B-cell acute lymphoblastic leukemia, pediatric

Section editor
	Wayne H. Liang, MD, MS, FAMIA UAB Birmingham, AL LinkedIn WayneLiangMD

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.

34 regimens on this page 40 variants on this page

Guidelines

"How I Treat"

• 2020: Hunger & Raetz. How I treat relapsed acute lymphoblastic leukemia in the pediatric population

NCCN

• NCCN Guidelines - Pediatric Acute Lymphoblastic Leukemia

COG AALL0932

For Standard Risk B-ALL

Induction

Pegaspargase, Vincristine, Dexamethasone

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Regimen

Study	Years of enrollment	Evidence
Maloney et al. 2019 (COG AALL0331)	2005-2010	Non-randomized portion of RCT
Angiolillo et al. 2021 (COG AALL0932)	2010-2018	Non-randomized portion of RCT

Note: there are very minor differences in timing between protocols; see papers for details.

Chemotherapy

• Pegaspargase (Oncaspar) 2500 units/m² IV once over 1 - 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
• Dexamethasone (Decadron) 3 mg/m² IV or PO twice per day on days 1 to 28

CNS prophylaxis

• Cytarabine (Ara-C) IT once on day 0

Age	Initial Dose
1 - 1.99 years	30 mg
2 - 2.99 years	50 mg
≥ 3 years	70 mg

CNS2 Patients will receive an additional dose of Cytarabine (Ara-C) IT on either day 4, 5, or 6, followed by Methotrexate (MTX) IT on day 8 and then another dose of Cytarabine (Ara-C) IT on either day 11 or 12 according to the following dosing.

Age	Subsequent Doses
1 - 1.99	20 mg
2 - 2.99	30 mg
≥ 3	40 mg

• Methotrexate (MTX) IT once per day on days 8 & 29

Age	Dose
1 - 1.99	8 mg
2 - 2.99	10 mg
3 - 8.99	12 mg
≥ 9	15 mg

DS Arm

• Folinic acid (Leucovorin) 5 mg/m² x 2 doses given 48 and 60 hours after the lumbar puncture on days 10-11 and 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

References

1. 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 contains verified protocol PubMed NCT00103285
2. 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 contains verified protocol PubMed NCT01190930

Consolidation

For AR B-ALL patients, LR-C Arm, and B-LLy

Mercaptopurine & Vincristine

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Regimen

Study	Years of enrollment	Evidence
Angiolillo et al. 2021 (COG AALL0932)	2010-2018	Non-randomized portion of 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 prophylaxis

• Methotrexate (MTX) IT once per day on days 1, 8, 15

Age	Dose
1 - 1.99	8 mg
2 - 2.99	10 mg
3 - 8.99	12 mg
≥ 9	15 mg

DS Arm

• Folinic acid (Leucovorin) 5 mg/m² x 2 doses given 48 and 60 hours after the lumbar puncture on days 3-4, 10-11, and 17-18.

28-day course

Subsequent treatment

• MTX & Vincristine interim maintenance

References

1. 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 contains verified protocol PubMed NCT01190930

Interim Maintenance I

For AR B-ALL patients, LR-C Arm, and B-LLy

Methotrexate & Vincristine

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Matloub et al. 2011 (COG CCG-1991)	2000-2005	Phase III (E-de-esc)	Mercaptopurine, MTX, Vincristine, Dexamethasone	Superior EFS
Angiolillo et al. 2021 (COG AALL0932)	2010-2018	Non-randomized portion of 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
  • Given over 2 - 5 minutes (undiluted) or over 10 - 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 prophylaxis

• Methotrexate (MTX) IT once on day 31

Age	Dose
1 - 1.99	8 mg
2 - 2.99	10 mg
3 - 8.99	12 mg
≥ 9	15 mg

DS Arm

• Folinic acid (Leucovorin) 5 mg/m² x 2 doses given 48 and 60 hours after the lumbar puncture on days 33-34

8-week course

Subsequent treatment

• COG AALL0932: AALL0932 delayed intensification

References

1. 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 PubMed NCT00005945
2. 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 contains verified protocol PubMed NCT01190930

Delayed Intensification

For AR B-ALL patients, LR-C Arm, and B-LLy

AALL0932 delayed intensification

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Regimen

Study	Years of enrollment	Evidence
Angiolillo et al. 2021 (COG AALL0932)	2010-2018	Non-randomized portion of RCT

Preceding treatment

• MTX & Vincristine interim maintenance

Chemotherapy

• Cyclophosphamide (Cytoxan) 1000 mg/m² IV over 30 - 60 minutes once on day 29
• Cytarabine (Ara-C) 75 mg/m²/day SC or IV over 1 - 30 minutes on days 29 to 32, 36 to 39
• Doxorubicin (Adriamycin) 25 mg/m² IV push/infusion over 1 - 15 minutes once per day on days 1, 8, 15
• Pegaspargase (Oncaspar) 2500 units/m² IV over 1 - 2 hours once on day 4
• Thioguanine (Tabloid) 60 mg/m²/day 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
• Dexamethasone (Decadron) 5 mg/m²/dose PO twice daily on days 1 to 7, 15 to 21 (10 mg/m²/day)

CNS prophylaxis

• Methotrexate (MTX) IT once per day on days 1 & 29

Age	Dose
1 - 1.99	8 mg
2 - 2.99	10 mg
3 - 8.99	12 mg
≥ 9	15 mg

DS Arm

• Folinic acid (Leucovorin) 5 mg/m² x 2 doses given 48 and 60 hours after the lumbar puncture on days 3-4 and 31-32.

8-week course

Subsequent treatment

• MTX & Vincristine interim maintenance II

References

1. 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 contains verified protocol PubMed NCT01190930

Interim Maintenance II

For AR B-ALL patients, LR-C Arm, and B-LLy

Methotrexate & Vincristine

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Matloub et al. 2011 (COG CCG-1991)	2000-2005	Phase III (E-de-esc)	Mercaptopurine, MTX, Vincristine, Dexamethasone	Superior EFS
Angiolillo et al. 2021 (COG AALL0932)	2010-2018	Non-randomized portion of 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
  • Given over 2 - 5 minutes (undiluted) or over 10 - 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 prophylaxis

• Methotrexate (MTX) IT once on day 31

Age	Dose
1 - 1.99	8 mg
2 - 2.99	10 mg
3 - 8.99	12 mg
≥ 9	15 mg

DS Arm

• Folinic acid (Leucovorin) 5 mg/m² x 2 doses given 48 and 60 hours after the lumbar puncture on days 3-4 and 33-34.

8-week course

Subsequent treatment

• COG AALL0932: AALL0932 delayed intensification

References

1. 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 PubMed NCT00005945
2. 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 contains verified protocol PubMed NCT01190930

Maintenance Arm A and C

For AR B-ALL patients, and LR-C Arm

Vincristine/Dexamethasone Pulses

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Regimen

Study	Years of enrollment	Evidence
Angiolillo et al. 2021 (COG AALL0932)	2010-2018	Randomized portion of RCT

Preceding treatment

• COG AALL0932: MTX & Vincristine interim maintenance

Chemotherapy

• Methotrexate (MTX) 20 mg/m² PO once on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71 and 78.
• Vincristine (Oncovin) 1.5 mg/m² (maximum dose of 2 mg) IV once per day on days 1, 29, and 57
• Dexamethasone (Decadron) 3 mg/m²/dose PO twice daily on days 1 to 5, 29 - 33, and 578 - 61 (6 mg/m²/day)
• Mercaptopurine (6-MP) 75 mg/m²/dose PO once per day on days 1 to 84

CNS prophylaxis

• Methotrexate (MTX) IT once on day 1

Age	Dose
1 - 1.99	8 mg
2 - 2.99	10 mg
3 - 8.99	12 mg
≥ 9	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

1. 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 PubMed NCT00005945
2. 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 contains verified protocol PubMed NCT01190930

Maintenance Arm B and D

Vincristine/Dexamethasone Pulses

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Regimen

Study	Years of enrollment	Evidence
Angiolillo et al. 2021 (COG AALL0932)	2010-2018	Randomized portion of RCT

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 and 78.
• Vincristine (Oncovin) 1.5 mg/m² (maximum dose of 2 mg) IV once per day on days 1, 29, and 57
• Dexamethasone (Decadron) 3 mg/m²/dose PO twice daily on days 1 to 5, 29 - 33, and 57 - 61 (6 mg/m²/day)
• Mercaptopurine (6-MP) 75 mg/m²/dose PO once per day on days 1 to 84

CNS prophylaxis

• Methotrexate (MTX) IT once on day 1

Age	Dose
1 - 1.99	8 mg
2 - 2.99	10 mg
3 - 8.99	12 mg
≥ 9	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

1. 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 PubMed NCT00005945
2. 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 contains verified protocol PubMed NCT01190930

Maintenance Arm DS

For DS AR B-ALL patients and DS B-LLy

Vincristine/Dexamethasone

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Regimen

Study	Years of enrollment	Evidence
Angiolillo et al. 2021 (COG AALL0932)	2010-2018	Randomized portion of RCT

Preceding treatment

• COG AALL0932: MTX & Vincristine interim maintenance

Chemotherapy

• Methotrexate (MTX) 20 mg/m² PO once on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71 and 78.
• Vincristine (Oncovin) 1.5 mg/m² (maximum dose of 2 mg) IV once per day on days 1
• Dexamethasone (Decadron) 3 mg/m²/dose IV or PO twice daily on days 1 to 5 (6 mg/m²/day) (DO NOT TAPER)
• Mercaptopurine (6-MP) 75 mg/m²/dose PO once per day on days 1 to 84

CNS prophylaxis

• Methotrexate (MTX) IT once on day 1

Age	Dose
1 - 1.99	8 mg
2 - 2.99	10 mg
3 - 8.99	12 mg
≥ 9	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

1. 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 PubMed NCT00005945
2. 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 contains verified protocol PubMed NCT01190930

Arm LR-M

Consolidation

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Regimen

Study	Years of enrollment	Evidence
Angiolillo et al. 2021 (COG AALL0932)	2010-2018	Randomized portion of RCT

Chemotherapy

• Methotrexate (MTX) IV at 1000 mg/m² on days 8, 29, 50, 71, 92, and 113.

Given as a 200 mg/m2 bolus over 20 - 30 minutes followed by 800 mg/m2 over 23.5 hours (initial bolus of 30 minutes) or 23 hours and 40 minutes (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, and 85.
• Dexamethasone (Decadron) 3 mg/m²/dose IV or PO twice daily on days 15 - 21, and 78 - 84. (6 mg/m²/day)
• Mercaptopurine (6-MP) 50 mg/m²/dose PO once per day on days 1 to 33
• Folinic acid (Leucovorin) 10 mg/m² x 2 doses PO or IV (given 48 and 60 hours after the START of MTX infusion, continuing until MTX level < 0.2 μM) on days 9 - 10, 30 - 31, 51 - 52, 72 - 73, 93 - 94, and 114 - 115.

CNS prophylaxis

• Methotrexate (MTX) IT once on day 8, 29, 50, 71, 92, and 113 (To be delivered within 6 hours of the beginning of the IV MTX infusion, -6hr to + 6 hr)

Age	Dose
1 - 1.99	8 mg
2 - 2.99	10 mg
3 - 8.99	12 mg
≥ 9	15 mg

19-week cycle

References

1. 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 PubMed NCT00005945
2. 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 contains verified protocol PubMed NCT01190930

Maintenance

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Regimen

Study	Years of enrollment	Evidence
Angiolillo et al. 2021 (COG AALL0932)	2010-2018	Randomized portion of RCT

Chemotherapy

MTX DATES CHANGE DEPENDING ON CYCLE NUMBER

Cycles 1 and 4:

• Methotrexate (MTX) PO at 20 mg/m² on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, 92, 99, and 106.
• Vincristine (Oncovin) 1.5 mg/m² (maximum dose of 2 mg) IV once per day on days 1 and 8.
• Dexamethasone (Decadron) 3 mg/m²/dose PO twice daily on days 1 - 7. (6 mg/m²/day, do not taper)
• Mercaptopurine (6-MP) 75 mg/m²/dose PO once per day on days 1 - 112. (NOTE: Higher 6-MP dose than in consolidation)

Cycles 2 and 5:

• Methotrexate (MTX) PO at 20 mg/m² on days 1, 8, 15, 22, 29, 36, 43, 50, 64, 71, 78, 85, 92, 99, and 106.
• Vincristine (Oncovin) 1.5 mg/m² (maximum dose of 2 mg) IV once per day on days 1 and 8.
• Dexamethasone (Decadron) 3 mg/m²/dose PO twice daily on days 1 - 7. (6 mg/m²/day, do not taper)
• Mercaptopurine (6-MP) 75 mg/m²/dose PO once per day on days 1 - 112. (NOTE: Higher 6-MP dose than in consolidation)

Cycles 3 and 6:

• Methotrexate (MTX) PO at 20 mg/m² on days 1, 8, 15, 22, 36, 43, 50, 57, 64, 71, 78, 85, 92, 99, and 106.
• Vincristine (Oncovin) 1.5 mg/m² (maximum dose of 2 mg) IV once per day on days 1 and 8.
• Dexamethasone (Decadron) 3 mg/m²/dose PO twice daily on days 1 - 7. (6 mg/m²/day, do not taper)
• Mercaptopurine (6-MP) 75 mg/m²/dose PO once per day on days 1 - 112. (NOTE: Higher 6-MP dose than in consolidation)

Cycle 7:

• Methotrexate (MTX) PO at 20 mg/m² on days 1, 8, 15, 29, 22, 36, 43, 50, 57, and 64
• Vincristine (Oncovin) 1.5 mg/m² (maximum dose of 2 mg) IV once per day on days 1 and 8.
• Dexamethasone (Decadron) 3 mg/m²/dose PO twice daily on days 1 - 7. (6 mg/m²/day, do not taper)
• Mercaptopurine (6-MP) 75 mg/m²/dose PO once per day on days 1 - 70. (NOTE: Higher 6-MP dose than in consolidation)

CNS prophylaxis

DATES CHANGE DEPENDING ON CYCLE NUMBER

Cycles 1 and 4:

• Methotrexate (MTX) IT once on day 1 and 85.

Cycles 2 and 5:

• Methotrexate (MTX) IT once on day 57.

Cycles 3 and 6:

• Methotrexate (MTX) IT once on day 29.

Cycle 7: NO MTX IT on Cycle 7

Age	Dose
1 - 1.99	8 mg
2 - 2.99	10 mg
3 - 8.99	12 mg
≥ 9	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.

References

1. 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 PubMed NCT00005945
2. 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 contains verified protocol PubMed NCT01190930

Maintenance Arm LLy

Vincristine/Dexamethasone

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Regimen

Study	Years of enrollment	Evidence
Angiolillo et al. 2021 (COG AALL0932)	2010-2018	Randomized portion of RCT

Preceding treatment

• COG AALL0932: MTX & Vincristine interim maintenance

Chemotherapy

• Methotrexate (MTX) 20 mg/m² PO once on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71 and 78.
• Vincristine (Oncovin) 1.5 mg/m² (maximum dose of 2 mg) IV once per day on days 1, 29, and 57. (4 Week Intervals)
• Dexamethasone (Decadron) 3 mg/m²/dose PO twice daily on days 1 - 5, 29 - 33, and 57 - 61. (6 mg/m²/day) (DO NOT TAPER)
• Mercaptopurine (6-MP) 75 mg/m²/dose PO once per day on days 1 to 84.

CNS prophylaxis

• Methotrexate (MTX) IT once on day 1

Age	Dose
1 - 1.99	8 mg
2 - 2.99	10 mg
3 - 8.99	12 mg
≥ 9	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

1. 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 PubMed NCT00005945
2. 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 contains verified protocol PubMed NCT01190930

AALL1131

Induction

Daunorubicin, Pegaspargase, Vincristine, Dexamethasone

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Regimen

Study	Evidence
Burke et al. 2019 (COG AALL1131)	Non-randomized portion of 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

Patients < 10 years ONLY:

• Dexamethasone (Decadron) 5 mg/m² IV or PO twice per day on days 1 to 14

Patients ≥ 10 years ONLY:

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

CNS prophylaxis

• Cytarabine (Ara-C) as follows:
  • Ages 1 to 1.99: 30 mg IT once on day 1
  • Ages 2 to 2.99: 50 mg IT once on day 1
  • Age 3 and older: 70 mg IT once on day 1

CNS2 Patients will receive an additional dose of Cytarabine (Ara-C) IT on either day 4, 5, or 6, and then another dose of Cytarabine (Ara-C) IT on either day 11 or 12 according to the following dosing.

• Cytarabine (Ara-C) as follows:
  • Ages 1 to 1.99: 20 mg IT once
  • Ages 2 to 2.99: 30 mg IT once
  • Age 3 and older: 40 mg IT once

• Methotrexate (MTX) as follows: (CNS3 also on Days 15 and 22)
  • Ages 1 to 1.99: 8 mg IT once per day on days 8 & 29
  • Ages 2 to 2.99: 10 mg IT once per day on days 8 & 29
  • Ages 3 to 8.99: 12 mg IT once per day on days 8 & 29
  • Age 9 and older: 15 mg IT once per day on days 8 & 29

4-week course

Subsequent treatment

• See protocol for details of treatment beyond induction

References

1. 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 PubMed NCT02883049

HR B-ALL

Consolidation

Regimen

Study	Evidence
Burke et al. 2019 (COG AALL1131)	Randomized portion of RCT

Chemotherapy

• Cyclophosphamide (Cytoxan) 1000 mg/m² IV over 30 - 60 minutes once on days 1 and 29
• Cytarabine (Ara-C) 75 mg/m²/day SC or IV over 1 - 30 minutes on days 1 - 4, 8 - 11, 29 - 32, 36 - 39.
• Pegaspargase (Oncaspar) 2500 units/m² IV over 1 - 2 hours once on days 15, and 43.
• Vincristine (Oncovin) 1.5 mg/m² (maximum dose of 2 mg) IV once per day on days 15, 22, 43, and 50.
• Mercaptopurine (6-MP) 60 mg/m²/dose PO once per day on days 1 - 14, and 29 - 42.

CNS prophylaxis

• Methotrexate (MTX) IT once per day on days 1, 8, 15, and 22.

Age	Dose
1 - 1.99	8 mg
2 - 2.99	10 mg
3 - 8.99	12 mg
≥ 9	15 mg

56-Day Course

References

1. 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 PubMed NCT02883049
2. 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 contains verified protocol PubMed NCT01190930

Interim Maintenance with HD MTX

Regimen

Study	Evidence
Burke et al. 2019 (COG AALL1131)	Randomized portion of RCT

Chemotherapy

• Vincristine (Oncovin) 1.5 mg/m² (maximum dose of 2 mg) IV once per day on days 1, 15, 29, and 43.
• Mercaptopurine (6-MP) 25 mg/m²/dose PO once per day on days 1 - 56.
• High Dose Methotrexate (MTX) 5000 mg/m² IV over 24 hours on days 1, 15, 29, and 43.
  • MTX 500 mg/m² IV infused over 30 minutes. This is followed, immediately, by MTX 4500 mg/m² given by continuous IV infusion over 23.5 hours.

ANC must be ≥ 750/µL and platelets must be ≥ 75,000/µL prior to each dose of HD MTX

• Folinic acid (Leucovorin) 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 - 4, 17 - 18, 31 - 32, and 45 - 46.

CNS prophylaxis

• Methotrexate (MTX) IT once per day on days 1 and 29.

Age	Dose
1 - 1.99	8 mg
2 - 2.99	10 mg
3 - 8.99	12 mg
≥ 9	15 mg

When IT therapy and HD MTX are scheduled for the same day, deliver the IT therapy within 6 hours of the beginning of the IV MTX infusion. (hour -6 or +6, with 0 being the start of the MTX bolus). 

63-Day Course

References

1. 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 PubMed NCT02883049
2. 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 contains verified protocol PubMed NCT01190930

Delayed Intensification

Regimen

Study	Evidence
Burke et al. 2019 (COG AALL1131)	Randomized portion of RCT

Chemotherapy

• Doxorubicin (Adriamycin) 25 mg/m² IV push over 1 to 15 minutes once per day on days 1, 8, and 15.
• Pegaspargase (Oncaspar) 2500 units/m² IV over 1 to 2 hours once on days 4 and 43.
• Vincristine (Oncovin) 1.5 mg/m² (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 43, and 50.
• Dexamethasone (Decadron) 5 mg/m² IV or PO twice per day on days 1 - 7 and 15 - 21.
• Cyclophosphamide (Cytoxan) 1000 mg/m² IV over 30 - 60 minutes once on day 29 ONLY.
• Cytarabine (Ara-C) 75 mg/m²/day SC or IV over 1 - 30 minutes on days 29 - 32 and 36 - 39.
• Thioguanine (Tabloid) 60 mg/m²/day PO once per day on days 29 to 42.

CNS prophylaxis

• Methotrexate (MTX) IT once per day on days 1, 29, and 36.

Age	Dose
1 - 1.99	8 mg
2 - 2.99	10 mg
3 - 8.99	12 mg
≥ 9	15 mg

56-Day course

References

1. 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 PubMed NCT02883049

Maintenance HR B-ALL

Regimen

Study	Evidence
Burke et al. 2019 (COG AALL1131)	Randomized portion of RCT

Chemotherapy

Cycles 1-4

• Mercaptopurine (6-MP) 75 mg/m²/dose PO once per day on days 1 - 84.
• Vincristine (Oncovin) 1.5 mg/m² (maximum dose of 2 mg) IV once per day on days 1, 29, and 57.
• Methotrexate (MTX) 20 mg/m² PO once on days 8, 15, 22, 36, 43, 50, 57, 64, 71 and 78.
• Prednisone (Sterapred) 20 mg/m²/dose PO or IV (methylprednisolone given at 80% of the oral dose) twice per day on days 1 - 5, 29 - 33, and 57 - 61.

Cycles 5 and Later

• Mercaptopurine (6-MP) 75 mg/m²/dose PO once per day on days 1 - 84.
• Vincristine (Oncovin) 1.5 mg/m² (maximum dose of 2 mg) IV once per day on days 1, 29, and 57.
• Methotrexate (MTX) 20 mg/m² PO once on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71 and 78.
• Prednisone (Sterapred) 20 mg/m²/dose PO or IV (methylprednisolone given at 80% of the oral dose) twice per day on days 1 - 5, 29 - 33, and 57 - 61.

CNS prophylaxis

Cycles 1-4

• Methotrexate (MTX) IT once per day on days 1 and 29.

Cycles 5 and Later

• Methotrexate (MTX) IT once per day on day 1.

Age	Dose
1 - 1.99	8 mg
2 - 2.99	10 mg
3 - 8.99	12 mg
≥ 9	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

1. 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 PubMed NCT02883049

VHR B-ALL

Consolidation

Regimen

Study	Evidence
Burke et al. 2019 (COG AALL1131)	Randomized portion of RCT

Chemotherapy

• Pegaspargase (Oncaspar) 2500 units/m² IV over 1 to 2 hours once on day 15 and 43.
• Vincristine (Oncovin) 1.5 mg/m² (maximum dose of 2 mg) IV once per day on days 15, 22, 43, and 50.
• Cyclophosphamide (Cytoxan) 1000 mg/m² IV over 30 - 60 minutes once on day 1 and 29.
• Cytarabine (Ara-C) 75 mg/m²/day SC or IV over 1 - 30 minutes on days 1 - 4, 8 - 11, 29 - 32, and 36 - 39.
• Mercaptopurine (6-MP) 60 mg/m²/dose PO once per day on days 1 - 14 and 29 - 42.

CNS prophylaxis

• Methotrexate (MTX) IT once per day on days 1, 8, 15, and 22. (Omit days 15 and 22 for CNS3 Patients)

Age	Dose
1 - 1.99	8 mg
2 - 2.99	10 mg
3 - 8.99	12 mg
≥ 9	15 mg

56-Day course

References

1. 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 PubMed NCT02883049

Interim Maintenance I with HD MTX

Regimen

Study	Evidence
Burke et al. 2019 (COG AALL1131)	Randomized portion of RCT

Chemotherapy

• Vincristine (Oncovin) 1.5 mg/m² (maximum dose of 2 mg) IV once per day on days 1, 15, 29, and 43.
• Mercaptopurine (6-MP) 60 mg/m²/dose PO once per day on days 1 - 56.
• High Dose Methotrexate (MTX) 5000 mg/m² IV over 24 hours on days 1, 15, 29, and 43.
  • MTX 500 mg/m² IV infused over 30 minutes. This is followed, immediately, by MTX 4500 mg/m² given by continuous IV infusion over 23.5 hours.

ANC must be ≥ 750/µL and platelets must be ≥ 75,000/µL prior to each dose of HD MTX

• Folinic acid (Leucovorin) 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 - 4, 17 - 18, 31 - 32, and 45 - 46.

CNS prophylaxis

• Methotrexate (MTX) IT once per day on days 1 and 29.

Age	Dose
1 - 1.99	8 mg
2 - 2.99	10 mg
3 - 8.99	12 mg
≥ 9	15 mg

28-Day course

References

1. 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 PubMed NCT02883049

Delayed Intensification

Regimen

Study	Evidence
Burke et al. 2019 (COG AALL1131)	Randomized portion of RCT

Chemotherapy

• Doxorubicin (Adriamycin) 25 mg/m² IV push over 1 to 15 minutes once per day on days 1, 8, and 15.
• Pegaspargase (Oncaspar) 2500 units/m² IV over 1 to 2 hours once on day 4 and 43.
• Vincristine (Oncovin) 1.5 mg/m² (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 43, and 50.
• Dexamethasone (Decadron) 5 mg/m² IV or PO twice per day on days 1 - 7 and 15 - 21.
• Cyclophosphamide (Cytoxan) 1000 mg/m² IV over 30 - 60 minutes once on day 29 ONLY.
• Cytarabine (Ara-C) 75 mg/m²/day SC or IV over 1 - 30 minutes on days 29 - 32 and 36 - 39.
• Thioguanine (Tabloid) 60 mg/m²/day PO once per day on days 29 to 42.

CNS prophylaxis

• Methotrexate (MTX) IT once per day on day 1, 29, and 36.

Age	Dose
1 - 1.99	8 mg
2 - 2.99	10 mg
3 - 8.99	12 mg
≥ 9	15 mg

56-Day course

References

1. 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 PubMed NCT02883049

Interim Maintenance II with Capizzi MTX

Regimen

Study	Evidence
Burke et al. 2019 (COG AALL1131)	Randomized portion of RCT

Chemotherapy

• Vincristine (Oncovin) 1.5 mg/m² (maximum dose of 2 mg) IV once per day on day 1, 11, 21, 31, and 41.
• Methotrexate (MTX) 100 mg/m² IV over 2 - 5 minutes (undiluted) or over 10 - 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) 2500 units/m² IV over 1 to 2 hours once on day 2 and 22.

CNS prophylaxis

• Methotrexate (MTX) IT once per day on days 1 and 31.

Age	Dose
1 - 1.99	8 mg
2 - 2.99	10 mg
3 - 8.99	12 mg
≥ 9	15 mg

56-Day course

References

1. 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 PubMed NCT02883049

VHR Arm Maintenance

Regimen

Study	Evidence
Burke et al. 2019 (COG AALL1131)	Randomized portion of RCT

Radiotherapy

For Patients with CNS3 Disease

• Total body irradiation (TBI) 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/dose PO once per day on days 1 - 84.
• Vincristine (Oncovin) 1.5 mg/m² (maximum dose of 2 mg) IV once per day on days 1, 29, and 57.
• Methotrexate (MTX) 20 mg/m² PO once on days 8, 15, 22, (29), 36, 43, 50, 57, 64, 71 and 78. (OMIT DAY 29 WHEN CNS RADIATION IS GIVEN, DUE TO IT MTX).
• Prednisone (Sterapred) 20 mg/m²/dose PO or IV (methylprednisolone given at 80% of the oral dose) twice per day on days 1 - 5, 29 - 33, and 57 - 61.

CNS 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	Dose
1 - 1.99	8 mg
2 - 2.99	10 mg
3 - 8.99	12 mg
≥ 9	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

1. 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 PubMed NCT02883049

Ph-Like B-ALL (Dasatinib Arm)

Consolidation (Dasatinib Arm)

Regimen

Study	Evidence
Burke et al. 2019 (COG AALL1131)	Randomized portion of RCT

Chemotherapy

• Cyclophosphamide (Cytoxan) 1000 mg/m² IV over 30 - 60 minutes once on days 1 and 29
• Cytarabine (Ara-C) 75 mg/m²/day SC or IV over 1 - 30 minutes on days 1 - 4, 8 - 11, 29 - 32, 36 - 39.
• Pegaspargase (Oncaspar) 2500 units/m² IV over 1 - 2 hours once on days 15, and 43.
• Vincristine (Oncovin) 1.5 mg/m² (maximum dose of 2 mg) IV once per day on days 15, 22, 43, and 50.
• Mercaptopurine (6-MP) 60 mg/m²/dose PO once per day on days 1 - 14, and 29 - 42.
• Dasatinib (Sprycel) 60 mg (rounded to the nearest 5 mg, max of 140 mg/day) PO once daily on days 1 to 56.

CNS prophylaxis

• Methotrexate (MTX) IT once per day on days 1, 8, 15, and 22.

Age	Dose
1 - 1.99	8 mg
2 - 2.99	10 mg
3 - 8.99	12 mg
≥ 9	15 mg

• Dasatinib (Sprycel) 60 mg (rounded to the nearest 5 mg, max of 140 mg/day) PO once daily on days 1 to 56.

56-Day Course

References

1. 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 PubMed NCT02883049
2. 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 contains verified protocol PubMed NCT01190930

Interim Maintenance with HD MTX (Dasatinib Arm)

Regimen

Study	Evidence
Burke et al. 2019 (COG AALL1131)	Randomized portion of RCT

Chemotherapy

• Vincristine (Oncovin) 1.5 mg/m² (maximum dose of 2 mg) IV once per day on days 1, 15, 29, and 43.
• Mercaptopurine (6-MP) 25 mg/m²/dose PO once per day on days 1 - 56.
• High Dose Methotrexate (MTX) 5000 mg/m² IV over 24 hours on days 1, 15, 29, and 43.
  • MTX 500 mg/m² IV infused over 30 minutes. This is followed, immediately, by MTX 4500 mg/m² given by continuous IV infusion over 23.5 hours.

ANC must be ≥ 750/µL and platelets must be ≥ 75,000/µL prior to each dose of HD MTX

• Folinic acid (Leucovorin) 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 - 4, 17 - 18, 31 - 32, and 45 - 46.
• Dasatinib (Sprycel) 60 mg (rounded to the nearest 5 mg, max of 140 mg/day) PO once daily on days 1 to 63.

CNS prophylaxis

• Methotrexate (MTX) IT once per day on days 1 and 29.

Age	Dose
1 - 1.99	8 mg
2 - 2.99	10 mg
3 - 8.99	12 mg
≥ 9	15 mg

When IT therapy and HD MTX are scheduled for the same day, deliver the IT therapy within 6 hours of the beginning of the IV MTX infusion. (hour -6 or +6, with 0 being the start of the MTX bolus). 

63-Day Course

References

1. 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 PubMed NCT02883049
2. 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 contains verified protocol PubMed NCT01190930

Delayed Intensification (Dasatinib Arm)

Regimen

Study	Evidence
Burke et al. 2019 (COG AALL1131)	Randomized portion of RCT

Chemotherapy

• Doxorubicin (Adriamycin) 25 mg/m² IV push over 1 to 15 minutes once per day on days 1, 8, and 15.
• Pegaspargase (Oncaspar) 2500 units/m² IV over 1 to 2 hours once on days 4 and 43.
• Vincristine (Oncovin) 1.5 mg/m² (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 43, and 50.
• Dexamethasone (Decadron) 5 mg/m² IV or PO twice per day on days 1 - 7 and 15 - 21.
• Cyclophosphamide (Cytoxan) 1000 mg/m² IV over 30 - 60 minutes once on day 29 ONLY.
• Cytarabine (Ara-C) 75 mg/m²/day SC or IV over 1 - 30 minutes on days 29 - 32 and 36 - 39.
• Thioguanine (Tabloid) 60 mg/m²/day PO once per day on days 29 to 42.
• Dasatinib (Sprycel) 60 mg (rounded to the nearest 5 mg, max of 140 mg/day) PO once daily on days 1 to 56.

CNS prophylaxis

• Methotrexate (MTX) IT once per day on days 1, 29, and 36.

Age	Dose
1 - 1.99	8 mg
2 - 2.99	10 mg
3 - 8.99	12 mg
≥ 9	15 mg

56-Day course

References

1. 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

Interim Maintenance II with Capizzi MTX (Dasatinib Arm)

Regimen

Study	Evidence
Burke et al. 2019 (COG AALL1131)	Randomized portion of RCT

Chemotherapy

• Vincristine (Oncovin) 1.5 mg/m² (maximum dose of 2 mg) IV once per day on day 1, 11, 21, 31, and 41.
• Methotrexate (MTX) 100 mg/m² IV over 2 - 5 minutes (undiluted) or over 10 - 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) 2500 units/m² IV over 1 to 2 hours once on day 2 and 22.
• Dasatinib (Sprycel) 60 mg (rounded to the nearest 5 mg, max of 140 mg/day) PO once daily on days 1 to 56.

CNS prophylaxis

• Methotrexate (MTX) IT once per day on days 1 and 31.

Age	Dose
1 - 1.99	8 mg
2 - 2.99	10 mg
3 - 8.99	12 mg
≥ 9	15 mg

56-Day course

References

1. 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 PubMed NCT02883049

Maintenance (Dasatinib Arm)

Regimen

Study	Evidence
Burke et al. 2019 (COG AALL1131)	Randomized portion of RCT

Radiotherapy

For Patients with CNS3 Disease

• Total body irradiation (TBI) 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/dose PO once per day on days 1 - 84.
• Vincristine (Oncovin) 1.5 mg/m² (maximum dose of 2 mg) IV once per day on days 1, 29, and 57.
• Methotrexate (MTX) 20 mg/m² PO once on days 8, 15, 22, (29), 36, 43, 50, 57, 64, 71 and 78. (OMIT DAY 29 WHEN CNS RADIATION IS GIVEN, DUE TO IT MTX).
• Prednisone (Sterapred) 20 mg/m²/dose PO or IV (methylprednisolone given at 80% of the oral dose) twice per day on days 1 - 5, 29 - 33, and 57 - 61.
• Dasatinib (Sprycel) 60 mg (rounded to the nearest 5 mg, max of 140 mg/day) PO once daily on days 1 to 84.

CNS 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	Dose
1 - 1.99	8 mg
2 - 2.99	10 mg
3 - 8.99	12 mg
≥ 9	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

1. 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 PubMed NCT02883049

DS HR B-ALL

Induction

Daunorubicin, Pegaspargase, Vincristine, Dexamethasone

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Regimen

Study	Evidence
Burke et al. 2019 (COG AALL1131)	Randomized portion of 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

• 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, and 22

Patients < 10 years ONLY:

• Dexamethasone (Decadron) 3 mg/m² IV or PO twice per day on days 1 to 28 (DO NOT TAPER)

Patients ≥ 10 years ONLY:

• Prednisone (Sterapred) 30 mg/m²/dose PO twice per day on days 1 to 28 (DO NOT TAPER)
• Folinic acid (Leucovorin) 5 mg/m² x 2 doses PO (given at 48 and 60 hours after the lumbar puncture) on days 10 - 11 and 31 - 32. (CNS3 also on days 17 - 18 and 24 - 25).

RER - M1 Marrow at Day 15

• Add Daunorubicin (Cerubidine) 50 mg/m² IV over 1 to 15 minutes once on days 15.

CNS prophylaxis

• Cytarabine (Ara-C) as follows:
  • Ages 1 to 1.99: 30 mg IT once on day 1
  • Ages 2 to 2.99: 50 mg IT once on day 1
  • Age 3 and older: 70 mg IT once on day 1

• Methotrexate (MTX) as follows:
  • Ages 1 to 1.99: 8 mg IT once per day on days 8 and 29 (CNS 3 also on days 15 and 22)
  • Ages 2 to 2.99: 10 mg IT once per day on days 8 and 29 (CNS 3 also on days 15 and 22)
  • Ages 3 to 8.99: 12 mg IT once per day on days 8 and 29 (CNS 3 also on days 15 and 22)
  • Age 9 and 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

References

1. 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 PubMed NCT02883049

Consolidation

Regimen

Study	Evidence
Burke et al. 2019 (COG AALL1131)	Randomized portion of RCT

Chemotherapy

• Cyclophosphamide (Cytoxan) 1000 mg/m² IV over 30 - 60 minutes once on days 1 and 29
• Cytarabine (Ara-C) 75 mg/m²/day SC or IV over 1 - 30 minutes on days 1 - 4, 8 - 11, 29 - 32, 36 - 39.
• Pegaspargase (Oncaspar) 2500 units/m² IV over 1 - 2 hours once on days 15, and 43.
• Vincristine (Oncovin) 1.5 mg/m² (maximum dose of 2 mg) IV once per day on days 15, 22, 43, and 50.
• Mercaptopurine (6-MP) 60 mg/m²/dose PO once per day on days 1 - 14, and 29 - 42.

CNS prophylaxis

• Methotrexate (MTX) IT once per day on days 1, 8, 15, and 22.

Age	Dose
1 - 1.99	8 mg
2 - 2.99	10 mg
3 - 8.99	12 mg
≥ 9	15 mg

DS Arm

• Folinic acid (Leucovorin) 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, and 24 - 25.

56-Day Course

References

1. 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 PubMed NCT02883049
2. 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 contains verified protocol PubMed NCT01190930

Interim Maintenance with ID MTX

Regimen

Study	Evidence
Burke et al. 2019 (COG AALL1131)	Randomized portion of RCT

Chemotherapy

• Vincristine (Oncovin) 1.5 mg/m² (maximum dose of 2 mg) IV once per day on days 1, 15, 29, and 43.
• Mercaptopurine (6-MP) 25 mg/m²/dose PO once per day on days 1 - 56.
• Intermediate Dose Methotrexate (MTX) 2000 mg/m² IV over 24 hours on days 1, 15, 29, and 43.
  • MTX 200 mg/m² IV infused over 30 minutes. This is followed, immediately, by MTX 1800 mg/m² given by continuous IV infusion over 23.5 hours.

ANC must be ≥ 750/µL and platelets must be ≥ 75,000/µL prior to each dose of HD MTX

• Folinic acid (Leucovorin) 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 ID MTX infusion) on days 2 - 3, 17 - 18, 31 - 32, and 45 - 46.

CNS prophylaxis

• Methotrexate (MTX) IT once per day on days 1 and 29.

Age	Dose
1 - 1.99	8 mg
2 - 2.99	10 mg
3 - 8.99	12 mg
≥ 9	15 mg

When IT therapy and HD MTX are scheduled for the same day, deliver the IT therapy within 6 hours of the beginning of the IV MTX infusion. (hour -6 or +6, with 0 being the start of the MTX bolus). 

63-Day Course

References

1. 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 PubMed NCT02883049
2. 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 contains verified protocol PubMed NCT01190930

Delayed Intensification

Regimen

Study	Evidence
Burke et al. 2019 (COG AALL1131)	Randomized portion of RCT

Chemotherapy

• Doxorubicin (Adriamycin) 25 mg/m² IV push over 1 to 15 minutes once per day on days 1, 8, and 15.
• Pegaspargase (Oncaspar) 2500 units/m² IV over 1 to 2 hours once on days 4 and 43.
• Vincristine (Oncovin) 1.5 mg/m² (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 43, and 50.
• Dexamethasone (Decadron) 5 mg/m² IV or PO twice per day on days 1 - 7 and 15 - 21.
• Cyclophosphamide (Cytoxan) 1000 mg/m² IV over 30 - 60 minutes once on day 29 ONLY.
• Cytarabine (Ara-C) 75 mg/m²/day SC or IV over 1 - 30 minutes on days 29 - 32 and 36 - 39.
• Thioguanine (Tabloid) 60 mg/m²/day PO once per day on days 29 to 42.
• Folinic acid (Leucovorin) 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, and 38 - 39.

CNS prophylaxis

• Methotrexate (MTX) IT once per day on days 1, 29, and 36.

Age	Dose
1 - 1.99	8 mg
2 - 2.99	10 mg
3 - 8.99	12 mg
≥ 9	15 mg

56-Day course

References

1. 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 PubMed NCT02883049

DS HR Arm Maintenance

Regimen

Study	Evidence
Burke et al. 2019 (COG AALL1131)	Randomized portion of RCT

Radiotherapy

For Patients with CNS3 Disease

• Total body irradiation (TBI) 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/dose PO once per day on days 1 - 84.
• Vincristine (Oncovin) 1.5 mg/m² (maximum dose of 2 mg) IV once per day on day 1 ONLY.
• Methotrexate (MTX) 20 mg/m² PO once on days 8, 15, 22, (29), 36, 43, 50, 57, 64, 71 and 78. (OMIT DAY 29 WHEN CNS RADIATION IS GIVEN, DUE TO IT MTX).
• Prednisone (Sterapred) 20 mg/m²/dose PO or IV (methylprednisolone given at 80% of the oral dose) twice per day on days 1 - 5.

CNS 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	Dose
1 - 1.99	8 mg
2 - 2.99	10 mg
3 - 8.99	12 mg
≥ 9	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

1. 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 PubMed NCT02883049

Prephase

Methylprednisolone monotherapy

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Regimen

Study	Years of enrollment	Evidence
Place et al. 2015 (DFCI 05-001)	2005-2011	Non-randomized portion of RCT
Burns et al. 2020 (DFCI 11-001)	2012-2015	Non-randomized portion of RCT

Note: Burns et al. 2020 is both an update of DFCI 05-001 and the primary publication of DFCI 11-001.

Chemotherapy

• 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 induction versus Doxorubicin, Methotrexate, Pegaspargase, Vincristine, Methylprednisolone induction
• DFCI 11-001: Calaspargase, Doxorubicin, Methotrexate, Vincristine, Methylprednisolone induction versus Doxorubicin, Methotrexate, Pegaspargase, Vincristine, Methylprednisolone induction

References

1. 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 PubMed NCT00400946
   1. 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 contains verified protocol in supplement PubMed
2. 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 contains verified protocol in supplement PubMed NCT01574274

Prednisone monotherapy

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Regimen

Study	Years of enrollment	Evidence
Möricke et al. 2016 (AIEOP-BFM ALL 2000)	2000-2006	Non-randomized portion of RCT

Chemotherapy

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

CNS 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

1. 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 contains verified protocol in supplement PubMed NCT00430118; NCT00613457

Vincristine & Prednisone

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VP: Vincristine & Prednisone

Regimen

Study	Years 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
• Prednisone (Sterapred) 40 mg/m²/day PO on days 1 to 21

21-day course

References

1. 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 contains verified protocol PubMed

Upfront induction therapy

Calaspargase, Daunorubicin, Vincristine, Prednisone

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Regimen

Study	Years 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

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
• 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

1. 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 contains verified protocol PubMed NCT00671034

Daunorubicin, Pegaspargase, Vincristine, Dexamethasone

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Regimen

Study	Evidence
Burke et al. 2019 (COG AALL1131)	Non-randomized portion of 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
• Dexamethasone (Decadron) 5 mg/m² IV or PO twice per day on days 1 to 14

CNS prophylaxis

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

4-week course

Subsequent treatment

• See protocol for details of treatment beyond induction

References

1. 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 PubMed NCT02883049

DOLP

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

Regimen variant #1, 25/6000/1.5/60

Study	Evidence
Seibel et al. 2008 (COG CCG-1961)	Non-randomized portion of RCT

Note: exact days were not specified for the L-asparaginase; suggested days are similar to those used in subsequent parts of the protocol.

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) 6000 units/m² IM once per day on days 3, 5, 7, 10, 12, 14, 17, 19, 21
• Prednisone (Sterapred) 60 mg/m²/day PO on days 1 to 28

CNS therapy

• Cytarabine (Ara-C) IT once on day 0 (dose not specified)
• Methotrexate (MTX) IT once per day on days 7 & 28 (dose not specified)

4-week course

Subsequent treatment

• Standard versus increased intensity post-remission therapy (see paper for details)

Regimen variant #2, 30/5000/1.5/60 ("Phase A" of ALL-BFM 95)

Study	Evidence
Möricke et al. 2008 (ALL-BFM 95)	Non-randomized

Note: see paper 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) 5000 units IV over 60 minutes once per day on days 12, 15, 18, 21, 24, 27, 30, 33
• 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, 12, 33

5-week course

Subsequent treatment

• See paper for details

Regimen variant #3, 30/10,000/1.5/60 ("Protocol I")

Study	Evidence
Schrappe et al. 2000 (ALL-BFM 90)	Non-randomized
Kamps et al. 2002 (DCLSG ALL-8)	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
• 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, 40/10,000/1.5/60 ("Induction Protocol I" of ALL-BFM 86)

Study	Evidence
Reiter et al. 1994 (ALL-BFM 86)	Non-randomized portion of RCT
Kamps et al. 1999 (DCLSG ALL-7)	Non-randomized portion 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
• L-Asparaginase 10,000 units/m² IV once per day on days 19, 22, 25, 28, 31, 34, 37, 40
• Prednisone (Sterapred) 60 mg/m²/day PO on days 1 to 28

6-week course

Subsequent treatment

• Induction phase II (see papers for details)

References

1. 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 contains verified protocol PubMed
2. 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 PubMed
3. 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 contains verified protocol PubMed
   1. 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 PubMed
4. 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 PubMed
5. 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. link to original article link to PMC article contains verified protocol PubMed
6. 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 contains verified protocol PubMed
   1. 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 PubMed

DOLP (Prednisolone)

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DOLP: Daunorubicin, Oncovin (Vincristine), L-Asparaginase, Prednisolone

Regimen variant #1, 30/10,000/1.5/60

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
de Moerloose et al. 2010 (EORTC CLG 58951)	1999-2002	Phase III (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
• 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	Evidence
Chessells et al. 1992 (UK MRC ALLX)	Non-randomized portion 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
• 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

1. 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 contains verified protocol PubMed
   1. 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 PubMed
2. 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 contains verified protocol PubMed NCT00003728
   1. 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 PubMed
   2. 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 PubMed

Doxorubicin, Mercaptopurine, Pegaspargase, Vincristine, Prednisolone

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Regimen

Study	Years of enrollment	Evidence
Albertsen et al. 2019 (NOPHO ALL2008)	2008-2016	Non-randomized portion of RCT

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) as follows:
  • Younger than 18: 2 mg/m² (maximum dose of 2.5 mg) IV once per day on days 1, 8, 15, 22, 29
  • 18 or older: 2 mg/m² (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22, 29
• 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 prophylaxis

• Methotrexate (MTX) as follows:
  • Ages 1 to 1.9: 8 mg IT once per day on days 1, 8, 15, 29
  • Ages 2 to 2.9: 10 mg IT once per day on days 1, 8, 15, 29
  • Age 3 and 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

1. 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 contains verified protocol in supplement PubMed NCT00819351

Doxorubicin, Methotrexate, Pegaspargase, Vincristine, Methylprednisolone

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Place et al. 2015 (DFCI 05-001)	2005-2011	Phase III (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 III (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
• Methylprednisolone (Solumedrol) 8 mg/m² IV three times per day on days 4 to 32

Supportive medications

• Dexrazoxane (Zinecard) 300 mg/m² IV once per day on days 4 & 5

28-day course

CNS 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

1. 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 PubMed NCT00400946
   1. 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 contains verified protocol in supplement PubMed
2. 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 contains verified protocol in supplement PubMed NCT01574274

Pegaspargase, Vincristine, Dexamethasone

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Regimen

Study	Years of enrollment	Evidence
Maloney et al. 2019 (COG AALL0331)	2005-2010	Non-randomized portion of RCT
Angiolillo et al. 2021 (COG AALL0932)	2010-2018	Non-randomized portion of 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
• Dexamethasone (Decadron) 3 mg/m² PO twice per day on days 1 to 28

CNS 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

1. 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 contains verified protocol PubMed NCT00103285
2. 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 contains verified protocol PubMed NCT01190930

Pegaspargase, Vincristine, Prednisone

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Regimen

Study	Years 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)
• Vincristine (Oncovin)
• Prednisone (Sterapred)

Subsequent treatment

• See protocol for details of treatment beyond induction

References

1. 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 PubMed

Early intensification therapy

Cyclophosphamide, Etoposide, Methotrexate

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Dreyer et al. 2014 (COG P9407)	2001-2006	Non-randomized
Brown et al. 2021 (COG AALL0631)	2008-2014	Phase III (C)	Cyclophosphamide, Etoposide, Lestaurtinib, Methotrexate	Did not meet primary endpoint of EFS

Biomarker eligibility criteria

• COG AALL0631: KMT2A rearrangement

Preceding treatment

• Induction

Chemotherapy

• Cyclophosphamide (Cytoxan) 300 mg/m² IV over 30 minutes once per day on days 15 to 19
• Etoposide (Vepesid) 100 mg/m² IV over 2 hours once per day on days 15 to 19
• Methotrexate (MTX) 200 mg/m² IV over 20 minutes, then 3800 mg/m² IV continuous infusion over 23 hours and 40 minutes on days 1 & 8 (total dose: 8000 mg/m²)

Subsequent treatment

• Reinduction

References

1. COG P9407: Dreyer ZE, Hilden JM, Jones TL, Devidas M, Winick NJ, Willman CL, Harvey RC, Chen IM, Behm FG, Pullen J, Wood BL, Carroll AJ, Heerema NA, Felix CA, Robinson B, Reaman GH, Salzer WL, Hunger SP, Carroll WL, Camitta BM. Intensified chemotherapy without SCT in infant ALL: results from COG P9407 (Cohort 3). Pediatr Blood Cancer. 2015 Mar;62(3):419-26. Epub 2014 Nov 14. link to original article link to PMC article PubMed NCT00002756
2. COG AALL0631: Brown PA, Kairalla JA, Hilden JM, Dreyer ZE, Carroll AJ, Heerema NA, Wang C, Devidas M, Gore L, Salzer WL, Winick NJ, Carroll WL, Raetz EA, Borowitz MJ, Small D, Loh ML, Hunger SP. FLT3 inhibitor lestaurtinib plus chemotherapy for newly diagnosed KMT2A-rearranged infant acute lymphoblastic leukemia: Children's Oncology Group trial AALL0631. Leukemia. 2021 May;35(5):1279-1290. Epub 2021 Feb 23. Erratum in: Leukemia. 2021 Apr 12. link to original article contains verified protocol in supplement PubMed NCT00557193

Mercaptopurine & Methotrexate

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Mahoney et al. 1998 (POG 9005)	1991-1993	Phase III (E-switch-ic)	LDMTX/IVMP	Seems to have superior CCR
Lauer et al. 2001 (POG 9006)	1991-1994	Phase III (C)	Intensive chemotherapy	Might have inferior EFS

Preceding treatment

• POG 9006: DOLP induction

Chemotherapy

• Mercaptopurine (6-MP)
• Methotrexate (MTX)

Subsequent treatment

• POG 9006: 6-MP & MTX maintenance

References

1. 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 PubMed
2. 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 PubMed

Consolidation after upfront therapy (including post-remission therapy)

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

AALL0232 consolidation

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Regimen

Study	Evidence
Larsen et al. 2016 (COG AALL0232)	Non-randomized portion of 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

1. 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 contains verified protocol PubMed NCT00075725

Augmented BFM consolidation

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Nachman et al. 1998	1991-1995	Phase III (E-esc)	Standard BFM consolidation	Seems to have superior OS

Unlikely to be completed, but of historic interest.

Chemotherapy

• Cyclophosphamide (Cytoxan)
• Cytarabine (Ara-C)
• Asparaginase (Elspar)
• Mercaptopurine (6-MP)
• Vincristine (Oncovin)

References

1. 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 PubMed

Cyclophosphamide & TBI, then allo HSCT

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Cy/TBI: Cyclophosphamide & Total Body Irradiation

Regimen

Study	Years of enrollment	Evidence
Thomas et al. 1979	1976-1977	Non-randomized

Details in most of the manuscripts are limited.

Chemotherapy

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

Radiotherapy

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

Immunotherapy

• Allogeneic stem cells transfused on day 0

One course

Immunotherapy

• Allogeneic stem cells

Stem cells transfused on day 0

References

1. Thomas ED, Sanders JE, Flournoy N, Johnson FL, Buckner CD, Clift RA, Fefer A, Goodell BW, Storb R, Weiden PL. Marrow transplantation for patients with acute lymphoblastic leukemia in remission. Blood. 1979 Aug;54(2):468-76. link to original article contains protocol PubMed

Etoposide & TBI, then allo HSCT

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Balduzzi et al. 2005	1995-2000	Quasi-randomized	Chemotherapy	Seems to have superior DFS
Peters et al. 2015 (ALL-SCT-BFM 2003)	2003-2011	Non-randomized

Chemotherapy

• Etoposide (Vepesid) 60 mg/kg (maximum dose of 3600 mg) IV once on day -3

Radiotherapy

• Total body irradiation (TBI) 200 cGy twice per day in 6 fractions on days -6 to -4 with lung shielding at 1000 cGy (total dose: 1200 cGy)

Immunotherapy

• Allogeneic stem cells transfused on day 0

One course

Immunotherapy

• Allogeneic stem cells

Stem cells transfused on day 0

References

1. 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 contains verified protocol PubMed
2. 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 PubMed

Mercaptopurine & Vincristine

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Regimen

Study	Years of enrollment	Evidence
Angiolillo et al. 2021 (COG AALL0932)	2010-2018	Non-randomized portion of 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 prophylaxis

• Methotrexate (MTX) IT once per day on days 1, 8, 15

28-day course

Subsequent treatment

• MTX & Vincristine interim maintenance

References

1. 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 contains verified protocol PubMed NCT01190930

Interim maintenance

Mercaptopurine, Methotrexate, Vincristine

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Larsen et al. 2016 (COG AALL0232)	2004-2011	Phase III (E-switch-ic)	Mercaptopurine, Capizzi MTX, Pegaspargase, Vincristine	Superior EFS

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

Intrathecal component

• Methotrexate (MTX) once per day on days 1 & 29

References

1. 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 contains verified protocol PubMed NCT00075725

Methotrexate & Vincristine

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Matloub et al. 2011 (COG CCG-1991)	2000-2005	Phase III (E-de-esc)	Mercaptopurine, MTX, Vincristine, Dexamethasone	Superior EFS
Angiolillo et al. 2021 (COG AALL0932)	2010-2018	Non-randomized portion of 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 prophylaxis

• Methotrexate (MTX) IT once on day 31

8-week course

Subsequent treatment

• COG AALL0932: AALL0932 delayed intensification

References

1. 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 PubMed NCT00005945
2. 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 contains verified protocol PubMed NCT01190930

Delayed intensification

AALL0932 delayed intensification

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Regimen

Study	Years of enrollment	Evidence
Angiolillo et al. 2021 (COG AALL0932)	2010-2018	Non-randomized portion of 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
• Dexamethasone (Decadron) 10 mg/m²/day PO on days 1 to 7, 15 to 21

CNS prophylaxis

• Methotrexate (MTX) IT once per day on days 1 & 29

8-week course

Subsequent treatment

• MTX & Vincristine interim maintenance II

References

1. 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 contains verified protocol PubMed NCT01190930

Interim maintenance II

Methotrexate & Vincristine

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Regimen

Study	Years of enrollment	Evidence
Angiolillo et al. 2021 (COG AALL0932)	2010-2018	Non-randomized portion of 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 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

1. 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 contains verified protocol PubMed NCT01190930

Maintenance after upfront therapy

Mercaptopurine & Methotrexate

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Millot et al. 2001 (EORTC 58881)	1990-1996	Phase III (C)	6-MP & MTX; IV 6-MP & PO MTX	Superior DFS1
Conter et al. 2007 (I-BFM-SG IR ALL)	1995-2000	Phase III (C)	D-OMP	Did not meet primary endpoint of DFS

¹Reported efficacy for EORTC 58881 is based on the 2005 update.

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

1. 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 PubMed
   1. 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 PubMed
   2. 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 PubMed
2. 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 contains verified protocol PubMed NCT00411541

Relapsed or refractory

Blinatumomab monotherapy

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Regimen

Study	Years of enrollment	Evidence
von Stackelberg et al. 2016 (MT103-205)	2012-2014	Phase I/II (RT)

Note: this is the MTD of a phase I/II 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

1. 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. link to original article contains verified protocol PubMed NCT01471782

CCE

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CCE: Clofarabine, Cyclophosphamide, Etoposide

Regimen

Study	Evidence
Locatelli et al. 2009	Non-randomized

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

Chemotherapy

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

• 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

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

Clofarabine monotherapy

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Regimen

Study	Years of enrollment	Evidence
Jeha et al. 2003	2000-2002	Phase 1, <20 pts (RT)
Jeha et al. 2006	2002-2004	Phase II (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

1. Phase 1: 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 PubMed
2. 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 contains protocol PubMed

DOLP

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

Regimen

Study	Evidence
Rivera et al. 1986	Non-randomized

Chemotherapy

• Daunorubicin (Cerubidine)
• Vincristine (Oncovin)
• Asparaginase (Elspar)
• Prednisone (Sterapred)

4-week course

Subsequent treatment

• See paper for details of treatment beyond induction

References

1. 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 PubMed

Doxorubicin, Pegaspargase, Vincristine, Prednisone

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Abshire et al. 2000 (POG 9310)	NR	Non-randomized
Raetz et al. 2008 (COG AALL01P2)	2003-2005	Non-randomized portion of RCT
Lew et al. 2021 (COG AALL0433)	2007-2013	Phase III (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.

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
• Prednisone (Sterapred) 40 mg/m²/day PO on days 1 to 29

CNS prophylaxis (CNS-)

• Methotrexate (MTX) once per day on days 8 & 29

CNS treatment (CNS+)

• Methotrexate (MTX)
• Cytarabine (Ara-C)
• Hydrocortisone (Cortef)

5-week course

Subsequent treatment

• See papers for details of treatment beyond induction block 1

References

1. 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 PubMed
2. 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 contains verified protocol PubMed
3. 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 protocol PubMed NCT00381680

Inotuzumab ozogamicin monotherapy

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Regimen

Study	Years of enrollment	Evidence
Kantarjian et al. 2012 (MDACC 2009-0872)	2010-2011	Phase II

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
  • For patients achieving CR or CRi, day 1 dose was reduced to 0.5 mg/m²

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

References

1. MDACC 2009-0872: Kantarjian H, Thomas D, Jorgensen J, Jabbour E, Kebriaei P, Rytting M, York S, Ravandi F, Kwari M, Faderl S, Rios MB, Cortes J, Fayad L, Tarnai R, Wang SA, Champlin R, Advani A, O'Brien S. Inotuzumab ozogamicin, an anti-CD22-calecheamicin conjugate, for refractory and relapsed acute lymphocytic leukaemia: a phase 2 study. Lancet Oncol. 2012 Apr;13(4):403-11. Epub 2012 Feb 21. link to original article contains protocol PubMed NCT01134575

Mitoxantrone, Asparaginase Erwinia chrysanthemi, Vincristine, Dexamethasone

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Parker et al. 2010 (CCLG ALL R3)	2003-2007	Phase III (E-switch-ic)	Idarubicin, Asparaginase Erwinia chrysanthemi, Vincristine, Dexamethasone	Superior OS

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
• Dexamethasone (Decadron) 20 mg/m² PO once per day on days 1 to 5, 15 to 19

CNS prophylaxis

• Methotrexate (MTX) as follows:
  • Age less than 2: 8 mg IT once per day on days 1 & 8
  • Age 2: 10 mg IT once per day on days 1 & 8
  • Age older than 2: 12 mg IT once per day on days 1 & 8

4-week course

Subsequent treatment

• See paper for details of treatment beyond induction

References

1. 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 contains verified protocol link to PMC article PubMed ISRCTN45724312

Mitoxantrone, Pegaspargase, Vincristine, Dexamethasone

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Parker et al. 2010 (CCLG ALL R3)	2003-2007	Phase III (E-switch-ic)	Idarubicin, Pegaspargase, Vincristine, Dexamethasone	Superior OS

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
• Dexamethasone (Decadron) 20 mg/m² PO once per day on days 1 to 5, 15 to 19

CNS prophylaxis

• Methotrexate (MTX) as follows:
  • Age less than 2: 8 mg IT once per day on days 1 & 8
  • Age 2: 10 mg IT once per day on days 1 & 8
  • Age older than 2: 12 mg IT once per day on days 1 & 8

4-week course

Subsequent treatment

• See paper for details of treatment beyond induction

References

1. 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 contains verified protocol link to PMC article PubMed ISRCTN45724312

Tisagenlecleucel monotherapy

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Regimen

Study	Years of enrollment	Evidence	Efficacy
Grupp et al. 2013 (Pedi CART19)	2011-NR	Pilot
Maude et al. 2014 (UPCC04409)	2012-2014	Phase I/IIa
Maude et al. 2018 (ELIANA)	2015-2017	Phase II (RT)	ORR: 81%

Note: dosing instructions are based on ELIANA.

Preceding treatment

• Lymphodepleting therapy with FC or CYVE

Immunotherapy

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

One course

References

1. 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 PubMed NCT01626495
2. UPCC04409: Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, Chew A, Gonzalez VE, Zheng Z, Lacey SF, Mahnke YD, Melenhorst JJ, Rheingold SR, Shen A, Teachey DT, Levine BL, June CH, Porter DL, Grupp SA. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014 Oct 16;371(16):1507-17. Erratum in: N Engl J Med. 2016 Mar 10;374(10):998. link to original article link to PMC article PubMed NCT01029366
3. ELIANA: Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, Bader P, Verneris MR, Stefanski HE, Myers GD, Qayed M, De Moerloose B, Hiramatsu H, Schlis K, Davis KL, Martin PL, Nemecek ER, Yanik GA, Peters C, Baruchel A, Boissel N, Mechinaud F, Balduzzi A, Krueger J, June CH, Levine BL, Wood P, Taran T, Leung M, Mueller KT, Zhang Y, Sen K, Lebwohl D, Pulsipher MA, Grupp SA. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018 Feb 1;378(5):439-448. link to original article link to supplementary protocol contains verified protocol in supplement link to PMC article PubMed NCT02435849

Consolidation after salvage therapy

Blinatumomab monotherapy

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Regimen variant #1, 1 cycle

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Locatelli et al. 2021 (Amgen 20120215)	2015-2019	Phase III (E-switch-ooc)	Standard salvage consolidation chemotherapy	Superior EFS

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

Regimen variant #2, 2 cycles

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

Note: insufficient dosing information was present in the abstract.

Immunotherapy

• Blinatumomab (Blincyto)

Subsequent treatment

• Allogeneic hematopoietic stem cell transplant

References

1. COG AALL1331: Brown PA, Ji L, Xu X, Devidas M, Hogan LE, Borowitz MJ, Raetz EA, Zugmaier G, Sharon E, Bernhardt MB, Terezakis SA, Gore L, Whitlock JA, Pulsipher MA, Hunger SP, Loh ML. Effect of Postreinduction Therapy Consolidation With Blinatumomab vs Chemotherapy on Disease-Free Survival in Children, Adolescents, and Young Adults With First Relapse of B-Cell Acute Lymphoblastic Leukemia: A Randomized Clinical Trial. JAMA. 2021 Mar 2;325(9):833-842. link to original article PubMed NCT02101853
2. 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 contains protocol PubMed NCT02393859

Cyclophosphamide & TBI, then allo HSCT

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Cy/TBI: Cyclophosphamide & Total Body Irradiation

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Johnson et al. 1981	1976-1980	Non-randomized
Kersey et al. 1987	1982-1985	Quasi-randomized	Auto HSCT	Superior RFS

Details in most of the manuscripts are limited.

Chemotherapy

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

Radiotherapy

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

Immunotherapy

• Allogeneic stem cells transfused on day 0

One course

Immunotherapy

• Allogeneic stem cells

Stem cells transfused on day 0

References

1. 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 PubMed
2. Kersey JH, Weisdorf D, Nesbit ME, LeBien TW, Woods WG, McGlave PB, Kim T, Vallera DA, Goldman AI, Bostrom B, Hurd D, Ramsay NKC. Comparison of autologous and allogeneic bone marrow transplantation for treatment of high-risk refractory acute lymphoblastic leukemia. N Engl J Med. 1987 Aug 20;317(8):461-7. link to original article PubMed

Further notes

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