B-cell acute lymphoblastic leukemia, pediatric

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This page contains studies that are specific to pediatric populations. For the more general B-cell acute lymphoblastic leukemia page, including regimens for adolescents and young adults, follow this link.
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. For placebo or observational studies in this condition, please visit this page.
Note: certain regimens are to be found on dedicated pages:
*Pediatric B-cell ALL, Ph-positive
*Infant ALL
Last updated on 2024-09-06:40 regimens on this page
46 variants on this page
=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.
==NCCN==
*NCCN does not currently have guidelines at this granular level; please see NCCN Guidelines - Pediatric Acute Lymphoblastic Leukemia.
=Upfront therapy, standard-risk (SR)=
==COG AALL0932 protocol for standard-risk==
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Matloub et al. 2011 (COG CCG-1991) 	2000-2005 	Phase 3 (E-de-esc) 	Mercaptopurine, MTX, Vincristine, Dexamethasone	Longer EFS (co-primary endpoint)
Maloney et al. 2019 (COG AALL0331) 	2005-2010 	Non-randomized part of phase 3 RCT	 	
Angiolillo et al. 2021 (COG AALL0932)	2010-2018 	Non-randomized part of phase 3 RCT	 	
Note: there are very minor differences in timing between protocols; see papers for details.
===Induction, Pegaspargase, Vincristine, Dexamethasone===
====Chemotherapy====
*Pegaspargase (Oncaspar) 2,500 units/m2 IV once over 1 to 2 hours 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====
*Dexamethasone (Decadron) 3 mg/m2 IV or PO twice per day on days 1 to 28
====CNS therapy, prophylaxis====
*Cytarabine (Ara-C) IT once on day 0
Age in years, rounded to the nearest hundredth	Initial Dose
1.00 to 1.99 	30 mg
2.00 to 2.99 	50 mg
3.00 or older 	70 mg
 CNS2 Patients will receive an additional dose of cytarabine IT on either day 4, 5, or 6, followed by Methotrexate (MTX) IT on day 8 and then another dose of cytarabine IT on either day 11 or 12 according to the following dosing.
Age in years, rounded to the nearest hundredth	Subsequent Doses
1.00 to 1.99 	20 mg
2.00 to 2.99 	30 mg
3.00 or older 	40 mg
*Methotrexate (MTX) IT once per day on days 8, 29
Age in years, rounded to the nearest hundredth	Dose
1.00 to 1.99 	8 mg
2.00 to 2.99 	10 mg
3.00 to 8.99 	12 mg
9.00 or older 	15 mg
====Supportive therapy, DS Arm====
*Leucovorin (Folinic acid) 5 mg/m2 PO x 2 doses given 48 and 60 hours after the lumbar puncture on days 10, 11, 31, 32
35-day course
====Subsequent treatment====
*COG AALL0331, M2 marrow or M1 marrow with MRD of at least 1% at day 29: Extended induction
*COG AALL0932: 6-MP & Vincristine consolidation
===Consolidation, Mercaptopurine & Vincristine===
For AR B-ALL patients, LR-C Arm, and B-LLy
====Preceding treatment====
*Pegaspargase, Vincristine, Dexamethasone induction
====Chemotherapy====
*Mercaptopurine (6-MP) 75 mg/m2/day PO on days 1 to 28
*Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once on day 1
====CNS therapy, prophylaxis====
*Methotrexate (MTX) IT once per day on days 1, 8, 15
Age in years, rounded to the nearest hundredth	Dose
1.00 to 1.99 	8 mg
2.00 to 2.99 	10 mg
3.00 to 8.99 	12 mg
9.00 or older 	15 mg
====Supportive therapy, DS Arm====
*Leucovorin (Folinic acid) 5 mg/m2 PO x 2 doses given 48 and 60 hours after the lumbar puncture on days 3, 4, 10, 11, 17, 18.
28-day course
====Subsequent treatment====
*MTX & Vincristine interim maintenance
===Interim Maintenance, I (Methotrexate & Vincristine)===
For AR B-ALL patients, LR-C Arm, and B-LLy
====Preceding treatment====
*COG AALL0932: 6-MP & Vincristine consolidation
====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
**Given over 2 to 5 minutes (undiluted) or over 10 to 15 minutes (diluted).
*Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 11, 21, 31, 41
====CNS therapy, prophylaxis====
*Methotrexate (MTX) IT once on day 31
Age in years, rounded to the nearest hundredth	Dose
1.00 to 1.99 	8 mg
2.00 to 2.99 	10 mg
3.00 to 8.99 	12 mg
9.00 or older 	15 mg
====Supportive therapy, DS Arm====
*Leucovorin (Folinic acid) 5 mg/m2 PO x 2 doses given 48 and 60 hours after the lumbar puncture on days 33, 34
8-week course, followed by:
===Delayed Intensification===
For AR B-ALL patients, LR-C Arm, and B-LLy
====Preceding treatment====
*MTX & Vincristine interim maintenance
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 1000 mg/m2 IV over 30 to 60 minutes once on day 29
*Cytarabine (Ara-C) 75 mg/m2 SC or IV over 1 to 30 minutes on days 29 to 32, 36 to 39
*Doxorubicin (Adriamycin) 25 mg/m2 IV push/infusion over 1 to 15 minutes once per day on days 1, 8, 15
*Pegaspargase (Oncaspar) 2,500 units/m2 IV over 1 to 2 hours once on day 4
*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, 15
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 5 mg/m2/dose PO twice per day on days 1 to 7, 15 to 21 (10 mg/m2/day)
====CNS therapy, prophylaxis====
*Methotrexate (MTX) IT once per day on days 1 & 29
Age in years, rounded to the nearest hundredth	Dose
1.00 to 1.99 	8 mg
2.00 to 2.99 	10 mg
3.00 to 8.99 	12 mg
9.00 or older 	15 mg
====Supportive therapy, DS Arm====
*Leucovorin (Folinic acid) 5 mg/m2 PO x 2 doses given 48 and 60 hours after the lumbar puncture on days 3 to 4, 31 to 32
8-week course
====Subsequent treatment====
*MTX & Vincristine interim maintenance II
===Interim Maintenance, II (Methotrexate & Vincristine)===
For AR B-ALL patients, LR-C Arm, and B-LLy
====Preceding treatment====
*COG AALL0932: 6-MP & Vincristine consolidation
====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
**Given over 2 to 5 minutes (undiluted) or over 10 to 15 minutes (diluted)
*Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 11, 21, 31, 41
====CNS therapy, prophylaxis====
*Methotrexate (MTX) IT once on day 31
Age in years, rounded to the nearest hundredth	Dose
1.00 to 1.99 	8 mg
2.00 to 2.99 	10 mg
3.00 to 8.99 	12 mg
9.00 or older 	15 mg
====Supportive therapy, DS Arm====
*Leucovorin (Folinic acid) 5 mg/m2 PO x 2 doses given 48 and 60 hours after the lumbar puncture on days 3 to 4, 33 to 34
8-week course
====Subsequent treatment====
*COG AALL0932: AALL0932 delayed intensification
===Maintenance, Arm A and C (Vincristine/Dexamethasone Pulses)===
For AR B-ALL patients, and LR-C Arm
====Preceding treatment====
*COG AALL0932: MTX & Vincristine interim maintenance
====Chemotherapy====
*Methotrexate (MTX) 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/m2 (maximum dose of 2 mg) IV once per day on days 1, 29, 57
*Mercaptopurine (6-MP) 75 mg/m2 PO once per day on days 1 to 84
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 3 mg/m2 PO twice per day on days 1 to 5, 29 to 33, 57 to 61 (6 mg/m2/day)
====CNS therapy, prophylaxis====
*Methotrexate (MTX) IT once on day 1
Age in years, rounded to the nearest hundredth	Dose
1.00 to 1.99 	8 mg
2.00 to 2.99 	10 mg
3.00 to 8.99 	12 mg
9.00 or older 	15 mg
12-week cycles until total duration of therapy is 2 years for female and 3 years for male from the start of Interim I
===Maintenance, Arm B and D (Vincristine/Dexamethasone Pulses)===
====Preceding treatment====
*COG AALL0932: MTX & Vincristine interim maintenance
====Chemotherapy====
*Currently maintenance arm B and D are also treated with Methotrexate (MTX) PO at 20 mg/m2 (decreased from the starting dose of 40 mg/m2) on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78
*Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 29, 57
*Mercaptopurine (6-MP) 75 mg/m2 PO once per day on days 1 to 84
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 3 mg/m2 PO twice per day on days 1 to 5, 29 to 33, 57 to 61 
====CNS therapy, prophylaxis====
*Methotrexate (MTX) IT once on day 1
Age in years, rounded to the nearest hundredth	Dose
1.00 to 1.99 	8 mg
2.00 to 2.99 	10 mg
3.00 to 8.99 	12 mg
9.00 or older 	15 mg
12-week cycles until total duration of therapy is 2 years for female and 3 years for male from the start of Interim I
===Maintenance, Arm DS (Vincristine/Dexamethasone)===
For DS AR B-ALL patients and DS B-LLy
====Preceding treatment====
*COG AALL0932: MTX & Vincristine interim maintenance
====Chemotherapy====
*Methotrexate (MTX) 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/m2 (maximum dose of 2 mg) IV once per day on days 1
*Mercaptopurine (6-MP) 75 mg/m2 PO once per day on days 1 to 84
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 3 mg/m2 IV or PO twice per day on days 1 to 5 (DO NOT TAPER)
====CNS therapy, prophylaxis====
*Methotrexate (MTX) IT once on day 1
Age in years, rounded to the nearest hundredth	Dose
1.00 to 1.99 	8 mg
2.00 to 2.99 	10 mg
3.00 to 8.99 	12 mg
9.00 or older 	15 mg
12-week cycles until total duration of therapy is 2 years for female and 3 years for male from the start of Interim I
===Consolidation, Arm LR-M===
====Chemotherapy====
*Methotrexate (MTX) 1000 mg/m2 IV on days 8, 29, 50, 71, 92, 113
 Given as a 200 mg/m2 bolus over 20 to 30 minutes followed by 800 mg/m2 over 23.5 hours (initial bolus of 30 minutes) or 23.67 hours (if initial bolus was over 20 minutes)
*Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 15, 22, 78, 85
*Mercaptopurine (6-MP) 50 mg/m2 PO once per day on days 1 to 33
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 3 mg/m2 IV or PO twice per day on days 15 to 21, 78 to 84
====Supportive therapy====
*Leucovorin (Folinic acid) 10 mg/m2 x 2 doses PO or IV (given 48 and 60 hours after the START of methotrexate infusion, continuing until methotrexate level less than 0.2 μM) on days 9, 10, 30, 31, 51, 52, 72, 73, 93, 94, 114, 115
====CNS therapy, prophylaxis====
*Methotrexate (MTX) IT once on days 8, 29, 50, 71, 92, 113 (To be delivered within 6 hours of the beginning of the IV methotrexate infusion, -6hr to + 6 hr)
Age in years, rounded to the nearest hundredth	Dose
1.00 to 1.99 	8 mg
2.00 to 2.99 	10 mg
3.00 to 8.99 	12 mg
9.00 or older 	15 mg
19-week cycle
===Maintenance, Arm LR-M===
====Chemotherapy====
*Methotrexate (MTX) as follows:
**Cycles 1 to 4: 20 mg/m2/day PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, 92, 99, 106
**Cycles 2 & 5: 20 mg/m2/day PO on days 1, 8, 15, 22, 29, 36, 43, 50, 64, 71, 78, 85, 92, 99, 106
**Cycles 3 & 6: 20 mg/m2/day PO on days 1, 8, 15, 22, 36, 43, 50, 57, 64, 71, 78, 85, 92, 99, 106
**Cycle 7: 20 mg/m2/day PO on days 1, 8, 15, 29, 22, 36, 43, 50, 57, 64
*Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1 & 8
*Mercaptopurine (6-MP) 75 mg/m2 PO once per day on days 1 to 112 (NOTE: Higher 6-MP dose than in consolidation)
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 3 mg/m2 PO twice per day on days 1 to 7 (6 mg/m2/day, do not taper)
====CNS therapy, prophylaxis====
*Methotrexate (MTX) as follows:
**Cycles 1 to 4: IT once on day 1, 85
**Cycles 2 & 5: IT once on day 57
**Cycles 3 & 6: IT once on day 29
Age in years, rounded to the nearest hundredth	Dose
1.00 to 1.99 	8 mg
2.00 to 2.99 	10 mg
3.00 to 8.99 	12 mg
9.00 or older 	15 mg
16-week cycles until a total duration of therapy of 2.5 years from the date of diagnosis is reached for both boys and girls.
===Maintenance, Arm LLy (Vincristine/Dexamethasone)===
====Preceding treatment====
*COG AALL0932: MTX & Vincristine interim maintenance
====Chemotherapy====
*Methotrexate (MTX) 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/m2 (maximum dose of 2 mg) IV once per day on days 1, 29, 57 (4 Week Intervals)
*Mercaptopurine (6-MP) 75 mg/m2 PO once per day on days 1 to 84
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 3 mg/m2 PO twice per day on days 1 to 5, 29 to 33, 57 to 61 (6 mg/m2/day) (DO NOT TAPER)
====CNS therapy, prophylaxis====
*Methotrexate (MTX) IT once on day 1
Age in years, rounded to the nearest hundredth	Dose
1.00 to 1.99 	8 mg
2.00 to 2.99 	10 mg
3.00 to 8.99 	12 mg
9.00 or older 	15 mg
12-week cycles until total duration of therapy is 2 years for female and 3 years for male from the start of Interim I
===References===
#COG CCG-1991: Matloub Y, Bostrom BC, Hunger SP, Stork LC, Angiolillo A, Sather H, La M, Gastier-Foster JM, Heerema NA, Sailer S, Buckley PJ, Thomson B, Cole C, Nachman JB, Reaman G, Winick N, Carroll WL, Devidas M, Gaynon PS. Escalating intravenous methotrexate improves event-free survival in children with standard-risk acute lymphoblastic leukemia: a report from the Children's Oncology Group. Blood. 2011 Jul 14;118(2):243-51. Epub 2011 May 11. link to original article link to PMC article EuroPMC NCT00005945
#COG AALL0331: Maloney KW, Devidas M, Wang C, Mattano LA, Friedmann AM, Buckley P, Borowitz MJ, Carroll AJ, Gastier-Foster JM, Heerema NA, Kadan-Lottick N, Loh ML, Matloub YH, Marshall DT, Stork LC, Raetz EA, Wood B, Hunger SP, Carroll WL, Winick NJ. Outcome in Children With Standard-Risk B-Cell Acute Lymphoblastic Leukemia: Results of Children's Oncology Group Trial AALL0331. J Clin Oncol. 2020 Feb 20;38(6):602-612. Epub 2019 Dec 11. link to original article link to PMC article EuroPMC
#COG AALL0932: Angiolillo AL, Schore RJ, Kairalla JA, Devidas M, Rabin KR, Zweidler-McKay P, Borowitz MJ, Wood B, Carroll AJ, Heerema NA, Relling MV, Hitzler J, Lane AR, Maloney KW, Wang C, Bassal M, Carroll WL, Winick NJ, Raetz EA, Loh ML, Hunger SP. Excellent Outcomes With Reduced Frequency of Vincristine and Dexamethasone Pulses in Standard-Risk B-Lymphoblastic Leukemia: Results From Children's Oncology Group AALL0932. J Clin Oncol. 2021 May 1;39(13):1437-1447. Epub 2021 Jan 7. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01190930
==COG AALL1731 protocol with blinatumomab==
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Gupta et al. 2024 (COG AALL1731)	2019-06 to 2024-06 	Phase 3 (E-esc)	COG AALL1731 protocol without blinatumomab	Longer DFS (primary endpoint)DFS36: 96% vs 87.9%
Details to be added
===References===
#COG AALL1731: Gupta S, Rau RE, Kairalla JA, Rabin KR, Wang C, Angiolillo AL, Alexander S, Carroll AJ, Conway S, Gore L, Kirsch I, Kubaney HR, Li AM, McNeer JL, Militano O, Miller TP, Moyer Y, O'Brien MM, Okada M, Reshmi SC, Shago M, Wagner E, Winick N, Wood BL, Haworth-Wright T, Zaman F, Zugmaier G, Zupanec S, Devidas M, Hunger SP, Teachey DT, Raetz EA, Loh ML. Blinatumomab in Standard-Risk B-Cell Acute Lymphoblastic Leukemia in Children. N Engl J Med. 2024 Dec 7. Epub ahead of print. link to original article EuroPMC NCT03914625
=Upfront therapy, high-risk (HR)=
==COG AALL1131 protocol for HR B-ALL==
Study 	Dates of enrollment 	Evidence
Burke et al. 2019 (COG AALL1131)	2012-02-27 to 2017-02-15	Non-randomized part of phase 3 RCT
===Consolidation, Cyclophosphamide, Cytarabine, Mercaptopurine, Pegaspargase, Vincristine===
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 1000 mg/m2 IV over 30 to 60 minutes once on days 1, 29
*Cytarabine (Ara-C) 75 mg/m2 SC or IV over 1 to 30 minutes on days 1 to 4, 8 to 11, 29 to 32, 36 to 39
*Pegaspargase (Oncaspar) 2,500 units/m2 IV over 1 to 2 hours once 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
*Mercaptopurine (6-MP) 60 mg/m2 PO once per day on days 1 to 14, 29 to 42
====CNS therapy, prophylaxis====
*Methotrexate (MTX) IT once per day on days 1, 8, 15, 22
Age in years, rounded to the nearest hundredth	Dose
1.00 to 1.99 	8 mg
2.00 to 2.99 	10 mg
3.00 to 8.99 	12 mg
9.00 or older 	15 mg
56-day course
===Interim Maintenance, with HD MTX===
====Chemotherapy====
*Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 15, 29, 43
*Mercaptopurine (6-MP) 25 mg/m2 PO once per day on days 1 to 56
*High Dose Methotrexate (MTX) 500 mg/m2 IV over 30 minutes once per day on days 1, 15, 29, 43, then 4500 mg/m2 IV continuous infusion over 23.5 hours, started on days 1, 15, 29, 43
**ANC must be at least 750/µL and platelets must be at least 75,000/µL prior to each dose of high dose MTX
====Supportive therapy====
*Leucovorin (Folinic acid) 15 mg/m2 x a minimum of 3 doses PO or IV (given at 42, 48, and 54 hours after the START of high dose methotrexate infusion) on days 3 to 4, 17 to 18, 31 to 32, 45 to 46
====CNS therapy, prophylaxis====
*Methotrexate (MTX) IT once per day on days 1, 29
Age in years, rounded to the nearest hundredth	Dose
1.00 to 1.99 	8 mg
2.00 to 2.99 	10 mg
3.00 to 8.99 	12 mg
9.00 or older 	15 mg
 When IT methotrexate therapy and high dose methotrexate are scheduled for the same day, deliver the IT methotrexate within 6 hours of the beginning of the IV methotrexate infusion. (hour -6 or +6, with 0 being the start of the methotrexate bolus). 
63-day course
===Delayed Intensification===
====Chemotherapy====
*Doxorubicin (Adriamycin) 25 mg/m2 IV push over 1 to 15 minutes once per day on days 1, 8, 15
*Pegaspargase (Oncaspar) 2,500 units/m2 IV over 1 to 2 hours once on days 4, 43
*Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 43, 50
*Cyclophosphamide (Cytoxan) 1000 mg/m2 IV over 30 to 60 minutes once on day 29 ONLY
*Cytarabine (Ara-C) 75 mg/m2 SC or IV over 1 to 30 minutes on days 29 to 32, 36 to 39
*Thioguanine (Tabloid) 60 mg/m2 PO once per day on days 29 to 42
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 5 mg/m2 IV or PO twice per day on days 1 to 7, 15 to 21
====CNS therapy, prophylaxis====
*Methotrexate (MTX) IT once per day on days 1, 29, 36
Age in years, rounded to the nearest hundredth	Dose
1.00 to 1.99 	8 mg
2.00 to 2.99 	10 mg
3.00 to 8.99 	12 mg
9.00 or older 	15 mg
56-day course
===Maintenance, HR B-ALL===
====Chemotherapy====
*Mercaptopurine (6-MP) as follows:
**Cycles 1 to 4: 75 mg/m2 PO once per day on days 1 to 84
*Vincristine (Oncovin) as follows:
**Cycles 1 to 4: 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 29, 57
*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
**Cycle 5 onwards: 20 mg/m2 PO once per day on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78
====Glucocorticoid therapy====
*Prednisone (Sterapred) 20 mg/m2 PO or IV (methylprednisolone given at 80% of the oral dose) 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: IT once per day on days 1, 29
**Cycle 5 onwards: IT once per day on day 1
Age in years, rounded to the nearest hundredth	Dose
1.00 to 1.99 	8 mg
2.00 to 2.99 	10 mg
3.00 to 8.99 	12 mg
9.00 or older 	15 mg
12-week cycles repeated until the total duration of therapy is 2 years for female patients and 3 years for male patients from the start of interim maintenance.
===References===
#COG AALL1131: Burke MJ, Salzer WL, Devidas M, Dai Y, Gore L, Hilden JM, Larsen E, Rabin KR, Zweidler-McKay PA, Borowitz MJ, Wood B, Heerema NA, Carroll AJ, Winick N, Carroll WL, Raetz EA, Loh ML, Hunger SP. Replacing cyclophosphamide/cytarabine/mercaptopurine with cyclophosphamide/etoposide during consolidation/delayed intensification does not improve outcomes for pediatric B-cell acute lymphoblastic leukemia: a report from the COG. Haematologica. 2019 May;104(5):986-992. Epub 2018 Dec 13. link to original article link to PMC article EuroPMC NCT02883049
==COG AALL1131 protocol for Ph-like B-ALL (Dasatinib Arm)==
Study 	Dates of enrollment 	Evidence
Burke et al. 2019 (COG AALL1131)	2012-02-27 to 2017-02-15	Non-randomized part of phase 3 RCT
===Consolidation===
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 1000 mg/m2 IV over 30 to 60 minutes once on days 1, 29
*Cytarabine (Ara-C) 75 mg/m2 SC or IV over 1 to 30 minutes once per day on days 1 to 4, 8 to 11, 29 to 32, 36 to 39
*Pegaspargase (Oncaspar) 2,500 units/m2 IV over 1 to 2 hours once 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
*Mercaptopurine (6-MP) 60 mg/m2 PO once per day on days 1 to 14, 29 to 42
====Targeted therapy====
*Dasatinib (Sprycel) 60 mg/m2 (rounded to the nearest 5 mg, maximum dose of 140 mg/day) PO once per day on days 1 to 56
====CNS therapy, prophylaxis====
*Methotrexate (MTX) IT once per day on days 1, 8, 15, 22
Age in years, rounded to the nearest hundredth	Dose
1.00 to 1.99 	8 mg
2.00 to 2.99 	10 mg
3.00 to 8.99 	12 mg
9.00 or older 	15 mg
56-day course
===Interim Maintenance, with HD MTX===
====Chemotherapy====
*Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 15, 29, 43
*Mercaptopurine (6-MP) 25 mg/m2 PO once per day on days 1 to 56.
*High Dose Methotrexate (MTX) 500 mg/m2 IV over 30 minutes once per day on days 1, 15, 29, 43, then 4500 mg/m2 IV continuous infusion over 23.5 hours, started on days 1, 15, 29, 43
**ANC must be at least 750/µL and platelets must be at least 75,000/µL prior to each dose of high dose MTX
====Targeted therapy====
*Dasatinib (Sprycel) 60 mg/m2 (rounded to the nearest 5 mg, maximum dose of 140 mg/day) PO once per day on days 1 to 63
====Supportive therapy====
*Leucovorin (Folinic acid) 15 mg/m2 for a minimum of 3 doses PO or IV (given at 42, 48, and 54 hours after the START of high dose methotrexate infusion) on days 3, 4, 17, 18, 31, 32, 45, 46
====CNS therapy, prophylaxis====
*Methotrexate (MTX) IT once per day on days 1, 29
Age in years, rounded to the nearest hundredth	Dose
1.00 to 1.99 	8 mg
2.00 to 2.99 	10 mg
3.00 to 8.99 	12 mg
9.00 or older 	15 mg
 When IT methotrexate therapy and high dose methotrexate are scheduled for the same day, deliver the IT therapy within 6 hours of the beginning of the IV methotrexate infusion. (hour -6 or +6, with 0 being the start of the methotrexate bolus). 
63-day course
===Delayed Intensification===
====Chemotherapy====
*Doxorubicin (Adriamycin) 25 mg/m2 IV push over 1 to 15 minutes once per day on days 1, 8, 15
*Pegaspargase (Oncaspar) 2,500 units/m2 IV over 1 to 2 hours once on days 4, 43
*Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 43, 50
*Cyclophosphamide (Cytoxan) 1000 mg/m2 IV over 30 to 60 minutes once on day 29 ONLY
*Cytarabine (Ara-C) 75 mg/m2 SC or IV over 1 to 30 minutes on days 29 to 32, 36 to 39
*Thioguanine (Tabloid) 60 mg/m2 PO once per day on days 29 to 42
====Targeted therapy====
*Dasatinib (Sprycel) 60 mg/m2 (rounded to the nearest 5 mg, maximum dose of 140 mg/day) PO once per day on days 1 to 56
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 5 mg/m2 IV or PO twice per day on days 1 to 7, 15 to 21
====CNS therapy, prophylaxis====
*Methotrexate (MTX) IT once per day on days 1, 29, 36
Age in years, rounded to the nearest hundredth	Dose
1.00 to 1.99 	8 mg
2.00 to 2.99 	10 mg
3.00 to 8.99 	12 mg
9.00 or older 	15 mg
56-day course
===Interim Maintenance, II with Capizzi MTX===
====Chemotherapy====
*Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on day 1, 11, 21, 31, 41
*Methotrexate (MTX) 100 mg/m2 IV over 2 to 5 minutes (undiluted) or over 10 to 15 minutes (diluted) on days 1, 150 mg/m2 on day 11, 200 mg/m2 on day 21, 250 mg/m2 on day 31, and 300 mg/m2 on day 41
*Pegaspargase (Oncaspar) 2,500 units/m2 IV over 1 to 2 hours once on day 2, 22
====Targeted therapy====
*Dasatinib (Sprycel) 60 mg/m2 (rounded to the nearest 5 mg, maximum dose of 140 mg/day) PO once per day on days 1 to 56
====CNS therapy, prophylaxis====
*Methotrexate (MTX) IT once per day on days 1, 31
Age in years, rounded to the nearest hundredth	Dose
1.00 to 1.99 	8 mg
2.00 to 2.99 	10 mg
3.00 to 8.99 	12 mg
9.00 or older 	15 mg
56-day course
===Maintenance===
====Radiotherapy====
*Total body irradiation (TBI) by the following risk-based criteria:
**CNS3: 1800 cGy in 10 fractions, during the first 4 weeks of Maintenance therapy and should be completed by day 29 of Maintenance
====Chemotherapy====
*Mercaptopurine (6-MP) 75 mg/m2 PO once per day on days 1 to 84
*Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 29, 57
*Methotrexate (MTX) 20 mg/m2 PO once per day on days 8, 15, 22, (29), 36, 43, 50, 57, 64, 71, 78 (OMIT DAY 29 WHEN CNS RADIATION IS GIVEN, DUE TO IT MTX)
====Glucocorticoid therapy====
*Prednisone (Sterapred) 20 mg/m2 PO or IV (methylprednisolone given at 80% of the oral dose) twice per day on days 1 to 5, 29 to 33, 57 to 61
====Targeted therapy====
*Dasatinib (Sprycel) 60 mg/m2 (rounded to the nearest 5 mg, maximum of 140 mg/day) PO once per day on days 1 to 84
====CNS therapy, prophylaxis====
*Methotrexate (MTX) IT once per day on day 1 (also Day 29 of cycles 1 and 2, for patients who did NOT receive CNS Radiation)
Age in years, rounded to the nearest hundredth	Dose
1.00 to 1.99 	8 mg
2.00 to 2.99 	10 mg
3.00 to 8.99 	12 mg
9.00 or older 	15 mg
12-week cycles repeated until total duration of therapy is 2 years for female patients and 3 years for male patients from the start of interim maintenance.
===References===
#COG AALL1131: Burke MJ, Salzer WL, Devidas M, Dai Y, Gore L, Hilden JM, Larsen E, Rabin KR, Zweidler-McKay PA, Borowitz MJ, Wood B, Heerema NA, Carroll AJ, Winick N, Carroll WL, Raetz EA, Loh ML, Hunger SP. Replacing cyclophosphamide/cytarabine/mercaptopurine with cyclophosphamide/etoposide during consolidation/delayed intensification does not improve outcome for pediatric B-cell acute lymphoblastic leukemia: a report from the COG. Haematologica. 2019 May;104(5):986-992. Epub 2018 Dec 13. link to original article link to PMC article EuroPMC NCT02883049
==COG AALL1131 protocol for DS HR B-ALL==
Study 	Dates of enrollment 	Evidence
Burke et al. 2019 (COG AALL1131)	2012-02-27 to 2017-02-15	Non-randomized part of phase 3 RCT
Note: the referenced publication does not specifically focus on induction; the full regimen is available as a protocol. Per the protocol, it is intended only for patients less than 10 years old.
===Induction, Daunorubicin, Pegaspargase, Vincristine, Dexamethasone===
====Chemotherapy====
*Pegaspargase (Oncaspar) 2,500 units/m2 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
 RER - M1 Marrow at Day 15
*Add Daunorubicin (Cerubidine) 50 mg/m2 IV over 1 to 15 minutes once on days 15
====Glucocorticoid therapy====
*Dexamethasone (Decadron) by the following age-based criteria:
**Younger than 10 years old: 3 mg/m2 IV or PO twice per day on days 1 to 28 (DO NOT TAPER)
*Prednisone (Sterapred) by the following age-based criteria:
**10 years old or older: 30 mg/m2 PO twice per day on days 1 to 28 (DO NOT TAPER)
====Supportive therapy====
*Leucovorin (Folinic acid) 5 mg/m2 x 2 doses PO (given at 48 and 60 hours after the lumbar puncture) on days 10, 11, 31, 32 (CNS3 also on days 17, 18, 24, 25)
====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 and 29 (CNS 3 also on days 15 and 22)
**2 to 2.99 years old: 10 mg IT once per day on days 8 and 29 (CNS 3 also on days 15 and 22)
**3 to 8.99 years old: 12 mg IT once per day on days 8 and 29 (CNS 3 also on days 15 and 22)
**9 years old or older: 15 mg IT once per day on days 8 and 29 (CNS 3 also on days 15 and 22)
4-week course
====Subsequent treatment====
*See protocol for details of treatment beyond induction
===Consolidation===
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 1000 mg/m2 IV over 30 to 60 minutes once on days 1, 29
*Cytarabine (Ara-C) 75 mg/m2 SC or IV over 1 to 30 minutes on days 1 to 4, 8 to 11, 29 to 32, 36 to 39
*Pegaspargase (Oncaspar) 2,500 units/m2 IV over 1 to 2 hours once 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
*Mercaptopurine (6-MP) 60 mg/m2 PO once per day on days 1 to 14, 29 to 42
====CNS therapy, prophylaxis====
*Methotrexate (MTX) IT once per day on days 1, 8, 15, 22
Age in years, rounded to the nearest hundredth	Dose
1.00 to 1.99 	8 mg
2.00 to 2.99 	10 mg
3.00 to 8.99 	12 mg
9.00 or older 	15 mg
 DS Arm
====Supportive therapy====
*Leucovorin (Folinic acid) 5 mg/m2 x 2 doses PO (given at 48 and 60 hours after the lumbar puncture) on days 3, 4, 10, 11, 17, 18, 24, 25
56-day course
===Interim Maintenance, with ID MTX===
====Chemotherapy====
*Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 15, 29, 43
*Mercaptopurine (6-MP) 25 mg/m2/dose PO once per day on days 1 to 56
*Intermediate Dose Methotrexate (MTX) 200 mg/m2 IV over 30 minutes once per day on days 1, 15, 29, 43, then 1800 mg/m2 IV continuous infusion over 23.5 hours, started on days 1, 15, 29, 43
**ANC must be at least 750/µL and platelets must be at least 75,000/µL prior to each dose of high dose MTX
====Supportive therapy====
*Leucovorin (Folinic acid) 15 mg/m2 x a minimum of 5 doses PO or IV (given at 30, 36, 42, 48, and 54 hours after the START of intermediate dose methotrexate infusion) on days 2, 3, 17, 18, 31, 32, 45, 46
====CNS therapy, prophylaxis====
*Methotrexate (MTX) IT once per day on days 1, 29
Age in years, rounded to the nearest hundredth	Dose
1.00 to 1.99 	8 mg
2.00 to 2.99 	10 mg
3.00 to 8.99 	12 mg
9.00 or older 	15 mg
 When IT methotrexate therapy and high dose methotrexate are scheduled for the same day, deliver the IT therapy within 6 hours of the beginning of the IV methotrexate infusion. (hour -6 or +6, with 0 being the start of the methotrexate bolus). 
63-day course
===Delayed Intensification===
====Chemotherapy====
*Doxorubicin (Adriamycin) 25 mg/m2 IV push over 1 to 15 minutes once per day on days 1, 8, 15
*Pegaspargase (Oncaspar) 2,500 units/m2 IV over 1 to 2 hours once on days 4, 43
*Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 43, 50
*Cyclophosphamide (Cytoxan) 1000 mg/m2 IV over 30 to 60 minutes once on day 29 ONLY
*Cytarabine (Ara-C) 75 mg/m2 SC or IV over 1 to 30 minutes on days 29 to 32, 36 to 39
*Thioguanine (Tabloid) 60 mg/m2 PO once per day on days 29 to 42
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 5 mg/m2 IV or PO twice per day on days 1 to 7, 15 to 21
====Supportive therapy====
*Leucovorin (Folinic acid) 5 mg/m2 x 2 doses PO or IV (given at 48, and 60 hours after the lumbar puncture) on days 3, 4, 31, 32, 38, 39
====CNS therapy, prophylaxis====
*Methotrexate (MTX) IT once per day on days 1, 29, 36
Age in years, rounded to the nearest hundredth	Dose
1.00 to 1.99 	8 mg
2.00 to 2.99 	10 mg
3.00 to 8.99 	12 mg
9.00 or older 	15 mg
56-day course
===Maintenance, DS HR Arm===
====Radiotherapy====
*Total body irradiation (TBI) by the following risk-based criteria:
**CNS3: 1800 cGy in 10 fractions, during the first 4 weeks of Maintenance therapy and should be completed by day 29 of Maintenance
====Chemotherapy====
*Mercaptopurine (6-MP) 75 mg/m2 PO once per day on days 1 to 84
*Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once on day 1
*Methotrexate (MTX) 20 mg/m2 PO once per day on days 8, 15, 22, (29), 36, 43, 50, 57, 64, 71, 78 (OMIT DAY 29 WHEN CNS RADIATION IS GIVEN, DUE TO IT MTX)
====Glucocorticoid therapy====
*Prednisone (Sterapred) 20 mg/m2 PO or IV (methylprednisolone given at 80% of the oral dose) twice per day on days 1 to 5
====CNS therapy, prophylaxis====
*Methotrexate (MTX) IT once per day on day 1 (also Day 29 of cycles 1 and 2, for patients who did NOT receive CNS Radiation)
Age in years, rounded to the nearest hundredth	Dose
1.00 to 1.99 	8 mg
2.00 to 2.99 	10 mg
3.00 to 8.99 	12 mg
9.00 or older 	15 mg
12-week cycles repeated until total duration of therapy is 2 years for female patients and 3 years for male patients from the start of interim maintenance.
===References===
#COG AALL1131: Burke MJ, Salzer WL, Devidas M, Dai Y, Gore L, Hilden JM, Larsen E, Rabin KR, Zweidler-McKay PA, Borowitz MJ, Wood B, Heerema NA, Carroll AJ, Winick N, Carroll WL, Raetz EA, Loh ML, Hunger SP. Replacing cyclophosphamide/cytarabine/mercaptopurine with cyclophosphamide/etoposide during consolidation/delayed intensification does not improve outcome for pediatric B-cell acute lymphoblastic leukemia: a report from the COG. Haematologica. 2019 May;104(5):986-992. Epub 2018 Dec 13. link to original article link to PMC article EuroPMC NCT02883049
=Upfront therapy, very high-risk (VHR)=
==COG AALL1131 protocol==
===Induction, Daunorubicin, Pegaspargase, Vincristine, Dexamethasone===
Study 	Dates of enrollment 	Evidence
Burke et al. 2019 (COG AALL1131)	2012-02-27 to 2017-02-15	Non-randomized part of phase 3 RCT
Note: the referenced publication does not specifically focus on induction; the full regimen is available as a protocol. Per the protocol, it is intended only for patients less than 10 years old.
====Chemotherapy====
*Daunorubicin (Cerubidine) 25 mg/m2 IV over 1 to 15 minutes once per day on days 1, 8, 15, 22
*Pegaspargase (Oncaspar) 2,500 units/m2 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====
*Dexamethasone (Decadron) by the following age-based criteria:
**Younger than 10 years old: 5 mg/m2 IV or PO twice per day on days 1 to 14
*Prednisone (Sterapred) by the following age-based criteria:
**10 years old or older: 30 mg/m2 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
 CNS2 Patients will receive an additional dose of cytarabine IT on either day 4, 5, or 6, and then another dose of cytarabine IT on either day 11 or 12 according to the following dosing.
*Cytarabine (Ara-C) by the following age-based criteria:
**1 to 1.99 years old: 20 mg IT once
**2 to 2.99 years old: 30 mg IT once
**3 years old or older: 40 mg IT once
*Methotrexate (MTX) by the following age-based criteria: (CNS3 also on Days 15 and 22)
**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====
*See protocol for details of treatment beyond induction
===References===
#COG AALL1131: Burke MJ, Salzer WL, Devidas M, Dai Y, Gore L, Hilden JM, Larsen E, Rabin KR, Zweidler-McKay PA, Borowitz MJ, Wood B, Heerema NA, Carroll AJ, Winick N, Carroll WL, Raetz EA, Loh ML, Hunger SP. Replacing cyclophosphamide/cytarabine/mercaptopurine with cyclophosphamide/etoposide during consolidation/delayed intensification does not improve outcome for pediatric B-cell acute lymphoblastic leukemia: a report from the COG. Haematologica. 2019 May;104(5):986-992. Epub 2018 Dec 13. link to original article link to PMC article EuroPMC NCT02883049
==COG AALL1131 protocol for VHR B-ALL==
Study 	Dates of enrollment 	Evidence
Burke et al. 2019 (COG AALL1131)	2012-02-27 to 2017-02-15	Non-randomized part of phase 3 RCT
===Consolidation===
====Chemotherapy====
*Pegaspargase (Oncaspar) 2,500 units/m2 IV over 1 to 2 hours once on day 15, 43
*Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 15, 22, 43, 50
*Cyclophosphamide (Cytoxan) 1000 mg/m2 IV over 30 to 60 minutes once on day 1, 29
*Cytarabine (Ara-C) 75 mg/m2 SC or IV over 1 to 30 minutes 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
====CNS therapy, prophylaxis====
*Methotrexate (MTX) IT once per day on days 1, 8, 15, 22 (Omit days 15 and 22 for CNS3 Patients)
Age in years, rounded to the nearest hundredth	Dose
1.00 to 1.99 	8 mg
2.00 to 2.99 	10 mg
3.00 to 8.99 	12 mg
9.00 or older 	15 mg
56-day course
===Interim Maintenance, I with HD MTX===
====Chemotherapy====
*Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 15, 29, 43
*Mercaptopurine (6-MP) 60 mg/m2 PO once per day on days 1 to 56
*High Dose Methotrexate (MTX) 500 mg/m2 IV over 30 minutes once per day on days 1, 15, 29, 43, then 4500 mg/m2 IV continuous infusion over 23.5 hours, started on days 1, 15, 29, 43
**ANC must be at least 750/µL and platelets must be at least 75,000/µL prior to each dose of high dose MTX
====Supportive therapy====
*Leucovorin (Folinic acid) 15 mg/m2 x a minimum of 3 doses PO or IV (given at 42, 48, and 54 hours after the START of HD MTX infusion) on days 3 to 4, 17 to 18, 31 to 32, 45 to 46
====CNS therapy, prophylaxis====
*Methotrexate (MTX) IT once per day on days 1, 29
Age in years, rounded to the nearest hundredth	Dose
1.00 to 1.99 	8 mg
2.00 to 2.99 	10 mg
3.00 to 8.99 	12 mg
9.00 or older 	15 mg
63-day course
===Delayed Intensification===
====Chemotherapy====
*Doxorubicin (Adriamycin) 25 mg/m2 IV push over 1 to 15 minutes once per day on days 1, 8, 15
*Pegaspargase (Oncaspar) 2,500 units/m2 IV over 1 to 2 hours once on day 4, 43
*Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 43, 50
*Cyclophosphamide (Cytoxan) 1000 mg/m2 IV over 30 to 60 minutes once on day 29 ONLY
*Cytarabine (Ara-C) 75 mg/m2 SC or IV over 1 to 30 minutes on days 29 to 32, 36 to 39
*Thioguanine (Tabloid) 60 mg/m2 PO once per day on days 29 to 42
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 5 mg/m2 IV or PO twice per day on days 1 to 7, 15 to 21
====CNS therapy, prophylaxis====
*Methotrexate (MTX) IT once per day on day 1, 29, 36
Age in years, rounded to the nearest hundredth	Dose
1.00 to 1.99 	8 mg
2.00 to 2.99 	10 mg
3.00 to 8.99 	12 mg
9.00 or older 	15 mg
56-day course
===Interim Maintenance, II with Capizzi MTX===
====Chemotherapy====
*Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on day 1, 11, 21, 31, 41
*Methotrexate (MTX) 100 mg/m2 IV over 2 to 5 minutes (undiluted) or over 10 to 15 minutes (diluted) on days 1, 150 mg/m2 on day 11, 200 mg/m2 on day 21, 250 mg/m2 on day 31, and 300 mg/m2 on day 41
*Pegaspargase (Oncaspar) 2,500 units/m2 IV over 1 to 2 hours once on day 2, 22
====CNS therapy, prophylaxis====
*Methotrexate (MTX) IT once per day on days 1, 31
Age in years, rounded to the nearest hundredth	Dose
1.00 to 1.99 	8 mg
2.00 to 2.99 	10 mg
3.00 to 8.99 	12 mg
9.00 or older 	15 mg
56-day course
===Maintenance, VHR Arm===
====Radiotherapy====
*Total body irradiation (TBI) by the following risk-based criteria:
**CNS3: 1800 cGy in 10 fractions, during the first 4 weeks of Maintenance therapy and should be completed by day 29 of Maintenance
====Chemotherapy====
*Mercaptopurine (6-MP) 75 mg/m2 PO once per day on days 1 to 84
*Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 29, 57
*Methotrexate (MTX) 20 mg/m2 PO once per day on days 8, 15, 22, (29), 36, 43, 50, 57, 64, 71, 78 (OMIT DAY 29 WHEN CNS RADIATION IS GIVEN, DUE TO IT MTX)
====Glucocorticoid therapy====
*Prednisone (Sterapred) 20 mg/m2 PO or IV (methylprednisolone given at 80% of the oral dose) twice per day on days 1 to 5, 29 to 33, 57 to 61
====CNS therapy, prophylaxis====
*Methotrexate (MTX) IT once per day on day 1 (also Day 29 of cycles 1 and 2, for patients who did NOT receive CNS Radiation)
Age in years, rounded to the nearest hundredth	Dose
1.00 to 1.99 	8 mg
2.00 to 2.99 	10 mg
3.00 to 8.99 	12 mg
9.00 or older 	15 mg
12-week cycles repeated until total duration of therapy is 2 years for female patients and 3 years for male patients from the start of interim maintenance.
===References===
#COG AALL1131: Burke MJ, Salzer WL, Devidas M, Dai Y, Gore L, Hilden JM, Larsen E, Rabin KR, Zweidler-McKay PA, Borowitz MJ, Wood B, Heerema NA, Carroll AJ, Winick N, Carroll WL, Raetz EA, Loh ML, Hunger SP. Replacing cyclophosphamide/cytarabine/mercaptopurine with cyclophosphamide/etoposide during consolidation/delayed intensification does not improve outcomes for pediatric B-cell acute lymphoblastic leukemia: a report from the COG. Haematologica. 2019 May;104(5):986-992. Epub 2018 Dec 13. link to original article link to PMC article EuroPMC NCT02883049
=Pre-phase=
==Methylprednisolone monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Place et al. 2015 (DFCI 05-001)	2005-2011 	Non-randomized part of phase 3 RCT
Burns et al. 2020 (DFCI 11-001)	2012-2015 	Non-randomized part of phase 3 RCT
Note: Burns et al. 2020 is both an update of DFCI 05-001 and the primary publication of DFCI 11-001. 
====Glucocorticoid therapy====
*Methylprednisolone (Solumedrol) 8 mg/m2 IV three times per day on days 1 to 3
3-day course
====Subsequent treatment====
*DFCI 05-001: Doxorubicin, L-asparaginase, Methotrexate, Vincristine, Methylprednisolone versus Doxorubicin, Methotrexate, Pegaspargase, Vincristine, Methylprednisolone induction
*DFCI 11-001: Calaspargase, Doxorubicin, Methotrexate, Vincristine, Methylprednisolone versus Doxorubicin, Methotrexate, Pegaspargase, Vincristine, Methylprednisolone induction
===References===
#DFCI 05-001: Place AE, Stevenson KE, Vrooman LM, Harris MH, Hunt SK, O'Brien JE, Supko JG, Asselin BL, Athale UH, Clavell LA, Cole PD, Kelly KM, Laverdiere C, Leclerc JM, Michon B, Schorin MA, Welch JJ, Lipshultz SE, Kutok JL, Blonquist TM, Neuberg DS, Sallan SE, Silverman LB. Intravenous pegylated asparaginase versus intramuscular native Escherichia coli L-asparaginase in newly diagnosed childhood acute lymphoblastic leukaemia (DFCI 05-001): a randomised, open-label phase 3 trial. Lancet Oncol. 2015 Dec;16(16):1677-90. Epub 2015 Nov 6. link to original article EuroPMC NCT00400946
##Pooled update: Burns MA, Place AE, Stevenson KE, Gutiérrez A, Forrest S, Pikman Y, Vrooman LM, Harris MH, Hunt SK, O'Brien JE, Asselin BL, Athale UH, Clavell LA, Cole PD, Gennarini LM, Kahn JM, Kelly KM, Laverdiere C, Leclerc JM, Michon B, Schorin MA, Sulis ML, Welch JJG, Neuberg DS, Sallan SE, Silverman LB. Identification of prognostic factors in childhood T-cell acute lymphoblastic leukemia: Results from DFCI ALL Consortium Protocols 05-001 and 11-001. Pediatr Blood Cancer. 2021 Jan;68(1):e28719. Epub 2020 Oct 7. Erratum in: Pediatr Blood Cancer. 2021 Mar;68(3):e28885. link to original article dosing details in supplement have been reviewed by our editors link to PMC article EuroPMC
#DFCI 11-001: Burns MA, Place AE, Stevenson KE, Gutiérrez A, Forrest S, Pikman Y, Vrooman LM, Harris MH, Hunt SK, O'Brien JE, Asselin BL, Athale UH, Clavell LA, Cole PD, Gennarini LM, Kahn JM, Kelly KM, Laverdiere C, Leclerc JM, Michon B, Schorin MA, Sulis ML, Welch JJG, Neuberg DS, Sallan SE, Silverman LB. Identification of prognostic factors in childhood T-cell acute lymphoblastic leukemia: Results from DFCI ALL Consortium Protocols 05-001 and 11-001. Pediatr Blood Cancer. 2021 Jan;68(1):e28719. Epub 2020 Oct 7. Erratum in: Pediatr Blood Cancer. 2021 Mar;68(3):e28885. link to original article dosing details in supplement have been reviewed by our editors link to PMC article EuroPMC NCT01574274
## Update: Vrooman LM, Blonquist TM, Stevenson KE, Supko JG, Hunt SK, Cronholm SM, Koch V, Kay-Green S, Athale UH, Clavell LA, Cole PD, Harris MH, Kelly KM, Laverdiere C, Leclerc JM, Michon B, Place AE, Schorin MA, Welch JJG, Neuberg DS, Sallan SE, Silverman LB. Efficacy and Toxicity of Pegaspargase and Calaspargase Pegol in Childhood Acute Lymphoblastic Leukemia: Results of DFCI 11-001. J Clin Oncol. 2021 Nov 1;39(31):3496-3505. Epub 2021 Jul 6. link to original article EuroPMC
==Prednisone monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Möricke et al. 2016 (AIEOP-BFM ALL 2000)	2000-2006 	Non-randomized part of phase 3 RCT
====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====
*Daunorubicin, L-Asparaginase, Vincristine, Prednisone versus Daunorubicin, L-Asparaginase, Vincristine, Dexamethasone induction
===References===
#AIEOP-BFM ALL 2000: Möricke A, Zimmermann M, Valsecchi MG, Stanulla M, Biondi A, Mann G, Locatelli F, Cazzaniga G, Niggli F, Aricò M, Bartram CR, Attarbaschi A, Silvestri D, Beier R, Basso G, Ratei R, Kulozik AE, Lo Nigro L, Kremens B, Greiner J, Parasole R, Harbott J, Caruso R, von Stackelberg A, Barisone E, Rössig C, Conter V, Schrappe M. Dexamethasone vs prednisone in induction treatment of pediatric ALL: results of the randomized trial AIEOP-BFM ALL 2000. Blood. 2016 Apr 28;127(17):2101-12. Epub 2016 Feb 17. link to original article dosing details in supplement have been reviewed by our editors EuroPMC NCT00430118; NCT00613457
==Vincristine & Prednisone==
VP: Vincristine & Prednisone
===Regimen===
Study 	Dates of enrollment	Evidence
Sallan et al. 1978	1973-1977 	Non-randomized
Note: this regimen is of historic interest as an induction regimen; it is still occasionally used as pre-phase in patients too ill to get cytotoxic chemotherapy at time of diagnosis.
====Chemotherapy====
*Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 8, 15
====Glucocorticoid therapy====
*Prednisone (Sterapred) 40 mg/m2/day PO on days 1 to 21
21-day course
===References===
#Sallan SE, Cammita BM, Cassady JR, Nathan DG, Frei E 3rd. Intermittent combination chemotherapy with adriamycin for childhood acute lymphoblastic leukemia: clinical results. Blood. 1978 Mar;51(3):425-33. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
=Upfront induction therapy=
==Calaspargase, Daunorubicin, Vincristine, Prednisone==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Angiolillo et al. 2014 (COG AALL07P4)	2008-2010 	Randomized (E-RT-switch-ic)	Daunorubicin, Pegaspargase, Vincristine, Prednisone	Longer half-life (primary endpoint)
====Chemotherapy====
*Calaspargase (Asparlas) 2500 units/m2 IV once on day 4
*Daunorubicin (Cerubidine) 25 mg/m2 IV once per day on days 1, 8, 15, 22
*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 PO twice per day on days 1 to 28
5-week course
====Subsequent treatment====
*See protocol for details of treatment beyond induction
===References===
#COG AALL07P4: Angiolillo AL, Schore RJ, Devidas M, Borowitz MJ, Carroll AJ, Gastier-Foster JM, Heerema NA, Keilani T, Lane AR, Loh ML, Reaman GH, Adamson PC, Wood B, Wood C, Zheng HW, Raetz EA, Winick NJ, Carroll WL, Hunger SP. Pharmacokinetic and pharmacodynamic properties of calaspargase pegol Escherichia coli L-asparaginase in the treatment of patients with acute lymphoblastic leukemia: results from Children's Oncology Group Study AALL07P4. J Clin Oncol. 2014 Dec 1;32(34):3874-82. Epub 2014 Oct 27. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00671034
==Daunorubicin, Pegaspargase, Vincristine, Dexamethasone==
===Regimen===
Study 	Dates of enrollment 	Evidence
Burke et al. 2019 (COG AALL1131)	2012-02-27 to 2017-02-15	Non-randomized part of phase 3 RCT
Note: the referenced publication does not specifically focus on induction; the full regimen is available as a protocol. Per the protocol, it is intended only for patients less than 10 years old.
====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 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====
*Dexamethasone (Decadron) 5 mg/m2 IV or PO twice per day on days 1 to 14
====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====
*See protocol for details of treatment beyond induction
===References===
#COG AALL1131: Burke MJ, Salzer WL, Devidas M, Dai Y, Gore L, Hilden JM, Larsen E, Rabin KR, Zweidler-McKay PA, Borowitz MJ, Wood B, Heerema NA, Carroll AJ, Winick N, Carroll WL, Raetz EA, Loh ML, Hunger SP. Replacing cyclophosphamide/cytarabine/mercaptopurine with cyclophosphamide/etoposide during consolidation/delayed intensification does not improve outcome for pediatric B-cell acute lymphoblastic leukemia: a report from the COG. Haematologica. 2019 May;104(5):986-992. Epub 2018 Dec 13. link to original article link to PMC article EuroPMC NCT02883049
==Daunorubicin, Pegaspargase, Vincristine, Prednisone==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Angiolillo et al. 2014 (COG AALL07P4)	2008-2010 	Randomized (C)	Calaspargase, Daunorubicin, Vincristine, Prednisone	Shorter half-life (primary endpoint)
====Chemotherapy====
*Daunorubicin (Cerubidine) 25 mg/m2 IV once per day on days 1, 8, 15, 22
*Pegaspargase (Oncaspar) 2500 units/m2 IV 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 PO twice per day on days 1 to 28
5-week course
====Subsequent treatment====
*See protocol for details of treatment beyond induction
===References===
#COG AALL07P4: Angiolillo AL, Schore RJ, Devidas M, Borowitz MJ, Carroll AJ, Gastier-Foster JM, Heerema NA, Keilani T, Lane AR, Loh ML, Reaman GH, Adamson PC, Wood B, Wood C, Zheng HW, Raetz EA, Winick NJ, Carroll WL, Hunger SP. Pharmacokinetic and pharmacodynamic properties of calaspargase pegol Escherichia coli L-asparaginase in the treatment of patients with acute lymphoblastic leukemia: results from Children's Oncology Group Study AALL07P4. J Clin Oncol. 2014 Dec 1;32(34):3874-82. Epub 2014 Oct 27. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00671034
==DOLP==
DOLP: Daunorubicin, Oncovin (Vincristine), L-Asparaginase, Prednisone
DVPA: Daunorubicin, Vincristine, Prednisone, Asparaginase
===Regimen variant #1, 25/1.5/6000/60===
Study 	Dates of enrollment	Evidence
Seibel et al. 2007 (COG CCG-1961)	1996-2002 	Non-randomized part of phase 3 RCT
Termuhlen et al. 2012 (COG A5971)	2000-2005 	Non-randomized part of phase 3 RCT
Note: COG A5971 was intended for patients with localized lymphoblastic lymphoma, of which 75% had B-cell immunophenotype. Exact days were not specified for the L-asparaginase; suggested days are similar to those used in other protocols. COG CCG-1961 did not specify a tapering schedule for prednisone, and did not cap vincristine.
====Chemotherapy====
*Daunorubicin (Cerubidine) 25 mg/m2 IV once per day on days 0, 7, 14, 21
*Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 0, 7, 14, 21
*Asparaginase (Elspar) 6000 units/m2 IM once per day on days 3, 5, 7, 10, 12, 14, 17, 19, 21
====Glucocorticoid therapy====
*Prednisone (Sterapred) 60 mg/m2/day PO on days 0 to 27, then tapered from days 28 to 38 (see note)
====CNS therapy====
*Cytarabine (Ara-C) by the following age-based criteria:
**1 to 1.99 years old: 30 mg IT once on day 0
**2 to 2.99 years old: 50 mg IT once on day 0
**3 years old or older: 70 mg IT once on day 0
*Methotrexate (MTX) by the following age-based criteria:
**1 to 1.99 years old: 8 mg IT once per day on days 7 & 28
**2 to 2.99 years old: 10 mg IT once per day on days 7 & 28
**3 years old or older: 12 mg IT once per day on days 7 & 28
5-week course
====Subsequent treatment====
*COG CCG-1961: Standard versus increased intensity post-remission therapy (see paper for details)
*COG A5971: Consolidation (see paper for details)
===Regimen variant #2, 30/1.5/5000/60 ("Phase A" of ALL-BFM 95; "Phase 1" of ALL IC-BFM 2002; "Phase IA" of ALL IC-BFM 2009)===
Study 	Dates of enrollment	Evidence
Möricke et al. 2008 (ALL-BFM 95) 	1995-2000 	Non-randomized
Stary et al. 2013 (ALL IC-BFM 2002) 	2002-2007 	Non-randomized part of phase 3 RCT
Campbell et al. 2023 (ALL IC-BFM 2009)	2010-06 to 2018-03 	Non-randomized part of phase 3 RCT
Note: see papers for details on dose adjustments based on risk. For example, in ALL IC-BFM 2002, days 22 & 29 of daunorubicin were omitted for standard risk B-cell precursor acute lymphoblastic leukemia.
====Chemotherapy====
*Daunorubicin (Cerubidine) 30 mg/m2 IV over 60 minutes once per day on days 8, 15, 22, 29
*Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 8, 15, 22, 29
*Asparaginase (Elspar) 5000 units IV over 60 minutes once per day on days 12, 15, 18, 21, 24, 27, 30, 33
====Glucocorticoid therapy====
*Prednisone (Sterapred) 60 mg/m2/day PO on days 1 to 28, tapered over 9 days
====CNS therapy====
*Methotrexate (MTX) 12 mg IT once per day on days 1, 12, 33
5-week course
====Subsequent treatment====
*ALL-BFM 95 & ALL IC-BFM 2002: See papers for details
*ALL IC-BFM 2009, SR: Induction phase IB
*ALL IC-BFM 2009, IR/HR: Induction phase IB versus induction phase augmented IB
===Regimen variant #3, 30/1.5/10,000/60 ("Protocol I")===
Study 	Dates of enrollment 	Evidence
Schrappe et al. 2000 (ALL-BFM 90)	1990-04-01 to 1995-03-31	Non-randomized
Kamps et al. 2002 (DCLSG ALL-8) 	1991-10 to 1996-12 	Non-randomized
Note: see papers for details on dose adjustments based on risk.
====Chemotherapy====
*Daunorubicin (Cerubidine) 30 mg/m2 IV over 60 minutes once per day on days 8, 15, 22, 29
*Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 8, 15, 22, 29
*Asparaginase (Elspar) 10,000 units IV over 60 minutes once per day on days 12, 15, 18, 21, 24, 27, 30, 33
====Glucocorticoid therapy====
*Prednisone (Sterapred) 60 mg/m2/day PO on days 1 to 28
====CNS therapy====
*Methotrexate (MTX) 12 mg IT once per day on days 1, 15, 29
5-week course
====Subsequent treatment====
*See papers for details
===Regimen variant #4, 40/1.5/10,000/60 ("Induction Protocol I" of ALL-BFM 86)===
Study 	Dates of enrollment	Evidence
Reiter et al. 1994 (ALL-BFM 86)	1986-10 to 1990-03 	Non-randomized part of RCT
Kamps et al. 1999 (DCLSG ALL-7)	1988-07 to 1991-10 	Non-randomized part of RCT
====Chemotherapy====
*Daunorubicin (Cerubidine) 40 mg/m2 IV once per day on days 8, 15, 22, 29
*Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 8, 15, 22, 29
*Asparaginase (Elspar) 10,000 units/m2 IV once per day on days 19, 22, 25, 28, 31, 34, 37, 40
====Glucocorticoid therapy====
*Prednisone (Sterapred) 60 mg/m2/day PO on days 1 to 28
6-week course
====Subsequent treatment====
*ALL-BFM 86 & DCLSG ALL-7, standard-risk group (SRG) and risk group (RG): 6-MP & MTX consolidation
*ALL-BFM 86 & DCLSG ALL-7, experimental group (EG): Cytarabine, Ifosfamide, MTX, Mitoxantrone, Prednisone consolidation
===References===
#ALL-BFM 86: Reiter A, Schrappe M, Ludwig WD, Hiddemann W, Sauter S, Henze G, Zimmermann M, Lampert F, Havers W, Niethammer D, Odenwald E, Ritter J, Mann G, Welte K, Gadner H, Riehm H. Chemotherapy in 998 unselected childhood acute lymphoblastic leukemia patients: results and conclusions of the multicenter trial ALL-BFM 86. Blood. 1994 Nov 1;84(9):3122-33. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#DCLSG ALL-7: Kamps WA, Bökkerink JP, Hählen K, Hermans J, Riehm H, Gadner H, Schrappe M, Slater R, van den Berg-de Ruiter E, Smets LA, de Vaan GA, Weening RS, van Weerden JF, van Wering ER, den der Does-van den Berg A. Intensive treatment of children with acute lymphoblastic leukemia according to ALL-BFM-86 without cranial radiotherapy: results of Dutch Childhood Leukemia Study Group protocol ALL-7 (1988-1991). Blood. 1999 Aug 15;94(4):1226-36. link to original article EuroPMC
#ALL-BFM 90: Schrappe M, Reiter A, Ludwig WD, Harbott J, Zimmermann M, Hiddemann W, Niemeyer C, Henze G, Feldges A, Zintl F, Kornhuber B, Ritter J, Welte K, Gadner H, Riehm H; German-Austrian-Swiss ALL-BFM Study Group. Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL-BFM 90. Blood. 2000 Jun 1;95(11):3310-22. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
##Pooled subgroup analysis: Schrauder A, Reiter A, Gadner H, Niethammer D, Klingebiel T, Kremens B, Peters C, Ebell W, Zimmermann M, Niggli F, Ludwig WD, Riehm H, Welte K, Schrappe M. Superiority of allogeneic hematopoietic stem-cell transplantation compared with chemotherapy alone in high-risk childhood T-cell acute lymphoblastic leukemia: results from ALL-BFM 90 and 95. J Clin Oncol. 2006 Dec 20;24(36):5742-9. link to original article EuroPMC
#DCLSG ALL-8: Kamps WA, Bökkerink JP, Hakvoort-Cammel FG, Veerman AJ, Weening RS, van Wering ER, van Weerden JF, Hermans J, Slater R, van den Berg E, Kroes WG, van der Does-van den Berg A. BFM-oriented treatment for children with acute lymphoblastic leukemia without cranial irradiation and treatment reduction for standard risk patients: results of DCLSG protocol ALL-8 (1991-1996). Leukemia. 2002 Jun;16(6):1099-111. link to original article refers to ALL-BFM 90 protocol EuroPMC
#COG CCG-1961: Seibel NL, Steinherz PG, Sather HN, Nachman JB, Delaat C, Ettinger LJ, Freyer DR, Mattano LA Jr, Hastings CA, Rubin CM, Bertolone K, Franklin JL, Heerema NA, Mitchell TL, Pyesmany AF, La MK, Edens C, Gaynon PS. Early postinduction intensification therapy improves survival for children and adolescents with high-risk acute lymphoblastic leukemia: a report from the Children's Oncology Group. Blood. 2008 Mar 1;111(5):2548-55. Epub 2007 Nov 26. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00002812
#ALL-BFM 95: Möricke A, Reiter A, Zimmermann M, Gadner H, Stanulla M, Dördelmann M, Löning L, Beier R, Ludwig WD, Ratei R, Harbott J, Boos J, Mann G, Niggli F, Feldges A, Henze G, Welte K, Beck JD, Klingebiel T, Niemeyer C, Zintl F, Bode U, Urban C, Wehinger H, Niethammer D, Riehm H, Schrappe M; German-Austrian-Swiss ALL-BFM Study Group. Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. Blood. 2008 May 1;111(9):4477-89. Epub 2008 Feb 19. Erratum in: Blood. 2009 Apr 30;113(18):4478. Dosage error in article text. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
##Pooled subgroup analysis: Schrauder A, Reiter A, Gadner H, Niethammer D, Klingebiel T, Kremens B, Peters C, Ebell W, Zimmermann M, Niggli F, Ludwig WD, Riehm H, Welte K, Schrappe M. Superiority of allogeneic hematopoietic stem-cell transplantation compared with chemotherapy alone in high-risk childhood T-cell acute lymphoblastic leukemia: results from ALL-BFM 90 and 95. J Clin Oncol. 2006 Dec 20;24(36):5742-9. link to original article EuroPMC
#COG A5971: Termuhlen AM, Smith LM, Perkins SL, Lones M, Finlay JL, Weinstein H, Gross TG, Abromowitch M. Outcome of newly diagnosed children and adolescents with localized lymphoblastic lymphoma treated on Children's Oncology Group trial A5971: a report from the Children's Oncology Group. Pediatr Blood Cancer. 2012 Dec 15;59(7):1229-33. Epub 2012 Apr 5. link to original article dosing details in supplement have been reviewed by our editors link to PMC article EuroPMC NCT00004228
#ALL IC-BFM 2002: Stary J, Zimmermann M, Campbell M, Castillo L, Dibar E, Donska S, Gonzalez A, Izraeli S, Janic D, Jazbec J, Konja J, Kaiserova E, Kowalczyk J, Kovacs G, Li CK, Magyarosy E, Popa A, Stark B, Jabali Y, Trka J, Hrusak O, Riehm H, Masera G, Schrappe M. Intensive chemotherapy for childhood acute lymphoblastic leukemia: results of the randomized intercontinental trial ALL IC-BFM 2002. J Clin Oncol. 2014 Jan 20;32(3):174-84. Epub 2013 Dec 16. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00764907
#ALL IC-BFM 2009: Campbell M, Kiss C, Zimmermann M, Riccheri C, Kowalczyk J, Felice MS, Kuzmanovic M, Kovacs G, Kosmidis H, Gonzalez A, Bilic E, Castillo L, Kolenova A, Jazbec J, Popa A, Konstantinov D, Kappelmayer J, Szczepanski T, Dworzak M, Buldini B, Gaipa G, Marinov N, Rossi J, Nagy A, Gaspar I, Stary J, Schrappe M. Childhood Acute Lymphoblastic Leukemia: Results of the Randomized Acute Lymphoblastic Leukemia Intercontinental-Berlin-Frankfurt-Münster 2009 Trial. J Clin Oncol. 2023 Jul 1;41(19):3499-3511. Epub 2023 May 4. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC EudraCT 2010-019722-13
##Update: Conter V, Valsecchi MG, Cario G, Zimmermann M, Attarbaschi A, Stary J, Niggli F, Dalla Pozza L, Elitzur S, Silvestri D, Locatelli F, Möricke A, Engstler G, Smisek P, Bodmer N, Barbaric D, Izraeli S, Rizzari C, Boos J, Buldini B, Zucchetti M, von Stackelberg A, Matteo C, Lehrnbecher T, Lanvers-Kaminsky C, Cazzaniga G, Gruhn B, Biondi A, Schrappe M. Four Additional Doses of PEG-L-Asparaginase During the Consolidation Phase in the AIEOP-BFM ALL 2009 Protocol Do Not Improve Outcome and Increase Toxicity in High-Risk ALL: Results of a Randomized Study. J Clin Oncol. 2024 Mar 10;42(8):915-926. Epub 2023 Dec 14. link to original article EuroPMC
==DOLP (Prednisolone)==
DOLP: Daunorubicin, Oncovin (Vincristine), L-Asparaginase, Prednisolone
===Regimen variant #1, 30/10,000/1.5/60===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
de Moerloose et al. 2010 (EORTC CLG 58951)	1999-2002 	Phase 3 (C)	Daunorubicin, L-Asparaginase, Vincristine, Dexamethasone	Did not meet primary endpoint of EFS
Note: see paper for details on CNS therapy and dose adjustments based on risk; these instructions include a 7-day pre-phase and are for AR1 patients.
====Chemotherapy====
*Daunorubicin (Cerubidine) 30 mg/m2 IV once per day on days 8, 15, 22, 29
*Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 8, 15, 22, 29
*Asparaginase (Elspar) 10,000 units (route not specified) once per day on days 12, 15, 18, 22, 25, 29, 32, 35
====Glucocorticoid therapy====
*Prednisolone (Millipred) 60 mg/m2/day PO on days 1 to 28, then tapered over 9 days
5-week course
====Subsequent treatment====
*See paper for details
===Regimen variant #2, 45/6000/1.5/40===
Study 	Dates of enrollment	Evidence
Chessells et al. 1992 (UK MRC ALLX)	1985-01 to 1990-09 	Non-randomized part of RCT
Note: exact days for L-asparaginase were not specified in the protocol.
====Chemotherapy====
*Daunorubicin (Cerubidine) 45 mg/m2 IV once per day on days 1 & 2
*Vincristine (Oncovin) 1.5 mg/m2 IV once per day on days 1, 8, 15, 22, 29
*Asparaginase (Elspar) 6000 units/m2 SC once per day on days 3, 5, 7, 10, 12, 14, 17, 19, 21
====Glucocorticoid therapy====
*Prednisolone (Millipred) 40 mg/m2/day PO on days 1 to 28
29-day course
====Subsequent treatment====
*Intensification (randomized) or Cy/TBI with allo HSCT, depending on donor availability
===References===
#UK MRC ALLX: Chessells JM, Bailey C, Wheeler K, Richards SM. Bone marrow transplantation for high-risk childhood lymphoblastic leukaemia in first remission: experience in MRC UKALL X. Lancet. 1992 Sep 5;340(8819):565-8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
##Update: Chessells JM, Bailey C, Richards SM; Medical Research Council Working Party on Childhood Leukaemia. Intensification of treatment and survival in all children with lymphoblastic leukaemia: results of UK Medical Research Council trial UKALL X. Lancet. 1995 Jan 21;345(8943):143-8. link to original article EuroPMC
#EORTC CLG 58951: De Moerloose B, Suciu S, Bertrand Y, Mazingue F, Robert A, Uyttebroeck A, Yakouben K, Ferster A, Margueritte G, Lutz P, Munzer M, Sirvent N, Norton L, Boutard P, Plantaz D, Millot F, Philippet P, Baila L, Benoit Y, Otten J; Children's Leukemia Group of the European Organisation for Research and Treatment of Cancer. Improved outcome with pulses of vincristine and corticosteroids in continuation therapy of children with average risk acute lymphoblastic leukemia (ALL) and lymphoblastic non-Hodgkin lymphoma (NHL): report of the EORTC randomized phase 3 trial 58951. Blood. 2010 Jul 8;116(1):36-44. Epub 2010 Apr 20. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00003728
##Update: Domenech C, Suciu S, De Moerloose B, Mazingue F, Plat G, Ferster A, Uyttebroeck A, Sirvent N, Lutz P, Yakouben K, Munzer M, Röhrlich P, Plantaz D, Millot F, Philippet P, Dastugue N, Girard S, Cavé H, Benoit Y, Bertrand Y; Children's Leukemia Group (CLG) of European Organisation for Research and Treatment of Cancer. Dexamethasone (6 mg/m2/day) and prednisolone (60 mg/m2/day) were equally effective as induction therapy for childhood acute lymphoblastic leukemia in the EORTC CLG 58951 randomized trial. Haematologica. 2014 Jul;99(7):1220-7. Epub 2014 Apr 11. link to original article link to PMC article EuroPMC
##Update: Mondelaers V, Suciu S, De Moerloose B, Ferster A, Mazingue F, Plat G, Yakouben K, Uyttebroeck A, Lutz P, Costa V, Sirvent N, Plouvier E, Munzer M, Poirée M, Minckes O, Millot F, Plantaz D, Maes P, Hoyoux C, Cavé H, Rohrlich P, Bertrand Y, Benoit Y; Children's Leukemia Group (CLG) of the European Organisation for Research and Treatment of Cancer. Prolonged versus standard native E coli asparaginase therapy in childhood acute lymphoblastic leukemia and non-Hodgkin lymphoma: final results of the EORTC-CLG randomized phase III trial 58951. Haematologica. 2017 Oct;102(10):1727-1738. Epub 2017 Jul 27. link to original article link to PMC article EuroPMC
==Doxorubicin, Mercaptopurine, Pegaspargase, Vincristine, Prednisolone==
===Regimen===
Study 	Dates of enrollment	Evidence
Albertsen et al. 2019 (NOPHO ALL2008)	2008-2016 	Non-randomized part of RCT
Note: See protocol for initiation dependencies of 6-MP and pegaspargase.
====Chemotherapy====
*Doxorubicin (Adriamycin) 40 mg/m2 IV over 4 hours once per day on days 1 & 22
*Mercaptopurine (6-MP) 25 mg/m2 PO once per day on days 30 to 35
*Pegaspargase (Oncaspar) 1000 units/m2 IM once on day 30
*Vincristine (Oncovin) by the following age-based criteria:
**Younger than 18 years old: 2 mg/m2 (maximum dose of 2.5 mg) IV once per day on days 1, 8, 15, 22, 29
**18 years old or older: 2 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22, 29
====Glucocorticoid therapy====
*Prednisolone (Millipred) 20 mg/m2 PO three times per day on days 1 to 29, then 10 mg/m2 PO three times per day on days 30 to 32, then 5 mg/m2 PO three times per day on days 33 to 35, then 2.5 mg/m2 PO three times per day on days 36 to 38
====CNS therapy, prophylaxis====
*Methotrexate (MTX) by the following age-based criteria:
**1 to 1.9 years old: 8 mg IT once per day on days 1, 8, 15, 29
**2 to 2.9 years old: 10 mg IT once per day on days 1, 8, 15, 29
**3 years old or older: 12 mg IT once per day on days 1, 8, 15, 29
5-week course
====Subsequent treatment====
*See protocol for details of treatment beyond induction
===References===
#NOPHO ALL2008: Albertsen BK, Grell K, Abrahamsson J, Lund B, Vettenranta K, Jónsson ÓG, Frandsen TL, Wolthers BO, Heyman M, Schmiegelow K. Intermittent versus continuous PEG-asparaginase to reduce asparaginase-associated toxicities: a NOPHO ALL2008 randomized study. J Clin Oncol. 2019 Jul 1;37(19):1638-1646. Epub 2019 Apr 12. link to original article dosing details in supplement have been reviewed by our editors EuroPMC NCT00819351
==Doxorubicin, Methotrexate, Pegaspargase, Vincristine, Methylprednisolone==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy 	Comparative Toxicity
Place et al. 2015 (DFCI 05-001)	2005-2011 	Phase 3 (E-switch-ic)	Doxorubicin, L-asparaginase, Methotrexate, Vincristine, Methylprednisolone	Did not meet secondary endpoint of DFS	Less anxiety
Burns et al. 2020 (DFCI 11-001)	2012-2015 	Phase 3 (C) 	Calaspargase, Doxorubicin, Methotrexate, Vincristine, Methylprednisolone 	Not reported 	
Note: Burns et al. 2020 is both an update of DFCI 05-001 and the primary publication of DFCI 11-001. Day numbering takes into account the pre-phase.
====Preceding treatment====
*Methylprednisolone pre-phase
====Chemotherapy====
*Doxorubicin (Adriamycin) 30 mg/m2 IV once per day on days 4 & 5
*Methotrexate (MTX) 40 mg/m2 IV once on day 6
*Pegaspargase (Oncaspar) 2500 units/m2 IV once on day 7
*Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 4, 11, 18, 25
====Glucocorticoid therapy====
*Methylprednisolone (Solumedrol) 8 mg/m2 IV three times per day on days 4 to 32
====Supportive therapy====
*Dexrazoxane (Zinecard) 300 mg/m2 IV once per day on days 4 & 5
28-day course
====CNS therapy, prophylaxis====
*Cytarabine (Ara-C) IT once per day on days 1 & 18
**Day 18 dose is admixed with MTX and HC
*Methotrexate (MTX) IT once per day on days 18 & 32
**Day 18 dose is admixed with Ara-C and HC
*Hydrocortisone (Cortef) IT once on day 18, admixed with Ara-C and MTX
====Subsequent treatment====
*Doxorubicin, Mercaptopurine, Methotrexate, Vincristine consolidation (IA)
===References===
#DFCI 05-001: Place AE, Stevenson KE, Vrooman LM, Harris MH, Hunt SK, O'Brien JE, Supko JG, Asselin BL, Athale UH, Clavell LA, Cole PD, Kelly KM, Laverdiere C, Leclerc JM, Michon B, Schorin MA, Welch JJ, Lipshultz SE, Kutok JL, Blonquist TM, Neuberg DS, Sallan SE, Silverman LB. Intravenous pegylated asparaginase versus intramuscular native Escherichia coli L-asparaginase in newly diagnosed childhood acute lymphoblastic leukaemia (DFCI 05-001): a randomised, open-label phase 3 trial. Lancet Oncol. 2015 Dec;16(16):1677-90. Epub 2015 Nov 6. link to original article EuroPMC NCT00400946
##Pooled update: Burns MA, Place AE, Stevenson KE, Gutiérrez A, Forrest S, Pikman Y, Vrooman LM, Harris MH, Hunt SK, O'Brien JE, Asselin BL, Athale UH, Clavell LA, Cole PD, Gennarini LM, Kahn JM, Kelly KM, Laverdiere C, Leclerc JM, Michon B, Schorin MA, Sulis ML, Welch JJG, Neuberg DS, Sallan SE, Silverman LB. Identification of prognostic factors in childhood T-cell acute lymphoblastic leukemia: Results from DFCI ALL Consortium Protocols 05-001 and 11-001. Pediatr Blood Cancer. 2021 Jan;68(1):e28719. Epub 2020 Oct 7. Erratum in: Pediatr Blood Cancer. 2021 Mar;68(3):e28885. link to original article dosing details in supplement have been reviewed by our editors link to PMC article EuroPMC
#DFCI 11-001: Burns MA, Place AE, Stevenson KE, Gutiérrez A, Forrest S, Pikman Y, Vrooman LM, Harris MH, Hunt SK, O'Brien JE, Asselin BL, Athale UH, Clavell LA, Cole PD, Gennarini LM, Kahn JM, Kelly KM, Laverdiere C, Leclerc JM, Michon B, Schorin MA, Sulis ML, Welch JJG, Neuberg DS, Sallan SE, Silverman LB. Identification of prognostic factors in childhood T-cell acute lymphoblastic leukemia: Results from DFCI ALL Consortium Protocols 05-001 and 11-001. Pediatr Blood Cancer. 2021 Jan;68(1):e28719. Epub 2020 Oct 7. Erratum in: Pediatr Blood Cancer. 2021 Mar;68(3):e28885. link to original article dosing details in supplement have been reviewed by our editors link to PMC article EuroPMC NCT01574274
## Update: Vrooman LM, Blonquist TM, Stevenson KE, Supko JG, Hunt SK, Cronholm SM, Koch V, Kay-Green S, Athale UH, Clavell LA, Cole PD, Harris MH, Kelly KM, Laverdiere C, Leclerc JM, Michon B, Place AE, Schorin MA, Welch JJG, Neuberg DS, Sallan SE, Silverman LB. Efficacy and Toxicity of Pegaspargase and Calaspargase Pegol in Childhood Acute Lymphoblastic Leukemia: Results of DFCI 11-001. J Clin Oncol. 2021 Nov 1;39(31):3496-3505. Epub 2021 Jul 6. link to original article EuroPMC
==Pegaspargase, Vincristine, Dexamethasone==
===Regimen===
Study 	Dates of enrollment	Evidence
Maloney et al. 2019 (COG AALL0331) 	2005-2010 	Non-randomized part of phase 3 RCT
Angiolillo et al. 2021 (COG AALL0932)	2010-2018 	Non-randomized part of phase 3 RCT
Note: there are very minor differences in timing between protocols; see papers for details.
====Chemotherapy====
*Pegaspargase (Oncaspar) 2500 units/m2 IV 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====
*Dexamethasone (Decadron) 3 mg/m2 PO twice per day on days 1 to 28
====CNS therapy, prophylaxis====
*Cytarabine (Ara-C) IT once at some point between days -2 and 1
*Methotrexate (MTX) IT once per day on days 8 & 29
35-day course
====Subsequent treatment====
*COG AALL0331, M2 marrow or M1 marrow with MRD of at least 1% at day 29: Extended induction
*COG AALL0932: 6-MP & Vincristine consolidation
===References===
#COG AALL0331: Maloney KW, Devidas M, Wang C, Mattano LA, Friedmann AM, Buckley P, Borowitz MJ, Carroll AJ, Gastier-Foster JM, Heerema NA, Kadan-Lottick N, Loh ML, Matloub YH, Marshall DT, Stork LC, Raetz EA, Wood B, Hunger SP, Carroll WL, Winick NJ. Outcome in Children With Standard-Risk B-Cell Acute Lymphoblastic Leukemia: Results of Children's Oncology Group Trial AALL0331. J Clin Oncol. 2020 Feb 20;38(6):602-612. Epub 2019 Dec 11. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00103285
#COG AALL0932: Angiolillo AL, Schore RJ, Kairalla JA, Devidas M, Rabin KR, Zweidler-McKay P, Borowitz MJ, Wood B, Carroll AJ, Heerema NA, Relling MV, Hitzler J, Lane AR, Maloney KW, Wang C, Bassal M, Carroll WL, Winick NJ, Raetz EA, Loh ML, Hunger SP. Excellent Outcomes With Reduced Frequency of Vincristine and Dexamethasone Pulses in Standard-Risk B-Lymphoblastic Leukemia: Results From Children's Oncology Group AALL0932. J Clin Oncol. 2021 May 1;39(13):1437-1447. Epub 2021 Jan 7. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01190930
==Pegaspargase, Vincristine, Prednisone==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Avramis et al. 2002 (CCG 1962)	1997-1998 	Randomized (E-RT-switch-ic)	L-Asparaginase, Vincristine, Prednisone	Did not meet secondary endpoint of EFS
Note: the primary endpoint of CCG 1962 was incidence of high-titer ASNase antibodies in the first dose intensification, which is neither an efficacy nor a toxicity endpoint.
====Chemotherapy====
*Pegaspargase (Oncaspar) 2500 IU/m2 IM once on day 3
*Vincristine (Oncovin) 1.5 mg/m2 IV once per day on days 0, 7, 14, 21
====Glucocorticoid therapy====
*Prednisone (Sterapred) 40 mg/m2/day PO on days 0 to 28, then tapered off over 10 days
====CNS prophylaxis====
*Cytarabine (Ara-C) IT once on day 0
*Methotrexate (MTX) IT once per day on days 7 & 28
4-week course
====Subsequent treatment====
*See protocol for details of treatment beyond induction
===References===
#CCG 1962: Avramis VI, Sencer S, Periclou AP, Sather H, Bostrom BC, Cohen LJ, Ettinger AG, Ettinger LJ, Franklin J, Gaynon PS, Hilden JM, Lange B, Majlessipour F, Mathew P, Needle M, Neglia J, Reaman G, Holcenberg JS, Stork L. A randomized comparison of native Escherichia coli asparaginase and polyethylene glycol conjugated asparaginase for treatment of children with newly diagnosed standard-risk acute lymphoblastic leukemia: a Children's Cancer Group study. Blood. 2002 Mar 15;99(6):1986-94. Erratum in: Blood 2002 Sep 1;100(5):1531. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
=Early intensification therapy=
==Mercaptopurine & Methotrexate==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Mahoney et al. 1998 (POG 9005)	1991-1993 	Phase 3 (E-switch-ic)	6-MP & MTX; LDMTX/IVMP	Seems to have higher CCR
Lauer et al. 2001 (POG 9006) 	1991-1994 	Phase 3 (C) 	Intensive chemotherapy	Might have shorter EFS
====Preceding treatment====
*POG 9005: L-asparaginase, Vincristine, Prednisone induction
*POG 9006: DOLP induction
====Chemotherapy====
*Mercaptopurine (6-MP) 1000 mg/m2 IV over 6 hours once on day 1, then 50 mg/m2 PO once per day on days 8 to 14
*Methotrexate (MTX) 1000 mg/m2 IV continuous infusion over 24 hours, started on day 1, then 20 mg/m2 IM once on day 8
====Supportive therapy====
*Leucovorin (Folinic acid) 5 mg/m2 (route not specified) every 6 hours for at least 5 doses, started 48 hours after start of methotrexate and continued until methotrexate level less than 0.1 Lmol/L
14-day cycle for 12 cycles
====Subsequent treatment====
*POG 9005: 6-MP & MTX continuation
*POG 9006: 6-MP & MTX maintenance
===References===
#POG 9005: Mahoney DH Jr, Shuster J, Nitschke R, Lauer SJ, Winick N, Steuber CP, Camitta B. Intermediate-dose intravenous methotrexate with intravenous mercaptopurine is superior to repetitive low-dose oral methotrexate with intravenous mercaptopurine for children with lower-risk B-lineage acute lymphoblastic leukemia: a Pediatric Oncology Group phase III trial. J Clin Oncol. 1998 Jan;16(1):246-54. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#POG 9006: Lauer SJ, Shuster JJ, Mahoney DH Jr, Winick N, Toledano S, Munoz L, Kiefer G, Pullen JD, Steuber CP, Camitta BM. A comparison of early intensive methotrexate/mercaptopurine with early intensive alternating combination chemotherapy for high-risk B-precursor acute lymphoblastic leukemia: a Pediatric Oncology Group phase III randomized trial. Leukemia. 2001 Jul;15(7):1038-45. link to original 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
Larsen et al. 2016 (COG AALL0232)	2004-2011 	Non-randomized part of phase 3 RCT
====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, Vincristine interim maintenance versus 6-MP, HD-MTX, Vincristine interim maintenance
===References===
#COG AALL0232: Larsen EC, Devidas M, Chen S, Salzer WL, Raetz EA, Loh ML, Mattano LA Jr, Cole C, Eicher A, Haugan M, Sorenson M, Heerema NA, Carroll AA, Gastier-Foster JM, Borowitz MJ, Wood BL, Willman CL, Winick NJ, Hunger SP, Carroll WL. Dexamethasone and high-dose methotrexate improve outcome for children and young adults with high-risk B-acute lymphoblastic leukemia: a report from Children's Oncology Group study AALL0232. J Clin Oncol. 2016 Jul 10;34(20):2380-8. Epub 2016 Apr 25. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00075725
==Augmented BFM consolidation==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Nachman et al. 1998	1991-1995 	Phase 3 (E-esc)	Standard BFM consolidation	Seems to have longer OS
====Preceding treatment====
*BFM induction
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 1000 mg/m2 IV once per day on days 0 & 28
*Cytarabine (Ara-C) 75 mg/m2 SC or IV once per day on days 1 to 4, 8 to 11, 29 to 32, 36 to 39
*Mercaptopurine (6-MP) 60 mg/m2/day PO on days 0 to 13, 28 to 41
*Vincristine (Oncovin) 1.5 mg/m2 IV once per day on days 14, 21, 42, 49
*Asparaginase (Elspar) 6000 units/m2 IM once per day on days 14, 16, 18, 21, 23, 25, 42, 44, 46, 49, 51, 53
====CNS prophylaxis====
*Methotrexate (MTX) IT once per day on days 1, 8, 15, 22
*Craniocaudal and testicular irradiation
9-week course
====Subsequent treatment====
*Interim maintenance I
===References===
#Nachman JB, Sather HN, Sensel MG, Trigg ME, Cherlow JM, Lukens JN, Wolff L, Uckun FM, Gaynon PS. Augmented post-induction therapy for children with high-risk acute lymphoblastic leukemia and a slow response to initial therapy. N Engl J Med. 1998 Jun 4;338(23):1663-71. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Cyclophosphamide & TBI, then allo HSCT==
Cy/TBI: Cyclophosphamide & Total Body Irradiation
===Regimen===
Study 	Dates of enrollment	Evidence
Thomas et al. 1979	1976-1977 	Non-randomized
===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
==Etoposide & TBI, then allo HSCT==
===Regimen variant #1, weight-based===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Balduzzi et al. 2005 	1995-2000 	Quasi-randomized	Chemotherapy	Seems to have longer DFS
Peters et al. 2015 (ALL-SCT-BFM 2003)	2003-2011 	Non-randomized 	 	
===Regimen variant #2, BSA-based===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Peters et al. 2020 (FORUM)	2013-2018 	Phase 3 (C)	1a. Busulfan, Fludarabine, Thiotepa1b. Fludarabine, Thiotepa, Treosulfan	Longer OS (primary endpoint)
===References===
#Balduzzi A, Valsecchi MG, Uderzo C, De Lorenzo P, Klingebiel T, Peters C, Stary J, Felice MS, Magyarosy E, Conter V, Reiter A, Messina C, Gadner H, Schrappe M. Chemotherapy versus allogeneic transplantation for very-high-risk childhood acute lymphoblastic leukaemia in first complete remission: comparison by genetic randomisation in an international prospective study. Lancet. 2005 Aug 20-26;366(9486):635-42. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#ALL-SCT-BFM-2003: Peters C, Schrappe M, von Stackelberg A, Schrauder A, Bader P, Ebell W, Lang P, Sykora KW, Schrum J, Kremens B, Ehlert K, Albert MH, Meisel R, Matthes-Martin S, Gungor T, Holter W, Strahm B, Gruhn B, Schulz A, Woessmann W, Poetschger U, Zimmermann M, Klingebiel T. Stem-cell transplantation in children with acute lymphoblastic leukemia: a prospective international multicenter trial comparing sibling donors with matched unrelated donors-the ALL-SCT-BFM-2003 trial. J Clin Oncol. 2015 Apr 10;33(11):1265-74. Epub 2015 Mar 9. link to original article EuroPMC NCT01423747
#FORUM: Peters C, Dalle JH, Locatelli F, Poetschger U, Sedlacek P, Buechner J, Shaw PJ, Staciuk R, Ifversen M, Pichler H, Vettenranta K, Svec P, Aleinikova O, Stein J, Güngör T, Toporski J, Truong TH, Diaz-de-Heredia C, Bierings M, Ariffin H, Essa M, Burkhardt B, Schultz K, Meisel R, Lankester A, Ansari M, Schrappe M, von Stackelberg A, Balduzzi A, Corbacioglu S, Bader P; IBFM Study Group; IntReALL Study Group; I-BFM SCT Study Group; EBMT Paediatric Diseases Working Party. Total Body Irradiation or Chemotherapy Conditioning in Childhood ALL: A Multinational, Randomized, Noninferiority Phase III Study. J Clin Oncol. 2021 Feb 1;39(4):295-307. Epub 2020 Dec 17. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01949129
==Mercaptopurine & Vincristine==
===Regimen===
Study 	Dates of enrollment	Evidence
Angiolillo et al. 2021 (COG AALL0932)	2010-2018 	Non-randomized part of phase 3 RCT
====Preceding treatment====
*Pegaspargase, Vincristine, Dexamethasone induction
====Chemotherapy====
*Mercaptopurine (6-MP) 75 mg/m2/day PO on days 1 to 28
*Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once on day 1
====CNS therapy, prophylaxis====
*Methotrexate (MTX) IT once per day on days 1, 8, 15
28-day course
====Subsequent treatment====
*MTX & Vincristine interim maintenance
===References===
#COG AALL0932: Angiolillo AL, Schore RJ, Kairalla JA, Devidas M, Rabin KR, Zweidler-McKay P, Borowitz MJ, Wood B, Carroll AJ, Heerema NA, Relling MV, Hitzler J, Lane AR, Maloney KW, Wang C, Bassal M, Carroll WL, Winick NJ, Raetz EA, Loh ML, Hunger SP. Excellent Outcomes With Reduced Frequency of Vincristine and Dexamethasone Pulses in Standard-Risk B-Lymphoblastic Leukemia: Results From Children's Oncology Group AALL0932. J Clin Oncol. 2021 May 1;39(13):1437-1447. Epub 2021 Jan 7. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01190930
=Interim maintenance=
==Mercaptopurine, Methotrexate, Vincristine==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Larsen et al. 2016 (COG AALL0232)	2004-2011 	Phase 3 (E-switch-ic)	6-MP, Capizzi MTX, Pegaspargase, Vincristine	Longer EFS (primary endpoint)
====Chemotherapy====
*Mercaptopurine (6-MP) 25 mg/m2 PO once per day on days 1 to 56
*Methotrexate (MTX) 5000 mg/m2 IV once per day on days 1, 15, 29, 43
*Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 15, 29, 43
====CNS therapy====
*Methotrexate (MTX) IT once per day on days 1 & 29
8-week course
===References===
#COG AALL0232: Larsen EC, Devidas M, Chen S, Salzer WL, Raetz EA, Loh ML, Mattano LA Jr, Cole C, Eicher A, Haugan M, Sorenson M, Heerema NA, Carroll AA, Gastier-Foster JM, Borowitz MJ, Wood BL, Willman CL, Winick NJ, Hunger SP, Carroll WL. Dexamethasone and high-dose methotrexate improve outcome for children and young adults with high-risk B-acute lymphoblastic leukemia: a report from Children's Oncology Group study AALL0232. J Clin Oncol. 2016 Jul 10;34(20):2380-8. Epub 2016 Apr 25. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00075725
==Methotrexate & Vincristine==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Matloub et al. 2011 (COG CCG-1991) 	2000-2005 	Phase 3 (E-de-esc) 	6-MP, MTX, Vincristine, Dexamethasone	Longer EFS (co-primary endpoint)
Angiolillo et al. 2021 (COG AALL0932)	2010-2018 	Non-randomized part of phase 3 RCT	 	
====Preceding treatment====
*COG AALL0932: 6-MP & Vincristine consolidation
====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
*Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 11, 21, 31, 41
====CNS therapy, prophylaxis====
*Methotrexate (MTX) IT once on day 31
8-week course
====Subsequent treatment====
*COG AALL0932: AALL0932 delayed intensification
===References===
#COG CCG-1991: Matloub Y, Bostrom BC, Hunger SP, Stork LC, Angiolillo A, Sather H, La M, Gastier-Foster JM, Heerema NA, Sailer S, Buckley PJ, Thomson B, Cole C, Nachman JB, Reaman G, Winick N, Carroll WL, Devidas M, Gaynon PS. Escalating intravenous methotrexate improves event-free survival in children with standard-risk acute lymphoblastic leukemia: a report from the Children's Oncology Group. Blood. 2011 Jul 14;118(2):243-51. Epub 2011 May 11. link to original article link to PMC article EuroPMC NCT00005945
#COG AALL0932: Angiolillo AL, Schore RJ, Kairalla JA, Devidas M, Rabin KR, Zweidler-McKay P, Borowitz MJ, Wood B, Carroll AJ, Heerema NA, Relling MV, Hitzler J, Lane AR, Maloney KW, Wang C, Bassal M, Carroll WL, Winick NJ, Raetz EA, Loh ML, Hunger SP. Excellent Outcomes With Reduced Frequency of Vincristine and Dexamethasone Pulses in Standard-Risk B-Lymphoblastic Leukemia: Results From Children's Oncology Group AALL0932. J Clin Oncol. 2021 May 1;39(13):1437-1447. Epub 2021 Jan 7. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01190930
=Delayed intensification=
==AALL0932 delayed intensification==
===Regimen===
Study 	Dates of enrollment	Evidence
Angiolillo et al. 2021 (COG AALL0932)	2010-2018 	Non-randomized part of phase 3 RCT
====Preceding treatment====
*MTX & Vincristine interim maintenance
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 1000 mg/m2 IV once on day 29
*Cytarabine (Ara-C) 75 mg/m2/day SC or IV on days 29 to 32, 36 to 39
*Doxorubicin (Adriamycin) 25 mg/m2 IV once per day on days 1, 8, 15
*Pegaspargase (Oncaspar) 2500 units/m2 IV once on day 4
*Thioguanine (Tabloid) 60 mg/m2/day PO on days 29 to 42
*Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 8, 15
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 10 mg/m2/day PO on days 1 to 7, 15 to 21
====CNS therapy, prophylaxis====
*Methotrexate (MTX) IT once per day on days 1 & 29
8-week course
====Subsequent treatment====
*MTX & Vincristine interim maintenance II
===References===
#COG AALL0932: Angiolillo AL, Schore RJ, Kairalla JA, Devidas M, Rabin KR, Zweidler-McKay P, Borowitz MJ, Wood B, Carroll AJ, Heerema NA, Relling MV, Hitzler J, Lane AR, Maloney KW, Wang C, Bassal M, Carroll WL, Winick NJ, Raetz EA, Loh ML, Hunger SP. Excellent Outcomes With Reduced Frequency of Vincristine and Dexamethasone Pulses in Standard-Risk B-Lymphoblastic Leukemia: Results From Children's Oncology Group AALL0932. J Clin Oncol. 2021 May 1;39(13):1437-1447. Epub 2021 Jan 7. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01190930
=Interim maintenance II=
==Methotrexate & Vincristine==
===Regimen===
Study 	Dates of enrollment	Evidence
Angiolillo et al. 2021 (COG AALL0932)	2010-2018 	Non-randomized part of phase 3 RCT
Note: starting dose of the systemic MTX is 2/3 of the MTD from interim maintenance I; dosage below assumes that the final maximum dose was tolerated.
====Preceding treatment====
*AALL0932 delayed intensification
====Chemotherapy====
*Methotrexate (MTX) 200 mg/m2 IV once on day 1, then 250 mg/m2 IV once on day 11, then 300 mg/m2 IV once on day 21, then 350 mg/m2 IV once on day 31, then 400 mg/m2 IV once on day 41
*Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 11, 21, 31, 41
====CNS therapy, prophylaxis====
*Methotrexate (MTX) IT once per day on days 1 & 31
8-week course
====Subsequent treatment====
*Randomization to one of four maintenance arms; see paper for details.
===References===
#COG AALL0932: Angiolillo AL, Schore RJ, Kairalla JA, Devidas M, Rabin KR, Zweidler-McKay P, Borowitz MJ, Wood B, Carroll AJ, Heerema NA, Relling MV, Hitzler J, Lane AR, Maloney KW, Wang C, Bassal M, Carroll WL, Winick NJ, Raetz EA, Loh ML, Hunger SP. Excellent Outcomes With Reduced Frequency of Vincristine and Dexamethasone Pulses in Standard-Risk B-Lymphoblastic Leukemia: Results From Children's Oncology Group AALL0932. J Clin Oncol. 2021 May 1;39(13):1437-1447. Epub 2021 Jan 7. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01190930
=Maintenance after upfront therapy=
==Mercaptopurine & Methotrexate==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Millot et al. 2001 (EORTC 58881) 	1990-1996 	Phase 3 (C)	6-MP & MTX; IV 6-MP & PO MTX 	Longer DFS1
Conter et al. 2007 (I-BFM-SG IR ALL)	1995-2000 	Phase 3 (C)	D-OMP 	Did not meet primary endpoint of DFS
Qiu et al. 2023 (GD-ALL-2008) 	2008-02-28 to 2016-06-30	Phase 3 (C)	6-MP & MTX with Vincristine & Dexamethasone pulses	Did not meet primary endpoint of EFS120a
1Reported efficacy for EORTC 58881 is based on the 2005 update.
aThe subgroup with high-risk (HR) ALL randomized to this arm had inferior EFS; see paper for details.
====Preceding treatment====
*I-BFM-SG IR ALL: BFM re-induction
====Chemotherapy====
*Mercaptopurine (6-MP) 50 mg/m2 PO once per day
*Methotrexate (MTX) 20 mg/m2 PO once on day 1
7-day cycle for 74 cycles or a total of 2 years from start of treatment
===References===
#EORTC 58881: Millot F, Suciu S, Philippe N, Benoit Y, Mazingue F, Uyttebroeck A, Lutz P, Mechinaud F, Robert A, Boutard P, Marguerite G, Ferster A, Plouvier E, Rialland X, Behard C, Plantaz D, Dresse MF, Philippet P, Norton L, Thyss A, Dastugue N, Waterkeyn C, Vilmer E, Otten J; Children's Leukemia Cooperative Group of the European Organiztaion for Research and Treatment of Cancer. Value of high-dose cytarabine during interval therapy of a Berlin-Frankfurt-Munster-based protocol in increased-risk children with acute lymphoblastic leukemia and lymphoblastic lymphoma: results of the European Organisation for Research and Treatment of Cancer 58881 randomized phase III trial. J Clin Oncol. 2001 Apr 1;19(7):1935-42. link to original article EuroPMC
##Update: Duval M, Suciu S, Ferster A, Rialland X, Nelken B, Lutz P, Benoit Y, Robert A, Manel AM, Vilmer E, Otten J, Philippe N. Comparison of Escherichia coli-asparaginase with Erwinia-asparaginase in the treatment of childhood lymphoid malignancies: results of a randomized European Organisation for Research and Treatment of Cancer-Children's Leukemia Group phase 3 trial. Blood. 2002 Apr 15;99(8):2734-9. link to original article EuroPMC
##Update: van der Werff Ten Bosch J, Suciu S, Thyss A, Bertrand Y, Norton L, Mazingue F, Uyttebroeck A, Lutz P, Robert A, Boutard P, Ferster A, Plouvier E, Maes P, Munzer M, Plantaz D, Dresse MF, Philippet P, Sirvent N, Waterkeyn C, Vilmer E, Philippe N, Otten J. Value of intravenous 6-mercaptopurine during continuation treatment in childhood acute lymphoblastic leukemia and non-Hodgkin's lymphoma: final results of a randomized phase III trial (58881) of the EORTC CLG. Leukemia. 2005 May;19(5):721-6. link to original article EuroPMC
#I-BFM-SG IR ALL: Conter V, Valsecchi MG, Silvestri D, Campbell M, Dibar E, Magyarosy E, Gadner H, Stary J, Benoit Y, Zimmermann M, Reiter A, Riehm H, Masera G, Schrappe M. Pulses of vincristine and dexamethasone in addition to intensive chemotherapy for children with intermediate-risk acute lymphoblastic leukaemia: a multicentre randomised trial. Lancet. 2007 Jan 13;369(9556):123-31. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00411541
#GD-ALL-2008: Qiu KY, Wang JY, Huang LB, Li CG, Xu LH, Liu RY, Chen HQ, Ruan YS, Zhen ZJ, Li CK, Fang JP. Vincristine and dexamethasone pulses in addition to maintenance therapy among pediatric acute lymphoblastic leukemia (GD-ALL-2008): An open-label, multicentre, randomized, phase III clinical trial. Am J Hematol. 2023 Jun;98(6):869-880. Epub 2023 Mar 17. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00846703
=Relapsed or refractory=
==Blinatumomab monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
von Stackelberg et al. 2016 (MT103-205)	2012-2014 	Phase 1/2 (RT)
Note: this is the MTD of a phase 1/2 trial enrolling children under the age of 18.
====Immunotherapy====
*Blinatumomab (Blincyto) as follows:
**Cycle 1: 5 mcg/day IV continuous infusion over 7 days, started on day 1, then 15 mcg/day IV continuous infusion over 21 days, started on day 8 (total dose: 350 mcg)
**Cycles 2 to 5: 28 mcg/day IV continuous infusion over 28 days, started on day 1 (total dose per cycle: 784 mcg)
42-day cycle for up to 5 cycles
===References===
#MT103-205: von Stackelberg A, Locatelli F, Zugmaier G, Handgretinger R, Trippett TM, Rizzari C, Bader P, O'Brien MM, Brethon B, Bhojwani D, Schlegel PG, Borkhardt A, Rheingold SR, Cooper TM, Zwaan CM, Barnette P, Messina C, Michel G, DuBois SG, Hu K, Zhu M, Whitlock JA, Gore L. Phase I/Phase II Study of Blinatumomab in Pediatric Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia. J Clin Oncol. 2016 Dec 20;34(36):4381-4389. Epub 2016 Oct 31. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01471782
==CCE==
CCE: Clofarabine, Cyclophosphamide, Etoposide
===Regimen===
Study 	Dates of enrollment	Evidence
Locatelli et al. 2009	2006-10 to 2008-08 	Non-randomized
Note: Patients in this study were pediatric: No more than 15 years old at diagnosis and no more than 21 years old at time of treatment. No patients had CNS disease at time of treatment, and no patients received CNS prophylaxis.
====Chemotherapy====
*Clofarabine (Clolar) 40 mg/m2 IV over 2 hours once per day on days 1 to 5, given first
*Cyclophosphamide (Cytoxan) 400 mg/m2 IV over 60 minutes once per day on days 1 to 5
*Etoposide (Vepesid) 150 mg/m2 IV over 2 hours once per day on days 1 to 5
====Supportive therapy====
*Prophylactic steroids used for patients with greater than 30 x 109 blasts/L in the peripheral blood prior to treatment
5-day course
2 out of 25 patients received a second course of CCE as consolidation therapy. Responding patients were given allogeneic HSCT if a suitable donor was immediately available or were given consolidation courses of chemotherapy including multiple agents active against ALL cells, chosen according to the treating physician's preference."
===References===
#Locatelli F, Testi AM, Bernardo ME, Rizzari C, Bertaina A, Merli P, Pession A, Giraldi E, Parasole R, Barberi W, Zecca M. Clofarabine, cyclophosphamide and etoposide as single-course re-induction therapy for children with refractory/multiple relapsed acute lymphoblastic leukaemia. Br J Haematol. 2009 Nov;147(3):371-8. Epub 2009 Aug 29. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Clofarabine monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Jeha et al. 2003 	2000-2002 	Phase 1, fewer than 20 pts (RT)
Jeha et al. 2006 (CLO212)	2002-2004 	Phase 2 (RT)
Note: this dose was the MTD in Jeha et al. 2003.
====Chemotherapy====
*Clofarabine (Clolar) 52 mg/m2 IV over 2 hours once per day on days 1 to 5
2- to 6-week cycles, depending on response count recovery
===References===
#Jeha S, Gandhi V, Chan KW, McDonald L, Ramirez I, Madden R, Rytting M, Brandt M, Keating M, Plunkett W, Kantarjian H. Clofarabine, a novel nucleoside analog, is active in pediatric patients with advanced leukemia. Blood. 2004 Feb 1;103(3):784-9. Epub 2003 Oct 9. link to original article EuroPMC
#CLO212: Jeha S, Gaynon PS, Razzouk BI, Franklin J, Kadota R, Shen V, Luchtman-Jones L, Rytting M, Bomgaars LR, Rheingold S, Ritchey K, Albano E, Arceci RJ, Goldman S, Griffin T, Altman A, Gordon B, Steinherz L, Weitman S, Steinherz P. Phase II study of clofarabine in pediatric patients with refractory or relapsed acute lymphoblastic leukemia. J Clin Oncol. 2006 Apr 20;24(12):1917-23. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT00042341
==DOLP==
DOLP: Daunorubicin, Oncovin (Vincristine), L-Asparaginase, Prednisone
PVDA: Prednisone, Vincristine, Daunorubicin, L-Asparaginase
===Regimen===
Study 	Dates of enrollment	Evidence
Rivera et al. 1986	1982-01 to 1983-01 	Non-randomized
====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) 10,000 IU/m2 IM once per day on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, 26
====Glucocorticoid therapy====
*Prednisone (Sterapred) 40 mg/m2 PO once per day on days 1 to 28
4-week course
====Subsequent treatment====
*Ara-C & Teniposide consolidation (see paper for details)
===References===
#Rivera GK, Buchanan G, Boyett JM, Camitta B, Ochs J, Kalwinsky D, Amylon M, Vietti TJ, Crist WM; Pediatric Oncology Group. Intensive retreatment of childhood acute lymphoblastic leukemia in first bone marrow relapse: a Pediatric Oncology Group study. N Engl J Med. 1986 Jul 31;315(5):273-8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Doxorubicin, Pegaspargase, Vincristine, Prednisone==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Abshire et al. 2000 (POG 9310) 	Not reported 	Non-randomized 	 	
Raetz et al. 2008 (COG AALL01P2)	2003-2005 	Non-randomized part of phase 2 RCT	 	
Lew et al. 2021 (COG AALL0433) 	2007-2013 	Phase 3 (C) 	Doxorubicin, Pegaspargase, Vincristine, Prednisone; high-dose vincristine	Not reported
Note: This is "Block 1" of re-induction. Randomization in COG AALL0433 was discontinued early due to high rates of neuropathy in the experimental arm. Intrathecal therapy was dosed according to age; details were not provided.
====Chemotherapy====
*Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
*Pegaspargase (Oncaspar) 2500 units/m2 IM once per day on days 2, 9, 16, 23
*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) 40 mg/m2/day PO on days 1 to 29
====CNS prophylaxis (all patients)====
*Cytarabine (Ara-C) (dose not specified) IT once on day 1
====CNS prophylaxis (CNS-)====
*Methotrexate (MTX) (dose not specified) IT once per day on days 8 & 29
====CNS treatment (CNS+)====
*Methotrexate (MTX) (dose not specified) IT once per day on days 8, 15, 22, 29
*Cytarabine (Ara-C) (dose not specified) IT once per day on days 8, 15, 22, 29
*Hydrocortisone (Cortef) (dose not specified) IT once per day on days 8, 15, 22, 29
5-week course
====Subsequent treatment====
*See papers for details of treatment beyond induction block 1
===References===
#POG 9310: Abshire TC, Pollock BH, Billett AL, Bradley P, Buchanan GR. Weekly polyethylene glycol conjugated L-asparaginase compared with biweekly dosing produces superior induction remission rates in childhood relapsed acute lymphoblastic leukemia: a Pediatric Oncology Group Study. Blood. 2000 Sep 1;96(5):1709-15. link to original article EuroPMC
#COG AALL01P2: Raetz EA, Borowitz MJ, Devidas M, Linda SB, Hunger SP, Winick NJ, Camitta BM, Gaynon PS, Carroll WL. Reinduction platform for children with first marrow relapse of acute lymphoblastic Leukemia: A Children's Oncology Group Study[corrected]. J Clin Oncol. 2008 Aug 20;26(24):3971-8. Erratum in: J Clin Oncol. 2008 Oct 1;26(28): 4697. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00049569
#COG AALL0433: Lew G, Chen Y, Lu X, Rheingold SR, Whitlock JA, Devidas M, Hastings CA, Winick NJ, Carroll WL, Wood BL, Borowitz MJ, Pulsipher MA, Hunger SP. Outcomes after late bone marrow and very early central nervous system relapse of childhood B-acute lymphoblastic leukemia: a report from the Children's Oncology Group phase III study AALL0433. Haematologica. 2021 Jan 1;106(1):46-55. link to original article link to PMC article does not contain dosing details EuroPMC NCT00381680
==Inotuzumab ozogamicin monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Kantarjian et al. 2012 (MDACC 2009-0872)	2010-2011 	Phase 2
====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
==Mitoxantrone, Asparaginase Erwinia chrysanthemi, Vincristine, Dexamethasone==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Parker et al. 2010 (CCLG ALL R3)	2003-2007 	Phase 3 (E-switch-ic)	1a. Idarubicin, Asparaginase Erwinia chrysanthemi, Vincristine, Dexamethasone1b. Idarubicin, Pegaspargase, Vincristine, Dexamethasone	Longer OS (secondary endpoint)OS36: 69% vs 45.2%(HR 0.56, 95% CI 0.36-0.87)
Note: per the protocol, this regimen is intended only for patients 18 and younger. This regimen is for patients allergic to pegaspargase.
====Chemotherapy====
*Mitoxantrone (Novantrone) 10 mg/m2 IV once per day on days 1 & 8
*Asparaginase Erwinia chrysanthemi (Erwinaze) 20,000 units IM once per day on days 3, 5, 7, 9, 11, 13, 18, 20, 22, 24, 26, 28
*Vincristine (Oncovin) 1.5 mg/m2 IV once per day on days 3, 10, 17, 24
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 20 mg/m2 PO once per day on days 1 to 5, 15 to 19
====CNS therapy, prophylaxis====
*Methotrexate (MTX) by the following age-based criteria:
**Younger than 2 years old: 8 mg IT once per day on days 1 & 8
**2 years old: 10 mg IT once per day on days 1 & 8
**Older than 2 years old: 12 mg IT once per day on days 1 & 8
4-week course
====Subsequent treatment====
*See paper for details of treatment beyond induction
===References===
#CCLG ALL R3: Parker C, Waters R, Leighton C, Hancock J, Sutton R, Moorman AV, Ancliff P, Morgan M, Masurekar A, Goulden N, Green N, Révész T, Darbyshire P, Love S, Saha V. Effect of mitoxantrone on outcome of children with first relapse of acute lymphoblastic leukaemia (ALL R3): an open-label randomised trial. Lancet. 2010 Dec 11;376(9757):2009-17. Epub 2010 Dec 3. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00967057
==Mitoxantrone, Pegaspargase, Vincristine, Dexamethasone==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Parker et al. 2010 (CCLG ALL R3)	2003-2007 	Phase 3 (E-switch-ic)	1a. Idarubicin, Asparaginase Erwinia chrysanthemi, Vincristine, Dexamethasone1b. Idarubicin, Pegaspargase, Vincristine, Dexamethasone	Longer OS (secondary endpoint)OS36: 69% vs 45.2%(HR 0.56, 95% CI 0.36-0.87)
Note: per the protocol, this regimen is intended only for patients 18 and younger.
====Chemotherapy====
*Mitoxantrone (Novantrone) 10 mg/m2 IV once per day on days 1 & 8
*Pegaspargase (Oncaspar) 1000 units/m2 IM once per day on days 3 & 18
*Vincristine (Oncovin) 1.5 mg/m2 IV once per day on days 3, 10, 17, 24
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 20 mg/m2 PO once per day on days 1 to 5, 15 to 19
====CNS therapy, prophylaxis====
*Methotrexate (MTX) by the following age-based criteria:
**Younger than 2 years old: 8 mg IT once per day on days 1 & 8
**2 years old: 10 mg IT once per day on days 1 & 8
**Older than 2 years old: 12 mg IT once per day on days 1 & 8
4-week course
====Subsequent treatment====
*See paper for details of treatment beyond induction
===References===
#CCLG ALL R3: Parker C, Waters R, Leighton C, Hancock J, Sutton R, Moorman AV, Ancliff P, Morgan M, Masurekar A, Goulden N, Green N, Révész T, Darbyshire P, Love S, Saha V. Effect of mitoxantrone on outcome of children with first relapse of acute lymphoblastic leukaemia (ALL R3): an open-label randomised trial. Lancet. 2010 Dec 11;376(9757):2009-17. Epub 2010 Dec 3. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00967057
==Tisagenlecleucel monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Efficacy
Grupp et al. 2013 (Pedi CART19)	2011 to not reported	Pilot 	
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===
#Pedi CART19: Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, Teachey DT, Chew A, Hauck B, Wright JF, Milone MC, Levine BL, June CH. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med. 2013 Apr 18;368(16):1509-1518. Epub 2013 Mar 25. Erratum in: N Engl J Med. 2016 Mar 10;374(10):998. link to original article link to PMC article EuroPMC NCT01626495
#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
##Update: Laetsch TW, Maude SL, Rives S, Hiramatsu H, Bittencourt H, Bader P, Baruchel A, Boyer M, De Moerloose B, Qayed M, Buechner J, Pulsipher MA, Myers GD, Stefanski HE, Martin PL, Nemecek E, Peters C, Yanik G, Khaw SL, Davis KL, Krueger J, Balduzzi A, Boissel N, Tiwari R, O'Donovan D, Grupp SA. Three-Year Update of Tisagenlecleucel in Pediatric and Young Adult Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia in the ELIANA Trial. J Clin Oncol. 2023 Mar 20;41(9):1664-1669. Epub 2022 Nov 18. link to original article link to PMC article EuroPMC
=Consolidation after salvage therapy=
==Blinatumomab monotherapy==
===Regimen variant #1, 1 cycle===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Locatelli et al. 2021 (Amgen 20120215)	2015-2019 	Phase 3 (E-RT-switch-ooc)	Standard salvage consolidation chemotherapy	Longer EFS (primary endpoint)EFS24: 66.2% vs 27.1%(HR 0.33, 95% CI 0.18-0.61)
====Immunotherapy====
*Blinatumomab (Blincyto) 15 mcg/m2/day IV continuous infusion over 28 days, started on day 1 (total dose: 420 mcg/m2)
42-day course
====Subsequent treatment====
*Allogeneic hematopoietic stem cell transplant consolidation
===Regimen variant #2, 2 cycles===
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)
Hogan et al. 2023 (COG AALL1331 LR relapse)	2014-01 to 2019-09 	Phase 3 (E-switch-ooc) 	Standard salvage consolidation chemotherapy	Did not meet primary endpoint of DFS
====Preceding treatment====
*UKALLR3 salvage re-induction
====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 consolidation
===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
#Amgen 20120215: Locatelli F, Zugmaier G, Rizzari C, Morris JD, Gruhn B, Klingebiel T, Parasole R, Linderkamp C, Flotho C, Petit A, Micalizzi C, Mergen N, Mohammad A, Kormany WN, Eckert C, Möricke A, Sartor M, Hrusak O, Peters C, Saha V, Vinti L, von Stackelberg A. Effect of Blinatumomab vs Chemotherapy on Event-Free Survival Among Children With High-risk First-Relapse B-Cell Acute Lymphoblastic Leukemia: A Randomized Clinical Trial. JAMA. 2021 Mar 2;325(9):843-854. link to original article dosing details in abstract have been reviewed by our editors link to PMC article EuroPMC NCT02393859
#COG AALL1331 LR relapse: Hogan LE, Brown PA, Ji L, Xu X, Devidas M, Bhatla T, Borowitz MJ, Raetz EA, Carroll A, Heerema NA, Zugmaier G, Sharon E, Bernhardt MB, Terezakis SA, Gore L, Whitlock JA, Hunger SP, Loh ML. Children's Oncology Group AALL1331: Phase III Trial of Blinatumomab in Children, Adolescents, and Young Adults With Low-Risk B-Cell ALL in First Relapse. J Clin Oncol. 2023 Sep 1;41(25):4118-4129. Epub 2023 May 31. link to original article EuroPMC link to PMC article NCT02101853
==Cyclophosphamide & TBI, then allo HSCT==
Cy/TBI: Cyclophosphamide & Total Body Irradiation
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Johnson et al. 1981	1976-1980 	Non-randomized 	 	
Kersey et al. 1987 	1982-1985 	Quasi-randomized	Auto HSCT 	Longer RFS
===References===
#Johnson FL, Thomas ED, Clark BS, Chard RL, Hartmann JR, Storb R. A comparison of marrow transplantation with chemotherapy for children with acute lymphoblastic leukemia in second or subsequent remission. N Engl J Med. 1981 Oct 8;305(15):846-51. 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
Category:B-cell acute lymphoblastic leukemia regimens
Category:Disease-specific pages
Category:Acute lymphoblastic leukemias
Category:Pediatric hematologic neoplasms