B-cell acute lymphoblastic leukemia

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Are you looking for a regimen, but can't find it here? It is possible that we've moved it to the historical regimens page. If you still can't find it, please let us know so we can add it!
Note: certain regimens are to be found on dedicated pages:
*B-cell ALL, Ph-positive
*CNS leukemia
*T-cell acute lymphoblastic leukemia
*Pediatric B-cell ALL
**Pediatric B-cell ALL, Ph-positive
*Infant ALL
*We have moved How I Treat articles to a dedicated page.
Last updated on 2024-09-06:52 regimens on this page
66 variants on this page
Please note, mature B-cell ALL (L3) is now classified as Burkitt lymphoma/leukemia. Regimens for this variant are available here
=Guidelines=
Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.
==ESMO==
*2016: Hoelzer et al. Acute lymphoblastic leukaemia in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
==EWALL/EBMT==
*2019: Giebel et al. Hematopoietic stem cell transplantation for adults with Philadelphia chromosome-negative acute lymphoblastic leukemia in first remission: a position statement of the European Working Group for Adult Acute Lymphoblastic Leukemia (EWALL) and the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT) EuroPMC
==NCCN==
*NCCN does not currently have guidelines at this granular level; please see NCCN Guidelines - Acute Lymphoblastic Leukemia.
==SITC==
*2020: Boyiadzis et al. The Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of acute leukemia link to PMC article EuroPMC
=Protocols=
==ECOG-ACRIN E1910 protocol with blinatumomab==
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Litzow et al. 2024 (ECOG-ACRIN E1910)	2013-12 to 2019-10 	Phase 3 (E-esc)	ECOG-ACRIN E1910, no blinatumomab	Longer OS (primary endpoint)OS36: 85% vs 68%(HR 0.41, 95% CI 0.23-0.73)
===Induction, cycle 1===
====Chemotherapy====
*Daunorubicin (Cerubidine) 25 mg/m2 IV once per day on days 1, 8, 15, 22
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
*Pegaspargase (Oncaspar) by the following age-based criteria:
**Younger than 55 years old: 2000 IU/m2 (maximum dose of 3750 IU) IM or IV once on day 18
====Glucocorticoid therapy====
*Dexamethasone (Decadron) by the following age-based criteria:
**Younger than 55 years old: 10 mg/m2/day (maximum dose of 20 mg/day) PO on days 1 to 7, 15 to 21
**55 years old and older: 10 mg/m2/day (maximum dose of 20 mg/day) PO on days 1 to 7
====Targeted therapy====
*Rituximab (Rituxan) by the following biomarker-based criteria:
**CD20-positive: 375 mg/m2 IV once per day on days 8 & 15
====CNS therapy, prophylaxis====
*Cytarabine (Ara-C) 70 mg IT once on day 1
*Methotrexate (MTX) 12.5 mg IT once on day 14
28-day course
===Induction, cycle 2===
====Chemotherapy====
*Cyclophosphamide (Cytoxan) by the following age-based criteria:
**60 years old and younger: 1000 mg/m2 IV once per day on days 1 & 29
**Older than 60 years old: 800 mg/m2 IV once per day on days 1 & 29
*Cytarabine (Ara-C) 75 mg/m2 IV or SC once per day on days 1 to 4, 8 to 11, 29 to 32, 36 to 39
*Mercaptopurine (6-MP) 60 mg/m2 PO once per day on days 1 to 14, 29 to 42
*Pegaspargase (Oncaspar) by the following age-based criteria:
**Younger than 55 years old: 2000 IU/m2 (maximum dose of 3750 IU) IM or IV once on day 15
====Targeted therapy====
*Rituximab (Rituxan) by the following biomarker-based criteria:
**CD20-positive: 375 mg/m2 IV once per day on days 8 & 15
====CNS therapy, prophylaxis====
*Methotrexate (MTX) 12.5 mg IT once per day on days 1, 8, 15, 22
42-day course
===Intensification===
====Chemotherapy====
*Methotrexate (MTX) 3000 mg/m2 IV once per day on days 1 & 8
*Pegaspargase (Oncaspar) by the following age-based criteria:
**Younger than 55 years old: 2000 IU/m2 (maximum dose of 3750 IU) IM or IV once on day 9
**55 years old and older: 1000 IU/m2 (maximum dose of 3750 IU) IM or IV once on day 9
====Supportive therapy====
*Leucovorin (Folinic acid) 10 mg/m2 IV every 6 hours for 4 doses, starting 22 to 24 hours after completion of each dose of methotrexate, then 10 mg/m2 PO every 6 hours for 12 doses
28-day course
===Consolidation, cycle 1===
====Targeted therapy====
*Blinatumomab (Blincyto) 28 mcg/day IV continuous infusion over 28 days, started on day 1 (total dose: 784 mcg)
42-day course
===Consolidation, cycle 2===
====Targeted therapy====
*Blinatumomab (Blincyto) 28 mcg/day IV continuous infusion over 28 days, started on day 1 (total dose: 784 mcg)
28-day course
===Consolidation, cycle 3===
====Chemotherapy====
*Cytarabine (Ara-C) 75 mg/m2 IV or SC once per day on days 1 to 5
*Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 5
*Pegaspargase (Oncaspar) by the following age-based criteria:
**Younger than 55 years old: 2000 IU/m2 (maximum dose of 3750 IU) IM or IV once on day 5
**55 years old and older: 1000 IU/m2 (maximum dose of 3750 IU) IM or IV once on day 5
====Targeted therapy====
*Rituximab (Rituxan) by the following biomarker-based criteria:
**CD20-positive: 375 mg/m2 IV once on day 5
====CNS therapy, prophylaxis====
*Methotrexate (MTX) 12.5 mg IT once on day 1
28-day course
===Consolidation, cycle 4===
====Chemotherapy====
*Cytarabine (Ara-C) 75 mg/m2 IV or SC once per day on days 1 to 5
*Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 5
====Targeted therapy====
*Rituximab (Rituxan) by the following biomarker-based criteria:
**CD20-positive: 375 mg/m2 IV once on day 5
====CNS therapy, prophylaxis====
*Methotrexate (MTX) 12.5 mg IT once on day 1
28-day course
===Consolidation, cycle 5===
====Chemotherapy====
*Daunorubicin (Cerubidine) 25 mg/m2 IV push once per day on days 1, 8, 15, 22
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
*Cyclophosphamide (Cytoxan) 650 mg/m2 IV once on day 29
*Cytarabine (Ara-C) 75 mg/m2 IV or SC once per day on days 30 to 33, 37 to 40
*Mercaptopurine (6-MP) 60 mg/m2 PO once per day on days 29 to 42
====Glucocorticoid therapy====
*Dexamethasone (Decadron) by the following age-based criteria:
**Younger than 55 years old: 10 mg/m2/day (maximum dose of 20 mg/day) PO on days 1 to 7, 15 to 21
**55 years old and older: 10 mg/m2/day (maximum dose of 20 mg/day) PO on days 1 to 7
====Targeted therapy====
*Rituximab (Rituxan) by the following biomarker-based criteria:
**CD20-positive: 375 mg/m2 IV once on day 8
====CNS therapy, prophylaxis====
*Methotrexate (MTX) 12.5 mg IT once on day 2
42-day course
===Consolidation, cycle 6===
====Targeted therapy====
*Blinatumomab (Blincyto) 28 mcg/day IV continuous infusion over 28 days, started on day 1 (total dose: 784 mcg)
28-day course
===Consolidation, cycle 7===
====Chemotherapy====
*Cytarabine (Ara-C) 75 mg/m2 IV or SC once per day on days 1 to 5
*Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 5
====Targeted therapy====
*Rituximab (Rituxan) by the following biomarker-based criteria:
**CD20-positive: 375 mg/m2 IV once on day 5
====CNS therapy, prophylaxis====
*Methotrexate (MTX) 12.5 mg IT once on day 1
28-day course
===Consolidation, cycle 8===
====Targeted therapy====
*Blinatumomab (Blincyto) 28 mcg/day IV continuous infusion over 28 days, started on day 1 (total dose: 784 mcg)
28-day course
===Maintenance===
====Chemotherapy====
*Mercaptopurine (6-MP) 75 mg/m2 PO once per day
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
*Methotrexate (MTX) 20 mg/m2 IV or PO once per week
====Glucocorticoid therapy====
*Prednisone (Sterapred) 60 mg/m2 PO once per day on days 1 to 5
====CNS therapy, prophylaxis====
*Methotrexate (MTX) 12.5 mg IT once on day 1
3-month cycle for 10 cycles
===References===
#ECOG-ACRIN E1910: Litzow MR, Sun Z, Mattison RJ, Paietta EM, Roberts KG, Zhang Y, Racevskis J, Lazarus HM, Rowe JM, Arber DA, Wieduwilt MJ, Liedtke M, Bergeron J, Wood BL, Zhao Y, Wu G, Chang TC, Zhang W, Pratz KW, Dinner SN, Frey N, Gore SD, Bhatnagar B, Atallah EL, Uy GL, Jeyakumar D, Lin TL, Willman CL, DeAngelo DJ, Patel SB, Elliott MA, Advani AS, Tzachanis D, Vachhani P, Bhave RR, Sharon E, Little RF, Erba HP, Stone RM, Luger SM, Mullighan CG, Tallman MS. Blinatumomab for MRD-Negative Acute Lymphoblastic Leukemia in Adults. N Engl J Med. 2024 Jul 25;391(4):320-333. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02003222
==ECOG-ACRIN E1910 protocol without blinatumomab==
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Litzow et al. 2024 (ECOG-ACRIN E1910)	2013-12 to 2019-10 	Phase 3 (C)	ECOG-ACRIN E1910, blinatumomab	Shorter OSOS36: 68% vs 85%(HR 2.44, 95% CI 1.37-4.35)
===Induction, cycle 1===
====Chemotherapy====
*Daunorubicin (Cerubidine) 25 mg/m2 IV once per day on days 1, 8, 15, 22
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
*Pegaspargase (Oncaspar) by the following age-based criteria:
**Younger than 55 years old: 2000 IU/m2 (maximum dose of 3750 IU) IM or IV once on day 18
====Glucocorticoid therapy====
*Dexamethasone (Decadron) by the following age-based criteria:
**Younger than 55 years old: 10 mg/m2/day (maximum dose of 20 mg/day) PO on days 1 to 7, 15 to 21
**55 years old and older: 10 mg/m2/day (maximum dose of 20 mg/day) PO on days 1 to 7
====Targeted therapy====
*Rituximab (Rituxan) by the following biomarker-based criteria:
**CD20-positive: 375 mg/m2 IV once per day on days 8 & 15
====CNS therapy, prophylaxis====
*Cytarabine (Ara-C) 70 mg IT once on day 1
*Methotrexate (MTX) 12.5 mg IT once on day 14
28-day course
===Induction, cycle 2===
====Chemotherapy====
*Cyclophosphamide (Cytoxan) by the following age-based criteria:
**60 years old and younger: 1000 mg/m2 IV once per day on days 1 & 29
**Older than 60 years old: 800 mg/m2 IV once per day on days 1 & 29
*Cytarabine (Ara-C) 75 mg/m2 IV or SC once per day on days 1 to 4, 8 to 11, 29 to 32, 36 to 39
*Mercaptopurine (6-MP) 60 mg/m2 PO once per day on days 1 to 14, 29 to 42
*Pegaspargase (Oncaspar) by the following age-based criteria:
**Younger than 55 years old: 2000 IU/m2 (maximum dose of 3750 IU) IM or IV once on day 15
====Targeted therapy====
*Rituximab (Rituxan) by the following biomarker-based criteria:
**CD20-positive: 375 mg/m2 IV once per day on days 8 & 15
====CNS therapy, prophylaxis====
*Methotrexate (MTX) 12.5 mg IT once per day on days 1, 8, 15, 22
42-day course
===Intensification===
====Chemotherapy====
*Methotrexate (MTX) 3000 mg/m2 IV once per day on days 1 & 8
*Pegaspargase (Oncaspar) by the following age-based criteria:
**Younger than 55 years old: 2000 IU/m2 (maximum dose of 3750 IU) IM or IV once on day 9
**55 years old and older: 1000 IU/m2 (maximum dose of 3750 IU) IM or IV once on day 9
====Supportive therapy====
*Leucovorin (Folinic acid) 10 mg/m2 IV every 6 hours for 4 doses, starting 22 to 24 hours after completion of each dose of methotrexate, then 10 mg/m2 PO every 6 hours for 12 doses
28-day course
===Consolidation, cycle 1===
====Chemotherapy====
*Cytarabine (Ara-C) 75 mg/m2 IV or SC once per day on days 1 to 5
*Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 5
*Pegaspargase (Oncaspar) by the following age-based criteria:
**Younger than 55 years old: 2000 IU/m2 (maximum dose of 3750 IU) IM or IV once on day 5
**55 years old and older: 1000 IU/m2 (maximum dose of 3750 IU) IM or IV once on day 5
====Targeted therapy====
*Rituximab (Rituxan) by the following biomarker-based criteria:
**CD20-positive: 375 mg/m2 IV once on day 5
====CNS therapy, prophylaxis====
*Methotrexate (MTX) 12.5 mg IT once on day 1
28-day course
===Consolidation, cycle 2===
====Chemotherapy====
*Cytarabine (Ara-C) 75 mg/m2 IV or SC once per day on days 1 to 5
*Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 5
====Targeted therapy====
*Rituximab (Rituxan) by the following biomarker-based criteria:
**CD20-positive: 375 mg/m2 IV once on day 5
====CNS therapy, prophylaxis====
*Methotrexate (MTX) 12.5 mg IT once on day 1
28-day course
===Consolidation, cycle 3===
====Chemotherapy====
*Daunorubicin (Cerubidine) 25 mg/m2 IV push once per day on days 1, 8, 15, 22
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
*Cyclophosphamide (Cytoxan) 650 mg/m2 IV once on day 29
*Cytarabine (Ara-C) 75 mg/m2 IV or SC once per day on days 30 to 33, 37 to 40
*Mercaptopurine (6-MP) 60 mg/m2 PO once per day on days 29 to 42
====Glucocorticoid therapy====
*Dexamethasone (Decadron) by the following age-based criteria:
**Younger than 55 years old: 10 mg/m2/day (maximum dose of 20 mg/day) PO on days 1 to 7, 15 to 21
**55 years old and older: 10 mg/m2/day (maximum dose of 20 mg/day) PO on days 1 to 7
====Targeted therapy====
*Rituximab (Rituxan) by the following biomarker-based criteria:
**CD20-positive: 375 mg/m2 IV once on day 8
====CNS therapy, prophylaxis====
*Methotrexate (MTX) 12.5 mg IT once on day 2
42-day course
===Consolidation, cycle 4===
====Chemotherapy====
*Cytarabine (Ara-C) 75 mg/m2 IV or SC once per day on days 1 to 5
*Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 5
====Targeted therapy====
*Rituximab (Rituxan) by the following biomarker-based criteria:
**CD20-positive: 375 mg/m2 IV once on day 5
====CNS therapy, prophylaxis====
*Methotrexate (MTX) 12.5 mg IT once on day 1
28-day course
===Maintenance===
====Chemotherapy====
*Mercaptopurine (6-MP) 75 mg/m2 PO once per day
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
*Methotrexate (MTX) 20 mg/m2 IV or PO once per week
====Glucocorticoid therapy====
*Prednisone (Sterapred) 60 mg/m2 PO once per day on days 1 to 5
====CNS therapy, prophylaxis====
*Methotrexate (MTX) 12.5 mg IT once on day 1
3-month cycle for 10 cycles
===References===
#ECOG-ACRIN E1910: Litzow MR, Sun Z, Mattison RJ, Paietta EM, Roberts KG, Zhang Y, Racevskis J, Lazarus HM, Rowe JM, Arber DA, Wieduwilt MJ, Liedtke M, Bergeron J, Wood BL, Zhao Y, Wu G, Chang TC, Zhang W, Pratz KW, Dinner SN, Frey N, Gore SD, Bhatnagar B, Atallah EL, Uy GL, Jeyakumar D, Lin TL, Willman CL, DeAngelo DJ, Patel SB, Elliott MA, Advani AS, Tzachanis D, Vachhani P, Bhave RR, Sharon E, Little RF, Erba HP, Stone RM, Luger SM, Mullighan CG, Tallman MS. Blinatumomab for MRD-Negative Acute Lymphoblastic Leukemia in Adults. N Engl J Med. 2024 Jul 25;391(4):320-333. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02003222
=Pre-phase=
==Prednisone monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Huguet et al. 2009 (GRAALL-2003)	2003-2005 	Phase 2
Note: in GRAALL-2003, this regimen was meant for patients up to 60 years old. The original Huguet et al. 2009 article Table 1 has several errors which were corrected in the erratum and the online Table 1. These corrected doses are replicated here. See paper for details on CNS prophylaxis and treatment.
====Glucocorticoid therapy====
*Prednisone (Sterapred) 60 mg/m2/day PO on days 1 to 7
====CNS therapy, prophylaxis====
*Methotrexate (MTX) 15 mg IT once on day 1
7-day course
====Subsequent treatment====
*Cyclophosphamide, Daunorubicin, L-asparaginase, Vincristine, Prednisone induction
===References===
# GRAALL-2003: Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00222027
==Vincristine & Prednisone==
VP: Vincristine & Prednisone
===Regimen===
Study 	Dates of enrollment	Evidence
McCredie et al. 1983 (SWOG-7416)	1975-1977 	Non-randomized part of RCT
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
====Chemotherapy====
*Vincristine (Oncovin) 2 mg IV once on day 1
====Glucocorticoid therapy====
*Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5
5-day course
===References===
# SWOG-7416: McCredie KB, Gehan EA, Freireich EJ, Hewlett JS, Coltman CA Jr, Hussein KK, Balcerzak SP, Chen TT. Management of adult acute leukemia: a Southwest Oncology Group study. Cancer. 1983 Sep 15;52(6):958-66. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
=Upfront induction therapy=
==Blinatumomab monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence
Advani et al. 2022 (SWOG S1318)	2015 to not reported	Phase 2
====Immunotherapy====
*Blinatumomab (Blincyto) as follows:
**Cycle 1: 9 mcg/m2/day IV continuous infusion over 7 days, started on day 1, then 28 mcg/m2/day IV continuous infusion over 21 days, started on day 1 (total dose per cycle: 651 mcg/m2)
**Cycle 2: 28 mcg/m2/day IV continuous infusion over 28 days, started on day 1 (total dose per cycle: 784 mcg/m2)
2 cycles
====Subsequent treatment====
*SWOG S1318, CR or CRi: Blinatumomab consolidation, then POMP maintenance
===References===
# SWOG S1318: Advani AS, Moseley A, O'Dwyer KM, Wood BL, Fang M, Wieduwilt MJ, Aldoss I, Park JH, Klisovic RB, Baer MR, Stock W, Bhave RR, Othus M, Harvey RC, Willman CL, Litzow MR, Stone RM, Sharon E, Erba HP. SWOG 1318: A Phase II Trial of Blinatumomab Followed by POMP Maintenance in Older Patients With Newly Diagnosed Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia. J Clin Oncol. 2022 May 10;40(14):1574-1582. Epub 2022 Feb 14. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02143414
==Cyclophosphamide, Cytarabine, Mercaptopurine==
===Regimen===
Study 	Dates of enrollment	Evidence
Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)	1993-2003 	Non-randomized part of phase 3 RCT
====Preceding treatment====
*MRC UKALL XII/ECOG E2993, Ph-: "Phase 1" induction: DOLP
*MRC UKALL XII/ECOG E2993, Ph+: "Phase 1" induction: Daunorubicin, L-asparaginase, Vincristine, Prednisone, Imatinib
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 650 mg/m2 IV once per day on days 1, 15, 29
*Cytarabine (Ara-C) 75 mg/m2 IV once per day on days 1 to 4, 8 to 11, 15 to 18, 22 to 25
*Mercaptopurine (6-MP) 6 mg/m2 PO once per day on days 1 to 28
====CNS therapy, prophylaxis====
*Methotrexate (MTX) 12 mg IT once per day on days 1, 8, 15, 22
29-day course
====Subsequent treatment====
*L-asparaginase & Methotrexate early intensification
===References===
# MRC UKALL XII/ECOG E2993: Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00002514
## Update: Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, Burnett AK, Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J, McMillan A, Franklin IM, Luger S, Ciobanu N, Rowe JM. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008 Feb 15;111(4):1827-33. Epub 2007 Nov 29. link to original article EuroPMC 
## Update: Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, Marks DI, McMillan AK, Litzow MR, Lazarus HM, Foroni L, Dewald G, Franklin IM, Luger SM, Paietta E, Wiernik PH, Tallman MS, Goldstone AH. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009 May 7;113(19):4489-96. Epub 2009 Feb 24. link to original article link to PMC article EuroPMC 
## 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
==Cyclophosphamide, Daunorubicin, Vincristine, Prednisone==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Thomas et al. 2004 (LALA-94)	1994-2002 	Phase 3 (C)	Cyclophosphamide, Idarubicin, Vincristine, Prednisone	Seems to have shorter DFS
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once per day on days 1 & 8
*Daunorubicin (Cerubidine) 30 mg/m2 IV once per day on days 1 to 3, 15, 16
*Vincristine (Oncovin) 2 mg IV once per day on days 1, 8, 15, 22
====Glucocorticoid therapy====
*Prednisone (Sterapred) 60 mg/m2/day IV or PO on days 1 to 7, 15 to 21
28-day course
====Subsequent treatment====
*Consolidation (see paper for details)
===References===
# LALA-94: Thomas X, Boiron JM, Huguet F, Dombret H, Bradstock K, Vey N, Kovacsovics T, Delannoy A, Fegueux N, Fenaux P, Stamatoullas A, Vernant JP, Tournilhac O, Buzyn A, Reman O, Charrin C, Boucheix C, Gabert J, Lhéritier V, Fiere D. Outcome of treatment in adults with acute lymphoblastic leukemia: analysis of the LALA-94 trial. J Clin Oncol. 2004 Oct 15;22(20):4075-86. Epub 2004 Sep 7. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00002700
## Update: Vey N, Thomas X, Picard C, Kovascovicz T, Charin C, Cayuela JM, Dombret H, Dastugue N, Huguet F, Bastard C, Stamatoulas A, Giollant M, Tournilhac O, Macintyre E, Buzyn A, Bories D, Kuentz M, Dreyfus F, Delannoy A, Raynaud S, Gratecos N, Bordessoule D, de Botton S, Preudhomme C, Reman O, Troussard X, Pigneux A, Bilhou C, Vernant JP, Boucheix C, Gabert J; GET-LALA Group the Swiss Group for Clinical Cancer Research (SAKK). Allogeneic stem cell transplantation improves the outcome of adults with t(1;19)/E2A-PBX1 and t(4;11)/MLL-AF4 positive B-cell acute lymphoblastic leukemia: results of the prospective multicenter LALA-94 study. Leukemia. 2006 Dec;20(12):2155-61. Epub 2006 Oct 12. link to original article EuroPMC
==Cyclophosphamide, Daunorubicin, Vincristine, Prednisolone==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Labar et al. 2010 (EORTC ALL-4)	1995-2003 	Phase 3 (C)	Cyclophosphamide, Daunorubicin, Vincristine, Dexamethasone	Did not meet primary endpoint of EFS72
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once per day on days 1 & 8
*Daunorubicin (Cerubidine) 30 mg/m2 IV once per day on days 1 to 3, 15, 16
*Vincristine (Oncovin) 2 mg IV once per day on days 1, 8, 15, 23
====Glucocorticoid therapy====
*Prednisolone (Millipred) 60 mg/m2/day IV or PO on days 1 to 8, 15 to 22
====CNS therapy, prophylaxis====
*Methotrexate (MTX) 15 mg IT once per day on days 1, 8, 15, 22, 28
28-day course
====Subsequent treatment====
*HAM consolidation
===References===
# EORTC ALL-4: Labar B, Suciu S, Willemze R, Muus P, Marie JP, Fillet G, Berneman Z, Jaksic B, Feremans W, Bron D, Sinnige H, Mistrik M, Vreugdenhil G, De Bock R, Nemet D, Gilotay C, Amadori S, de Witte T; EORTC Leukemia Group. Dexamethasone compared to prednisolone for adults with acute lymphoblastic leukemia or lymphoblastic lymphoma: final results of the ALL-4 randomized, phase III trial of the EORTC Leukemia Group. Haematologica. 2010 Sep;95(9):1489-95. Epub 2010 Apr 7. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC
==Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone==
===Regimen variant #1===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Huguet et al. 2009 (GRAALL-2003) 	2003-2005 	Phase 2 	 	
Maury et al. 2016 (GRAALL-2005/R)	2006-2014 	Phase 3 (C)	Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone, Rituximab 	Seems to have shorter EFSEFS24: 52% vs 65%(HR 1.52, 95% CI 1.02-2.22)
Huguet et al. 2018 (GRAALL-2005) 	2006-2014 	Phase 3 (C)	Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone; hyperfractionated cyclophosphamide	Did not meet primary endpoint of EFS
Note: this "pediatric-like" regimen was meant for patients up to 60 years old. The original Huguet et al. 2009 article Table 1 has several errors which were corrected in the erratum and the online Table 1. These corrected doses are replicated here. See paper for details on CNS treatment. This is the "standard-dose cyclophosphamide" arm of GRAALL-2005.
====Preceding treatment====
*Prednisone pre-phase
====Chemotherapy====
*Cyclophosphamide (Cytoxan) by the following study-specific criteria:
**GRAALL-2003, good early responders: 750 mg/m2 IV over 3 hours once per day on days 1 & 15
**GRAALL-2005: 750 mg/m2 IV over 3 hours once per day on days 1 & 15
**GRAALL-2003, poor early responders: 750 mg/m2 IV once on day 1, then 500 mg/m2 IV every 12 hours on days 15 & 16
*Daunorubicin (Cerubidine) 50 mg/m2 IV once per day on days 1 to 3, then 30 mg/m2 IV once per day on days 15 & 16
*Asparaginase (Elspar) 6000 units/m2 IV over 60 minutes once per day on days 8, 10, 12, 20, 22, 24, 26, 28
*Vincristine (Oncovin) 2 mg IV once per day on days 1, 8, 15, 22
====Glucocorticoid therapy====
*Prednisone (Sterapred) 60 mg/m2/day PO on days 1 to 14
====CNS therapy, prophylaxis====
*Methotrexate (MTX) 15 mg IT once per day on days 1 & 8
*Cytarabine (Ara-C) 40 mg IT once per day on days 1 & 8
*Methylprednisolone (Solumedrol) 40 mg IT once per day on days 1 & 8
====Supportive therapy====
*Lenograstim (Granocyte) by the following study-specific criteria:
**GRAALL-2003: 150 mcg/m2 SC once per day from day 17 until myeloid recovery
**GRAALL-2005: 263 mcg SC once per day from day 18 until first day with ANC greater than 1000/μL
====Subsequent treatment====
*GRAALL-2005/R, patients with resistant disease: Cytarabine & idarubicin salvage prior to further consolidation
*GRAALL-2005/R, responders: Pediatric-like GRAALL consolidation
===Regimen variant #2, "HyperC"===
Historic variant
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Maury et al. 2016 (GRAALL-2005/R)	2006-2014 	Phase 3 (C) 	Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone, Rituximab 	Seems to have shorter EFSEFS24: 52% vs 65%(HR 1.52, 95% CI 1.02-2.22)
Huguet et al. 2018 (GRAALL-2005) 	2006-2014 	Phase 3 (E-esc)	Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone; standard-dose cyclophosphamide	Did not meet primary endpoint of EFS
This is the "HyperC" arm of GRAALL-2005. Given the negative report in 2018, this experimental arm should be considered as historic reference.
====Preceding treatment====
*Prednisone pre-phase
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV over 3 hours once on day 1, then 300 mg/m2 IV over 3 hours every 12 hours on days 15 to 17 (total dose: 2550 mg/m2)
*Daunorubicin (Cerubidine) 50 mg/m2 IV once per day on days 1 to 3, then 30 mg/m2 IV once per day on days 15 & 16
*Asparaginase (Elspar) 6000 units/m2 IV over 60 minutes once per day on days 8, 10, 12, 20, 22, 24, 26, 28
*Vincristine (Oncovin) 2 mg IV once per day on days 1, 8, 15, 22
====Glucocorticoid therapy====
*Prednisone (Sterapred) 60 mg/m2/day PO on days 1 to 14
====CNS therapy, prophylaxis====
*Methotrexate (MTX) 15 mg IT once per day on days 1 & 8
*Cytarabine (Ara-C) 40 mg IT once per day on days 1 & 8
*Methylprednisolone (Solumedrol) 40 mg IT once per day on days 1 & 8
====Supportive therapy====
*Lenograstim (Granocyte) 263 mcg SC once per day from day 18 until first day with ANC greater than 1000/μL
28-day course
====Subsequent treatment====
*GRAALL-2005/R, patients with resistant disease: Cytarabine & idarubicin salvage prior to further consolidation
*GRAALL-2005/R, responders: Pediatric-like GRAALL consolidation
===Regimen variant #3===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Annino et al. 2002 (GIMEMA ALL 0288)	1988-1996 	Phase 3 (E-esc)	DOLP 	Did not meet primary endpoint of CR rate
Note: vincristine is clearly shown as 2 mg/m2 in Table 1, but this is an unusual dose; consider discussing with the authors if you are going to utilize this regimen.
====Chemotherapy, "Induction phase I"====
*Cyclophosphamide (Cytoxan) 800 mg/m2 IV once per day on days 1 & 2
*Daunorubicin (Cerubidine) 40 mg/m2 IV once per day on days 1, 8, 15, 22
*L-Asparaginase 6000 units/m2 SC once per day on days 22 to 31
*Vincristine (Oncovin) 2 mg/m2 IV once per day on days 1, 8, 15, 22
====Glucocorticoid therapy====
*Prednisone (Sterapred) 60 mg/m2/day PO on days 1 to 14, then 40 mg/m2/day PO on days 15 to 31
31-day course
====Subsequent treatment====
*GIMEMA ALL 0288, responders: Induction phase II, see paper for details
*GIMEMA ALL 0288, non-responders: Salvage, see paper for details
===Regimen variant #4, "Larson regimen"===
Study 	Dates of enrollment	Evidence
Larson et al. 1995 (CALGB 8811)	1988-1991 	Phase 2
====Chemotherapy, "Course I"====
*Cyclophosphamide (Cytoxan) by the following age-based criteria:
**Younger than 60 years old: 1200 mg/m2 IV once on day 1
**60 years old or older: 800 mg/m2 IV once on day 1
*Daunorubicin (Cerubidine) by the following age-based criteria:
**Younger than 60 years old: 45 mg/m2 IV once per day on days 1 to 3
**60 years old or older: 30 mg/m2 IV once per day on days 1 to 3
*Asparaginase (Elspar) 6000 units/m2 SC once per day on days 5, 8, 11, 15, 18, 22
*Vincristine (Oncovin) 2 mg IV once per day on days 1, 8, 15, 22
====Glucocorticoid therapy====
*Prednisone (Sterapred) by the following age-based criteria:
**Younger than 60 years old: 60 mg/m2 PO once per day on days 1 to 21
**60 years old or older: 60 mg/m2 PO once per day on days 1 to 7
28-day course
====Subsequent treatment====
*Larson regimen (CALGB 8811) early intensification ("Course II")
===References===
# CALGB 8811: Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR, Hooberman AL, Westbrook CA, Arthur DC, George SL, Bloomfield CD, Schiffer CA. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: Cancer and Leukemia Group B study 8811. Blood. 1995 Apr 15;85(8):2025-37. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# GIMEMA ALL 0288: Annino L, Vegna ML, Camera A, Specchia G, Visani G, Fioritoni G, Ferrara F, Peta A, Ciolli S, Deplano W, Fabbiano F, Sica S, Di Raimondo F, Cascavilla N, Tabilio A, Leoni P, Invernizzi R, Baccarani M, Rotoli B, Amadori S, Mandelli F; GIMEMA. Treatment of adult acute lymphoblastic leukemia (ALL): long-term follow-up of the GIMEMA ALL 0288 randomized study. Blood. 2002 Feb 1;99(3):863-71. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# GRAALL-2003: Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00222027
# GRAALL-2005/R: Maury S, Chevret S, Thomas X, Heim D, Leguay T, Huguet F, Chevallier P, Hunault M, Boissel N, Escoffre-Barbe M, Hess U, Vey N, Pignon JM, Braun T, Marolleau JP, Cahn JY, Chalandon Y, Lhéritier V, Beldjord K, Béné MC, Ifrah N, Dombret H; GRAALL. Rituximab in B-lineage adult acute lymphoblastic leukemia. N Engl J Med. 2016 Sep 15;375(11):1044-53. link to original article link to supplement dosing details in supplement have been reviewed by our editors EuroPMC NCT00327678
# GRAALL-2005: Huguet F, Chevret S, Leguay T, Thomas X, Boissel N, Escoffre-Barbe M, Chevallier P, Hunault M, Vey N, Bonmati C, Lepretre S, Marolleau JP, Pabst T, Rousselot P, Buzyn A, Cahn JY, Lhéritier V, Béné MC, Asnafi V, Delabesse E, Macintyre E, Chalandon Y, Ifrah N, Dombret H; Group of Research on Adult ALL. Intensified therapy of acute lymphoblastic leukemia in adults: report of the randomized GRAALL-2005 clinical trial. J Clin Oncol. 2018 Aug 20;36(24):2514-2523. Epub 2018 Jun 4. link to original article EuroPMC NCT00327678
==Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone, Rituximab==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Maury et al. 2016 (GRAALL-2005/R)	2006-2014 	Phase 3 (E-esc)	Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone	Seems to have longer EFS (primary endpoint)EFS24: 65% vs 52%(HR 0.66, 95% CI 0.45-0.98)
Note: this regimen was meant for CD20+ patients less than 60 years old. This is the "standard" arm of GRAALL-2005/R.
====Preceding treatment====
*Prednisone pre-phase
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV over 3 hours once per day on days 1 & 15
*Daunorubicin (Cerubidine) 50 mg/m2 IV once per day on days 1 to 3, then 30 mg/m2 IV once per day on days 15 & 16
*Asparaginase (Elspar) 6000 units/m2 IV over 60 minutes once per day on days 8, 10, 12, 20, 22, 24, 26, 28
*Vincristine (Oncovin) 2 mg IV once per day on days 1, 8, 15, 22
====Glucocorticoid therapy====
*Prednisone (Sterapred) 60 mg/m2/day PO on days 1 to 14
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once per day on days 1 & 7
====CNS therapy, prophylaxis====
*Methotrexate (MTX) 15 mg IT once per day on days 1 & 8
*Cytarabine (Ara-C) 40 mg IT once per day on days 1 & 8
*Methylprednisolone (Solumedrol) 40 mg IT once per day on days 1 & 8
====Supportive therapy====
*Lenograstim (Granocyte) by the following study-specific criteria:
**GRAALL-2003: 150 mcg/m2 SC once per day from day 17 until myeloid recovery
**GRAALL-2005: 263 mcg SC once per day from day 18 until first day with ANC greater than 1000/μL
One course
====Subsequent treatment====
*GRAALL-2005/R, patients with resistant disease: Cytarabine, idarubicin, rituximab salvage prior to further consolidation
*GRAALL-2005/R, PR or better: Pediatric-like GRAALL consolidation with rituximab
===References===
# GRAALL-2005/R: Maury S, Chevret S, Thomas X, Heim D, Leguay T, Huguet F, Chevallier P, Hunault M, Boissel N, Escoffre-Barbe M, Hess U, Vey N, Pignon JM, Braun T, Marolleau JP, Cahn JY, Chalandon Y, Lhéritier V, Beldjord K, Béné MC, Ifrah N, Dombret H; GRAALL. Rituximab in B-lineage adult acute lymphoblastic leukemia. N Engl J Med. 2016 Sep 15;375(11):1044-53. link to original article link to supplement dosing details in supplement have been reviewed by our editors EuroPMC NCT00327678
==Cyclophosphamide, Idarubicin, Vincristine, Prednisone==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Thomas et al. 2004 (LALA-94)	1994-2002 	Phase 3 (E-switch-ic)	Cyclophosphamide, Daunorubicin, Vincristine, Prednisone	Seems to have longer DFS (primary endpoint)
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once per day on days 1 & 8
*Idarubicin (Idamycin) 9 mg/m2 IV once per day on days 1, 2, 3, 8
*Vincristine (Oncovin) 2 mg IV once per day on days 1, 8, 15, 22
====Glucocorticoid therapy====
*Prednisone (Sterapred) 60 mg/m2/day IV or PO on days 1 to 7, 15 to 21
28-day course
====Subsequent treatment====
*Consolidation (see paper for details)
===References===
# LALA-94: Thomas X, Boiron JM, Huguet F, Dombret H, Bradstock K, Vey N, Kovacsovics T, Delannoy A, Fegueux N, Fenaux P, Stamatoullas A, Vernant JP, Tournilhac O, Buzyn A, Reman O, Charrin C, Boucheix C, Gabert J, Lhéritier V, Fiere D; SAKK. Outcome of treatment in adults with acute lymphoblastic leukemia: analysis of the LALA-94 trial. J Clin Oncol. 2004 Oct 15;22(20):4075-86. Epub 2004 Sep 7. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00002700
## Update: Vey N, Thomas X, Picard C, Kovascovicz T, Charin C, Cayuela JM, Dombret H, Dastugue N, Huguet F, Bastard C, Stamatoulas A, Giollant M, Tournilhac O, Macintyre E, Buzyn A, Bories D, Kuentz M, Dreyfus F, Delannoy A, Raynaud S, Gratecos N, Bordessoule D, de Botton S, Preudhomme C, Reman O, Troussard X, Pigneux A, Bilhou C, Vernant JP, Boucheix C, Gabert J; GET-LALA Group the Swiss Group for Clinical Cancer Research (SAKK). Allogeneic stem cell transplantation improves the outcome of adults with t(1;19)/E2A-PBX1 and t(4;11)/MLL-AF4 positive B-cell acute lymphoblastic leukemia: results of the prospective multicenter LALA-94 study. Leukemia. 2006 Dec;20(12):2155-61. Epub 2006 Oct 12. link to original article EuroPMC
==DOLP==
DOLP: Daunorubicin, Oncovin (Vincristine), L-Asparaginase, Prednisone
DVPA: Daunorubicin, Vincristine, Prednisone, Asparaginase
===Regimen variant #1, 25/5000/1.5/60===
Historic variant
Study 	Dates of enrollment	Evidence
Hoelzer et al. 1984	1978-1981 	Non-randomized
Note: This variant is of historic interest. This is "Phase 1" of induction.
====Chemotherapy====
*Daunorubicin (Cerubidine) 25 mg/m2 IV once per day on days 1, 8, 15, 22
*Vincristine (Oncovin) 1.5 mg/m2 IV once per day on days 1, 8, 15, 22
*Asparaginase (Elspar) 5000 units IV once per day on days 1 to 14
====Glucocorticoid therapy====
*Prednisone (Sterapred) 60 mg/m2/day PO on days 1 to 28
4-week course
====Subsequent treatment====
*See paper for details of treatment beyond induction
===Regimen variant #2, 40/6000/2/60-40 ("Phase I" of GIMEMA ALL 0288)===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Annino et al. 2002 (GIMEMA ALL 0288)	1988-1996 	Phase 3 (C)	Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone	Did not meet primary endpoint of CR rate
Note: vincristine is clearly shown as 2 mg/m2 in Table 1, but this is an unusual dose; consider discussing with the authors if you are going to utilize this regimen.
====Chemotherapy====
*Daunorubicin (Cerubidine) 40 mg/m2 IV once per day on days 1, 8, 15, 22
*Vincristine (Oncovin) 2 mg/m2 IV once per day on days 1, 8, 15, 22
*L-Asparaginase 6000 units/m2 SC once per day on days 22 to 31
====Glucocorticoid therapy====
*Prednisone (Sterapred) 60 mg/m2/day PO on days 1 to 14, then 40 mg/m2/day PO on days 15 to 31
31-day course
====Subsequent treatment====
*Induction phase II or salvage (see paper for details)
===Regimen variant #3, 45/500/2/40===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Gottlieb et al. 1984 (CALGB 7612)	1976-1980 	Randomized (E-RT-esc)	L-asparaginase, Vincristine, Prednisone	Higher CR rate
====Chemotherapy====
*Daunorubicin (Cerubidine) 45 mg/m2 IV once per day on days 1 to 3
*Vincristine (Oncovin) 2 mg IV once per day on days 1, 8, 15
*Asparaginase (Elspar) 500 units/kg IV once per day on days 22 to 31
====Glucocorticoid therapy====
*Prednisone (Sterapred) 40 mg/m2/day PO on days 1 to 22, then tapered to off by day 29
31-day course
====Subsequent treatment====
*See paper for details of treatment beyond induction
===Regimen variant #4, 50/6000/2/60 ("Linker regimen")===
Study 	Dates of enrollment	Evidence
Linker et al. 1987	1980-1986 	Phase 2
====Chemotherapy====
*Daunorubicin (Cerubidine) by the following response-based criteria:
**All patients: 50 mg/m2 IV once per day on days 1 to 3
**Bone marrow on day 14 has residual leukemia: 50 mg/m2 IV once on day 15
**Bone marrow on day 28 has residual leukemia: 50 mg/m2 IV once per day on days 29 & 30
*Vincristine (Oncovin) by the following response-based criteria:
**All patients: 2 mg IV once per day on days 1, 8, 15, 22
**Bone marrow on day 28 has residual leukemia: 2 mg IV once per day on days 29 & 36
*Asparaginase (Elspar) by the following response-based criteria:
**All patients: 6000 units/m2 IM once per day on days 17 to 28
**Bone marrow on day 28 has residual leukemia: 6000 units/m2 IM once per day on days 29 to 35
====Glucocorticoid therapy====
*Prednisone (Sterapred) by the following response-based criteria:
**All patients: 60 mg/m2 PO once per day on days 1 to 28
**Bone marrow on day 28 has residual leukemia: 60 mg/m2 PO once per day on days 29 to 42
====CNS therapy, prophylaxis====
*This is for patients without CNS involvement at diagnosis, and is started within 1 week of achieving complete remission:
*Cranial radiation, 1800 cGy total given in 10 fractions over 12 to 14 days
*Methotrexate (MTX) 12 mg IT once per week x 6 doses concurrent with radiation
====CNS therapy, treatment====
*This is for patients with CNS involvement at diagnosis:
*Cranial radiation, 2800 cGy total given
*Methotrexate (MTX) 12 mg IT once per week x 10 doses that starts while they are receiving induction therapy, then given once per month during the first year of therapy
4- to 6-week course
====Subsequent treatment====
*Linker regimen consolidation therapy
===Regimen variant #5, 60/10,000/1.4/60, daily dauno===
Study 	Dates of enrollment	Evidence
Pullarkat et al. 2008 (SWOG S9400)	1995-2000 	Phase 2
Note: this was the dosing used after the protocol amendment of September 1, 1999.
====Chemotherapy====
*Daunorubicin (Cerubidine) by the following response-based criteria:
**All patients: 60 mg/m2 IV once per day on days 1 to 3
**Persistent leukemia on day 21: 60 mg/m2 IV once per day on days 22 & 23
*Vincristine (Oncovin) by the following response-based criteria:
**All patients: 1.4 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
**Persistent leukemia on day 21: 1.4 mg/m2 (maximum dose of 2 mg) IV once per day on days 29 & 36
*Asparaginase (Elspar) 10,000 units IM or IV once per day on days 15 to 24
====Glucocorticoid therapy====
*Prednisone (Sterapred) by the following response-based criteria:
**All patients: 60 mg/m2/day PO on days 1 to 28
**No leukemia on day 21: taper to off by day 42
**Persistent leukemia on day 21: 60 mg/m2/day PO on days 29 to 42
6-week course
====Subsequent treatment====
*See paper for details
===Regimen variant #6, 60/10,000/1.4/60, weekly dauno ("Phase I" of E2993 regimen)===
Study 	Dates of enrollment	Evidence
Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)	1993-2003 	Non-randomized part of phase 3 RCT
Note: To our knowledge, this is the largest induction trial in adult ALL, N=1,646. CR rate was 91%.
====Chemotherapy====
*Daunorubicin (Cerubidine) 60 mg/m2 IV once per day on days 1, 8, 15, 22
*Vincristine (Oncovin) 1.4 mg/m2 IV once per day on days 1, 8, 15, 22
*Asparaginase (Elspar) 10,000 units IM or IV once per day on days 17 to 28
====Glucocorticoid therapy====
*Prednisone (Sterapred) 60 mg/m2/day PO in divided doses on days 1 to 28
====CNS therapy, prophylaxis====
*Methotrexate (MTX) 12.5 mg IT once on day 15
4-week course
====Subsequent treatment====
*Cyclophosphamide, Cytarabine, Mercaptopurine induction ("Phase 2")
===References===
# Hoelzer D, Thiel E, Löffler H, Bodenstein H, Plaumann L, Büchner T, Urbanitz D, Koch P, Heimpel H, Engelhardt R, Muller U, Wendt FC, Sodomann H, Ruhl H, Herrmann F, Kaboth W, Dietzfelbinger H, Pralle H, Lunscken Ch, Hellriegel KP, Spors S, Nowrousian RM, Fischer J, Fulle H, Mitrou PS, Pfreundschuh M, Gorg Ch, Emmerich B, Queisser W, Meyer P, Labedzki L, Essers U, Konig H, Mainzer K, Herrmann R, Messerer D, Zwingers T. Intensified therapy in acute lymphoblastic and acute undifferentiated leukemia in adults. Blood. 1984 Jul;64(1):38-47. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# CALGB 7612: Gottlieb AJ, Weinberg V, Ellison RR, Henderson ES, Terebelo H, Rafla S, Cuttner J, Silver RT, Carey RW, Levy RN, Hutchinson JL, Raich P, Cooper MR, Wiernik P, Anderson JR, Holland JF. Efficacy of daunorubicin in the therapy of adult acute lymphocytic leukemia: a prospective randomized trial by Cancer and Leukemia Group B. Blood. 1984 Jul;64(1):267-74. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
## 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# GIMEMA ALL 0288: Annino L, Vegna ML, Camera A, Specchia G, Visani G, Fioritoni G, Ferrara F, Peta A, Ciolli S, Deplano W, Fabbiano F, Sica S, Di Raimondo F, Cascavilla N, Tabilio A, Leoni P, Invernizzi R, Baccarani M, Rotoli B, Amadori S, Mandelli F; GIMEMA. Treatment of adult acute lymphoblastic leukemia (ALL): long-term follow-up of the GIMEMA ALL 0288 randomized study. Blood. 2002 Feb 1;99(3):863-71. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# MRC UKALL XII/ECOG E2993: Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00002514
## Update: Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, Burnett AK, Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J, McMillan A, Franklin IM, Luger S, Ciobanu N, Rowe JM. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008 Feb 15;111(4):1827-33. Epub 2007 Nov 29. link to original article EuroPMC 
## Update: Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, Marks DI, McMillan AK, Litzow MR, Lazarus HM, Foroni L, Dewald G, Franklin IM, Luger SM, Paietta E, Wiernik PH, Tallman MS, Goldstone AH. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009 May 7;113(19):4489-96. Epub 2009 Feb 24. link to original article link to PMC article EuroPMC 
## 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
# SWOG S9400: Pullarkat V, Slovak ML, Kopecky KJ, Forman SJ, Appelbaum FR. Impact of cytogenetics on the outcome of adult acute lymphoblastic leukemia: results of Southwest Oncology Group 9400 study. Blood. 2008 Mar 1;111(5):2563-72. Epub 2007 Dec 21. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00002665
==Daunorubicin, Pegaspargase, Vincristine, Dexamethasone==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Marks et al. 2022 (UKALL14)	2012-2017 	Phase 3 (C)	Daunorubicin, Pegaspargase, Vincristine, Dexamethasone, Rituximab	Did not meet primary endpoint of EFS
Note: the manuscript contains an error in the timing of daunorubicin and vincristine; the correct schedule is available in the supplement. The authors have been notified of the error, and the correct schedule is used below.
====Preceding treatment====
*Pre-phase dexamethasone
====Chemotherapy====
*Daunorubicin (Cerubidine) 30 mg/m2 IV over 1 to 15 minutes once per day on days 1, 8, 15, 22
*Pegaspargase (Oncaspar) by the following age-based criteria:
**40 years old or younger: 1000 units/m2 IV once per day on days 4 & 18
**41 years old or older: 1000 units/m2 IV once on day 18
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 10 mg/m2/day PO on days 1 to 4, 8 to 11, 15 to 18
====CNS therapy, prophylaxis====
*Methotrexate (MTX) 12.5 mg IT once on day 14
28-day course
====Subsequent treatment====
*See paper for protocol details
===References===
#UKALL14: Marks DI, Kirkwood AA, Rowntree CJ, Aguiar M, Bailey KE, Beaton B, Cahalin P, Castleton AZ, Clifton-Hadley L, Copland M, Goldstone AH, Kelly R, Lawrie E, Lee S, McMillan AK, McMullin MF, Menne TF, Mitchell RJ, Moorman AV, Patel B, Patrick P, Smith P, Taussig D, Yallop D, Alapi KZ, Fielding AK. Addition of four doses of rituximab to standard induction chemotherapy in adult patients with precursor B-cell acute lymphoblastic leukaemia (UKALL14): a phase 3, multicentre, randomised controlled trial. Lancet Haematol. 2022 Apr;9(4):e262-e275. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01085617
==Daunorubicin, Pegaspargase, Vincristine, Prednisone==
===Regimen variant #1, "ABFM"===
Study 	Dates of enrollment	Evidence
Rytting et al. 2014 	2006-2012 	Non-randomized
Stock et al. 2019 (CALGB 10403)	2007-2012 	Non-randomized
Note: ABFM stands for Augmented Berlin-Frankfurt-Münster regimen.
====Chemotherapy====
*Daunorubicin (Cerubidine) 25 mg/m2 IV over 1 to 15 minutes once per day on days 1, 8, 15, 22
*Pegaspargase (Oncaspar) 2500 units/m2 IM or IV over 1 to 2 hours once on day 4
*Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
====Glucocorticoid therapy====
*Prednisone (Sterapred) 30 mg/m2 IV or PO twice per day on days 1 to 28
====CNS therapy, prophylaxis====
*Cytarabine (Ara-C) by the following age-based criteria:
**1 to 1.99 years old: 30 mg IT once on day 1
**2 to 2.99 years old: 50 mg IT once on day 1
**3 years old or older: 70 mg IT once on day 1
*Methotrexate (MTX) by the following age-based criteria:
**1 to 1.99 years old: 8 mg IT once per day on days 8 & 29
**2 to 2.99 years old: 10 mg IT once per day on days 8 & 29
**3 to 8.99 years old: 12 mg IT once per day on days 8 & 29
**9 years old or older: 15 mg IT once per day on days 8 & 29
4-week course
====Subsequent treatment====
*Rytting et al. 2014: See protocol for details of treatment beyond induction
*CALGB 10403, CR: AALL0232 consolidation
*CALGB 10403, not CR: ABFM extended induction
===Regimen variant #2, higher-dose dauno===
Study 	Dates of enrollment	Evidence
Pullarkat et al. 2008 (SWOG S9400)	1995-2000 	Phase 2
Note: Table 1 lists vincristine as being given PO, which is surely an error. Likewise, prednisone is listed as IV. Pegaspargase was only given until the protocol amendment of September 1, 1999.
====Chemotherapy====
*Daunorubicin (Cerubidine) by the following response-based criteria:
**All patients: 60 mg/m2 IV once per day on days 1 to 3
**Persistent leukemia on day 21: 60 mg/m2 IV once per day on days 22 & 23
*Pegaspargase (Oncaspar) by the following response-based criteria:
**All patients: 2000 units/m2 IV once on day 15
**Persistent leukemia on day 21: 2000 units/m2 IV once on day 38
*Vincristine (Oncovin) by the following response-based criteria:
**All patients: 1.4 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
**Persistent leukemia on day 21: 1.4 mg/m2 (maximum dose of 2 mg) IV once per day on days 29 & 36
====Glucocorticoid therapy====
*Prednisone (Sterapred) by the following response-based criteria:
**All patients: 60 mg/m2/day PO on days 1 to 28
**CR on day 21: tapered from day 29 to 42
**Persistent leukemia on day 21: 60 mg/m2/day PO on days 29 to 42
42-day course
====Subsequent treatment====
*See protocol for details of treatment beyond induction
===References===
# SWOG S9400: Pullarkat V, Slovak ML, Kopecky KJ, Forman SJ, Appelbaum FR. Impact of cytogenetics on the outcome of adult acute lymphoblastic leukemia: results of Southwest Oncology Group 9400 study. Blood. 2008 Mar 1;111(5):2563-72. Epub 2007 Dec 21. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00002665
# Rytting ME, Thomas DA, O'Brien SM, Ravandi-Kashani F, Jabbour EJ, Franklin AR, Kadia TM, Pemmaraju N, Daver NG, Ferrajoli A, Garcia-Manero G, Konopleva MY, Cortes JE, Borthakur G, Garris R, Cardenas-Turanzas M, Schroeder K, Jorgensen JL, Kornblau SM, Kantarjian HM. Augmented Berlin-Frankfurt-Münster therapy in adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL). Cancer. 2014 Dec 1;120(23):3660-8. Epub 2014 Jul 17. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
## Update: Rytting ME, Jabbour EJ, Jorgensen JL, Ravandi F, Franklin AR, Kadia TM, Pemmaraju N, Daver NG, Ferrajoli A, Garcia-Manero G, Konopleva MY, Borthakur G, Garris R, Wang S, Pierce S, Schroeder K, Kornblau SM, Thomas DA, Cortes JE, O'Brien SM, Kantarjian HM. Final results of a single institution experience with a pediatric-based regimen, the augmented Berlin-Frankfurt-Münster (ABFM), in adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL), and comparison to the hyper-CVAD regimen. Am J Hematol. 2016 Aug;91(8):819-23. Epub 2016 Jun 30. link to original article link to PMC article EuroPMC
# CALGB 10403: Stock W, Luger SM, Advani AS, Yin J, Harvey RC, Mullighan CG, Willman CL, Fulton N, Laumann KM, Malnassy G, Paietta E, Parker E, Geyer S, Mrózek K, Bloomfield CD, Sanford B, Marcucci G, Liedtke M, Claxton DF, Foster MC, Bogart JA, Grecula JC, Appelbaum FR, Erba H, Litzow MR, Tallman MS, Stone RM, Larson RA. A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403. Blood. 2019 Apr 4;133(14):1548-1559. Epub 2019 Jan 18. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00558519
==Hyper-CVAD/MA==
Hyper-CVAD/MA: Hyperfractionated Cyclophosphamide, Vincristine, Adriamycin (Doxorubicin), Dexamethasone alternating with Methotrexate, Ara-C (Cytarabine)
===Regimen===
Study 	Dates of enrollment	Evidence
Koller et al. 1997 	1992-1995 	Non-randomized
Thomas et al. 1999 	1992-09 to 1997-06 	Phase 2
Kantarjian et al. 2000	1992-1998 	Phase 2
Thomas et al. 2004 	1992-2001 	Non-randomized
====Chemotherapy, Hyper-CVAD portion (cycles 1, 3, 5, 7; "Part A")====
*Cyclophosphamide (Cytoxan) 300 mg/m2 IV over 2 hours every 12 hours on days 1 to 3 (total dose per cycle: 1800 mg/m2)
*Vincristine (Oncovin) 2 mg IV once per day on days 4 & 11
*Doxorubicin (Adriamycin) by the following imaging-based criteria:
**Normal LVEF: 50 mg/m2 IV continuous infusion over 24 hours, started on day 4
**LVEF less than 50%: 25 mg/m2/day IV continuous infusion over 48 hours, started on day 4 (total dose per cycle: 50 mg/m2)
====Glucocorticoid therapy, Hyper-CVAD portion (cycles 1, 3, 5, 7; "Part A")====
*Dexamethasone (Decadron) 40 mg IV or PO once per day on days 1 to 4, 11 to 14
====Supportive therapy, Hyper-CVAD portion (cycles 1, 3, 5, 7; "Part A")====
*Mesna (Mesnex) 600 mg/m2/day IV continuous infusion over 72 hours, started on day 1, starting 1 hour prior to cyclophosphamide and completed 12 hours after the last dose of cyclophosphamide
*ONE of the following antibiotics:
**Ciprofloxacin (Cipro) 500 mg PO twice per day
**Levofloxacin (Levaquin) 500 mg PO once per day
**Trimethoprim-Sulfamethoxazole (Bactrim DS) 160/800 mg PO twice per day 
*Fluconazole (Diflucan) 200 mg PO once per day
*ONE of the following antivirals:
**Acyclovir (Zovirax) 200 mg PO twice per day
**Valacyclovir (Valtrex) 500 mg PO once per day
*Filgrastim (Neupogen) 10 mcg/kg SC once per day, starting 24 hours after completion of intensive courses of chemotherapy (day 5 for part A, day 4 for part B), continued until ANC greater than 1000/μL
Next cycle to start as soon as ANC is greater than 1000/μL at least 24 hours off of G-CSF and platelet count greater than 60 x 109/L
====Chemotherapy, MA portion (cycles 2, 4, 6, 8; "Part B")====
*Methotrexate (MTX) 200 mg/m2 IV over 2 hours once on day 1, then 800 mg/m2 IV over 22 hours (total dose per cycle: 1000 mg/m2)
*Cytarabine (Ara-C) by the following age-based criteria:
**Younger than 60 years old: 3000 mg/m2 IV over 2 hours every 12 hours on days 2 & 3 (total dose per cycle: 12,000 mg/m2)
**60 years old or older: 1000 mg/m2 IV over 2 hours every 12 hours on days 2 & 3 (total dose per cycle: 4000 mg/m2)
====Glucocorticoid therapy, MA portion (cycles 2, 4, 6, 8; "Part B")====
*Methylprednisolone (Solumedrol) 50 mg IV every 12 hours on days 1 to 3 (see note)
**Note: This is only mentioned in the Kantarjian et al. 2010 publication, and it isn't clear if it's meant to be a supportive or antineoplastic medication.
====Supportive therapy, MA portion (cycles 2, 4, 6, 8; "Part B")====
*Leucovorin (Folinic acid) 50 mg IV once on day 3, 12 hours after methotrexate is complete, then 15 mg IV every 6 hours until serum methotrexate level less than 100 nmol/L
*ONE of the following antibiotics:
**Ciprofloxacin (Cipro) 500 mg PO twice per day
**Levofloxacin (Levaquin) 500 mg PO once per day
**Trimethoprim-Sulfamethoxazole (Bactrim DS) 160/800 mg PO twice per day 
*Fluconazole (Diflucan) 200 mg PO once per day
*ONE of the following antivirals:
**Acyclovir (Zovirax) 200 mg PO twice per day
**Valacyclovir (Valtrex) 500 mg PO once per day
*Filgrastim (Neupogen) 10 mcg/kg SC once per day, starting 24 hours after completion of intensive courses of chemotherapy (day 5 for part A, day 4 for part B), continued until ANC greater than 1000/μL
Next cycle to start as soon as ANC is greater than 1000/μL at least 24 hours off of G-CSF and platelet count greater than 60 x 109/L
====CNS prophylaxis, both portions====
*Methotrexate (MTX) by the following route-based criteria:
**LP: 12 mg IT once on day 2
**Ommaya reservoir: 6 mg IT once on day 2
*Cytarabine (Ara-C) 100 mg IT once on either day 7 or 8
Given each cycle for a total of 6 or 8 intrathecal treatments (i.e. 3 each of methotrexate and cytarabine or 4 each of methotrexate and cytarabine), depending on risk for CNS relapse based serum lactate dehydrogenase (LDH) greater than 1400 IU/L and/or proliferative index percentage of S + G2M greater than or equal to 14%
====CNS treatment, both portions====
*Methotrexate (MTX) 12 mg (6 mg if given via Ommaya reservoir) IT alternating with Cytarabine (Ara-C) 100 mg IT, with both given every week until cell count in CSF normalizes and cytology is negative for malignancy
*Methotrexate (MTX) 12 mg (6 mg if given via Ommaya reservoir) IT once per week on weeks 1 & 3
*Cytarabine (Ara-C) 100 mg IT once per week on weeks 2 & 4
*Once those 4 weeks are complete, then intrathecal treatment is given similar to the prophylactic schedule, with each drug given once during every remaining cycle of induction therapy:
**Methotrexate (MTX) 12 mg (6 mg if given via Ommaya reservoir) IT once on day 2
**Cytarabine (Ara-C) 100 mg IT once on either day 7 or 8
====Subsequent treatment====
*Certain patient populations (see e.g. Kantarjian et al. 2004) proceed to receive POMP maintenance
===References===
# Review: Cortes J, O'Brien SM, Pierce S, Keating MJ, Freireich EJ, Kantarjian HM. The value of high-dose systemic chemotherapy and intrathecal therapy for central nervous system prophylaxis in different risk groups of adult acute lymphoblastic leukemia. Blood. 1995 Sep 15;86(6):2091-7. link to original article EuroPMC
# Koller CA, Kantarjian HM, Thomas D, O'Brien S, Rios MB, Kornblau S, Murphy S, Keating M. The hyper-CVAD regimen improves outcome in relapsed acute lymphoblastic leukemia. Leukemia. 1997 Dec;11(12):2039-44. link to original article EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 
## 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==Mini-Hyper-CVD/MA & Inotuzumab ozogamicin==
Mini-Hyper-CVD/MA & Inotuzumab ozogamicin: Mini (lower intensity) Hyperfractionated Cyclophosphamide, Vincristine, Dexamethasone alternating with Methotrexate and Ara-C (Cytarabine) & Inotuzumab ozogamicin
===Regimen===
Study 	Dates of enrollment	Evidence
Kantarjian et al. 2018 (MDACC 2010-0991)	2011-2017 	Phase 2
Note: please see the paper for details about intrathecal dosing.
====Chemotherapy, Mini-Hyper-CVD portion (cycles 1, 3, 5, 7; "Part A")====
*Cyclophosphamide (Cytoxan) 150 mg/m2 IV every 12 hours on days 1 to 3 (total dose per cycle: 900 mg/m2)
*Vincristine (Oncovin) 2 mg IV once per day on days 1 & 8
====Glucocorticoid therapy, Mini-Hyper-CVD portion (cycles 1, 3, 5, 7; "Part A")====
*Dexamethasone (Decadron) 20 mg IV or PO once per day on days 1 to 4, 11 to 14
====Antibody-drug conjugate therapy, Mini-Hyper-CVD portion ("Part A")====
*Inotuzumab ozogamicin (Besponsa) as follows:
**Cycles 1 & 3: 1.3 to 1.8 mg/m2 IV once on day 3
**Cycles 5 & 7: 1 to 1.3 mg/m2 IV once on day 3
====Chemotherapy, MA portion (cycles 2, 4, 6, 8; "Part B")====
*Methotrexate (MTX) 250 mg/m2 IV once on day 1
*Cytarabine (Ara-C) 500 mg/m2 IV every 12 hours on days 2 & 3 (total dose per cycle: 2000 mg/m2)
====Antibody-drug conjugate therapy, MA portion ("Part B")====
*Inotuzumab ozogamicin (Besponsa) as follows:
**Cycles 2 & 4: 1.3 to 1.8 mg/m2 IV once on day 3
**Cycles 6 & 8: 1 to 1.3 mg/m2 IV once on day 3
28-day cycle for 8 cycles
====Subsequent treatment====
*Dose-reduced POMP maintenance x 3 y
===References===
# MDACC 2010-0991: Kantarjian H, Ravandi F, Short NJ, Huang X, Jain N, Sasaki K, Daver N, Pemmaraju N, Khoury JD, Jorgensen J, Alvarado Y, Konopleva M, Garcia-Manero G, Kadia T, Yilmaz M, Bortakhur G, Burger J, Kornblau S, Wierda W, DiNardo C, Ferrajoli A, Jacob J, Garris R, O'Brien S, Jabbour E. Inotuzumab ozogamicin in combination with low-intensity chemotherapy for older patients with Philadelphia chromosome-negative acute lymphoblastic leukaemia: a single-arm, phase 2 study. Lancet Oncol. 2018 Feb;19(2):240-248. Epub 2018 Jan 16. link to original article EuroPMC NCT01371630
==R-Hyper-CVAD/R-MA==
R-Hyper-CVAD/R-MA: Rituximab, Hyperfractionated Cyclophosphamide, Vincristine, Adriamycin (Doxorubicin), Dexamethasone alternating with Rituximab, Methotrexate, Ara-C (Cytarabine)
===Regimen===
Study 	Dates of enrollment	Evidence
Thomas et al. 2010 (MDACC ID02-230)	1992-2009 	Non-randomized
Thomas et al. 2006 	2000-02 to 2005-01 	Pilot, fewer than 20 patients reported
Note: See papers for details of treatment beyond induction/consolidation, which differ substantially between "standard" and "modified" protocols.
====Targeted therapy, both portions====
*Rituximab (Rituxan) as follows:
**Cycles 1 & 3: 375 mg/m2 IV over 2 to 6 hours once per day on days 1 & 11
**Cycles 2 & 4: 375 mg/m2 IV over 2 to 6 hours once per day on days 2 & 8
====Chemotherapy, Hyper-CVAD portion (cycles 1, 3, 5, 7; "Part A")====
*Cyclophosphamide (Cytoxan) 300 mg/m2 IV over 2 hours every 12 hours on days 1 to 3 (total dose per cycle: 1800 mg/m2)
*Vincristine (Oncovin) 2 mg IV once per day on days 4 & 11
*Doxorubicin (Adriamycin) 50 mg/m2 IV continuous infusion over 24 hours, started on day 4
====Glucocorticoid therapy, Hyper-CVAD portion (cycles 1, 3, 5, 7; "Part A")====
*Dexamethasone (Decadron) 40 mg IV or PO once per day on days 1 to 4, 11 to 14
====Supportive therapy, Hyper-CVAD portion (cycles 1, 3, 5, 7; "Part A")====
*Mesna (Mesnex) 600 mg/m2/day IV continuous infusion over 72 hours, started on day 1, starting 1 hour prior to cyclophosphamide and completed 12 hours after the last dose of cyclophosphamide (total dose per cycle: 1800 mg/m2)
*Filgrastim (Neupogen) 10 mcg/kg SC once per day, starting 24 hours after completion of chemotherapy, continued until WBC greater than 3 x 109/L or bone pain present
*ONE of the following antibiotics:
**Fluoroquinolone
**Trimethoprim-Sulfamethoxazole (Bactrim DS) 160/800 mg dose/route not specified 
*Fluconazole (Diflucan) dose/route not specified
*ONE of the following antivirals:
**Acyclovir (Zovirax) dose/route not specified
**Valacyclovir (Valtrex) dose/route not specified
====Chemotherapy, MA portion (cycles 2, 4, 6, 8; "Part B")====
*Methotrexate (MTX) 1000 mg/m2 IV continuous infusion over 24 hours, started on day 1
*Cytarabine (Ara-C) 3000 mg/m2 IV over 2 hours every 12 hours on days 2 & 3 (total dose per cycle: 12,000 mg/m2)
====Supportive therapy, MA portion (cycles 2, 4, 6, 8; "Part B")====
*Leucovorin (Folinic acid) 50 mg IV once on day 3, 12 hours after methotrexate is complete, then 15 mg IV every 6 hours until serum methotrexate level less than 100 nmol/L
*Filgrastim (Neupogen) 10 mcg/kg SC once per day, starting on day 4, 24 hours after completion of chemotherapy, continued until WBC greater than 3 x 109/L or bone pain present
*ONE of the following antibiotics:
**Fluoroquinolone
**Trimethoprim-Sulfamethoxazole (Bactrim DS) 160/800 mg dose/route not specified 
*Fluconazole (Diflucan) dose/route not specified
*ONE of the following antivirals:
**Acyclovir (Zovirax) dose/route not specified
**Valacyclovir (Valtrex) dose/route not specified
8 cycles; next cycle to start no sooner than 14 days or as soon as "unmaintained" WBC count is greater than 3 x 109/L and platelet count greater than 50 x 109/L
====CNS prophylaxis, both portions====
*Methotrexate (MTX) 12 mg (6 mg if given via Ommaya reservoir) IT once on day 2
*Cytarabine (Ara-C) 100 mg IT once on day 7
Given each cycle for a total of 16 intrathecal treatments.
If CNS disease present, therapy augmented to twice per week alternating (MTX, ara-C) treatments until CSF cell count normalizes and cytology is negative, then continues for 4 more alternating once per week treatments; prophylaxis course then resumes.
====Dose and schedule modifications====
*Cytarabine (Ara-C) reduced to 1000 mg/m2 for patients greater than or equal to 60 years old, creatinine greater than or equal to 1.5 mg/dL or 0 hour MTX level greater than or equal to 20,000 nmol/L
*Vincristine (Oncovin) reduced to 1 mg for bilirubin greater than 2 mg/dL or NCI common toxicity criteria Grade 2+ peripheral neuropathy, omitted for bilirubin greater than 3 mg/dL or for ileus
*Doxorubicin (Adriamycin) reduced by 50% for bilirubin 2 to 3 mg/dL, by 75% for bilirubin 3 to 5 mg/dL (eliminated for bilirubin greater than 5 mg/dL or for gastric/small-bowel involvement with Course 1 to reduce duration of myelosuppression given risk of perforation)
*Methotrexate (MTX) reduced by 50% for CrCl 10 to 50 mL/min/1.73m2 (eliminated for CrCl less than 10 mL/min/1.73m2), by 25% to 75% for delayed excretion and/or nephrotoxicity with prior course (dependent on severity) or by 50% for pleural effusions/ascites with drainage of fluid as feasible.
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
## Update: Fayad L, Thomas D, Romaguera J. Update of the MD Anderson Cancer Center experience with hyper-CVAD and rituximab for the treatment of mantle cell and Burkitt-type lymphomas. Clin Lymphoma Myeloma. 2007 Dec;8 Suppl 2:S57-62. link to original article EuroPMC
# MDACC ID02-230: Thomas DA, O'Brien S, Faderl S, Garcia-Manero G, Ferrajoli A, Wierda W, Ravandi F, Verstovsek S, Jorgensen JL, Bueso-Ramos C, Andreeff M, Pierce S, Garris R, Keating MJ, Cortes J, Kantarjian HM. Chemoimmunotherapy with a modified hyper-CVAD and rituximab regimen improves outcome in de novo Philadelphia chromosome-negative precursor B-lineage acute lymphoblastic leukemia. J Clin Oncol. 2010 Aug 20;28(24):3880-9. Epub 2010 Jul 26. link to original article link to PMC article EuroPMC NCT00671658
=Extended induction therapy=
Note: these regimens are used when a pre-specified endpoint during remission induction was not achieved.
==Daunorubicin, Pegaspargase, Vincristine, Prednisone==
===Regimen, "ABFM"===
Study 	Dates of enrollment	Evidence
Stock et al. 2019 (CALGB 10403)	2007-2012 	Non-randomized
Note: ABFM stands for Augmented Berlin-Frankfurt-Münster regimen.
====Preceding treatment====
*ABFM induction, with inadequate response
====Chemotherapy====
*Daunorubicin (Cerubidine) 25 mg/m2 IV once on day 1
*Pegaspargase (Oncaspar) 2500 units/m2 IM or IV once on day 4
*Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1 & 8
====Glucocorticoid therapy====
*Prednisone (Sterapred) 30 mg/m2 IV or PO twice per day on days 1 to 14
2-week course
====Subsequent treatment====
*AALL0232 consolidation
===References===
# CALGB 10403: Stock W, Luger SM, Advani AS, Yin J, Harvey RC, Mullighan CG, Willman CL, Fulton N, Laumann KM, Malnassy G, Paietta E, Parker E, Geyer S, Mrózek K, Bloomfield CD, Sanford B, Marcucci G, Liedtke M, Claxton DF, Foster MC, Bogart JA, Grecula JC, Appelbaum FR, Erba H, Litzow MR, Tallman MS, Stone RM, Larson RA. A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403. Blood. 2019 Apr 4;133(14):1548-1559. Epub 2019 Jan 18. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00558519
=Early intensification therapy=
==CALGB 8811 early intensification==
===Regimen===
Study 	Dates of enrollment	Evidence
Larson et al. 1995 (CALGB 8811)	1988-1991 	Phase 2
====Preceding treatment====
*Cyclophosphamide, Daunorubicin, L-asparaginase, Vincristine, Prednisone induction ("Course I")
====Chemotherapy, "Course II"====
*Cyclophosphamide (Cytoxan) 1000 mg/m2 IV once on day 1
*Mercaptopurine (6-MP) 60 mg/m2 PO once per day on days 1 to 14
*Cytarabine (Ara-C) 75 mg/m2 SC once per day on days 1 to 4, 8 to 11
*Vincristine (Oncovin) 2 mg IV once per day on days 15 & 22
*Asparaginase (Elspar) 6000 units/m2 SC once per day on days 15, 18, 22, 25
====CNS therapy, prophylaxis====
*Methotrexate (MTX) 15 mg IT once on day 1
28-day cycle for 2 cycles
====Subsequent treatment====
*Mercaptopurine, Methotrexate, WB-XRT interim maintenance ("Course III")
===References===
# CALGB 8811: Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR, Hooberman AL, Westbrook CA, Arthur DC, George SL, Bloomfield CD, Schiffer CA. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: Cancer and Leukemia Group B study 8811. Blood. 1995 Apr 15;85(8):2025-37. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==L-Asparaginase & Methotrexate==
===Regimen===
Study 	Dates of enrollment	Evidence
Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)	1993-2003 	Non-randomized part of phase 3 RCT
Note: Asparaginase (Elspar) was discontinued by the manufacturer in December 2012, and is now essentially out of stock. Alternatives include Pegaspargase (Oncaspar) or Asparaginase Erwinia chrysanthemi (Erwinaze).
====Preceding treatment====
*Cyclophosphamide, Cytarabine, Mercaptopurine induction ("Phase 2")
====Chemotherapy====
*Methotrexate (MTX) 3000 mg/m2 IV once per day on days 1, 8, 22
*Asparaginase (Elspar) 10,000 units (route not specified) once per day on days 2, 9, 23
====Supportive therapy====
*Leucovorin (Folinic acid) at "standard" doses
3 cycles (length of cycle not specified in original reference)
====Subsequent treatment====
*MRC UKALL XII/ECOG E2993, patients who were younger than 50 years of age and had an HLA-matched sibling donor, as well as Ph+ patients with any donor: Etoposide & TBI, then allo HSCT consolidation
*MRC UKALL XII/ECOG E2993, all others: Etoposide & TBI, then auto HSCT versus International ALL Trial consolidation
===References===
# MRC UKALL XII/ECOG E2993: Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00002514
## Update: Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, Burnett AK, Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J, McMillan A, Franklin IM, Luger S, Ciobanu N, Rowe JM. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008 Feb 15;111(4):1827-33. Epub 2007 Nov 29. link to original article EuroPMC 
## Update: Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, Marks DI, McMillan AK, Litzow MR, Lazarus HM, Foroni L, Dewald G, Franklin IM, Luger SM, Paietta E, Wiernik PH, Tallman MS, Goldstone AH. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009 May 7;113(19):4489-96. Epub 2009 Feb 24. link to original article link to PMC article EuroPMC 
## 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
=Consolidation after upfront therapy (including post-remission therapy)=
Note that many of these regimens are complex and as such will be referred to by their study name, not by the individual drug names. This is also a phase of treatment often referred to as post-remission or postinduction therapy.
==AALL0232 consolidation==
===Regimen===
Study 	Dates of enrollment	Evidence
Stock et al. 2019 (CALGB 10403)	2007-2012 	Non-randomized
====Preceding treatment====
*ABFM induction
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 1000 mg/m2 IV once per day on days 1 & 29
*Cytarabine (Ara-C) 75 mg/m2 IV or SC once per day on days 1 to 4, 8 to 11, 29 to 32, 36 to 39
*Mercaptopurine (6-MP) 60 mg/m2 PO once per day on days 1 to 14, 29 to 42
*Pegaspargase (Oncaspar) 2500 units/m2 IM or IV once per day on days 15 & 43
*Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 15, 22, 43, 50
50-day course
====Subsequent treatment====
*6-MP, Capizzi MTX, Pegaspargase interim maintenance
===References===
# CALGB 10403: Stock W, Luger SM, Advani AS, Yin J, Harvey RC, Mullighan CG, Willman CL, Fulton N, Laumann KM, Malnassy G, Paietta E, Parker E, Geyer S, Mrózek K, Bloomfield CD, Sanford B, Marcucci G, Liedtke M, Claxton DF, Foster MC, Bogart JA, Grecula JC, Appelbaum FR, Erba H, Litzow MR, Tallman MS, Stone RM, Larson RA. A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403. Blood. 2019 Apr 4;133(14):1548-1559. Epub 2019 Jan 18. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00558519
==Blinatumomab monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Efficacy
Gökbuget et al. 2018 (BLAST)	2010-2014 	Phase 2 (RT)	CR after 1 cycle: 78%
Note: these patients had MRD after induction; also note that this is BSA-based dosing.
====Preceding treatment====
*"A minimum of 3 blocks of intensive chemotherapy"
====Immunotherapy====
*Blinatumomab (Blincyto) 15 mcg/m2/day IV continuous infusion over 28 days, started on day 1 (total dose per cycle: 420 mcg/m2)
42-day cycle for up to 4 cycles
====Subsequent treatment====
*BLAST, patients who had an allogeneic donor: proceed to allogeneic hematopoietic stem cell transplant any time after cycle 1
===References===
# BLAST: Gökbuget N, Dombret H, Bonifacio M, Reichle A, Graux C, Faul C, Diedrich H, Topp MS, Brüggemann M, Horst HA, Havelange V, Stieglmaier J, Wessels H, Haddad V, Benjamin JE, Zugmaier G, Nagorsen D, Bargou RC. Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood. 2018 Apr 5;131(14):1522-1531. Epub 2018 Jan 22. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01207388
## Update: Gökbuget N, Zugmaier G, Dombret H, Stein A, Bonifacio M, Graux C, Faul C, Brüggemann M, Taylor K, Mergen N, Reichle A, Horst HA, Havelange V, Topp MS, Bargou RC. Curative outcomes following blinatumomab in adults with minimal residual disease B-cell precursor acute lymphoblastic leukemia. Leuk Lymphoma. 2020 Nov;61(11):2665-2673. Epub 2020 Jul 3. link to original article EuroPMC
==Cyclophosphamide & TBI, then allo HSCT==
Cy/TBI: Cyclophosphamide & Total Body Irradiation
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy 	Non-relapse mortality
Thomas et al. 1979 	1976-1977 	Non-randomized 	 	 	
Sebban et al. 1994 (LALA 87)	1986-1991 	Phase 3 (E-esc) 	Chemotherapy or Auto HSCT	Did not meet primary endpoint of OS60	
Thomas et al. 2004 (LALA-94)	1994-2002 	Non-randomized part of RCT	 	 	
===References===
# Thomas ED, Sanders JE, Flournoy N, Johnson FL, Buckner CD, Clift RA, Fefer A, Goodell BW, Storb R, Weiden PL. Marrow transplantation for patients with acute lymphoblastic leukemia in remission. Blood. 1979 Aug;54(2):468-76. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
# LALA 87: Sebban C, Lepage E, Vernant JP, Gluckman E, Attal M, Reiffers J, Sutton L, Racadot E, Michallet M, Maraninchi D, Dreyfus F, Fiere D; French Group of Therapy of Adult Acute Lymphoblastic Leukemia. Allogeneic bone marrow transplantation in adult acute lymphoblastic leukemia in first complete remission: a comparative study. J Clin Oncol. 1994 Dec;12(12):2580-7. link to original article EuroPMC
## Update: Thiebaut A, Vernant JP, Degos L, Huguet FR, Reiffers J, Sebban C, Lepage E, Thomas X, Fière D. Adult acute lymphocytic leukemia study testing chemotherapy and autologous and allogeneic transplantation: a follow-up report of the French protocol LALA 87. Hematol Oncol Clin North Am. 2000 Dec;14(6):1353-66. link to original article EuroPMC
# LALA-94: Thomas X, Boiron JM, Huguet F, Dombret H, Bradstock K, Vey N, Kovacsovics T, Delannoy A, Fegueux N, Fenaux P, Stamatoullas A, Vernant JP, Tournilhac O, Buzyn A, Reman O, Charrin C, Boucheix C, Gabert J, Lhéritier V, Fiere D. Outcome of treatment in adults with acute lymphoblastic leukemia: analysis of the LALA-94 trial. J Clin Oncol. 2004 Oct 15;22(20):4075-86. Epub 2004 Sep 7. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00002700
## Update: Vey N, Thomas X, Picard C, Kovascovicz T, Charin C, Cayuela JM, Dombret H, Dastugue N, Huguet F, Bastard C, Stamatoulas A, Giollant M, Tournilhac O, Macintyre E, Buzyn A, Bories D, Kuentz M, Dreyfus F, Delannoy A, Raynaud S, Gratecos N, Bordessoule D, de Botton S, Preudhomme C, Reman O, Troussard X, Pigneux A, Bilhou C, Vernant JP, Boucheix C, Gabert J; GET-LALA Group the Swiss Group for Clinical Cancer Research (SAKK). Allogeneic stem cell transplantation improves the outcome of adults with t(1;19)/E2A-PBX1 and t(4;11)/MLL-AF4 positive B-cell acute lymphoblastic leukemia: results of the prospective multicenter LALA-94 study. Leukemia. 2006 Dec;20(12):2155-61. Epub 2006 Oct 12. link to original article EuroPMC
==Etoposide & TBI, then allo HSCT==
===Regimen===
Study 	Dates of enrollment	Evidence
Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)	1993-2003 	Non-randomized part of phase 3 RCT
===References===
# MRC UKALL XII/ECOG E2993: Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00002514
## Update: Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, Burnett AK, Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J, McMillan A, Franklin IM, Luger S, Ciobanu N, Rowe JM. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008 Feb 15;111(4):1827-33. Epub 2007 Nov 29. link to original article EuroPMC 
## Update: Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, Marks DI, McMillan AK, Litzow MR, Lazarus HM, Foroni L, Dewald G, Franklin IM, Luger SM, Paietta E, Wiernik PH, Tallman MS, Goldstone AH. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009 May 7;113(19):4489-96. Epub 2009 Feb 24. link to original article link to PMC article EuroPMC 
## 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
==International ALL Trial consolidation==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)	1993-2003 	Phase 3 (C)	Etoposide & TBI, then auto HSCT	Seems to have longer OS (primary endpoint)
====Preceding treatment====
*L-asparaginase & Methotrexate intensification
====Chemotherapy, first portion (course 1)====
*Cytarabine (Ara-C) 75 mg/m2 IV once per day on days 1 to 5
*Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 5
*Vincristine (Oncovin) 1.4 mg/m2 IV once per day on days 1, 8, 15, 22
====Glucocorticoid therapy, first portion (course 1)====
*Dexamethasone (Decadron) 10 mg/m2 PO once per day on days 1 to 28
====Chemotherapy, second portion (course 2)====
*Cytarabine (Ara-C) 75 mg/m2 IV once per day on days 1 to 5
*Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 5
====Chemotherapy, third portion (course 3)====
*Daunorubicin (Cerubidine) 25 mg/m2 IV once per day on days 1, 8, 15, 22
*Cyclophosphamide (Cytoxan) 650 mg/m2 IV once on day 29
*Cytarabine (Ara-C) 75 mg/m2 IV once per day on days 31 to 34, 38 to 41
*Thioguanine (Tabloid) 60 mg/m2 PO once per day on days 29 to 42
====Chemotherapy, fourth portion (course 4)====
*Cytarabine (Ara-C) 75 mg/m2 IV once per day on days 1 to 5
*Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 5
4-week course, then 4-week course, then 8-week course, then one course
====CNS prophylaxis====
*Cytarabine (Ara-C) 50 mg IT once per week for 4 weeks, then once per quarter for 4 doses
*Whole-brain irradiation to 2400 cGy
====Subsequent treatment====
*POMP maintenance
===References===
# MRC UKALL XII/ECOG E2993: Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00002514
## Update: Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, Burnett AK, Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J, McMillan A, Franklin IM, Luger S, Ciobanu N, Rowe JM. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008 Feb 15;111(4):1827-33. Epub 2007 Nov 29. link to original article EuroPMC 
## Update: Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, Marks DI, McMillan AK, Litzow MR, Lazarus HM, Foroni L, Dewald G, Franklin IM, Luger SM, Paietta E, Wiernik PH, Tallman MS, Goldstone AH. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009 May 7;113(19):4489-96. Epub 2009 Feb 24. link to original article link to PMC article EuroPMC 
## 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
==Mercaptopurine, Methotrexate, Vincristine==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Sakura et al. 2017 (JALSG ALL202-O)	2002-2011 	Phase 3 (E-esc)	MTX, 6-MP, Vincristine; intermediate-dose MTX	Seems to have longer DFS
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment. Given as cycles 2 and 5 of consolidation for patients younger than 50.
====Chemotherapy====
*Mercaptopurine (6-MP) 25 mg/m2 PO once per day on days 1 to 21
*Methotrexate (MTX) 3000 mg/m2 IV once per day on days 1 & 15
*Vincristine (Oncovin) 1.3 mg/m2 (maximum dose of 2 mg) IV once per day on days 1 & 15
====CNS therapy====
*Methotrexate (MTX) 15 mg IT once per day on days 1 & 15
*Dexamethasone (Decadron) 4 mg IT once per day on days 1 & 15
====Supportive therapy====
*Leucovorin (Folinic acid) 50 mg IV once, then 15 mg IV every 6 hours for a total of 8 doses, beginning 36 h after the start of methotrexate infusion
2 cycles (see note)
===References===
# JALSG ALL202-O: Sakura T, Hayakawa F, Sugiura I, Murayama T, Imai K, Usui N, Fujisawa S, Yamauchi T, Yujiri T, Kakihana K, Ito Y, Kanamori H, Ueda Y, Miyata Y, Kurokawa M, Asou N, Ohnishi K, Ohtake S, Kobayashi Y, Matsuo K, Kiyoi H, Miyazaki Y, Naoe T. High-dose methotrexate therapy significantly improved survival of adult acute lymphoblastic leukemia: a phase III study by JALSG. Leukemia. 2018 Mar;32(3):626-632. Epub 2017 Sep 15. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC UMIN C000000063
==Linker regimen (consolidation)==
===Regimen===
Study 	Dates of enrollment	Evidence
Linker et al. 1987	1980-1986 	Phase 2
Each cycle is approximately one month, based on recovery of ANC to greater than 1000/μL and platelet count to greater than 100 x 109/L.
====Preceding treatment====
*DOLP induction
====Chemotherapy, A portion (cycles 1, 3, 5, 7)====
*Daunorubicin (Cerubidine) 50 mg/m2 IV once per day on days 1 & 2
*Vincristine (Oncovin) 2 mg IV once per day on days 1 & 8
*Asparaginase (Elspar) 12,000 units/m2 IM once per day on days 2, 4, 7, 9, 11, 14
====Glucocorticoid therapy, A portion (cycles 1, 3, 5, 7)====
*Prednisone (Sterapred) 60 mg/m2 PO once per day on days 1 to 14
====Chemotherapy, B portion (cycles 2, 4, 6, 8)====
*Teniposide (Vumon) 165 mg/m2 IV once per day on days 1, 4, 8, 11
*Cytarabine (Ara-C) 300 mg/m2 IV once per day on days 1, 4, 8, 11
====Chemotherapy, C portion (cycle 9)====
*Methotrexate (MTX) 690 mg/m2 IV continuous infusion over 42 hours, started on day 1
*Asparaginase (Elspar) 12,000 units/m2 IM once per day on days 2, 4, 7, 9, 11, 14
====Glucocorticoid therapy, C portion (cycle 9)====
*Prednisone (Sterapred) 60 mg/m2 PO once per day on days 1 to 14
====Supportive therapy, C portion (cycle 9)====
*Leucovorin (Folinic acid) 15 mg/m2 IV every 6 hours on days 3 to 5, starting after methotrexate is complete (at 42 hours)
Approximately one-month cycle for 9 cycles
====Subsequent treatment====
*6-MP & MTX maintenance
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC content property of 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Pediatric-like GRAALL consolidation==
===Regimen===
Study 	Dates of enrollment	Evidence
Huguet et al. 2009 (GRAALL-2003)	2003-2005 	Phase 2
Note: the original article Table 1 has several errors which were corrected in the erratum and the online Table 1. These corrected doses are replicated here. Also note that each consolidation "block" flows into the next A->B->C and days are scheduled thusly; the total length of each 3-portion block is not specified and is dependent on count recovery. 
====Preceding treatment====
*Cyclophosphamide, Daunorubicin, L-asparaginase, Vincristine, Prednisone induction or Cytarabine & Idarubicin salvage
====Chemotherapy, A portion (cycles 1, 4, 7)====
*Cytarabine (Ara-C) 2000 mg/m2 IV every 12 hours on days 1 & 2
*Asparaginase (Elspar) 10,000 units/m2 (route not specified) once on day 3
====Glucocorticoid therapy, A portion (cycles 1, 4, 7)====
*Dexamethasone (Decadron) 10 mg (route not specified) every 12 hours on days 1 & 2
====Supportive therapy, A portion (cycles 1, 4, 7)====
*Lenograstim (Granocyte) 150 mcg/m2 SC once per day on days 7 to 13
====Chemotherapy, B portion (cycles 2, 5, 8)====
*Methotrexate (MTX) 3000 mg/m2 IV continuous infusion (duration not specified), started on day 15
*Vincristine (Oncovin) 2 mg IV once on day 15
*Asparaginase (Elspar) 10,000 units/m2 (route not specified) once on day 16
*Mercaptopurine (6-MP) 60 mg/m2 PO once per day on days 15 to 21
====Supportive therapy, B portion (cycles 2, 5, 8)====
*Lenograstim (Granocyte) 150 mcg/m2 SC once per day on days 22 to 27
====Chemotherapy, C portion (cycles 3, 6, 9)====
*Cyclophosphamide (Cytoxan) 500 mg/m2 IV once per day on days 29 & 30
*Etoposide (Vepesid) 75 mg/m2 IV once per day on days 29 & 30
*Methotrexate (MTX) 25 mg/m2 (route not specified) once on day 29
====Supportive therapy, C portion (cycles 3, 6, 9)====
*Lenograstim (Granocyte) 150 mcg/m2 SC once per day from day 31 until myeloid recovery
9 cycles
====Subsequent treatment====
*GRAALL-2003, CR after induction: Cyclophosphamide, daunorubicin, L-asparaginase, vincristine, prednisone late intensification between cycles 6 and 7
*GRAALL-2003, CR after salvage: Cytarabine & idarubicin late intensification between cycles 6 and 7
*GRAALL-2003, all patients: POMP maintenance after completion of consolidation
===References===
# GRAALL-2003: Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00222027
=Interim maintenance=
==Mercaptopurine, Methotrexate, WB-XRT ["Course III"]==
===Regimen===
Study 	Dates of enrollment	Evidence
Larson et al. 1995 (CALGB 8811)	1988-1991 	Phase 2
====Preceding treatment====
*Larson regimen (CALGB 8811) early intensification ("Course II")
====Chemotherapy====
*Mercaptopurine (6-MP) 60 mg/m2 PO once per day on days 1 to 70
*Methotrexate (MTX) 20 mg/m2 PO once per day on days 36, 43, 50, 57, 64
====Radiotherapy====
*Cranial radiation, 2400 cGy total given in 10 fractions from days 1 to 12
====CNS prophylaxis====
*Methotrexate (MTX) 15 mg IT once per day on days 1, 8, 15, 22, 29
12-week course
====Subsequent treatment====
*Larson regimen (CALGB 8811) late intensification ("Course IV")
===References===
# CALGB 8811: Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR, Hooberman AL, Westbrook CA, Arthur DC, George SL, Bloomfield CD, Schiffer CA. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: Cancer and Leukemia Group B study 8811. Blood. 1995 Apr 15;85(8):2025-37. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Methotrexate & Pegaspargase==
===Regimen===
Study 	Dates of enrollment	Evidence
Stock et al. 2019 (CALGB 10403)	2007-2012 	Non-randomized
Note: the instructions for dose escalation of MTX in the manuscript are confusing; the authors have been contacted for clarification.
====Preceding treatment====
*AALL0232 consolidation ("Course II")
====Chemotherapy====
*Methotrexate (MTX) 100 mg/m2 IV once on day 1, then 150 mg/m2 IV once on day 11, then 200 mg/m2 IV once on day 21, then 250 mg/m2 IV once on day 31, then 300 mg/m2 IV once on day 41
*Pegaspargase (Oncaspar) 2500 units IM or IV once per day on days 2 & 22
====CNS therapy, prophylaxis====
*Methotrexate (MTX) 15 mg IT once per day on days 1 & 31
42-day course
====Subsequent treatment====
*AALL0232 delayed intensification ("Course IV")
===References===
# CALGB 10403: Stock W, Luger SM, Advani AS, Yin J, Harvey RC, Mullighan CG, Willman CL, Fulton N, Laumann KM, Malnassy G, Paietta E, Parker E, Geyer S, Mrózek K, Bloomfield CD, Sanford B, Marcucci G, Liedtke M, Claxton DF, Foster MC, Bogart JA, Grecula JC, Appelbaum FR, Erba H, Litzow MR, Tallman MS, Stone RM, Larson RA. A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403. Blood. 2019 Apr 4;133(14):1548-1559. Epub 2019 Jan 18. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00558519
=Late intensification=
==Cyclophosphamide, Cytarabine, Pegaspargase, Thioguanine, Vincristine, Dexamethasone==
===Regimen===
Study 	Dates of enrollment	Evidence
Stock et al. 2019 (CALGB 10403)	2007-2012 	Non-randomized
Note: also known as delayed intensification "Course IV".
====Preceding treatment====
*MTX & Pegaspargase interim maintenance
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 1000 mg/m2 IV once on day 29
*Cytarabine (Ara-C) 75 mg/m2 IV or SC once per day on days 29 to 32, 36 to 39
*Pegaspargase (Oncaspar) 2500 units/m2 IM or IV once per day on days 4 +/-1 day & 43
*Thioguanine (Tabloid) 60 mg/m2 PO once per day on days 29 to 42
*Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 8, 43, 50
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 5 mg/m2 PO or IV twice per day on days 1 to 7, 15 to 21
====CNS therapy, prophylaxis====
*Methotrexate (MTX) 15 mg IT once per day on days 1, 29, 36
50-day course
====Subsequent treatment====
*Mercaptopurine, Methotrexate, Vincristine, Dexamethasone maintenance
===References===
# CALGB 10403: Stock W, Luger SM, Advani AS, Yin J, Harvey RC, Mullighan CG, Willman CL, Fulton N, Laumann KM, Malnassy G, Paietta E, Parker E, Geyer S, Mrózek K, Bloomfield CD, Sanford B, Marcucci G, Liedtke M, Claxton DF, Foster MC, Bogart JA, Grecula JC, Appelbaum FR, Erba H, Litzow MR, Tallman MS, Stone RM, Larson RA. A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403. Blood. 2019 Apr 4;133(14):1548-1559. Epub 2019 Jan 18. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00558519
==Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone==
===Regimen===
Study 	Dates of enrollment	Evidence
Huguet et al. 2009 (GRAALL-2003)	2003-2005 	Phase 2
Note: the original article Table 1 has several errors which were corrected in the erratum and the online Table 1. These corrected doses are replicated here.
====Preceding treatment====
*Pediatric-like GRAALL consolidation cycle 6, if patients achieved CR1 after cyclophosphamide, daunorubicin, L-asparaginase, vincristine, prednisone induction
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 500 mg/m2 IV every 12 hours on day 15
*Daunorubicin (Cerubidine) 30 mg/m2 IV once per day on days 1 to 3
*Asparaginase (Elspar) 6000 units/m2/day (route not specified) on days 8, 10, 12, 18, 20, 22
*Vincristine (Oncovin) 2 mg IV once per day on days 1, 8, 15
====Glucocorticoid therapy====
*Prednisone (Sterapred) 60 mg/m2/day PO on days 1 to 14
====Supportive therapy====
*Lenograstim (Granocyte) 150 mcg/m2 SC once per day if ANC less than 500/μL until myeloid recovery
====Subsequent treatment====
*Pediatric-like GRAALL consolidation
===References===
# GRAALL-2003: Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00222027
==Cytarabine & Idarubicin==
===Regimen===
Study 	Dates of enrollment	Evidence
Huguet et al. 2009 (GRAALL-2003)	2003-2005 	Phase 2
Note: the original article Table 1 has several errors which were corrected in the erratum and the online Table 1. These corrected doses are replicated here.
====Preceding treatment====
*Pediatric-like GRAALL consolidation cycle 6, if patients achieved CR1 after cytarabine & idarubicin salvage
====Chemotherapy====
*Cytarabine (Ara-C) 2000 mg/m2 IV every 12 hours on days 1 to 4
*Idarubicin (Idamycin) 9 mg/m2 IV once per day on days 1 to 3
====Supportive therapy====
*Lenograstim (Granocyte) 150 mcg/m2 SC once per day from day 9 until myeloid recovery
One course
====Subsequent treatment====
*Pediatric-like GRAALL consolidation
===References===
# GRAALL-2003: Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00222027
==CALGB 8811 late intensification==
===Regimen===
Study 	Dates of enrollment	Evidence
Larson et al. 1995 (CALGB 8811)	1988-1991 	Phase 2
====Preceding treatment====
*Mercaptopurine, Methotrexate, WB-XRT interim maintenance ("Course III")
====Chemotherapy====
*Doxorubicin (Adriamycin) 30 mg/m2 IV once per day on days 1, 8, 15
*Vincristine (Oncovin) 2 mg IV once per day on days 1, 8, 15
*Cyclophosphamide (Cytoxan) 1000 mg/m2 IV once on day 29
*Thioguanine (Tabloid) 60 mg/m2 PO once per day on days 29 to 42
*Cytarabine (Ara-C) 75 mg/m2 SC once per day on days 29 to 32, 36 to 39
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 10 mg/m2 PO once per day on days 1 to 14
8-week course
====Subsequent treatment====
*POMP maintenance ("Course V")
===References===
# CALGB 8811: Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR, Hooberman AL, Westbrook CA, Arthur DC, George SL, Bloomfield CD, Schiffer CA. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: Cancer and Leukemia Group B study 8811. Blood. 1995 Apr 15;85(8):2025-37. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
=Maintenance after upfront therapy=
==Mercaptopurine, Methotrexate, Vincristine, Dexamethasone==
===Regimen variant #1, 2 years===
Study 	Dates of enrollment	Evidence
Stock et al. 2019 (CALGB 10403)	2007-2012 	Non-randomized
Note: also known as maintenance "Course V". This duration was intended for female patients.
====Preceding treatment====
*CALGB 10403 delayed intensification "Course IV"
====Chemotherapy====
*Mercaptopurine (6-MP) 75 mg/m2 PO once per day
*Methotrexate (MTX) as follows:
**Cycles 1 to 4: 20 mg/m2 PO once per day on days 8, 15, 22, 36, 43, 50, 57, 64, 71, 78
**Cycles 5 to 8: 20 mg/m2 PO once per day on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78
*Vincristine (Oncovin) 1.5 mg (maximum dose of 2 mg) IV once per day on days 1, 29, 57
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 3 mg/m2 PO or IV twice per day on days 1 to 5, 29 to 33, 57 to 61
====CNS therapy, prophylaxis====
*Methotrexate (MTX) as follows:
**Cycles 1 to 4: 15 mg IT once per day on days 1 & 29
**Cycles 5 to 8: 15 mg IT once on day 1
12-week cycle for 8 cycles (2 years)
===Regimen variant #2, 3 years===
Study 	Dates of enrollment	Evidence
Stock et al. 2019 (CALGB 10403)	2007-2012 	Non-randomized
Note: also known as maintenance "Course V". This duration was intended for male patients.
====Preceding treatment====
*CALGB 10403 delayed intensification "Course IV"
====Chemotherapy====
*Mercaptopurine (6-MP) 75 mg/m2 PO once per day
*Methotrexate (MTX) as follows:
**Cycles 1 to 4: 20 mg/m2 PO once per day on days 8, 15, 22, 36, 43, 50, 57, 64, 71, 78
**Cycles 5 to 12: 20 mg/m2 PO once per day on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78
*Vincristine (Oncovin) 1.5 mg (maximum dose of 2 mg) IV once per day on days 1, 29, 57
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 3 mg/m2 PO or IV twice per day on days 1 to 5, 29 to 33, 57 to 61
====CNS therapy, prophylaxis====
*Methotrexate (MTX) as follows:
**Cycles 1 to 4: 15 mg IT once per day on days 1 & 29
**Cycles 5 to 12: 15 mg IT once on day 1
12-week cycle for 12 cycles (3 years)
===References===
# CALGB 10403: Stock W, Luger SM, Advani AS, Yin J, Harvey RC, Mullighan CG, Willman CL, Fulton N, Laumann KM, Malnassy G, Paietta E, Parker E, Geyer S, Mrózek K, Bloomfield CD, Sanford B, Marcucci G, Liedtke M, Claxton DF, Foster MC, Bogart JA, Grecula JC, Appelbaum FR, Erba H, Litzow MR, Tallman MS, Stone RM, Larson RA. A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403. Blood. 2019 Apr 4;133(14):1548-1559. Epub 2019 Jan 18. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00558519
==Mercaptopurine & Methotrexate==
===Regimen===
Study 	Dates of enrollment	Evidence
Linker et al. 1987	1980-1986 	Phase 2
====Preceding treatment====
*Linker regimen consolidation 
====Chemotherapy====
*Mercaptopurine (6-MP) 75 mg/m2 PO once per day
*Methotrexate (MTX) 20 mg/m2 PO once on day 1
7-day cycle for 130 cycles (30 months)
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
## 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==POMP==
POMP: Purinethol (Mercaptopurine), Oncovin (Vincristine), Methotrexate, Prednisone
===Regimen variant #1===
Study 	Dates of enrollment	Evidence
Huguet et al. 2009 (GRAALL-2003)	2003-2005 	Phase 2
====Preceding treatment====
*Pediatric-like GRAALL consolidation
====Chemotherapy====
*Mercaptopurine (6-MP) 60 mg/m2 PO once per day
*Vincristine (Oncovin) as follows:
**Months 1 to 12: 2 mg IV once on day 1
*Methotrexate (MTX) 25 mg/m2 PO once per day on days 1, 8, 15, 22
====Glucocorticoid therapy====
*Prednisone (Sterapred) as follows:
**Months 1 to 12: 40 mg/m2/day PO on days 1 to 7
1-month cycle for 24 cycles (2 years)
===Regimen variant #2===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)	1993-2003 	Phase 3 (C)	Etoposide & TBI, then auto HSCT	Seems to have longer OS (secondary endpoint)
====Preceding treatment====
*International ALL Trial consolidation
====Chemotherapy====
*Mercaptopurine (6-MP) 75 mg/m2 PO once per day
*Vincristine (Oncovin) 1.4 mg/m2 IV once on day 1
*Methotrexate (MTX) 20 mg/m2 IV or PO once per week
====Glucocorticoid therapy====
*Prednisone (Sterapred) 60 mg/m2 PO once per day on days 1 to 5
3-month cycle for 10 cycles (2.5 years from the start of phase III)
===Regimen variant #3===
Study 	Dates of enrollment	Evidence
Kantarjian et al. 2000	1992-1998 	Phase 2
Note: this is the IV POMP used from 1995 onwards. Exact timing of drugs is not given, for example, that certain drugs are taken on days 1 to 5 of the cycle.
====Preceding treatment====
*Induction Hyper-CVAD/MA x 8
====Chemotherapy====
*Mercaptopurine (6-MP) 1000 mg/m2 IV over 60 minutes once per day on days 1 to 5
*Vincristine (Oncovin) 2 mg IV once on day 1
*Methotrexate (MTX) 10 mg/m2 IV over 60 minutes once per day on days 1 to 5
====Glucocorticoid therapy====
*Prednisone (Sterapred) 200 mg PO once per day on days 1 to 5
====Supportive therapy====
*Trimethoprim/Sulfamethoxazole (dose not specified) PO twice per day on Saturday and Sunday for the first 6 months
*ONE of the following antivirals, for the first 6 months:
**Acyclovir (Zovirax) 200 mg PO once per day or 3 times per week
**Valacyclovir (Valtrex) 500 mg PO once per day or 3 times per week
1-month cycle for 24 cycles (2 years)
===Regimen variant #4, CALGB 8811 "Course V"===
Study 	Dates of enrollment	Evidence
Larson et al. 1995 (CALGB 8811)	1988-1991 	Phase 2
====Preceding treatment====
*Larson regimen (CALGB 8811) late intensification ("Course IV")
====Chemotherapy====
*Mercaptopurine (6-MP) 60 mg/m2 PO once per day on days 1 to 28
*Vincristine (Oncovin) 2 mg IV once on day 1
*Methotrexate (MTX) 20 mg/m2 PO once per day on days 1, 8, 15, 22
====Glucocorticoid therapy====
*Prednisone (Sterapred) 60 mg/m2 PO once per day on days 1 to 5
28-day cycles, continue until 24 months from diagnosis
===References===
# CALGB 8811: Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR, Hooberman AL, Westbrook CA, Arthur DC, George SL, Bloomfield CD, Schiffer CA. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: Cancer and Leukemia Group B study 8811. Blood. 1995 Apr 15;85(8):2025-37. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 
## 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# MRC UKALL XII/ECOG E2993: Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00002514
## Update: Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, Burnett AK, Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J, McMillan A, Franklin IM, Luger S, Ciobanu N, Rowe JM. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008 Feb 15;111(4):1827-33. Epub 2007 Nov 29. link to original article EuroPMC 
## Update: Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, Marks DI, McMillan AK, Litzow MR, Lazarus HM, Foroni L, Dewald G, Franklin IM, Luger SM, Paietta E, Wiernik PH, Tallman MS, Goldstone AH. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009 May 7;113(19):4489-96. Epub 2009 Feb 24. link to original article link to PMC article EuroPMC 
## 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
# GRAALL-2003: Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00222027
=Relapsed or refractory=
==7+3m==
MC: Mitoxantrone & Cytarabine
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Kantarjian et al. 2016 (INO-VATE ALL)	2012-2014 	Phase 3 (C)	Inotuzumab ozogamicin	Seems to have shorter OSMedian OS: 6.7 vs 7.7 mo(HR 1.30, 97.5% CI 0.97-1.72)
====Chemotherapy====
*Cytarabine (Ara-C) 200 mg/m2/day IV continuous infusion over 7 days, started on day 1 (total dose per cycle: 1400 mg/m2)
*Mitoxantrone (Novantrone) 12 mg/m2 IV over 20 minutes once per day on days 1 to 3
15- to 20-day cycle for up to 4 cycles
====Dose and schedule modifications====
*Mitoxantrone (Novantrone) dose reduction to 8 mg/m2 allowed on the basis of age, coexisting conditions, and previous anthracycline use
===References===
# INO-VATE ALL: Kantarjian HM, DeAngelo DJ, Stelljes M, Martinelli G, Liedtke M, Stock W, Gökbuget N, O'Brien S, Wang K, Wang T, Paccagnella ML, Sleight B, Vandendries E, Advani AS. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016 Aug 25;375(8):740-53. Epub 2016 Jun 12. link to original article link to original protocol dosing details in supplement have been reviewed by our editors link to PMC article EuroPMC NCT01564784
##PRO analysis: Kantarjian HM, Su Y, Jabbour EJ, Bhattacharyya H, Yan E, Cappelleri JC, Marks DI. Patient-reported outcomes from a phase 3 randomized controlled trial of inotuzumab ozogamicin versus standard therapy for relapsed/refractory acute lymphoblastic leukemia. Cancer. 2018 May 15;124(10):2151-2160. Epub 2018 Mar 6. link to original article EuroPMC
## Update: Kantarjian HM, DeAngelo DJ, Stelljes M, Liedtke M, Stock W, Gökbuget N, O'Brien SM, Jabbour E, Wang T, Liang White J, Sleight B, Vandendries E, Advani AS. Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia: Final report and long-term survival follow-up from the randomized, phase 3 INO-VATE study. Cancer. 2019 Jul 15;125(14):2474-2487. Epub 2019 Mar 28. link to original article link to PMC article EuroPMC
==Augmented Hyper-CVAD/MA & Asparaginase==
===Regimen===
Study 	Dates of enrollment	Evidence
Faderl et al. 2011	Not reported 	Phase 2
Note: it is not clear from the manuscript whether vincristine and dexamethasone were given in all cycle or just the A cycles, as is typical in most Hyper-CVAD regimens.
====Chemotherapy, Hyper-CVAD portion (cycles 1, 3, 5, 7; "Part A")====
*Cyclophosphamide (Cytoxan) 300 mg/m2 IV over 2 hours every 12 hours on days 1 to 3 (total dose per cycle: 1800 mg/m2)
*Vincristine (Oncovin) 2 mg IV once per day on days 1, 8, 15
*Doxorubicin (Adriamycin) 50 mg/m2 IV continuous infusion over 24 hours, started on day 4
*Pegaspargase (Oncaspar) 2500 units/m2 IV once on day 1
====Glucocorticoid therapy, Hyper-CVAD portion (cycles 1, 3, 5, 7; "Part A")====
*Dexamethasone (Decadron) 80 mg IV or PO once per day on days 1 to 4, 15 to 18
====Supportive therapy, Hyper-CVAD portion (cycles 1, 3, 5, 7; "Part A")====
*Mesna (Mesnex) 600 mg/m2/day IV continuous infusion over 72 hours, started on day 1, starting 1 hour prior to cyclophosphamide and completed 12 hours after the last dose of cyclophosphamide
*Filgrastim (Neupogen) 10 mcg/kg SC once per day, starting 24 hours after completion chemotherapy, continued until post-nadir ANC greater than 1000/μL
====Chemotherapy, MA portion (cycles 2, 4, 6, 8; "Part B")====
*Methotrexate (MTX) 1000 mg/m2 IV continuous infusion over 24 hours, started on day 1
*Cytarabine (Ara-C) 3000 mg/m2 IV every 12 hours on days 2 & 3 (total dose per cycle: 12,000 mg/m2)
*Pegaspargase (Oncaspar) 2500 units/m2 IV once on day 5
====Supportive therapy, MA portion (cycles 2, 4, 6, 8; "Part B")====
*Leucovorin (Folinic acid) 50 mg IV once on day 3, 12 hours after methotrexate is complete, then 15 mg IV every 6 hours until serum methotrexate level less than 100 nmol/L
*Filgrastim (Neupogen) 10 mcg/kg SC once per day, starting 24 hours after completion chemotherapy, continued until post-nadir ANC greater than 1000/μL
21- to 35-day cycle for 8 cycles
===References===
# Faderl S, Thomas DA, O'Brien S, Ravandi F, Garcia-Manero G, Borthakur G, Ferrajoli A, Verstovsek S, Ayoubi M, Rytting M, Feliu J, Kantarjian HM. Augmented hyper-CVAD based on dose-intensified vincristine, dexamethasone, and asparaginase in adult acute lymphoblastic leukemia salvage therapy. Clin Lymphoma Myeloma Leuk. 2011 Feb;11(1):54-9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Blinatumomab monotherapy==
===Regimen variant #1===
FDA-recommended dose
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Topp et al. 2014 (MT103-211) 	2012-2013 	Phase 2 (RT) 	 	
Kantarjian et al. 2017 (TOWER)	2014-01 to 2015-09 	Phase 3 (E-RT-switch-ooc)	Standard re-induction chemotherapy	Longer OS (primary endpoint)Median OS: 7.7 vs 4 mo(HR 0.71, 95% CI 0.55-0.93)
Note: The most common comparator in TOWER was FLAG +/- anthracycline. The first 2 cycles were considered induction and the next 3 consolidation.
====Immunotherapy====
*Blinatumomab (Blincyto) as follows:
**Cycle 1: 9 mcg/day IV continuous infusion over 7 days, started on day 1, then 28 mcg/day IV continuous infusion over 21 days, started on day 8 (total dose: 651 mcg)
**Cycles 2 to 5: 28 mcg/day IV continuous infusion over 28 days, started on day 1 (total dose per cycle: 784 mcg)
42-day cycle for 2 to 5 cycles
====Subsequent treatment====
*TOWER: Optional blinatumomab maintenance
===Regimen variant #2===
Study 	Dates of enrollment	Evidence
Topp et al. 2011 (MT103-202)	2008-2009 	Phase 2
Topp et al. 2014 (MT103-206)	2010-2012 	Phase 2
====Prior treatment criteria====
*MT103-202: Chemotherapy exposure
====Immunotherapy====
*Blinatumomab (Blincyto) 15 mcg/m2/day IV continuous infusion over 28 days, started on day 1 (total dose per cycle: 420 mcg/m2)
42-day course
====Subsequent treatment====
*Patients who had an allogeneic donor could receive an allogeneic hematopoietic stem cell transplant any time after cycle 1. Patients who had response could receive up to an additional 3 cycles of consolidation therapy--same as above.
===References===
# MT103-202: Topp MS, Kufer P, Gökbuget N, Goebeler M, Klinger M, Neumann S, Horst HA, Raff T, Viardot A, Schmid M, Stelljes M, Schaich M, Degenhard E, Köhne-Volland R, Brüggemann M, Ottmann O, Pfeifer H, Burmeister T, Nagorsen D, Schmidt M, Lutterbuese R, Reinhardt C, Baeuerle PA, Kneba M, Einsele H, Riethmüller G, Hoelzer D, Zugmaier G, Bargou RC. Targeted therapy with the T-cell-engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival. J Clin Oncol. 2011 Jun 20;29(18):2493-8. Epub 2011 May 16. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00560794
## Update: Topp MS, Gökbuget N, Zugmaier G, Degenhard E, Goebeler ME, Klinger M, Neumann SA, Horst HA, Raff T, Viardot A, Stelljes M, Schaich M, Köhne-Volland R, Brüggemann M, Ottmann OG, Burmeister T, Baeuerle PA, Nagorsen D, Schmidt M, Einsele H, Riethmüller G, Kneba M, Hoelzer D, Kufer P, Bargou RC. Long-term follow-up of hematologic relapse-free survival in a phase 2 study of blinatumomab in patients with MRD in B-lineage ALL. Blood. 2012 Dec 20;120(26):5185-7. Epub 2012 Sep 28. link to original article EuroPMC
## Update: Gökbuget N, Zugmaier G, Klinger M, Kufer P, Stelljes M, Viardot A, Horst HA, Neumann S, Brüggemann M, Ottmann OG, Burmeister T, Wessiepe D, Topp MS, Bargou R. Long-term relapse-free survival in a phase 2 study of blinatumomab for the treatment of patients with minimal residual disease in B-lineage acute lymphoblastic leukemia. Haematologica. 2017 Apr;102(4):e132-e135. Epub 2017 Jan 12. link to original article link to PMC article EuroPMC
# MT103-206: Topp MS, Gökbuget N, Zugmaier G, Klappers P, Stelljes M, Neumann S, Viardot A, Marks R, Diedrich H, Faul C, Reichle A, Horst HA, Brüggemann M, Wessiepe D, Holland C, Alekar S, Mergen N, Einsele H, Hoelzer D, Bargou RC. Phase II trial of the anti-CD19 bispecific T cell-engager blinatumomab shows hematologic and molecular remissions in patients with relapsed or refractory B-precursor acute lymphoblastic leukemia. J Clin Oncol. 2014 Dec 20;32(36):4134-40. Epub 2014 Nov 10. link to original article EuroPMC NCT01209286
## Update: Zugmaier G, Gökbuget N, Klinger M, Viardot A, Stelljes M, Neumann S, Horst HA, Marks R, Faul C, Diedrich H, Reichle A, Brüggemann M, Holland C, Schmidt M, Einsele H, Bargou RC, Topp MS. Long-term survival and T-cell kinetics in relapsed/refractory ALL patients who achieved MRD response after blinatumomab treatment. Blood. 2015 Dec 10;126(24):2578-84. Epub 2015 Oct 19. link to original article link to PMC article EuroPMC
# MT103-211: Topp MS, Gökbuget N, Stein AS, Zugmaier G, O'Brien S, Bargou RC, Dombret H, Fielding AK, Heffner L, Larson RA, Neumann S, Foà R, Litzow M, Ribera JM, Rambaldi A, Schiller G, Brüggemann M, Horst HA, Holland C, Jia C, Maniar T, Huber B, Nagorsen D, Forman SJ, Kantarjian HM. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol. 2015 Jan;16(1):57-66. Epub 2014 Dec 16. Erratum in: Lancet Oncol. 2015 Apr;16(4):e158. link to original article EuroPMC NCT01466179
# TOWER: Kantarjian H, Stein A, Gökbuget N, Fielding AK, Schuh AC, Ribera JM, Wei A, Dombret H, Foà R, Bassan R, Arslan Ö, Sanz MA, Bergeron J, Demirkan F, Lech-Maranda E, Rambaldi A, Thomas X, Horst HA, Brüggemann M, Klapper W, Wood BL, Fleishman A, Nagorsen D, Holland C, Zimmerman Z, Topp MS. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017 Mar 2;376(9):836-847. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02013167
## HRQoL analysis: Topp MS, Zimmerman Z, Cannell P, Dombret H, Maertens J, Stein A, Franklin J, Tran Q, Cong Z, Schuh AC. Health-related quality of life in adults with relapsed/refractory acute lymphoblastic leukemia treated with blinatumomab. Blood. 2018 Jun 28;131(26):2906-2914. Epub 2018 May 8. link to original article link to PMC article EuroPMC
==Brexucabtagene autoleucel monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment	Evidence
Shah et al. 2021 (ZUMA-3)	2018-2019 	Phase 2 (RT)
====Preceding treatment====
*FC lymphodepletion
====Immunotherapy====
*Brexucabtagene autoleucel (Tecartus) 1 x 106 CAR T cells/kg IV once on day 0
One course
===References===
#ZUMA-3: Shah BD, Ghobadi A, Oluwole OO, Logan AC, Boissel N, Cassaday RD, Leguay T, Bishop MR, Topp MS, Tzachanis D, O'Dwyer KM, Arellano ML, Lin Y, Baer MR, Schiller GJ, Park JH, Subklewe M, Abedi M, Minnema MC, Wierda WG, DeAngelo DJ, Stiff P, Jeyakumar D, Feng C, Dong J, Shen T, Milletti F, Rossi JM, Vezan R, Masouleh BK, Houot R. KTE-X19 for relapsed or refractory adult B-cell acute lymphoblastic leukaemia: phase 2 results of the single-arm, open-label, multicentre ZUMA-3 study. Lancet. 2021 Aug 7;398(10299):491-502. Epub 2021 Jun 4. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT02614066
==Clofarabine monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Kantarjian et al. 2003	Not reported 	Phase 2, fewer than 20 patients in this arm
====Chemotherapy====
*Clofarabine (Clolar) 40 mg/m2 IV over 60 minutes once per day on days 1 to 5
3- to 6-week cycles, depending on response count recovery
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 
==High-dose Cytarabine monotherapy (HiDAC)==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Kantarjian et al. 2016 (INO-VATE ALL)	2012-2014 	Phase 3 (C)	Inotuzumab ozogamicin	Seems to have shorter OSMedian OS: 6.7 vs 7.7 mo(HR 1.30, 97.5% CI 0.97-1.72)
====Chemotherapy====
*Cytarabine (Ara-C) by the following age-based criteria:
**Younger than 55 years old: 3000 mg/m2 IV every 12 hours on days 1 to 6 (total dose: 36,000 mg/m2)
**55 years old or older: 1500 mg/m2 IV every 12 hours on days 1 to 6 (total dose: 18,000 mg/m2)
6-day course
===References===
# INO-VATE ALL: Kantarjian HM, DeAngelo DJ, Stelljes M, Martinelli G, Liedtke M, Stock W, Gökbuget N, O'Brien S, Wang K, Wang T, Paccagnella ML, Sleight B, Vandendries E, Advani AS. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016 Aug 25;375(8):740-53. Epub 2016 Jun 12. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01564784
##PRO analysis: Kantarjian HM, Su Y, Jabbour EJ, Bhattacharyya H, Yan E, Cappelleri JC, Marks DI. Patient-reported outcomes from a phase 3 randomized controlled trial of inotuzumab ozogamicin versus standard therapy for relapsed/refractory acute lymphoblastic leukemia. Cancer. 2018 May 15;124(10):2151-2160. Epub 2018 Mar 6. link to original article EuroPMC
## Update: Kantarjian HM, DeAngelo DJ, Stelljes M, Liedtke M, Stock W, Gökbuget N, O'Brien SM, Jabbour E, Wang T, Liang White J, Sleight B, Vandendries E, Advani AS. Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia: Final report and long-term survival follow-up from the randomized, phase 3 INO-VATE study. Cancer. 2019 Jul 15;125(14):2474-2487. Epub 2019 Mar 28. link to original article link to PMC article EuroPMC
==Cytarabine & Idarubicin==
===Regimen===
Study 	Dates of enrollment	Evidence
Huguet et al. 2009 (GRAALL-2003) 	2003-2005 	Phase 2
Maury et al. 2016 (GRAALL-2005/R)	2006-2014 	Non-randomized part of phase 3 RCT
Note: the original GRAALL-2003 article Table 1 has several errors which were corrected in the erratum and the online Table 1. These corrected doses are replicated here. This regimen is for patients not achieving CR1 with induction.
====Preceding treatment====
*Cyclophosphamide, Daunorubicin, L-aspariginase, Vincristine, Prednisone induction
====Chemotherapy====
*Cytarabine (Ara-C) 2000 mg/m2 IV over 3 hours every 12 hours on days 1 to 4 (total dose: 16,000 mg/m2)
*Idarubicin (Idamycin) 12 mg/m2 IV over 60 minutes once per day on days 1 to 3
====Supportive therapy====
*Lenograstim (Granocyte) by the following study-specific criteria:
**GRAALL-2003: 150 mcg/m2 SC once per day from day 9 until myeloid recovery
**GRAALL-2005/R: 263 mcg IV or SC once per day from day 9 until first day with ANC greater than 1000/μL
One course
====Subsequent treatment====
*GRAALL-2005/R, CR1 after salvage: Pediatric-like GRAALL consolidation
===References===
# GRAALL-2003: Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00222027
# GRAALL-2005/R: Maury S, Chevret S, Thomas X, Heim D, Leguay T, Huguet F, Chevallier P, Hunault M, Boissel N, Escoffre-Barbe M, Hess U, Vey N, Pignon JM, Braun T, Marolleau JP, Cahn JY, Chalandon Y, Lhéritier V, Beldjord K, Béné MC, Ifrah N, Dombret H; GRAALL. Rituximab in B-lineage adult acute lymphoblastic leukemia. N Engl J Med. 2016 Sep 15;375(11):1044-53. link to original article link to supplement dosing details in supplement have been reviewed by our editors EuroPMC NCT00327678
==Cytarabine, Idarubicin, Rituximab==
===Regimen===
Study 	Dates of enrollment	Evidence
Maury et al. 2016 (GRAALL-2005/R)	2006-2014 	Non-randomized part of phase 3 RCT
This regimen is for patients not achieving CR1 with induction.
====Preceding treatment====
*Cyclophosphamide, Daunorubicin, L-aspariginase, Vincristine, Prednisone, Rituximab induction
====Chemotherapy====
*Cytarabine (Ara-C) 2000 mg/m2 IV over 3 hours every 12 hours on days 1 to 4 (total dose: 16,000 mg/m2)
*Idarubicin (Idamycin) 12 mg/m2 IV over 60 minutes once per day on days 1 to 3
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once per day on days 1 & 7
====Supportive therapy====
*Lenograstim (Granocyte) 263 mcg IV or SC once per day, starting on day 9, continuing until first day with ANC greater than 1000/μL
One course
====Subsequent treatment====
*GRAALL-2005/R, CR1 after salvage: Pediatric-like GRAALL consolidation with rituximab
===References===
# GRAALL-2005/R: Maury S, Chevret S, Thomas X, Heim D, Leguay T, Huguet F, Chevallier P, Hunault M, Boissel N, Escoffre-Barbe M, Hess U, Vey N, Pignon JM, Braun T, Marolleau JP, Cahn JY, Chalandon Y, Lhéritier V, Beldjord K, Béné MC, Ifrah N, Dombret H; GRAALL. Rituximab in B-lineage adult acute lymphoblastic leukemia. N Engl J Med. 2016 Sep 15;375(11):1044-53. link to original article link to supplement dosing details in supplement have been reviewed by our editors EuroPMC NCT00327678
==FLAG==
FLAG: FLudarabine, Ara-C (Cytarabine), G-CSF
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Kantarjian et al. 2016 (INO-VATE ALL)	2012-2014 	Phase 3 (C)	Inotuzumab ozogamicin	Seems to have shorter OSMedian OS: 6.7 vs 7.7 mo(HR 1.30, 97.5% CI 0.97-1.72)
====Chemotherapy====
*Fludarabine (Fludara) 30 mg/m2 IV once per day on days 2 to 6
*Cytarabine (Ara-C) 2000 mg/m2 IV once per day on days 1 to 6
====Growth factor therapy====
*G-CSF 5 mcg/kg (route not specified) or at the institutional standard dose once per day (interval not specified)
28-day cycle for up to 4 cycles
===References===
# INO-VATE ALL: Kantarjian HM, DeAngelo DJ, Stelljes M, Martinelli G, Liedtke M, Stock W, Gökbuget N, O'Brien S, Wang K, Wang T, Paccagnella ML, Sleight B, Vandendries E, Advani AS. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016 Aug 25;375(8):740-53. Epub 2016 Jun 12. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01564784
##PRO analysis: Kantarjian HM, Su Y, Jabbour EJ, Bhattacharyya H, Yan E, Cappelleri JC, Marks DI. Patient-reported outcomes from a phase 3 randomized controlled trial of inotuzumab ozogamicin versus standard therapy for relapsed/refractory acute lymphoblastic leukemia. Cancer. 2018 May 15;124(10):2151-2160. Epub 2018 Mar 6. link to original article EuroPMC
## Update: Kantarjian HM, DeAngelo DJ, Stelljes M, Liedtke M, Stock W, Gökbuget N, O'Brien SM, Jabbour E, Wang T, Liang White J, Sleight B, Vandendries E, Advani AS. Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia: Final report and long-term survival follow-up from the randomized, phase 3 INO-VATE study. Cancer. 2019 Jul 15;125(14):2474-2487. Epub 2019 Mar 28. link to original article link to PMC article EuroPMC
==Hyper-CVAD/MA & Everolimus==
Hyper-CVAD/MA & Everolimus: Hyperfractionated Cyclophosphamide, Vincristine, Adriamycin (Doxorubicin), Dexamethasone alternating with Methotrexate, Ara-C (Cytarabine), with Everolimus
===Regimen===
Study 	Dates of enrollment	Evidence
Daver et al. 2015 (MDACC 2009-0100)	2010-2014 	Phase 1/2
Note: there are some difference between this protocol and other published Hyper-CVAD protocols, including flexibility in the timing of vincristine and dexamethasone. Some details were missing, in particular the supportive medications for the B cycles. The everolimus dose is the MTD.
====Targeted therapy, all cycles====
*Everolimus (Afinitor) 5 mg PO once per day
====Chemotherapy, Hyper-CVAD portion (cycles 1, 3, 5, 7; "Part A")====
*Cyclophosphamide (Cytoxan) 300 mg/m2 IV over 3 hours every 12 hours on days 1 to 3 (total dose per cycle: 1800 mg/m2)
*Vincristine (Oncovin) by the following age-based criteria:
**Younger than 18 years old: 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 4 & 11 (+/- 2 days)
**18 years old or older: 2 mg IV once per day on days 4 & 11 (+/- 2 days)
*Doxorubicin (Adriamycin) 50 mg/m2 IV continuous infusion over 24 hours, started on day 4 
====Glucocorticoid therapy, Hyper-CVAD portion (cycles 1, 3, 5, 7; "Part A")====
*Dexamethasone (Decadron) by the following age-based criteria:
**Younger than 18 years old: 20 mg/m2 (maximum dose of 40 mg) IV or PO once per day on days 1 to 4, 11 to 14 (+/- 2 days)
**18 years old or older: 40 mg IV or PO once per day on days 1 to 4, 11 to 14 (+/- 2 days)
====Supportive therapy, Hyper-CVAD portion (cycles 1, 3, 5, 7; "Part A")====
*Mesna (Mesnex) 600 mg/m2/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 1800 mg/m2)
*Pegfilgrastim (Neulasta) 6 mg SC once, approximately 24 hours after completion of chemotherapy
====Chemotherapy, MA portion (cycles 2, 4, 6, 8; "Part B")====
*Methotrexate (MTX) 200 mg/m2 IV over 2 hours once on day 1, then 800 mg/m2 IV over 22 hours (total dose per cycle: 1000 mg/m2)
*Cytarabine (Ara-C) by the following age- and renal function-based criteria:
**Younger than 60 years old: 3000 mg/m2 IV over 2 hours every 12 hours on days 2 & 3 (total dose per cycle: 12,000 mg/m2)
**60 years old or older OR creatinine 1.5 x the upper limit of normal or more: 1000 mg/m2 IV over 2 hours every 12 hours on days 2 & 3 (total dose per cycle: 4000 mg/m2)
====Glucocorticoid therapy, MA portion (cycles 2, 4, 6, 8; "Part B")====
*Methylprednisolone (Solumedrol) by the following age-based criteria:
**Younger than 18 years old: 25 mg/m2 (maximum dose of 50 mg) IV over 2 hours every 12 hours on days 1 to 3 (total dose per cycle: 150 mg/m2)
**18 years old or older: 50 mg IV over 2 hours every 12 hours on days 1 to 3 (total dose per cycle: 300 mg/m2)
***It isn't clear if this is meant to be a supportive or antineoplastic medication.
8 cycles
===References===
# MDACC 2009-0100: Daver N, Boumber Y, Kantarjian H, Ravandi F, Cortes J, Rytting ME, Kawedia JD, Basnett J, Culotta KS, Zeng Z, Lu H, Richie MA, Garris R, Xiao L, Liu W, Baggerly KA, Jabbour E, O'Brien S, Burger J, Bendall LJ, Thomas D, Konopleva M. A Phase I/II study of the mTOR inhibitor everolimus in combination with HyperCVAD chemotherapy in patients with relapsed/refractory acute lymphoblastic leukemia. Clin Cancer Res. 2015 Jun 15;21(12):2704-14. Epub 2015 Feb 27. link to original article link to PMC article contains partial protocol in supplement EuroPMC NCT00968253
==Inotuzumab ozogamicin monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Kantarjian et al. 2012 (MDACC 2009-0872)	2010-2011 	Phase 2 	 	
Kantarjian et al. 2016 (INO-VATE ALL) 	2012-2014 	Phase 3 (E-RT-switch-ooc)	Investigator's choice of:1a. HiDAC1b. MC1c. FLAG	Seems to have longer OS (co-primary endpoint)Median OS: 7.7 vs 6.7 mo(HR 0.77, 97.5% CI 0.58-1.03)
====Biomarker eligibility criteria====
*INO-VATE ALL: CD22-positive
====Antibody-drug conjugate therapy====
*Inotuzumab ozogamicin (Besponsa) 0.8 mg/m2 IV once on day 1, then 0.5 mg/m2 IV once per day on days 8 & 15
21-day course, then 28-day cycle for up to 5 cycles
====Dose and schedule modifications====
*If patients achieved a CR or CRi, the day 1 dose was reduced to 0.5 mg/m2 for all subsequent cycles.
===References===
# MDACC 2009-0872: Kantarjian H, Thomas D, Jorgensen J, Jabbour E, Kebriaei P, Rytting M, York S, Ravandi F, Kwari M, Faderl S, Rios MB, Cortes J, Fayad L, Tarnai R, Wang SA, Champlin R, Advani A, O'Brien S. Inotuzumab ozogamicin, an anti-CD22-calecheamicin conjugate, for refractory and relapsed acute lymphocytic leukaemia: a phase 2 study. Lancet Oncol. 2012 Apr;13(4):403-11. Epub 2012 Feb 21. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT01134575
# INO-VATE ALL: Kantarjian HM, DeAngelo DJ, Stelljes M, Martinelli G, Liedtke M, Stock W, Gökbuget N, O'Brien S, Wang K, Wang T, Paccagnella ML, Sleight B, Vandendries E, Advani AS. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016 Aug 25;375(8):740-53. Epub 2016 Jun 12. link to original article link to original protocol dosing details in supplement have been reviewed by our editors link to PMC article EuroPMC NCT01564784
##PRO analysis: Kantarjian HM, Su Y, Jabbour EJ, Bhattacharyya H, Yan E, Cappelleri JC, Marks DI. Patient-reported outcomes from a phase 3 randomized controlled trial of inotuzumab ozogamicin versus standard therapy for relapsed/refractory acute lymphoblastic leukemia. Cancer. 2018 May 15;124(10):2151-2160. Epub 2018 Mar 6. link to original article EuroPMC
## Update: Kantarjian HM, DeAngelo DJ, Stelljes M, Liedtke M, Stock W, Gökbuget N, O'Brien SM, Jabbour E, Wang T, Liang White J, Sleight B, Vandendries E, Advani AS. Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia: Final report and long-term survival follow-up from the randomized, phase 3 INO-VATE study. Cancer. 2019 Jul 15;125(14):2474-2487. Epub 2019 Mar 28. link to original article link to PMC article EuroPMC
==Obecabtagene autoleucel monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Efficacy
Roddie et al. 2024 (FELIX)	Not reported 	Phase 1b/2 (RT)	ORR: 77%
====Preceding treatment====
*Lymphodepleting therapy with FC
====Immunotherapy====
*Obecabtagene autoleucel (Aucatzyl) by the following disease status-based criteria:
**More than 20% bone marrow blasts pre-lymphodepletion: 10 x 106 CAR T-cells IV once on day 0, then 400 x 106 CAR T-cells IV once on day 9
**20% bone marrow blasts or less pre-lymphodepletion: 100 x 106 CAR T-cells IV once on day 0, then 310 x 106 CAR T-cells IV once on day 9
One course
===References===
# FELIX: Roddie C, Sandhu KS, Tholouli E, Logan AC, Shaughnessy P, Barba P, Ghobadi A, Guerreiro M, Yallop D, Abedi M, Pantin JM, Yared JA, Beitinjaneh AM, Chaganti S, Hodby K, Menne T, Arellano ML, Malladi R, Shah BD, Mountjoy L, O'Dwyer KM, Peggs KS, Lao-Sirieix P, Zhang Y, Brugger W, Braendle E, Pule M, Bishop MR, DeAngelo DJ, Park JH, Jabbour E. Obecabtagene Autoleucel in Adults with B-Cell Acute Lymphoblastic Leukemia. N Engl J Med. 2024 Dec 12;391(23):2219-2230. Epub 2024 Nov 27. link to original article dosing details in supplement have been reviewed by our editors EuroPMC NCT04404660
==Tisagenlecleucel monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Efficacy
Maude et al. 2014 (UPCC04409)	2012-2014 	Phase 1/2a 	
Maude et al. 2018 (ELIANA) 	2015-2017 	Phase 2 (RT)	ORR: 81%
Note: dosing instructions are based on ELIANA.
====Preceding treatment====
*Lymphodepleting therapy with FC or CYVE
====Immunotherapy====
*Tisagenlecleucel (Kymriah) by the following weight-based criteria:
**Up to 50 kg: 2 to 5 x 106 CTL019 transduced viable T-cells per kg body weight IV once on day 0
**More than 50 kg: 1.0 to 2.5 x 108 CTL019 transduced viable T-cells IV once on day 0
One course
===References===
# UPCC04409: Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, Chew A, Gonzalez VE, Zheng Z, Lacey SF, Mahnke YD, Melenhorst JJ, Rheingold SR, Shen A, Teachey DT, Levine BL, June CH, Porter DL, Grupp SA. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014 Oct 16;371(16):1507-17. Erratum in: N Engl J Med. 2016 Mar 10;374(10):998. link to original article link to PMC article EuroPMC NCT01029366
# ELIANA: Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, Bader P, Verneris MR, Stefanski HE, Myers GD, Qayed M, De Moerloose B, Hiramatsu H, Schlis K, Davis KL, Martin PL, Nemecek ER, Yanik GA, Peters C, Baruchel A, Boissel N, Mechinaud F, Balduzzi A, Krueger J, June CH, Levine BL, Wood P, Taran T, Leung M, Mueller KT, Zhang Y, Sen K, Lebwohl D, Pulsipher MA, Grupp SA. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018 Feb 1;378(5):439-448. link to original article link to supplementary protocol dosing details in supplement have been reviewed by our editors link to PMC article EuroPMC NCT02435849
=Consolidation after salvage therapy=
==Blinatumomab monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Brown et al. 2021 (COG AALL1331)	2014-2019 	Phase 3 (E-RT-switch-ooc)	Standard salvage consolidation chemotherapy	Might have longer DFS (primary endpoint)DFS24: 54.4% vs 39%(HR 0.70, 95% CI 0.47-1.03)
====Immunotherapy====
*Blinatumomab (Blincyto) 15 mcg/m2/day IV continuous infusion over 28 days, started on day 1 (total dose per cycle: 420 mcg/m2)
35-day cycle for 2 cycles
====Subsequent treatment====
*Allogeneic hematopoietic stem cell transplant
===References===
# COG AALL1331: Brown PA, Ji L, Xu X, Devidas M, Hogan LE, Borowitz MJ, Raetz EA, Zugmaier G, Sharon E, Bernhardt MB, Terezakis SA, Gore L, Whitlock JA, Pulsipher MA, Hunger SP, Loh ML. Effect of Postreinduction Therapy Consolidation With Blinatumomab vs Chemotherapy on Disease-Free Survival in Children, Adolescents, and Young Adults With First Relapse of B-Cell Acute Lymphoblastic Leukemia: A Randomized Clinical Trial. JAMA. 2021 Mar 2;325(9):833-842. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02101853
==Cyclophosphamide & TBI, then allo HSCT==
Cy/TBI: Cyclophosphamide & Total Body Irradiation
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy	Non-relapse mortality
Rudolph et al. 1973	1968-1970 	Non-randomized, fewer than 20 pts in subgroup	 	 	
Kersey et al. 1987 	1982-1985 	Quasi-randomized 	Auto HSCT 	Longer RFS 	
Zhang et al. 2023 	2016-01 to 2020-02 	Phase 3 (C) 	BuCy 	Non-inferior OS24 	Similar NRM
===References===
# Rudolph RH, Fefer A, Thomas ED, Buckner CD, Clift RA, Storb R. Isogeneic marrow grafts for hematologic malignancy in man. Arch Intern Med. 1973 Aug;132(2):279-85. link to original article EuroPMC
## Update: Fefer A, Einstein AB, Thomas ED, Buckner CD, Clift RA, Glucksberg H, Neiman PE, Storb R. Bone-marrow transplantation for hematologic neoplasia in 16 patients with identical twins. N Engl J Med. 1974 Jun 20;290(25):1389-93. link to original article EuroPMC
# Kersey JH, Weisdorf D, Nesbit ME, LeBien TW, Woods WG, McGlave PB, Kim T, Vallera DA, Goldman AI, Bostrom B, Hurd D, Ramsay NKC. Comparison of autologous and allogeneic bone marrow transplantation for treatment of high-risk refractory acute lymphoblastic leukemia. N Engl J Med. 1987 Aug 20;317(8):461-7. link to original article EuroPMC
#Zhang H, Fan Z, Huang F, Han L, Xu Y, Xu N, Deng L, Wang S, Lin D, Luo X, Zhang Q, Liu X, Li X, Liang X, Xie S, Qu H, Yu S, Zhou H, Shi P, Xuan L, Lin R, Liu H, Jin H, Sun J, Liu Q. Busulfan Plus Cyclophosphamide Versus Total Body Irradiation Plus Cyclophosphamide for Adults Acute B Lymphoblastic Leukemia: An Open-Label, Multicenter, Phase III Trial. J Clin Oncol. 2023 Jan 10;41(2):343-353. Epub 2022 Sep 9. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02670252
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=Maintenance after subsequent lines of therapy=
==Blinatumomab monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Kantarjian et al. 2017 (TOWER)	2014-01 to 2015-09 	Phase 3 (E-RT-switch-ooc)	Standard maintenance chemotherapy	Longer OS (primary endpoint)Median OS: 7.7 vs 4 mo(HR 0.71, 95% CI 0.55-0.93)
Note: The most common comparator was not specified but is presumably POMP.
====Preceding treatment====
*Blinatumomab induction, then Blinatumomab consolidation
====Immunotherapy====
*Blinatumomab (Blincyto) 28 mcg/day IV continuous infusion over 28 days, started on day 1 (total dose per cycle: 784 mcg)
12-week cycle for up to 5 cycles (1 year) 
===References===
# TOWER: Kantarjian H, Stein A, Gökbuget N, Fielding AK, Schuh AC, Ribera JM, Wei A, Dombret H, Foà R, Bassan R, Arslan Ö, Sanz MA, Bergeron J, Demirkan F, Lech-Maranda E, Rambaldi A, Thomas X, Horst HA, Brüggemann M, Klapper W, Wood BL, Fleishman A, Nagorsen D, Holland C, Zimmerman Z, Topp MS. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017 Mar 2;376(9):836-847. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02013167
## HRQoL analysis: Topp MS, Zimmerman Z, Cannell P, Dombret H, Maertens J, Stein A, Franklin J, Tran Q, Cong Z, Schuh AC. Health-related quality of life in adults with relapsed/refractory acute lymphoblastic leukemia treated with blinatumomab. Blood. 2018 Jun 28;131(26):2906-2914. Epub 2018 May 8. link to original article link to PMC article EuroPMC
Category:B-cell acute lymphoblastic leukemia regimens
Category:Disease-specific pages
Category:Acute lymphoblastic leukemias