
 |[[Levels_of_Evidence#Evidence|'''Evidence''']]
 |-
-|[http://bloodjournal.hematologylibrary.org/content/69/4/1242.full.pdf+html Linker et al. 1987]
+|[http://jco.ascopubs.org/content/27/6/911.full Huguet et al. 2009 (GRAALL-2003)]
 |<span
 style="background:#EEEE00;
@@ Line 1,072: / Line 1,149: @@
 |-
 |}
-''Treatment preceded by [[#Linker_regimen|Linker regimen induction therapy]].''
+''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. Treatment preceded by [[#Cyclophosphamide.2C_Daunorubicin.2C_L-Asparaginase.2C_Vincristine.2C_Prednisone|cyclophosphamide, daunorubicin, L-asparaginase, vincristine, prednisone induction]] or [[#Cytarabine_.26_Idarubicin|cytarabine & idarubicin salvage]].''
-'''[[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)]].'''
+====Consolidation A (Cycles 1, 4, 7)====
+*[[Cytarabine (Cytosar)]] 2000 mg/m<sup>2</sup> IV q12h on days 1 & 2
+*[[Dexamethasone (Decadron)]] 10 mg (route not specified) q12h on days 1 & 2
+*[[Asparaginase (Elspar)]] 10,000 units/m<sup>2</sup> (route not specified) once on day 3
-====Treatment A (cycles 1, 3, 5, 7)====
+====Supportive medications====
-*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV once per day on days 1 & 2
+*[[Lenograstim (Granocyte)]] 150 μg/m<sup>2</sup> SC once per day on days 7 to 13
-*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 1 & 8
-*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 14
-*[[Asparaginase (Elspar)]] 12000 units/m<sup>2</sup> IM once per day on days 2, 4, 7, 9, 11, 14
-====Treatment B (cycles 2, 4, 6, 8)====
+====Consolidation B (Cycles 2, 5, 8)====
-*[[Teniposide (Vumon)]] 165 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
+*[[Methotrexate (MTX)]] 3000 mg/m<sup>2</sup> IV continuous infusion on day 15
-*[[Cytarabine (Cytosar)]] 300 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
+*[[Vincristine (Oncovin)]] 2 mg IV once on day 15
+*[[Asparaginase (Elspar)]] 10,000 units/m<sup>2</sup> (route not specified) once on day 16
+*[[Mercaptopurine (Purinethol)]] 60 mg/m<sup>2</sup> PO once per day on days 15 to 21
-====Treatment C (cycle 9)====
+====Supportive medications====
-*[[Methotrexate (MTX)]] 690 mg/m<sup>2</sup> IV over 42 hours on day 1
+*[[Lenograstim (Granocyte)]] 150 μg/m<sup>2</sup> SC once per day on days 22 to 27
-*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 14
-*[[Asparaginase (Elspar)]] 12000 units/m<sup>2</sup> IM once per day on days 2, 4, 7, 9, 11, 14
+====Consolidation C (Cycles 3, 6, 9)====
+*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once per day on days 29 & 30
+*[[Etoposide (Vepesid)]] 75 mg/m<sup>2</sup> IV once per day on days 29 & 30
+*[[Methotrexate (MTX)]] 25 mg/m<sup>2</sup> (route not specified) once on day 29
 ====Supportive medications====
-*[[Folinic acid (Leucovorin)]] 15 mg/m<sup>2</sup> IV every 6 hours x 12 doses, starting after [[Methotrexate (MTX)]] is complete (at 42 hours)
+*[[Lenograstim (Granocyte)]] 150 μg/m<sup>2</sup> SC once per day from day 31 until myeloid recovery
-Central nervous system (CNS) prophylaxis for patients without CNS involvement at diagnosis is started within 1 week of achieving complete remission:
+''Patients with CR after [[#Cyclophosphamide.2C_Daunorubicin.2C_L-Asparaginase.2C_Vincristine.2C_Prednisone|cyclophosphamide, daunorubicin, L-asparaginase, vincristine, prednisone induction]] received [[#Cyclophosphamide.2C_Daunorubicin.2C_L-Asparaginase.2C_Vincristine.2C_Prednisone_2|cyclophosphamide, daunorubicin, L-asparaginase, vincristine, prednisone late intensification]] between cycles 6 and 7. Patients with CR after [[#Cytarabine_.26_Idarubicin|cytarabine & idarubicin salvage]] received [[#Cytarabine_.26_Idarubicin_2|cytarabine & idarubicin late intensification]] between cycles 6 and 7. All patients proceeded to [[#POMP|POMP maintenance]] after completion of consolidation.''
-*Cranial radiation, 18 Gy total given in 10 fractions over 12 to 14 days
-*[[Methotrexate (MTX)]] 12 mg IT once per week x 6 doses concurrent with radiation
-''To be followed by [[#Linker_regimen_.28maintenance.29|Linker regimen maintenance therapy]].''
+===References===
+# 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. [http://jco.ascopubs.org/content/early/2015/12/07/JCO.2015.61.5385.long link to early article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19124805 PubMed]
-===References===
+=Late intensification=
-# 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. [http://bloodjournal.hematologylibrary.org/content/69/4/1242.full.pdf+html link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/3470055 PubMed] content property of [http://hemonc.org HemOnc.org]
-## '''Update:''' Linker CA, Levitt LJ, O'Donnell M, Forman SJ, Ries CA. Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report. Blood. 1991 Dec 1;78(11):2814-22. [http://bloodjournal.hematologylibrary.org/content/78/11/2814.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/1835410 PubMed]
-==Nilotinib-based consolidation {{#subobject:2b1576|Regimen=1}}==
+==Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone {{#subobject:51eb0e|Regimen=1}}==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#toc|back to top]]
 |}
+===Regimen {{#subobject:2b7045|Variant=1}}===
-===Regimen {{#subobject:e153b6|Variant=1}}===
 {| border="1" style="text-align:center;" !align="left"
 |'''Study'''
 |[[Levels_of_Evidence#Evidence|'''Evidence''']]
 |-
-|[http://www.bloodjournal.org/content/126/6/746.long Kim et al. 2015]
+|[http://jco.ascopubs.org/content/27/6/911.full Huguet et al. 2009 (GRAALL-2003)]
 |<span
 style="background:#EEEE00;
@@ Line 1,124: / Line 1,202: @@
 |-
 |}
+''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. Treatment preceded by [[#Pediatric-like_GRAALL_consolidation|pediatric-like GRAALL consolidation]] cycle 6, and is for patients achieving CR after [[#Cyclophosphamide.2C_Daunorubicin.2C_L-Asparaginase.2C_Vincristine.2C_Prednisone|cyclophosphamide, daunorubicin, L-asparaginase, vincristine, prednisone induction]].''
-''Treatment preceded by [[Acute_lymphocytic_leukemia#Nilotinib-based_induction|nilotinib-based induction]]. Duration of each cycle of consolidation is not specified but is presumably based on toxicities and count recovery. Nilotinib is taken continuously during consolidation.''
+====Chemotherapy====
+*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV q12h on days 15
-====Consolidation A (Cycle 1)====
+*[[Daunorubicin (Cerubidine)]] 30 mg/m<sup>2</sup> IV once per day on days 1 to 3
-*[[Daunorubicin (Cerubidine)]] 45 mg/m<sup>2</sup>/day IV continuous infusion on days 1 & 2 (total dose 90 mg/m<sup>2</sup>)
+*[[Asparaginase (Elspar)]] 6000 units/m<sup>2</sup>/day (route not specified) on days 8, 10, 12, 18, 20, 22
-*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 1 & 8
+*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 1, 8, 15
-*[[Prednisolone (Millipred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 14
+*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup>/day on days 1 to 14
-*[[Nilotinib (Tasigna)]] 400 mg PO BID
-====Consolidation B (Cycles 2 & 4)====
-*[[Cytarabine (Cytosar)]] 2000 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 to 4
-*[[Etoposide (Vepesid)]] 150 mg/m<sup>2</sup> IV over 3 hours once per day on days 1 to 4
-*[[Nilotinib (Tasigna)]] 400 mg PO BID
-====Consolidation C (Cycles 3 & 5)====
-*[[Methotrexate (MTX)]] 220 mg/m<sup>2</sup> IV bolus, then 60 mg/m<sup>2</sup>/hr IV continuous infusion for 36 hours twice per cycle (days 1 & 2, 15 & 16)
-*[[Nilotinib (Tasigna)]] 400 mg PO BID
 ====Supportive medications====
-*[[Folinic acid (Leucovorin)]] 50 mg/m<sup>2</sup> IV every 6 hours x 3 doses, then PO (dose not specified) until serum methotrexate level <0.05
+*[[Lenograstim (Granocyte)]] 150 μg/m<sup>2</sup> SC once per day "if ANC < 500" until myeloid recovery
-''Treatment followed by [[Acute_lymphocytic_leukemia#Nilotinib_.28Tasigna.29|nilotinib maintenance]].''
+''Patients then proceeded back to [[#Pediatric-like_GRAALL_consolidation|pediatric-like GRAALL consolidation]].''
 ===References===
-# Kim DY, Joo YD, Lim SN, Kim SD, Lee JH, Lee JH, Kim DH, Kim K, Jung CW, Kim I, Yoon SS, Park S, Ahn JS, Yang DH, Lee JJ, Lee HS, Kim YS, Mun YC, Kim H, Park JH, Moon JH, Sohn SK, Lee SM, Lee WS, Kim KH, Won JH, Hyun MS, Park J, Lee JH, Shin HJ, Chung JS, Lee H, Eom HS, Lee GW, Cho YU, Jang S, Park CJ, Chi HS, Lee KH; Adult Acute Lymphoblastic Leukemia Working Party of the Korean Society of Hematology. Nilotinib combined with multiagent chemotherapy for newly diagnosed Philadelphia-positive acute lymphoblastic leukemia. Blood. 2015 Aug 6;126(6):746-56. Epub 2015 Jun 11. [http://www.bloodjournal.org/content/126/6/746.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/26065651 PubMed]
+# 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. [http://jco.ascopubs.org/content/early/2015/12/07/JCO.2015.61.5385.long link to early article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19124805 PubMed]
-==Pediatric-like GRAALL consolidation {{#subobject:32d4f7|Regimen=1}}==
+==Cytarabine & Idarubicin {{#subobject:284aff|Regimen=1}}==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#toc|back to top]]
 |}
-===Regimen {{#subobject:5fe62b|Variant=1}}===
+===Regimen {{#subobject:3d4896|Variant=1}}===
 {| border="1" style="text-align:center;" !align="left"
 |'''Study'''
@@ Line 1,169: / Line 1,237: @@
 |-
 |}
+''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. Treatment preceded by [[#Pediatric-like_GRAALL_consolidation|pediatric-like GRAALL consolidation]] cycle 6, and is for patients achieving CR after [[#Cytarabine_.26_Idarubicin|cytarabine & idarubicin salvage]].''
-''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. Treatment preceded by [[#Pediatric-like_GRAALL_induction|pediatric-like GRAALL induction]] or [[#Pediatric-like_GRAALL_salvage|pediatric-like GRAALL salvage]].''
+====Chemotherapy====
+*[[Cytarabine (Cytosar)]] 2000 mg/m<sup>2</sup> IV q12h on days 1 to 4
-====Consolidation A (Cycles 1, 4, 7)====
+*[[Idarubicin (Idamycin)]] 9 mg/m<sup>2</sup> IV once per day on days 1 to 3
-*[[Cytarabine (Cytosar)]] 2000 mg/m<sup>2</sup> IV q12h on days 1 & 2
-*[[Dexamethasone (Decadron)]] 10 mg (route not specified) q12h on days 1 & 2
-*[[Asparaginase (Elspar)]] 10,000 units/m<sup>2</sup> (route not specified) once on day 3
 ====Supportive medications====
-*[[Lenograstim (Granocyte)]] 150 μg/m<sup>2</sup> SC once per day on days 7 to 13
+*[[Lenograstim (Granocyte)]] 150 μg/m<sup>2</sup> SC once per day from day 9 until myeloid recovery
-====Consolidation B (Cycles 2, 5, 8)====
+''Patients then proceeded back to [[#Pediatric-like_GRAALL_consolidation|pediatric-like GRAALL consolidation]].''
-*[[Methotrexate (MTX)]] 3000 mg/m<sup>2</sup> IV continuous infusion on day 15
-*[[Vincristine (Oncovin)]] 2 mg IV once on day 15
-*[[Asparaginase (Elspar)]] 10,000 units/m<sup>2</sup> (route not specified) once on day 16
-*[[Mercaptopurine (Purinethol)]] 60 mg/m<sup>2</sup> PO once per day on days 15 to 21
-====Supportive medications====
-*[[Lenograstim (Granocyte)]] 150 μg/m<sup>2</sup> SC once per day on days 22 to 27
-====Consolidation C (Cycles 3, 6, 9)====
-*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once per day on days 29 & 30
-*[[Etoposide (Vepesid)]] 75 mg/m<sup>2</sup> IV once per day on days 29 & 30
-*[[Methotrexate (MTX)]] 25 mg/m<sup>2</sup> (route not specified) once on day 29
-====Supportive medications====
-*[[Lenograstim (Granocyte)]] 150 μg/m<sup>2</sup> SC once per day from day 31 until myeloid recovery
-''Patients with CR after [[#Pediatric-like_GRAALL_induction|pediatric-like GRAALL induction]] received [[#Pediatric-like_GRAALL_late_intensification|pediatric-like GRAALL late intensification]] between cycles 6 and 7. Patients with CR after [[#Pediatric-like_GRAALL_salvage|pediatric-like GRAALL salvage]] received [[#Pediatric-like_GRAALL_late_intensification.2C_alternate|alternative pediatric-like GRAALL late intensification]] between cycles 6 and 7. All patients proceeded to [[#POMP|pediatric-like GRAALL maintenance (POMP)]] after completion of consolidation.''
 ===References===
 # 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. [http://jco.ascopubs.org/content/early/2015/12/07/JCO.2015.61.5385.long link to early article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19124805 PubMed]
-=Late intensification=
+==Larson regimen (CALGB 8811) {{#subobject:712de6|Regimen=1}}==
-==Pediatric-like GRAALL late intensification {{#subobject:51eb0e|Regimen=1}}==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#toc|back to top]]
 |}
-===Regimen {{#subobject:2b7045|Variant=1}}===
+===Regimen {{#subobject:2ea5b7|Variant=1}}===
 {| border="1" style="text-align:center;" !align="left"
 |'''Study'''
 |[[Levels_of_Evidence#Evidence|'''Evidence''']]
 |-
-|[http://jco.ascopubs.org/content/27/6/911.full Huguet et al. 2009 (GRAALL-2003)]
+|[http://bloodjournal.hematologylibrary.org/content/85/8/2025.full Larson et al. 1995 (CALGB 8811)]
 |<span
 style="background:#EEEE00;
@@ Line 1,223: / Line 1,269: @@
 |-
 |}
+''Treatment preceded by [[mercaptopurine, methotrexate, WB-XRT ("Course III")]].''
-''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. Treatment preceded by [[#Pediatric-like_GRAALL_consolidation|pediatric-like GRAALL consolidation]] cycle 6, and is for patients achieving CR after [[#Pediatric-like_GRAALL_induction|pediatric-like GRAALL induction]].''
+====Chemotherapy ("Course IV")====
-====Chemotherapy====
+*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
-*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup>/day on days 1 to 14
-*[[Daunorubicin (Cerubidine)]] 30 mg/m<sup>2</sup> IV once per day on days 1 to 3
 *[[Vincristine (Oncovin)]] 2 mg IV once per day on days 1, 8, 15
-*[[Asparaginase (Elspar)]] 6000 units/m<sup>2</sup>/day (route not specified) on days 8, 10, 12, 18, 20, 22
+*[[Dexamethasone (Decadron)]] 10 mg/m<sup>2</sup> PO once per day on days 1 to 14
-*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV q12h on days 15
+*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV once on day 29
+*[[Thioguanine (Tabloid)]] 60 mg/m<sup>2</sup> PO once per day on days 29 to 42
+*[[Cytarabine (Cytosar)]] 75 mg/m<sup>2</sup> SC once per day on days 29 to 32, 36 to 39
-====Supportive medications====
+'''8-week course'''
-*[[Lenograstim (Granocyte)]] 150 μg/m<sup>2</sup> SC once per day "if ANC < 500" until myeloid recovery
-''Patients then proceeded back to [[#Pediatric-like_GRAALL_consolidation|pediatric-like GRAALL consolidation]].''
+''To be followed by [[#POMP|POMP maintenance ("Course V")]].''
 ===References===
-# 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. [http://jco.ascopubs.org/content/early/2015/12/07/JCO.2015.61.5385.long link to early article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19124805 PubMed]
+# Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR et al. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study 8811. Blood. 1995 Apr 15;85(8):2025-37. [http://bloodjournal.hematologylibrary.org/content/85/8/2025.full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/7718875 PubMed]
-==Pediatric-like GRAALL late intensification, alternate {{#subobject:284aff|Regimen=1}}==
+=Maintenance therapy=
+==Dasatinib, Vincristine, Prednisone {{#subobject:71a41c|Regimen=1}}==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#toc|back to top]]
 |}
-===Regimen {{#subobject:3d4896|Variant=1}}===
+===Regimen {{#subobject:2efb7e|Variant=1}}===
 {| border="1" style="text-align:center;" !align="left"
 |'''Study'''
 |[[Levels_of_Evidence#Evidence|'''Evidence''']]
 |-
-|[http://jco.ascopubs.org/content/27/6/911.full Huguet et al. 2009 (GRAALL-2003)]
+|[http://bloodjournal.hematologylibrary.org/content/116/12/2070.long Ravandi et al. 2010]
 |<span
 style="background:#EEEE00;
@@ Line 1,260: / Line 1,307: @@
 |}
-''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. Treatment preceded by [[#Pediatric-like_GRAALL_consolidation|pediatric-like GRAALL consolidation]] cycle 6, and is for patients achieving CR after [[#Pediatric-like_GRAALL_salvage|pediatric-like GRAALL salvage]].''
+''Treatment preceded by [[#Hyper-CVAD_.26_Dasatinib|HyperCVAD & Dasatinib]] x 8, and only offered to patients who achieved a CR.''
 ====Chemotherapy====
-*[[Idarubicin (Idamycin)]] 9 mg/m<sup>2</sup> IV once per day on days 1 to 3
+*[[Dasatinib (Sprycel)]] 100 mg PO once per day on days 1 to 28
-*[[Cytarabine (Cytosar)]] 2000 mg/m<sup>2</sup> IV q12h on days 1 to 4
+*[[Vincristine (Oncovin)]] 2 mg IV once on day 1
+*[[Prednisone (Sterapred)]] 200 mg PO once per day on days 1 to 5
+'''28-day cycles for 2 years'''
-====Supportive medications====
+''Maintenance therapy could be interrupted by provider's choice--typically only given to people with at least minimal residual disease (MRD) or more--in month 6 and 13 to give Hyper-CVAD Part A x 1 cycle. Then, after 2 years of maintenance therapy, patients proceed to dasatinib monotherapy:''
-*[[Lenograstim (Granocyte)]] 150 μg/m<sup>2</sup> SC once per day from day 9 until myeloid recovery
-''Patients then proceeded back to [[#Pediatric-like_GRAALL_consolidation|pediatric-like GRAALL consolidation]].''
+*[[Dasatinib (Sprycel)]] 100 mg PO once per day, continued indefinitely
 ===References===
-# 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. [http://jco.ascopubs.org/content/early/2015/12/07/JCO.2015.61.5385.long link to early article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19124805 PubMed]
+# Ravandi F, O'Brien S, Thomas D, Faderl S, Jones D, Garris R, Dara S, Jorgensen J, Kebriaei P, Champlin R, Borthakur G, Burger J, Ferrajoli A, Garcia-Manero G, Wierda W, Cortes J, Kantarjian H. First report of phase 2 study of dasatinib with hyper-CVAD for the frontline treatment of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia. Blood. 2010 Sep 23;116(12):2070-7. Epub 2010 May 13. [http://bloodjournal.hematologylibrary.org/content/116/12/2070.long link to original article] '''contains verified protocol'''--parts of the protocol were not explicitly listed in this reference, which instead referred to [[#Hyper-CVAD_.26_Imatinib_.28Gleevec.29_.28induction_.26_maintenance.29|Thomas et al. 2004]] and [[#Hyper-CVAD_.28induction.29|Kantarjian et al. 2004]] [http://www.ncbi.nlm.nih.gov/pubmed/20466853 PubMed]
+## '''Update:''' Ravandi F, O'Brien SM, Cortes JE, Thomas DM, Garris R, Faderl S, Burger JA, Rytting ME, Ferrajoli A, Wierda WG, Verstovsek S, Champlin R, Kebriaei P, McCue DA, Huang X, Jabbour E, Garcia-Manero G, Estrov Z, Kantarjian HM. Long-term follow-up of a phase 2 study of chemotherapy plus dasatinib for the initial treatment of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Cancer. 2015 Dec 1;121(23):4158-64. Epub 2015 Aug 26. [http://onlinelibrary.wiley.com/doi/10.1002/cncr.29646/full link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/26308885 PubMed]
-=Maintenance therapy=
+==Mercaptopurine & Methotrexate {{#subobject:6366a6|Regimen=1}}==
-==Dasatinib, Vincristine, Prednisone {{#subobject:71a41c|Regimen=1}}==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
@@ Line 1,280: / Line 1,329: @@
 |}
-===Regimen {{#subobject:2efb7e|Variant=1}}===
+===Regimen {{#subobject:1fc958|Variant=1}}===
 {| border="1" style="text-align:center;" !align="left"
 |'''Study'''
 |[[Levels_of_Evidence#Evidence|'''Evidence''']]
 |-
-|[http://bloodjournal.hematologylibrary.org/content/116/12/2070.long Ravandi et al. 2010]
+|[http://bloodjournal.hematologylibrary.org/content/69/4/1242.full.pdf+html Linker et al. 1987]
 |<span
 style="background:#EEEE00;
@@ Line 1,294: / Line 1,343: @@
 |-
 |}
+''Treatment preceded by [[#Linker_regimen_.28consolidation.29|Linker regimen consolidation therapy]].''
+====Chemotherapy====
+*[[Mercaptopurine (Purinethol)]] 75 mg/m<sup>2</sup> PO once per day
+*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> PO once per week
-''Treatment preceded by [[#Hyper-CVAD_.26_Dasatinib|HyperCVAD & Dasatinib]] x 8, and only offered to patients who achieved a CR.''
+'''30-month course'''
-====Chemotherapy====
-*[[Dasatinib (Sprycel)]] 100 mg PO once per day on days 1 to 28
-*[[Vincristine (Oncovin)]] 2 mg IV once on day 1
-*[[Prednisone (Sterapred)]] 200 mg PO once per day on days 1 to 5
-'''28-day cycles for 2 years'''
-''Maintenance therapy could be interrupted by provider's choice--typically only given to people with at least minimal residual disease (MRD) or more--in month 6 and 13 to give Hyper-CVAD Part A x 1 cycle. Then, after 2 years of maintenance therapy, patients proceed to dasatinib monotherapy:''
-*[[Dasatinib (Sprycel)]] 100 mg PO once per day, continued indefinitely
 ===References===
-# Ravandi F, O'Brien S, Thomas D, Faderl S, Jones D, Garris R, Dara S, Jorgensen J, Kebriaei P, Champlin R, Borthakur G, Burger J, Ferrajoli A, Garcia-Manero G, Wierda W, Cortes J, Kantarjian H. First report of phase 2 study of dasatinib with hyper-CVAD for the frontline treatment of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia. Blood. 2010 Sep 23;116(12):2070-7. Epub 2010 May 13. [http://bloodjournal.hematologylibrary.org/content/116/12/2070.long link to original article] '''contains verified protocol'''--parts of the protocol were not explicitly listed in this reference, which instead referred to [[#Hyper-CVAD_.26_Imatinib_.28Gleevec.29_.28induction_.26_maintenance.29|Thomas et al. 2004]] and [[#Hyper-CVAD_.28induction.29|Kantarjian et al. 2004]] [http://www.ncbi.nlm.nih.gov/pubmed/20466853 PubMed]
+# Linker CA, Levitt LJ, O'Donnell M, Ries CA, Link MP, Forman SJ, Farbstein MJ. Improved results of treatment of adult acute lymphoblastic leukemia. Blood. 1987 Apr;69(4):1242-8. [http://bloodjournal.hematologylibrary.org/content/69/4/1242.full.pdf+html link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/3470055 PubMed]
-## '''Update:''' Ravandi F, O'Brien SM, Cortes JE, Thomas DM, Garris R, Faderl S, Burger JA, Rytting ME, Ferrajoli A, Wierda WG, Verstovsek S, Champlin R, Kebriaei P, McCue DA, Huang X, Jabbour E, Garcia-Manero G, Estrov Z, Kantarjian HM. Long-term follow-up of a phase 2 study of chemotherapy plus dasatinib for the initial treatment of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Cancer. 2015 Dec 1;121(23):4158-64. Epub 2015 Aug 26. [http://onlinelibrary.wiley.com/doi/10.1002/cncr.29646/full link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/26308885 PubMed]
+## '''Update:''' Linker CA, Levitt LJ, O'Donnell M, Forman SJ, Ries CA. Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report. Blood. 1991 Dec 1;78(11):2814-22. [http://bloodjournal.hematologylibrary.org/content/78/11/2814.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/1835410 PubMed]
-==Larson/CALGB 8811 regimen (maintenance) {{#subobject:badd67|Regimen=1}}==
+==Nilotinib (Tasigna) {{#subobject:2a3276|Regimen=1}}==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#toc|back to top]]
 |}
-===Regimen {{#subobject:91c8d4|Variant=1}}===
+===Regimen {{#subobject:f976b6|Variant=1}}===
 {| border="1" style="text-align:center;" !align="left"
 |'''Study'''
 |[[Levels_of_Evidence#Evidence|'''Evidence''']]
 |-
-|[http://bloodjournal.hematologylibrary.org/content/85/8/2025.full Larson et al. 1995 (CALGB 8811)]
+|[http://www.bloodjournal.org/content/126/6/746.long Kim et al. 2015]
 |<span
 style="background:#EEEE00;
@@ Line 1,331: / Line 1,374: @@
 |-
 |}
+''Treatment preceded by [[Acute_lymphocytic_leukemia#Nilotinib-based_consolidation|nilotinib-based consolidation]].''
+====Chemotherapy====
+*[[Nilotinib (Tasigna)]] 400 mg PO BID
-''Treatment preceded by [[#Larson.2FCALGB_8811_regimen_.28consolidation.29|Larson/CALGB 8811 regimen courses II to IV (consolidation)]].''
+'''2-year course'''
-====Course V (prolonged maintenance)====
+===References===
-*[[Vincristine (Oncovin)]] 2 mg IV once on day 1
+# Kim DY, Joo YD, Lim SN, Kim SD, Lee JH, Lee JH, Kim DH, Kim K, Jung CW, Kim I, Yoon SS, Park S, Ahn JS, Yang DH, Lee JJ, Lee HS, Kim YS, Mun YC, Kim H, Park JH, Moon JH, Sohn SK, Lee SM, Lee WS, Kim KH, Won JH, Hyun MS, Park J, Lee JH, Shin HJ, Chung JS, Lee H, Eom HS, Lee GW, Cho YU, Jang S, Park CJ, Chi HS, Lee KH; Adult Acute Lymphoblastic Leukemia Working Party of the Korean Society of Hematology. Nilotinib combined with multiagent chemotherapy for newly diagnosed Philadelphia-positive acute lymphoblastic leukemia. Blood. 2015 Aug 6;126(6):746-56. Epub 2015 Jun 11. [http://www.bloodjournal.org/content/126/6/746.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/26065651 PubMed]
-*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 5
-*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22
-*[[Mercaptopurine (Purinethol)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 28
-'''28-day cycles, continue until 24 months from diagnosis'''
+==POMP {{#subobject:31219|Regimen=1}}==
-===References===
-# Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR et al. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study 8811. Blood. 1995 Apr 15;85(8):2025-37. [http://bloodjournal.hematologylibrary.org/content/85/8/2025.full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/7718875 PubMed]
-==Linker regimen (maintenance) {{#subobject:6366a6|Regimen=1}}==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#toc|back to top]]
 |}
+POMP: '''<u>P</u>'''rednisone, '''<u>O</u>'''ncovin (Vincristine), '''<u>M</u>'''ethotrexate, '''<u>P</u>'''urinethol (Mercaptopurine)
-===Regimen {{#subobject:1fc958|Variant=1}}===
+===Regimen #1 {{#subobject:93b1b3|Variant=1}}===
 {| border="1" style="text-align:center;" !align="left"
 |'''Study'''
 |[[Levels_of_Evidence#Evidence|'''Evidence''']]
 |-
-|[http://bloodjournal.hematologylibrary.org/content/69/4/1242.full.pdf+html Linker et al. 1987]
+|[http://jco.ascopubs.org/content/27/6/911.full Huguet et al. 2009 (GRAALL-2003)]
 |<span
 style="background:#EEEE00;
@@ Line 1,365: / Line 1,404: @@
 |-
 |}
-''Treatment preceded by [[#Linker_regimen_.28consolidation.29|Linker regimen consolidation therapy]].''
+''Treatment preceded by [[#Pediatric-like_GRAALL_consolidation|pediatric-like GRAALL consolidation]].''
 ====Chemotherapy====
-*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> PO once per week x 30 months
+*[[Prednisone (Sterapred)]] 40 mg/m<sup>2</sup>/day PO on days 1 to 7 of each month x 12 months
-*[[Mercaptopurine (Purinethol)]] 75 mg/m<sup>2</sup> PO once per day x 30 months
+*[[Vincristine (Oncovin)]] 2 mg IV once on day 1 of each month x 12 months
+*[[Methotrexate (MTX)]] 25 mg/m<sup>2</sup> PO once per week x 24 months
+*[[Mercaptopurine (Purinethol)]] 60 mg/m<sup>2</sup> PO once per day x 24 months
-===References===
+'''24-month course'''
-# 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. [http://bloodjournal.hematologylibrary.org/content/69/4/1242.full.pdf+html link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/3470055 PubMed]
-## '''Update:''' Linker CA, Levitt LJ, O'Donnell M, Forman SJ, Ries CA. Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report. Blood. 1991 Dec 1;78(11):2814-22. [http://bloodjournal.hematologylibrary.org/content/78/11/2814.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/1835410 PubMed]
-==Nilotinib (Tasigna) {{#subobject:2a3276|Regimen=1}}==
+===Regimen #2 {{#subobject:7e9f28|Variant=1}}===
-{| class="wikitable" style="float:right; margin-left: 5px;"
+{| border="1" style="text-align:center;" !align="left"
+|'''Study'''
+|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+|'''Comparator'''
+|-
+|[http://bloodjournal.hematologylibrary.org/content/106/12/3760.long Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)]
+|<span
+style="background:#00cd00;
+padding:3px 6px 3px 6px;
+border-color:black;
+border-width:2px;
+border-style:solid;">Phase III</span>
+|[[Transplant_conditioning_regimens#Etoposide_.26_TBI|Etoposide & TBI -> autoHCT]]
 |-
-|[[#toc|back to top]]
 |}
+''Treatment preceded by [[#International_ALL_Trial_.28MRC_UKALL_XII.2FECOG_E2993.29_3|International ALL Trial consolidation]].''
+====Chemotherapy====
+*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day for 5 days every 3 months
+*[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> IV once every 3 months
+*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> PO or IV once per week
+*[[Mercaptopurine (Purinethol)]] 75 mg/m<sup>2</sup> PO once per day
+'''Continue for a total of 2.5 years from the start of phase III'''
-===Regimen {{#subobject:f976b6|Variant=1}}===
+===Regimen #3 {{#subobject:9374ec|Variant=1}}===
 {| border="1" style="text-align:center;" !align="left"
 |'''Study'''
 |[[Levels_of_Evidence#Evidence|'''Evidence''']]
 |-
-|[http://www.bloodjournal.org/content/126/6/746.long Kim et al. 2015]
+|[http://onlinelibrary.wiley.com/doi/10.1002/cncr.20668/full Kantarjian et al. 2004]
 |<span
 style="background:#EEEE00;
@@ Line 1,394: / Line 1,452: @@
 |-
 |}
+''Treatment preceded by [[Acute_lymphocytic_leukemia#Hyper-CVAD.2FMA|Hyper-CVAD (induction)]]. Kantarjian et al. 2004 said how many days each drug is given per month, but did not specifically say, for example, that certain drugs are taken on days 1 to 5 of the cycle.''
-''Treatment preceded by [[Acute_lymphocytic_leukemia#Nilotinib-based_consolidation|nilotinib-based consolidation]].''
 ====Chemotherapy====
-*[[Nilotinib (Tasigna)]] 400 mg PO BID
+*[[Prednisone (Sterapred)]] 200 mg PO once per day for 5 days, given with [[Vincristine (Oncovin)]]
+*[[Vincristine (Oncovin)]] 2 mg IV once per month
+*[[Methotrexate (MTX)]] 10 mg/m<sup>2</sup> IV over 1 hour once per day for 5 days
+*[[Mercaptopurine (Purinethol)]] 1000 mg/m<sup>2</sup> IV over 1 hour once per day for 5 days
-'''2-year course'''
+====Supportive medications====
+*[[Trimethoprim/Sulfamethoxazole (Bactrim DS)|Trimethoprim/Sulfamethoxazole]] (dosage not listed) PO BID on Saturday and Sunday for the first 6 months
+*One of the following antivirals:
+**EITHER [[Acyclovir (Zovirax)]] 200 mg PO once per day or 3 times per week for the first 6 months
+**OR [[Valacyclovir (Valtrex)]] 500 mg PO once per day or 3 times per week for the first 6 months
-===References===
+'''1-month cycles for 2 years'''
-# Kim DY, Joo YD, Lim SN, Kim SD, Lee JH, Lee JH, Kim DH, Kim K, Jung CW, Kim I, Yoon SS, Park S, Ahn JS, Yang DH, Lee JJ, Lee HS, Kim YS, Mun YC, Kim H, Park JH, Moon JH, Sohn SK, Lee SM, Lee WS, Kim KH, Won JH, Hyun MS, Park J, Lee JH, Shin HJ, Chung JS, Lee H, Eom HS, Lee GW, Cho YU, Jang S, Park CJ, Chi HS, Lee KH; Adult Acute Lymphoblastic Leukemia Working Party of the Korean Society of Hematology. Nilotinib combined with multiagent chemotherapy for newly diagnosed Philadelphia-positive acute lymphoblastic leukemia. Blood. 2015 Aug 6;126(6):746-56. Epub 2015 Jun 11. [http://www.bloodjournal.org/content/126/6/746.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/26065651 PubMed]
-==POMP {{#subobject:31219|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#toc|back to top]]
-|}
-POMP: '''<u>P</u>'''rednisone, '''<u>O</u>'''ncovin (Vincristine), '''<u>M</u>'''ethotrexate, '''<u>P</u>'''urinethol (Mercaptopurine)
-===Regimen #1 {{#subobject:93b1b3|Variant=1}}===
+===Regimen #4 {{#subobject:91c8d4|Variant=1}}===
 {| border="1" style="text-align:center;" !align="left"
 |'''Study'''
 |[[Levels_of_Evidence#Evidence|'''Evidence''']]
 |-
-|[http://jco.ascopubs.org/content/27/6/911.full Huguet et al. 2009 (GRAALL-2003)]
+|[http://bloodjournal.hematologylibrary.org/content/85/8/2025.full Larson et al. 1995 (CALGB 8811)]
 |<span
 style="background:#EEEE00;
@@ Line 1,425: / Line 1,481: @@
 |-
 |}
+''Treatment preceded by [[Larson regimen (CALGB 8811) late intensification ("Course IV")]].''
+====Chemotherapy ("Course V")====
+*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 5
+*[[Vincristine (Oncovin)]] 2 mg IV once on day 1
+*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22
+*[[Mercaptopurine (Purinethol)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 28
+'''28-day cycles, continue until 24 months from diagnosis'''
-''Treatment preceded by [[#Pediatric-like_GRAALL_consolidation|pediatric-like GRAALL consolidation]].''
+===References===
-====Chemotherapy====
+# Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR et al. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study 8811. Blood. 1995 Apr 15;85(8):2025-37. [http://bloodjournal.hematologylibrary.org/content/85/8/2025.full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/7718875 PubMed]
-*[[Prednisone (Sterapred)]] 40 mg/m<sup>2</sup>/day PO on days 1 to 7 of each month x 12 months
+# 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. [http://onlinelibrary.wiley.com/doi/10.1002/cncr.20668/full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/15481055 PubMed]
-*[[Vincristine (Oncovin)]] 2 mg IV once on day 1 of each month x 12 months
+# Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. [http://bloodjournal.hematologylibrary.org/content/106/12/3760.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/16105981 PubMed]
-*[[Methotrexate (MTX)]] 25 mg/m<sup>2</sup> PO once per week x 24 months
+## '''Update:''' Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, Burnett AK, Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J, McMillan A, Franklin IM, Luger S, Ciobanu N, Rowe JM. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008 Feb 15;111(4):1827-33. Epub 2007 Nov 29. [http://bloodjournal.hematologylibrary.org/content/111/4/1827.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/18048644 PubMed]
-*[[Mercaptopurine (Purinethol)]] 60 mg/m<sup>2</sup> PO once per day x 24 months
+## '''Update:''' Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, Marks DI, McMillan AK, Litzow MR, Lazarus HM, Foroni L, Dewald G, Franklin IM, Luger SM, Paietta E, Wiernik PH, Tallman MS, Goldstone AH. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009 May 7;113(19):4489-96. Epub 2009 Feb 24. [http://bloodjournal.hematologylibrary.org/content/113/19/4489.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/19244158 PubMed]
+## '''Update:''' Fielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow MR, Lazarus H, Luger SM, Marks DI, McMillan AK, Moorman AV, Patel B, Paietta E, Tallman MS, Goldstone AH. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014 Feb 6;123(6):843-50. Epub 2013 Nov 25. [http://bloodjournal.hematologylibrary.org/content/123/6/843.full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/24277073 PubMed]
+# 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. [http://jco.ascopubs.org/content/early/2015/12/07/JCO.2015.61.5385.long link to early article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19124805 PubMed]
+=Relapsed/refractory, Ph-negative=
-'''24-month course'''
+==Augmented Hyper-CVAD & Asparaginase {{#subobject:aab460|Regimen=1}}==
+{| class="wikitable" style="float:right; margin-left: 5px;"
+|-
+|[[#toc|back to top]]
+|}
-===Regimen #2 {{#subobject:7e9f28|Variant=1}}===
+===Regimen {{#subobject:d89fd9|Variant=1}}===
 {| border="1" style="text-align:center;" !align="left"
 |'''Study'''
 |[[Levels_of_Evidence#Evidence|'''Evidence''']]
 |-
-|[http://bloodjournal.hematologylibrary.org/content/106/12/3760.long Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)]
+|[http://www.sciencedirect.com/science/article/pii/S2152265011701288 Faderl et al. 2011]
 |<span
 style="background:#EEEE00;
@@ Line 1,449: / Line 1,521: @@
 |-
 |}
+To be completed
-''Treatment preceded by [[#International_ALL_Trial_.28MRC_UKALL_XII.2FECOG_E2993.29_3|E2993 consolidation]].''
+===References===
-====Chemotherapy====
+# Faderl S, Thomas DA, O'Brien S, Ravandi F, Garcia-Manero G, Borthakur G, Ferrajoli A, Verstovsek S, Ayoubi M, Rytting M, Feliu J, Kantarjian HM. Augmented hyper-CVAD based on dose-intensified vincristine, dexamethasone, and asparaginase in adult acute lymphoblastic leukemia salvage therapy. Clin Lymphoma Myeloma Leuk. 2011 Feb;11(1):54-9. [http://www.sciencedirect.com/science/article/pii/S2152265011701288 link to SD article] [http://www.ncbi.nlm.nih.gov/pubmed/21454191 PubMed]
-*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day for 5 days every 3 months
-*[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> IV once every 3 months
-*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> PO or IV once per week
-*[[Mercaptopurine (Purinethol)]] 75 mg/m<sup>2</sup> PO once per day
-'''Continue for a total of 2.5 years from the start of phase III'''
+==Blinatumomab (Blincyto) {{#subobject:e7b2c6|Regimen=1}}==
+{| class="wikitable" style="float:right; margin-left: 5px;"
+|-
+|[[#toc|back to top]]
+|}
-===Regimen #3 {{#subobject:9374ec|Variant=1}}===
+===Regimen #1 {{#subobject:2db105|Variant=1}}===
 {| border="1" style="text-align:center;" !align="left"
 |'''Study'''
 |[[Levels_of_Evidence#Evidence|'''Evidence''']]
 |-
-|[http://onlinelibrary.wiley.com/doi/10.1002/cncr.20668/full Kantarjian et al. 2004]
+|[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)71170-2/fulltext Topp et al. 2014 (MT103-211)]
 |<span
 style="background:#EEEE00;
@@ Line 1,474: / Line 1,547: @@
 |}
-''Treatment preceded by [[Acute_lymphocytic_leukemia#Hyper-CVAD.2FMA|Hyper-CVAD (induction)]]. Kantarjian et al. 2004 said how many days each drug is given per month, but did not specifically say, for example, that certain drugs are taken on days 1 to 5 of the cycle.''
+''This is the FDA-approved dose & schedule.''
 ====Chemotherapy====
-*[[Prednisone (Sterapred)]] 200 mg PO once per day for 5 days, given with [[Vincristine (Oncovin)]]
+*[[Blinatumomab (Blincyto)]] given as follows:
-*[[Vincristine (Oncovin)]] 2 mg IV once per month
+** Cycle 1: 9 μg/day IV continuous infusion on days 1 to 7, then 28 μg/day on days 8 to 28
-*[[Methotrexate (MTX)]] 10 mg/m<sup>2</sup> IV over 1 hour once per day for 5 days
+** Subsequent cycles: 28 μg/day IV continuous infusion on days 1 to 28
-*[[Mercaptopurine (Purinethol)]] 1000 mg/m<sup>2</sup> IV over 1 hour once per day for 5 days
-====Supportive medications====
+'''6-week cycle for up to 5 cycles''' (2 cycles for induction and 3 additional cycles for consolidation)
-*[[Trimethoprim/Sulfamethoxazole (Bactrim DS)|Trimethoprim/Sulfamethoxazole]] (dosage not listed) PO BID on Saturday and Sunday for the first 6 months
-*One of the following antivirals:
-**EITHER [[Acyclovir (Zovirax)]] 200 mg PO once per day or 3 times per week for the first 6 months
-**OR [[Valacyclovir (Valtrex)]] 500 mg PO once per day or 3 times per week for the first 6 months
-'''1-month cycles for 2 years'''
+===Regimen #2 {{#subobject:aadee8|Variant=1}}===
-===References===
-# 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. [http://onlinelibrary.wiley.com/doi/10.1002/cncr.20668/full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/15481055 PubMed]
-# Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. [http://bloodjournal.hematologylibrary.org/content/106/12/3760.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/16105981 PubMed]
-# 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. [http://jco.ascopubs.org/content/early/2015/12/07/JCO.2015.61.5385.long link to early article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19124805 PubMed]
-=Relapsed/refractory, Ph-negative=
-==Augmented Hyper-CVAD & Asparaginase {{#subobject:aab460|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#toc|back to top]]
-|}
-===Regimen {{#subobject:d89fd9|Variant=1}}===
 {| border="1" style="text-align:center;" !align="left"
 |'''Study'''
 |[[Levels_of_Evidence#Evidence|'''Evidence''']]
 |-
-|[http://www.sciencedirect.com/science/article/pii/S2152265011701288 Faderl et al. 2011]
+|[http://jco.ascopubs.org/content/29/18/2493.long Topp et al. 2011]
+|<span
+style="background:#EEEE00;
+padding:3px 6px 3px 6px;
+border-color:black;
+border-width:2px;
+border-style:solid;">Phase II</span>
+|-
+|[http://jco.ascopubs.org/content/early/2014/11/05/JCO.2014.56.3247.long Topp et al. 2014 (MT103-206)]
 |<span
 style="background:#EEEE00;
@@ Line 1,516: / Line 1,577: @@
 |-
 |}
-To be completed
+''This is not the FDA-approved dose & schedule.''
+====Chemotherapy====
+*[[Blinatumomab (Blincyto)]] 15 μg/m<sup>2</sup>/day IV continuous infusion for days 1 to 28
+'''6-week cycle'''; 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===
-# Faderl S, Thomas DA, O'Brien S, Ravandi F, Garcia-Manero G, Borthakur G, Ferrajoli A, Verstovsek S, Ayoubi M, Rytting M, Feliu J, Kantarjian HM. Augmented hyper-CVAD based on dose-intensified vincristine, dexamethasone, and asparaginase in adult acute lymphoblastic leukemia salvage therapy. Clin Lymphoma Myeloma Leuk. 2011 Feb;11(1):54-9. [http://www.sciencedirect.com/science/article/pii/S2152265011701288 link to SD article] [http://www.ncbi.nlm.nih.gov/pubmed/21454191 PubMed]
+<!-- # '''Abstract:''' Max S. Topp, Nicola Goekbuget, Anthony Selwyn Stein, Ralf C. Bargou, Hervé Dombret, Adele K. Fielding, Josep M. Ribera, Robin Foà, Gerhard Zugmaier, Chris Holland, Tapan Maniar, Birgit Huber, Dirk Nagorsen, Hagop M. Kantarjian. Confirmatory open-label, single-arm, multicenter phase 2 study of the BiTE antibody blinatumomab in patients (pts) with relapsed/refractory B-precursor acute lymphoblastic leukemia (r/r ALL). J Clin Oncol 32:5s, 2014 (suppl; abstr 7005^). [http://meetinglibrary.asco.org/content/129500-144 link to abstract] -->
+# 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. [http://jco.ascopubs.org/content/29/18/2493.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/21576633 PubMed]
+## '''Update:''' Topp MS, Gökbuget N, Zugmaier G, Degenhard E, Goebeler ME, Klinger M, Neumann SA, Horst HA, Raff T, Viardot A, Stelljes M, Schaich M, Köhne-Volland R, Brüggemann M, Ottmann OG, Burmeister T, Baeuerle PA, Nagorsen D, Schmidt M, Einsele H, Riethmüller G, Kneba M, Hoelzer D, Kufer P, Bargou RC. Long-term follow-up of hematologic relapse-free survival in a phase 2 study of blinatumomab in patients with MRD in B-lineage ALL. Blood. 2012 Dec 20;120(26):5185-7. [http://www.bloodjournal.org/content/120/26/5185.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/23024237 PubMed]
+# 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. [http://jco.ascopubs.org/content/early/2014/11/05/JCO.2014.56.3247.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/25385737 PubMed]
+## '''Update:''' Zugmaier G, Gökbuget N, Klinger M, Viardot A, Stelljes M, Neumann S, Horst HA, Marks R, Faul C, Diedrich H, Reichle A, Brüggemann M, Holland C, Schmidt M, Einsele H, Bargou RC, Topp MS. Long-term survival and T-cell kinetics in relapsed/refractory ALL patients who achieved MRD response after blinatumomab treatment. Blood. 2015 Dec 10;126(24):2578-84. Epub 2015 Oct 19. [http://www.bloodjournal.org/content/126/24/2578.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/26480933 PubMed]
+# 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. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)71170-2/fulltext link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/25524800 PubMed]
-==Blinatumomab (Blincyto) {{#subobject:e7b2c6|Regimen=1}}==
+==CCE {{#subobject:f74969|Regimen=1}}==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#toc|back to top]]
 |}
+CCE: '''<u>C</u>'''lofarabine, '''<u>C</u>'''yclophosphamide, '''<u>E</u>'''toposide
-===Regimen #1 {{#subobject:2db105|Variant=1}}===
+===Regimen {{#subobject:24f55b|Variant=1}}===
 {| border="1" style="text-align:center;" !align="left"
 |'''Study'''
 |[[Levels_of_Evidence#Evidence|'''Evidence''']]
 |-
-|[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)71170-2/fulltext Topp et al. 2014 (MT103-211)]
+|[http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2009.07882.x/full Locatelli et al. 2009]
 |<span
 style="background:#EEEE00;
@@ Line 1,538: / Line 1,610: @@
 border-color:black;
 border-width:2px;
-border-style:solid;">Phase II</span>
+border-style:solid;">Non-randomized</span>
 |-
 |}
+''Patients in this study were pediatric: ≤ 15 years old at diagnosis and ≤ 21 years old at time of treatment. No patients had CNS disease at time of treatment, and no patients received CNS prophylaxis.''
-''This is the FDA-approved dose & schedule.''
 ====Chemotherapy====
-*[[Blinatumomab (Blincyto)]] given as follows:
+*[[Clofarabine (Clolar)]] 40 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 to 5, given first
-** Cycle 1: 9 μg/day IV continuous infusion on days 1 to 7, then 28 μg/day on days 8 to 28
+*[[Cyclophosphamide (Cytoxan)]] 400 mg/m<sup>2</sup> IV over 1 hour once per day on days 1 to 5
-** Subsequent cycles: 28 μg/day IV continuous infusion on days 1 to 28
+*[[Etoposide (Vepesid)]] 150 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 to 5
-'''6-week cycle for up to 5 cycles''' (2 cycles for induction and 3 additional cycles for consolidation)
+====Supportive medications====
+*Prophylactic [[:Category:Steroids|steroids]] used for patients with >30 x 10<sup>9</sup> blasts/L in the peripheral blood prior to treatment
+'''5-day course'''
+''2 out of 25 patients received a second course of CCE as consolidation therapy. Responding patients were given allogeneic HSCT if a suitable donor was immediately available or were given consolidation courses of chemotherapy including multiple agents active against ALL cells, chosen according to the treating physician's preference."
+===References===
+# Locatelli F, Testi AM, Bernardo ME, Rizzari C, Bertaina A, Merli P, Pession A, Giraldi E, Parasole R, Barberi W, Zecca M. Clofarabine, cyclophosphamide and etoposide as single-course re-induction therapy for children with refractory/multiple relapsed acute lymphoblastic leukaemia. Br J Haematol. 2009 Nov;147(3):371-8. Epub 2009 Aug 29. [http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2009.07882.x/full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19747360 PubMed]
+==Clofarabine (Clolar) {{#subobject:6befdc|Regimen=1}}==
+{| class="wikitable" style="float:right; margin-left: 5px;"
+|-
+|[[#toc|back to top]]
+|}
-===Regimen #2 {{#subobject:aadee8|Variant=1}}===
+===Regimen {{#subobject:9e7379|Variant=1}}===
 {| border="1" style="text-align:center;" !align="left"
 |'''Study'''
 |[[Levels_of_Evidence#Evidence|'''Evidence''']]
 |-
-|[http://jco.ascopubs.org/content/29/18/2493.long Topp et al. 2011]
+|[http://www.bloodjournal.org/content/102/7/2379.long Kantarjian et al. 2003]
 |<span
-style="background:#EEEE00;
+style="background:#ff0000;
 padding:3px 6px 3px 6px;
 border-color:black;
 border-width:2px;
-border-style:solid;">Phase II</span>
+border-style:solid;">Phase II, <20 patients in this arm</span>
 |-
-|[http://jco.ascopubs.org/content/early/2014/11/05/JCO.2014.56.3247.long Topp et al. 2014 (MT103-206)]
+|}
-|<span
+====Chemotherapy====
-style="background:#EEEE00;
+*[[Clofarabine (Clolar)]] 40 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase II</span>
-|-
-|}
-''This is not the FDA-approved dose & schedule.''
+'''3 to 6-week cycles, depending on response count recovery'''
-====Chemotherapy====
-*[[Blinatumomab (Blincyto)]] 15 μg/m<sup>2</sup>/day IV continuous infusion for days 1 to 28
-'''6-week cycle'''; 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===
-<!-- # '''Abstract:''' Max S. Topp, Nicola Goekbuget, Anthony Selwyn Stein, Ralf C. Bargou, Hervé Dombret, Adele K. Fielding, Josep M. Ribera, Robin Foà, Gerhard Zugmaier, Chris Holland, Tapan Maniar, Birgit Huber, Dirk Nagorsen, Hagop M. Kantarjian. Confirmatory open-label, single-arm, multicenter phase 2 study of the BiTE antibody blinatumomab in patients (pts) with relapsed/refractory B-precursor acute lymphoblastic leukemia (r/r ALL). J Clin Oncol 32:5s, 2014 (suppl; abstr 7005^). [http://meetinglibrary.asco.org/content/129500-144 link to abstract] -->
+# Kantarjian H, Gandhi V, Cortes J, Verstovsek S, Du M, Garcia-Manero G, Giles F, Faderl S, O'Brien S, Jeha S, Davis J, Shaked Z, Craig A, Keating M, Plunkett W, Freireich EJ. Phase 2 clinical and pharmacologic study of clofarabine in patients with refractory or relapsed acute leukemia. Blood. 2003 Oct 1;102(7):2379-86. Epub 2003 Jun 5. [http://www.bloodjournal.org/content/102/7/2379.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/12791647 PubMed]
-# 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. [http://jco.ascopubs.org/content/29/18/2493.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/21576633 PubMed]
+# '''Retrospective:''' Barba P, Sampol A, Calbacho M, Gonzalez J, Serrano J, Martínez-Sánchez P, Fernández P, García-Boyero R, Bueno J, Ribera JM. Clofarabine-based chemotherapy for relapsed/refractory adult acute lymphoblastic leukemia and lymphoblastic lymphoma. The Spanish experience. Am J Hematol. 2012 Jun;87(6):631-4. Epub 2012 Mar 19. [http://onlinelibrary.wiley.com/doi/10.1002/ajh.23167/full link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/22431002 PubMed]
-## '''Update:''' Topp MS, Gökbuget N, Zugmaier G, Degenhard E, Goebeler ME, Klinger M, Neumann SA, Horst HA, Raff T, Viardot A, Stelljes M, Schaich M, Köhne-Volland R, Brüggemann M, Ottmann OG, Burmeister T, Baeuerle PA, Nagorsen D, Schmidt M, Einsele H, Riethmüller G, Kneba M, Hoelzer D, Kufer P, Bargou RC. Long-term follow-up of hematologic relapse-free survival in a phase 2 study of blinatumomab in patients with MRD in B-lineage ALL. Blood. 2012 Dec 20;120(26):5185-7. [http://www.bloodjournal.org/content/120/26/5185.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/23024237 PubMed]
-# 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. [http://jco.ascopubs.org/content/early/2014/11/05/JCO.2014.56.3247.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/25385737 PubMed]
-## '''Update:''' Zugmaier G, Gökbuget N, Klinger M, Viardot A, Stelljes M, Neumann S, Horst HA, Marks R, Faul C, Diedrich H, Reichle A, Brüggemann M, Holland C, Schmidt M, Einsele H, Bargou RC, Topp MS. Long-term survival and T-cell kinetics in relapsed/refractory ALL patients who achieved MRD response after blinatumomab treatment. Blood. 2015 Dec 10;126(24):2578-84. Epub 2015 Oct 19. [http://www.bloodjournal.org/content/126/24/2578.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/26480933 PubMed]
-# 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. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)71170-2/fulltext link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/25524800 PubMed]
-==CCE {{#subobject:f74969|Regimen=1}}==
+==Cytarabine (Cytosar) {{#subobject:4dcf05|Regimen=1}}==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#toc|back to top]]
 |}
-CCE: '''<u>C</u>'''lofarabine, '''<u>C</u>'''yclophosphamide, '''<u>E</u>'''toposide
-===Regimen {{#subobject:24f55b|Variant=1}}===
+===Regimen {{#subobject:045c1c|Variant=1}}===
 {| border="1" style="text-align:center;" !align="left"
 |'''Study'''
 |[[Levels_of_Evidence#Evidence|'''Evidence''']]
+|'''Comparator'''
 |-
-|[http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2009.07882.x/full Locatelli et al. 2009]
+|[http://www.nejm.org/doi/full/10.1056/NEJMoa1509277 Kantarjian et al. 2016]
 |<span
-style="background:#EEEE00;
+style="background:#00cd00;
 padding:3px 6px 3px 6px;
 border-color:black;
 border-width:2px;
-border-style:solid;">Non-randomized</span>
+border-style:solid;">Phase III</span>
+|[[Inotuzumab ozogamicin (CMC-544)|Inotuzumab ozogamicin]]
 |-
 |}
-''Patients in this study were pediatric: ≤ 15 years old at diagnosis and ≤ 21 years old at time of treatment.''
 ====Chemotherapy====
-*[[Clofarabine (Clolar)]] 40 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 to 5, given first
+*[[Cytarabine (Cytosar)]] 3000 mg/m<sup>2</sup> IV q12h
-*[[Cyclophosphamide (Cytoxan)]] 400 mg/m<sup>2</sup> IV over 1 hour once per day on days 1 to 5
+**Dose reduced to 1500 mg/m<sup>2</sup> IV q12h for patients ≥55 years
-*[[Etoposide (Vepesid)]] 150 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 to 5
-*No patients had CNS disease at time of treatment, and no patients received CNS prophylaxis.
-====Supportive medications====
+'''One course of up to 12 doses'''
-*Prophylactic [[:Category:Steroids|steroids]] used for patients with >30 x 10<sup>9</sup> blasts/L in the peripheral blood prior to treatment
-'''5-day course'''
-''2 out of 25 patients received a second course of CCE as consolidation therapy. Responding patients were given allogeneic HSCT if a suitable donor was immediately available or were given consolidation courses of chemotherapy including multiple agents active against ALL cells, chosen according to the treating physician's preference."
 ===References===
-# Locatelli F, Testi AM, Bernardo ME, Rizzari C, Bertaina A, Merli P, Pession A, Giraldi E, Parasole R, Barberi W, Zecca M. Clofarabine, cyclophosphamide and etoposide as single-course re-induction therapy for children with refractory/multiple relapsed acute lymphoblastic leukaemia. Br J Haematol. 2009 Nov;147(3):371-8. Epub 2009 Aug 29. [http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2009.07882.x/full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19747360 PubMed]
+# 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. [http://www.nejm.org/doi/full/10.1056/NEJMoa1509277 link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/27292104 PubMed]
-==Clofarabine (Clolar) {{#subobject:6befdc|Regimen=1}}==
+==Cytarabine & Idarubicin {{#subobject:d6d882|Regimen=1}}==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#toc|back to top]]
 |}
+===Regimen {{#subobject:9cfc92|Variant=1}}===
-===Regimen {{#subobject:9e7379|Variant=1}}===
 {| border="1" style="text-align:center;" !align="left"
 |'''Study'''
 |[[Levels_of_Evidence#Evidence|'''Evidence''']]
 |-
-|[http://www.bloodjournal.org/content/102/7/2379.long Kantarjian et al. 2003]
+|[http://jco.ascopubs.org/content/27/6/911.full Huguet et al. 2009 (GRAALL-2003)]
 |<span
-style="background:#ff0000;
+style="background:#EEEE00;
 padding:3px 6px 3px 6px;
 border-color:black;
 border-width:2px;
-border-style:solid;">Phase II, <20 patients in this arm</span>
+border-style:solid;">Phase II</span>
 |-
 |}
+''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. Treatment preceded by [[#Cyclophosphamide.2C_Daunorubicin.2C_L-Asparaginase.2C_Vincristine.2C_Prednisone|cyclophosphamide, daunorubicin, L-aspariginase, vincristine, prednisone induction]].''
 ====Chemotherapy====
-*[[Clofarabine (Clolar)]] 40 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5
+*[[Cytarabine (Cytosar)]] 2000 mg/m<sup>2</sup> IV q12h on days 1 to 4
+*[[Idarubicin (Idamycin)]] 12 mg/m<sup>2</sup> IV once per day on days 1 to 3
+====Supportive medications====
+*[[Lenograstim (Granocyte)]] 150 μg/m<sup>2</sup> SC once per day from day 9 until myeloid recovery
-'''3 to 6-week cycles, depending on response count recovery'''
+''Patients achieving CR after salvage proceeded to [[#Pediatric-like_GRAALL_consolidation|pediatric-like GRAALL consolidation]].''
 ===References===
-# Kantarjian H, Gandhi V, Cortes J, Verstovsek S, Du M, Garcia-Manero G, Giles F, Faderl S, O'Brien S, Jeha S, Davis J, Shaked Z, Craig A, Keating M, Plunkett W, Freireich EJ. Phase 2 clinical and pharmacologic study of clofarabine in patients with refractory or relapsed acute leukemia. Blood. 2003 Oct 1;102(7):2379-86. Epub 2003 Jun 5. [http://www.bloodjournal.org/content/102/7/2379.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/12791647 PubMed]
+# 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. [http://jco.ascopubs.org/content/early/2015/12/07/JCO.2015.61.5385.long link to early article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19124805 PubMed]
-# '''Retrospective:''' Barba P, Sampol A, Calbacho M, Gonzalez J, Serrano J, Martínez-Sánchez P, Fernández P, García-Boyero R, Bueno J, Ribera JM. Clofarabine-based chemotherapy for relapsed/refractory adult acute lymphoblastic leukemia and lymphoblastic lymphoma. The Spanish experience. Am J Hematol. 2012 Jun;87(6):631-4. Epub 2012 Mar 19. [http://onlinelibrary.wiley.com/doi/10.1002/ajh.23167/full link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/22431002 PubMed]
-==Cytarabine (Cytosar) {{#subobject:4dcf05|Regimen=1}}==
+==Cytarabine & Mitoxantrone {{#subobject:6237f0|Regimen=1}}==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
@@ Line 1,660: / Line 1,727: @@
 |}
-===Regimen {{#subobject:045c1c|Variant=1}}===
+===Regimen {{#subobject:395e92|Variant=1}}===
 {| border="1" style="text-align:center;" !align="left"
 |'''Study'''
@@ Line 1,676: / Line 1,743: @@
 |-
 |}
+''This regimen as reported resembles 7+3m; it is not clear whether the cytarabine is given as bolus or continuous infusion from the manuscript.''
 ====Chemotherapy====
-*[[Cytarabine (Cytosar)]] 3000 mg/m<sup>2</sup> IV q12h
+*[[Cytarabine (Cytosar)]] 200 mg/m<sup>2</sup>/day IV on days 1 to 7
-**Dose reduced to 1500 mg/m<sup>2</sup> IV q12h for patients ≥55 years
+*[[Mitoxantrone (Novantrone)]] 12 mg/m<sup>2</sup> IV once per day on days 1 to 3
+**Dose reduction to 8 mg/m<sup>2</sup> allowed on the basis of age, coexisting conditions, and previous anthracycline use
-'''One course of up to 12 doses'''
+'''15-to-20-day cycle for up to 4 cycles'''
 ===References===
-# 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. [http://www.nejm.org/doi/full/10.1056/NEJMoa1509277 link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/27292104 PubMed]
+# 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. [http://www.nejm.org/doi/full/10.1056/NEJMoa1509277 link to original article] '''contains protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/27292104 PubMed]
-==Cytarabine & Mitoxantrone {{#subobject:6237f0|Regimen=1}}==
+==FLAG {{#subobject:600e85|Regimen=1}}==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#toc|back to top]]
 |}
+FLAG: '''<u>FL</u>'''udarabine, '''<u>A</u>'''ra-C (Cytarabine), '''<u>G</u>'''-CSF
-===Regimen {{#subobject:395e92|Variant=1}}===
+===Regimen {{#subobject:e2c900|Variant=1}}===
 {| border="1" style="text-align:center;" !align="left"
 |'''Study'''
@@ Line 1,707: / Line 1,777: @@
 |-
 |}
-''This regimen as reported resembles 7+3m; it is not clear whether the cytarabine is given as bolus or continuous infusion from the manuscript.''
 ====Chemotherapy====
-*[[Cytarabine (Cytosar)]] 200 mg/m<sup>2</sup>/day IV on days 1 to 7
+*[[Fludarabine (Fludara)]] 30 mg/m<sup>2</sup> IV over 30 minutes once per day on days 2 to 6
-*[[Mitoxantrone (Novantrone)]] 12 mg/m<sup>2</sup> IV once per day on days 1 to 3
+*[[Cytarabine (Cytosar)]] 2000 mg/m<sup>2</sup> IV once per day on days 1 to 6
-**Dose reduction to 8 mg/m<sup>2</sup> allowed on the basis of age, coexisting conditions, and previous anthracycline use
+*[[:Category:Granulocyte_growth_factors|G-CSF]] 5 μg/kg or at the institutional standard dose once per day (interval not specified)
-'''15-to-20-day cycle for up to 4 cycles'''
+'''28-day cycle for up to 4 cycles'''
 ===References===
-# 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. [http://www.nejm.org/doi/full/10.1056/NEJMoa1509277 link to original article] '''contains protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/27292104 PubMed]
+# 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. [http://www.nejm.org/doi/full/10.1056/NEJMoa1509277 link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/27292104 PubMed]
-==FLAG {{#subobject:600e85|Regimen=1}}==
+==Hyper-CVAD & Everolimus {{#subobject:71a41c|Regimen=1}}==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#toc|back to top]]
 |}
-FLAG: '''<u>FL</u>'''udarabine, '''<u>A</u>'''ra-C (Cytarabine), '''<u>G</u>'''-CSF
+Hyper-CVAD: '''<u>Hyper</u>'''fractionated '''<u>C</u>'''yclophosphamide, '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>D</u>'''examethasone
+===Regimen {{#subobject:2efb7e|Variant=1}}===
-===Regimen {{#subobject:e2c900|Variant=1}}===
 {| border="1" style="text-align:center;" !align="left"
 |'''Study'''
 |[[Levels_of_Evidence#Evidence|'''Evidence''']]
-|'''Comparator'''
 |-
-|[http://www.nejm.org/doi/full/10.1056/NEJMoa1509277 Kantarjian et al. 2016]
+|[http://clincancerres.aacrjournals.org/content/21/12/2704.full Daver et al. 2015]
 |<span
-style="background:#00cd00;
+style="background:#EEEE00;
 padding:3px 6px 3px 6px;
 border-color:black;
 border-width:2px;
-border-style:solid;">Phase III</span>
+border-style:solid;">Phase II</span>
-|[[Inotuzumab ozogamicin (CMC-544)|Inotuzumab ozogamicin]]
 |-
 |}
-====Chemotherapy====
-*[[Fludarabine (Fludara)]] 30 mg/m<sup>2</sup> IV over 30 minutes once per day on days 2 to 6
-*[[Cytarabine (Cytosar)]] 2000 mg/m<sup>2</sup> IV once per day on days 1 to 6
-*[[:Category:Granulocyte_growth_factors|G-CSF]] 5 μg/kg or at the institutional standard dose once per day (interval not specified)
-'''28-day cycle for up to 4 cycles'''
+''To be completed''
 ===References===
-# 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. [http://www.nejm.org/doi/full/10.1056/NEJMoa1509277 link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/27292104 PubMed]
+# Daver N, Boumber Y, Kantarjian H, Ravandi F, Cortes J, Rytting ME, Kawedia JD, Basnett J, Culotta KS, Zeng Z, Lu H, Richie MA, Garris R, Xiao L, Liu W, Baggerly KA, Jabbour E, O'Brien S, Burger J, Bendall LJ, Thomas D, Konopleva M. A Phase I/II Study of the mTOR Inhibitor Everolimus in Combination with HyperCVAD Chemotherapy in Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia. Clin Cancer Res. 2015 Jun 15;21(12):2704-14. Epub 2015 Feb 27. [http://clincancerres.aacrjournals.org/content/21/12/2704.full link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/25724525 PubMed]
-==Hyper-CVAD & Everolimus {{#subobject:71a41c|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#toc|back to top]]
-|}
-Hyper-CVAD: '''<u>Hyper</u>'''fractionated '''<u>C</u>'''yclophosphamide, '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>D</u>'''examethasone
-===Regimen {{#subobject:2efb7e|Variant=1}}===
-{| border="1" style="text-align:center;" !align="left"
-|'''Study'''
-|[[Levels_of_Evidence#Evidence|'''Evidence''']]
-|-
-|[http://clincancerres.aacrjournals.org/content/21/12/2704.full Daver et al. 2015]
-|<span
-style="background:#EEEE00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase II</span>
-|-
-|}
-''To be completed''
-===References===
-# Daver N, Boumber Y, Kantarjian H, Ravandi F, Cortes J, Rytting ME, Kawedia JD, Basnett J, Culotta KS, Zeng Z, Lu H, Richie MA, Garris R, Xiao L, Liu W, Baggerly KA, Jabbour E, O'Brien S, Burger J, Bendall LJ, Thomas D, Konopleva M. A Phase I/II Study of the mTOR Inhibitor Everolimus in Combination with HyperCVAD Chemotherapy in Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia. Clin Cancer Res. 2015 Jun 15;21(12):2704-14. Epub 2015 Feb 27. [http://clincancerres.aacrjournals.org/content/21/12/2704.full link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/25724525 PubMed]
-==Pediatric-like GRAALL salvage {{#subobject:d6d882|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#toc|back to top]]
-|}
-===Regimen {{#subobject:9cfc92|Variant=1}}===
-{| border="1" style="text-align:center;" !align="left"
-|'''Study'''
-|[[Levels_of_Evidence#Evidence|'''Evidence''']]
-|-
-|[http://jco.ascopubs.org/content/27/6/911.full Huguet et al. 2009 (GRAALL-2003)]
-|<span
-style="background:#EEEE00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase II</span>
-|-
-|}
-''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. Treatment preceded by [[#Pediatric-like_GRAALL_induction|pediatric-like GRAALL induction]].''
-====Chemotherapy====
-*[[Idarubicin (Idamycin)]] 12 mg/m<sup>2</sup> IV once per day on days 1 to 3
-*[[Cytarabine (Cytosar)]] 2000 mg/m<sup>2</sup> IV q12h on days 1 to 4
-====Supportive medications====
-*[[Lenograstim (Granocyte)]] 150 μg/m<sup>2</sup> SC once per day from day 9 until myeloid recovery
-''Patients achieving CR after salvage proceeded to [[#Pediatric-like_GRAALL_consolidation|pediatric-like GRAALL consolidation]].''
-===References===
-# 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. [http://jco.ascopubs.org/content/early/2015/12/07/JCO.2015.61.5385.long link to early article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19124805 PubMed]
 ==Vincristine liposomal (Marqibo) {{#subobject:f19406|Regimen=1}}==
@@ Line 1,864: / Line 1,867: @@
 ====Chemotherapy====
 *[[Bosutinib (Bosulif)]] 500 mg PO once per day, take with food
-**If no grade 3 or higher drug-related toxicity occurs, dose of [[Bosutinib (Bosulif)]] can be escalated to 600 mg PO once per day if response is suboptimal.  Suboptimal response defined as no complete hematologic response (CHR) by week 8 or complete cytogenetic response (CCyR) by week 12.
+**If no grade 3 or higher drug-related toxicity occurs, dose of [[Bosutinib (Bosulif)]] can be escalated to 600 mg PO once per day if response is suboptimal. Suboptimal response defined as no complete hematologic response (CHR) by week 8 or complete cytogenetic response (CCyR) by week 12.
 '''Given until progression of disease or unacceptable toxicity'''

Difference between revisions of "B-cell acute lymphoblastic leukemia"

Revision as of 00:13, 14 September 2016

Prephase

Prednisone (Sterapred)

Regimen

Chemotherapy

CNS treatment

References

Induction therapy, Ph-negative

ABFM

Regimen

References

Cyclophosphamide, Cytarabine, Mercaptopurine

Regimen

Chemotherapy

CNS prophylaxis

References

Cyclophosphamide, Daunorubicin, Vincristine, Prednisone

Regimen

Chemotherapy

References

Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone

Regimen #1

Chemotherapy

Supportive medications

Regimen #2, "Larson regimen"

Chemotherapy ("Course I")

Regimen #3

Chemotherapy

References

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

Regimen

References

Cyclophosphamide, Doxorubicin, L-Asparaginase, Vincristine, Prednisolone

Regimen

Chemotherapy

References

Cyclophosphamide, Idarubicin, Vincristine, Prednisone

Regimen

Chemotherapy

References

Daunorubicin, L-Asparaginase, Vincristine, Prednisone +/- Imatinib

Regimen #1

Chemotherapy

Ph+ patients

CNS prophylaxis

Regimen #2

Chemotherapy

Regimen #3, "Linker regimen"

Chemotherapy, part 1

Chemotherapy, part 2

Chemotherapy, part 3

CNS prophylaxis

CNS treatment

References

Hyper-CVAD/MA

Regimen

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

Supportive medications

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

Supportive medications

CNS prophylaxis

For known CNS disease

References

R-Hyper-CVAD/R-MA

Regimen #1, modified hyper-CVAD

Regimen #2

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

Supportive medications

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

Supportive medications

CNS prophylaxis

Dose modifications

References

Induction therapy, Ph-positive

Daunorubicin, Vincristine, Prednisolone, Nilotinib

Regimen

Chemotherapy

CNS Prophylaxis

References