B-cell acute lymphoblastic leukemia, pediatric

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 David Noyd, MD, MPH
University of Washington
Seattle, WA, USA
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This page contains studies that are specific to pediatric populations. For the more general B-cell acute lymphoblastic leukemia page, including regimens for adolescents and young adults, follow this link.
Are you looking for a regimen but can't find it here? It is possible that we've moved it to the historical regimens page.
Note: certain regimens are to be found on dedicated pages:

34 regimens on this page
39 variants on this page


Guidelines

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

NCCN

Upfront therapy

COG AALL0932 protocol for standard-risk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Matloub et al. 2011 (COG CCG-1991) 2000-2005 Phase 3 (E-de-esc) Mercaptopurine, MTX, Vincristine, Dexamethasone Superior EFS (co-primary endpoint)
Maloney et al. 2019 (COG AALL0331) 2005-2010 Non-randomized part of phase 3 RCT
Angiolillo et al. 2021 (COG AALL0932) 2010-2018 Non-randomized part of phase 3 RCT

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

Induction, Pegaspargase, Vincristine, Dexamethasone

Chemotherapy

Glucocorticoid therapy

CNS therapy, prophylaxis

Age in years, rounded to the nearest hundredth Initial Dose
1.00 to 1.99 30 mg
2.00 to 2.99 50 mg
3.00 or older 70 mg 
CNS2 Patients will receive an additional dose of cytarabine IT on either day 4, 5, or 6, followed by Methotrexate (MTX) IT on day 8 and then another dose of cytarabine IT on either day 11 or 12 according to the following dosing.
Age in years, rounded to the nearest hundredth Subsequent Doses
1.00 to 1.99 20 mg
2.00 to 2.99 30 mg
3.00 or older 40 mg
Age in years, rounded to the nearest hundredth Dose
1.00 to 1.99 8 mg
2.00 to 2.99 10 mg
3.00 to 8.99 12 mg
9.00 or older 15 mg

Supportive therapy, DS Arm

35-day course

Subsequent treatment

  • COG AALL0331, M2 marrow or M1 marrow with MRD of at least 1% at day 29: Extended induction
  • COG AALL0932: 6-MP & Vincristine consolidation

Consolidation, Mercaptopurine & Vincristine

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

Preceding treatment

Chemotherapy

CNS therapy, prophylaxis

Age in years, rounded to the nearest hundredth Dose
1.00 to 1.99 8 mg
2.00 to 2.99 10 mg
3.00 to 8.99 12 mg
9.00 or older 15 mg

Supportive therapy, DS Arm

28-day course

Subsequent treatment


Interim Maintenance, I (Methotrexate & Vincristine)

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

Preceding treatment

Chemotherapy

  • Methotrexate (MTX) 100 mg/m2 IV once on day 1, then 150 mg/m2 IV once on day 11, then 200 mg/m2 IV once on day 21, then 250 mg/m2 IV once on day 31, then 300 mg/m2 IV once on day 41
    • Given over 2 to 5 minutes (undiluted) or over 10 to 15 minutes (diluted).
  • Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 11, 21, 31, 41

CNS therapy, prophylaxis

Age in years, rounded to the nearest hundredth Dose
1.00 to 1.99 8 mg
2.00 to 2.99 10 mg
3.00 to 8.99 12 mg
9.00 or older 15 mg

Supportive therapy, DS Arm

8-week course, followed by:


Delayed Intensification

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

Preceding treatment

Chemotherapy

Glucocorticoid therapy

CNS therapy, prophylaxis

Age in years, rounded to the nearest hundredth Dose
1.00 to 1.99 8 mg
2.00 to 2.99 10 mg
3.00 to 8.99 12 mg
9.00 or older 15 mg

Supportive therapy, DS Arm

8-week course

Subsequent treatment


Interim Maintenance, II (Methotrexate & Vincristine)

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

Preceding treatment

Chemotherapy

  • Methotrexate (MTX) 100 mg/m2 IV once on day 1, then 150 mg/m2 IV once on day 11, then 200 mg/m2 IV once on day 21, then 250 mg/m2 IV once on day 31, then 300 mg/m2 IV once on day 41
    • Given over 2 to 5 minutes (undiluted) or over 10 to 15 minutes (diluted)
  • Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 11, 21, 31, 41

CNS therapy, prophylaxis

Age in years, rounded to the nearest hundredth Dose
1.00 to 1.99 8 mg
2.00 to 2.99 10 mg
3.00 to 8.99 12 mg
9.00 or older 15 mg

Supportive therapy, DS Arm

8-week course

Subsequent treatment


Maintenance, Arm A and C (Vincristine/Dexamethasone Pulses)

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

Preceding treatment

Chemotherapy

Glucocorticoid therapy

CNS therapy, prophylaxis

Age in years, rounded to the nearest hundredth Dose
1.00 to 1.99 8 mg
2.00 to 2.99 10 mg
3.00 to 8.99 12 mg
9.00 or older 15 mg

12-week cycles until total duration of therapy is 2 years for female and 3 years for male from the start of Interim I


Maintenance, Arm B and D (Vincristine/Dexamethasone Pulses)

Preceding treatment

Chemotherapy

  • Currently maintenance arm B and D are also treated with Methotrexate (MTX) PO at 20 mg/m2 (decreased from the starting dose of 40 mg/m2) on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78
  • Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 29, 57
  • Mercaptopurine (6-MP) 75 mg/m2 PO once per day on days 1 to 84

Glucocorticoid therapy

CNS therapy, prophylaxis

Age in years, rounded to the nearest hundredth Dose
1.00 to 1.99 8 mg
2.00 to 2.99 10 mg
3.00 to 8.99 12 mg
9.00 or older 15 mg

12-week cycles until total duration of therapy is 2 years for female and 3 years for male from the start of Interim I


Maintenance, Arm DS (Vincristine/Dexamethasone)

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

Preceding treatment

Chemotherapy

Glucocorticoid therapy

CNS therapy, prophylaxis

Age in years, rounded to the nearest hundredth Dose
1.00 to 1.99 8 mg
2.00 to 2.99 10 mg
3.00 to 8.99 12 mg
9.00 or older 15 mg

12-week cycles until total duration of therapy is 2 years for female and 3 years for male from the start of Interim I


Consolidation, Arm LR-M

Chemotherapy

Given as a 200 mg/m2 bolus over 20 to 30 minutes followed by 800 mg/m2 over 23.5 hours (initial bolus of 30 minutes) or 23.67 hours (if initial bolus was over 20 minutes)

Glucocorticoid therapy

Supportive therapy

  • Leucovorin (Folinic acid) 10 mg/m2 x 2 doses PO or IV (given 48 and 60 hours after the START of methotrexate infusion, continuing until methotrexate level less than 0.2 μM) on days 9, 10, 30, 31, 51, 52, 72, 73, 93, 94, 114, 115

CNS therapy, prophylaxis

  • Methotrexate (MTX) IT once on days 8, 29, 50, 71, 92, 113 (To be delivered within 6 hours of the beginning of the IV methotrexate infusion, -6hr to + 6 hr)
Age in years, rounded to the nearest hundredth Dose
1.00 to 1.99 8 mg
2.00 to 2.99 10 mg
3.00 to 8.99 12 mg
9.00 or older 15 mg

19-week cycle


Maintenance, Arm LR-M

Chemotherapy

  • Methotrexate (MTX) as follows:
    • Cycles 1 to 4: 20 mg/m2/day PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, 92, 99, 106
    • Cycles 2 & 5: 20 mg/m2/day PO on days 1, 8, 15, 22, 29, 36, 43, 50, 64, 71, 78, 85, 92, 99, 106
    • Cycles 3 & 6: 20 mg/m2/day PO on days 1, 8, 15, 22, 36, 43, 50, 57, 64, 71, 78, 85, 92, 99, 106
    • Cycle 7: 20 mg/m2/day PO on days 1, 8, 15, 29, 22, 36, 43, 50, 57, 64
  • Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1 & 8
  • Mercaptopurine (6-MP) 75 mg/m2 PO once per day on days 1 to 112 (NOTE: Higher 6-MP dose than in consolidation)

Glucocorticoid therapy

CNS therapy, prophylaxis

  • Methotrexate (MTX) as follows:
    • Cycles 1 to 4: IT once on day 1, 85
    • Cycles 2 & 5: IT once on day 57
    • Cycles 3 & 6: IT once on day 29
Age in years, rounded to the nearest hundredth Dose
1.00 to 1.99 8 mg
2.00 to 2.99 10 mg
3.00 to 8.99 12 mg
9.00 or older 15 mg

16-week cycles until a total duration of therapy of 2.5 years from the date of diagnosis is reached for both boys and girls.


Maintenance, Arm LLy (Vincristine/Dexamethasone)

Preceding treatment

Chemotherapy

Glucocorticoid therapy

CNS therapy, prophylaxis

Age in years, rounded to the nearest hundredth Dose
1.00 to 1.99 8 mg
2.00 to 2.99 10 mg
3.00 to 8.99 12 mg
9.00 or older 15 mg

12-week cycles until total duration of therapy is 2 years for female and 3 years for male from the start of Interim I

References

  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 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 PubMed
  3. 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 dosing details in manuscript link to PMC article PubMed NCT01190930

COG AALL1131 protocol

Induction, Daunorubicin, Pegaspargase, Vincristine, Dexamethasone

Study Evidence
Burke et al. 2019 (COG AALL1131) Non-randomized part of phase 3 RCT

Note: the referenced publication does not specifically focus on induction; the full regimen is available as a protocol. Per the protocol, it is intended only for patients less than 10 years old.

Chemotherapy

Glucocorticoid therapy

  • Dexamethasone (Decadron) by the following age-based criteria:
    • Younger than 10 years old: 5 mg/m2 IV or PO twice per day on days 1 to 14
    • 10 years old or older: Not given
  • Prednisone (Sterapred) by the following age-based criteria:
    • Younger than 10 years old: Not given
    • 10 years old or older: 30 mg/m2 PO twice per day on days 1 to 28

CNS therapy, prophylaxis

  • Cytarabine (Ara-C) by the following age-based criteria:
    • 1 to 1.99 years old: 30 mg IT once on day 1
    • 2 to 2.99 years old: 50 mg IT once on day 1
    • 3 years old or older: 70 mg IT once on day 1
CNS2 Patients will receive an additional dose of cytarabine IT on either day 4, 5, or 6, and then another dose of cytarabine IT on either day 11 or 12 according to the following dosing.
  • Cytarabine (Ara-C) by the following age-based criteria:
    • 1 to 1.99 years old: 20 mg IT once
    • 2 to 2.99 years old: 30 mg IT once
    • 3 years old or older: 40 mg IT once
  • Methotrexate (MTX) by the following age-based criteria: (CNS3 also on Days 15 and 22)
    • 1 to 1.99 years old: 8 mg IT once per day on days 8 & 29
    • 2 to 2.99 years old: 10 mg IT once per day on days 8 & 29
    • 3 to 8.99 years old: 12 mg IT once per day on days 8 & 29
    • 9 years old or older: 15 mg IT once per day on days 8 & 29

4-week course

Subsequent treatment

  • See protocol for details of treatment beyond induction

References

  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

COG AALL1131 protocol for HR B-ALL

Study Evidence
Burke et al. 2019 (COG AALL1131) Non-randomized part of phase 3 RCT

Consolidation, Cyclophosphamide, Cytarabine, Mercaptopurine, Pegaspargase, Vincristine

Chemotherapy

CNS therapy, prophylaxis

Age in years, rounded to the nearest hundredth Dose
1.00 to 1.99 8 mg
2.00 to 2.99 10 mg
3.00 to 8.99 12 mg
9.00 or older 15 mg

56-day course


Interim Maintenance, with HD MTX

Chemotherapy

  • Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 15, 29, 43
  • Mercaptopurine (6-MP) 25 mg/m2 PO once per day on days 1 to 56
  • High Dose Methotrexate (MTX) 500 mg/m2 IV over 30 minutes once per day on days 1, 15, 29, 43, then 4500 mg/m2 IV continuous infusion over 23.5 hours, started on days 1, 15, 29, 43
    • ANC must be at least 750/µL and platelets must be at least 75,000/µL prior to each dose of high dose MTX

Supportive therapy

  • Leucovorin (Folinic acid) 15 mg/m2 x a minimum of 3 doses PO or IV (given at 42, 48, and 54 hours after the START of high dose methotrexate infusion) on days 3 to 4, 17 to 18, 31 to 32, 45 to 46

CNS therapy, prophylaxis

Age in years, rounded to the nearest hundredth Dose
1.00 to 1.99 8 mg
2.00 to 2.99 10 mg
3.00 to 8.99 12 mg
9.00 or older 15 mg 
When IT methotrexate therapy and high dose methotrexate are scheduled for the same day, deliver the IT methotrexate within 6 hours of the beginning of the IV methotrexate infusion. (hour -6 or +6, with 0 being the start of the methotrexate bolus).

63-day course


Delayed Intensification

Chemotherapy

Glucocorticoid therapy

CNS therapy, prophylaxis

Age in years, rounded to the nearest hundredth Dose
1.00 to 1.99 8 mg
2.00 to 2.99 10 mg
3.00 to 8.99 12 mg
9.00 or older 15 mg

56-day course


Maintenance, HR B-ALL

Chemotherapy

  • Mercaptopurine (6-MP) as follows:
    • Cycles 1 to 4: 75 mg/m2 PO once per day on days 1 to 84
  • Vincristine (Oncovin) as follows:
    • Cycles 1 to 4: 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 29, 57
  • Methotrexate (MTX) as follows:
    • Cycles 1 to 4: 20 mg/m2 PO once per day on days 8, 15, 22, 36, 43, 50, 57, 64, 71, 78
    • Cycle 5 onwards: 20 mg/m2 PO once per day on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78

Glucocorticoid therapy

  • Prednisone (Sterapred) 20 mg/m2 PO or IV (methylprednisolone given at 80% of the oral dose) twice per day on days 1 to 5, 29 to 33, 57 to 61

CNS therapy, prophylaxis

  • Methotrexate (MTX) as follows:
    • Cycles 1 to 4: IT once per day on days 1, 29
    • Cycle 5 onwards: IT once per day on day 1
Age in years, rounded to the nearest hundredth Dose
1.00 to 1.99 8 mg
2.00 to 2.99 10 mg
3.00 to 8.99 12 mg
9.00 or older 15 mg

12-week cycles repeated until the total duration of therapy is 2 years for female patients and 3 years for male patients from the start of interim maintenance.

References

  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 outcomes for pediatric B-cell acute lymphoblastic leukemia: a report from the COG. Haematologica. 2019 May;104(5):986-992. Epub 2018 Dec 13. link to original article link to PMC article PubMed NCT02883049

COG AALL1131 protocol for VHR B-ALL

Study Evidence
Burke et al. 2019 (COG AALL1131) Non-randomized part of phase 3 RCT

Consolidation

Chemotherapy

CNS therapy, prophylaxis

  • Methotrexate (MTX) IT once per day on days 1, 8, 15, 22 (Omit days 15 and 22 for CNS3 Patients)
Age in years, rounded to the nearest hundredth Dose
1.00 to 1.99 8 mg
2.00 to 2.99 10 mg
3.00 to 8.99 12 mg
9.00 or older 15 mg

56-day course


Interim Maintenance, I with HD MTX

Chemotherapy

  • Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 15, 29, 43
  • Mercaptopurine (6-MP) 60 mg/m2 PO once per day on days 1 to 56
  • High Dose Methotrexate (MTX) 500 mg/m2 IV over 30 minutes once per day on days 1, 15, 29, 43, then 4500 mg/m2 IV continuous infusion over 23.5 hours, started on days 1, 15, 29, 43
    • ANC must be at least 750/µL and platelets must be at least 75,000/µL prior to each dose of high dose MTX

Supportive therapy

  • Leucovorin (Folinic acid) 15 mg/m2 x a minimum of 3 doses PO or IV (given at 42, 48, and 54 hours after the START of HD MTX infusion) on days 3 to 4, 17 to 18, 31 to 32, 45 to 46

CNS therapy, prophylaxis

Age in years, rounded to the nearest hundredth Dose
1.00 to 1.99 8 mg
2.00 to 2.99 10 mg
3.00 to 8.99 12 mg
9.00 or older 15 mg

28-day course


Delayed Intensification

Chemotherapy

Glucocorticoid therapy

CNS therapy, prophylaxis

Age in years, rounded to the nearest hundredth Dose
1.00 to 1.99 8 mg
2.00 to 2.99 10 mg
3.00 to 8.99 12 mg
9.00 or older 15 mg

56-day course


Interim Maintenance, II with Capizzi MTX

Chemotherapy

  • Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on day 1, 11, 21, 31, 41
  • Methotrexate (MTX) 100 mg/m2 IV over 2 to 5 minutes (undiluted) or over 10 to 15 minutes (diluted) on days 1, 150 mg/m2 on day 11, 200 mg/m2 on day 21, 250 mg/m2 on day 31, and 300 mg/m2 on day 41
  • Pegaspargase (Oncaspar) 2,500 units/m2 IV over 1 to 2 hours once on day 2, 22

CNS therapy, prophylaxis

Age in years, rounded to the nearest hundredth Dose
1.00 to 1.99 8 mg
2.00 to 2.99 10 mg
3.00 to 8.99 12 mg
9.00 or older 15 mg

56-day course


Maintenance, VHR Arm

Radiotherapy

  • Total body irradiation (TBI) by the following risk-based criteria:
    • CNS3: 1800 cGy in 10 fractions, during the first 4 weeks of Maintenance therapy and should be completed by day 29 of Maintenance

Chemotherapy

  • Mercaptopurine (6-MP) 75 mg/m2 PO once per day on days 1 to 84
  • Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 29, 57
  • Methotrexate (MTX) 20 mg/m2 PO once per day on days 8, 15, 22, (29), 36, 43, 50, 57, 64, 71, 78 (OMIT DAY 29 WHEN CNS RADIATION IS GIVEN, DUE TO IT MTX)

Glucocorticoid therapy

  • Prednisone (Sterapred) 20 mg/m2 PO or IV (methylprednisolone given at 80% of the oral dose) twice per day on days 1 to 5, 29 to 33, 57 to 61

CNS therapy, prophylaxis

  • Methotrexate (MTX) IT once per day on day 1 (also Day 29 of cycles 1 and 2, for patients who did NOT receive CNS Radiation)
Age in years, rounded to the nearest hundredth Dose
1.00 to 1.99 8 mg
2.00 to 2.99 10 mg
3.00 to 8.99 12 mg
9.00 or older 15 mg

12-week cycles repeated until total duration of therapy is 2 years for female patients and 3 years for male patients from the start of interim maintenance.

References

  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 outcomes for pediatric B-cell acute lymphoblastic leukemia: a report from the COG. Haematologica. 2019 May;104(5):986-992. Epub 2018 Dec 13. link to original article link to PMC article PubMed NCT02883049

COG AALL1131 protocol for Ph-like B-ALL (Dasatinib Arm)

Study Evidence
Burke et al. 2019 (COG AALL1131) Non-randomized part of phase 3 RCT

Consolidation

Chemotherapy

Targeted therapy

  • Dasatinib (Sprycel) 60 mg/m2 (rounded to the nearest 5 mg, maximum dose of 140 mg/day) PO once per day on days 1 to 56

CNS therapy, prophylaxis

Age in years, rounded to the nearest hundredth Dose
1.00 to 1.99 8 mg
2.00 to 2.99 10 mg
3.00 to 8.99 12 mg
9.00 or older 15 mg

56-day course


Interim Maintenance, with HD MTX

Chemotherapy

  • Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 15, 29, 43
  • Mercaptopurine (6-MP) 25 mg/m2 PO once per day on days 1 to 56.
  • High Dose Methotrexate (MTX) 500 mg/m2 IV over 30 minutes once per day on days 1, 15, 29, 43, then 4500 mg/m2 IV continuous infusion over 23.5 hours, started on days 1, 15, 29, 43
    • ANC must be at least 750/µL and platelets must be at least 75,000/µL prior to each dose of high dose MTX

Targeted therapy

  • Dasatinib (Sprycel) 60 mg/m2 (rounded to the nearest 5 mg, maximum dose of 140 mg/day) PO once per day on days 1 to 63

Supportive therapy

  • Leucovorin (Folinic acid) 15 mg/m2 for a minimum of 3 doses PO or IV (given at 42, 48, and 54 hours after the START of high dose methotrexate infusion) on days 3, 4, 17, 18, 31, 32, 45, 46

CNS therapy, prophylaxis

Age in years, rounded to the nearest hundredth Dose
1.00 to 1.99 8 mg
2.00 to 2.99 10 mg
3.00 to 8.99 12 mg
9.00 or older 15 mg 
When IT methotrexate therapy and high dose methotrexate are scheduled for the same day, deliver the IT therapy within 6 hours of the beginning of the IV methotrexate infusion. (hour -6 or +6, with 0 being the start of the methotrexate bolus).

63-day course


Delayed Intensification

Chemotherapy

Targeted therapy

  • Dasatinib (Sprycel) 60 mg/m2 (rounded to the nearest 5 mg, maximum dose of 140 mg/day) PO once per day on days 1 to 56

Glucocorticoid therapy

CNS therapy, prophylaxis

Age in years, rounded to the nearest hundredth Dose
1.00 to 1.99 8 mg
2.00 to 2.99 10 mg
3.00 to 8.99 12 mg
9.00 or older 15 mg

56-day course


Interim Maintenance, II with Capizzi MTX

Chemotherapy

  • Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on day 1, 11, 21, 31, 41
  • Methotrexate (MTX) 100 mg/m2 IV over 2 to 5 minutes (undiluted) or over 10 to 15 minutes (diluted) on days 1, 150 mg/m2 on day 11, 200 mg/m2 on day 21, 250 mg/m2 on day 31, and 300 mg/m2 on day 41
  • Pegaspargase (Oncaspar) 2,500 units/m2 IV over 1 to 2 hours once on day 2, 22

Targeted therapy

  • Dasatinib (Sprycel) 60 mg/m2 (rounded to the nearest 5 mg, maximum dose of 140 mg/day) PO once per day on days 1 to 56

CNS therapy, prophylaxis

Age in years, rounded to the nearest hundredth Dose
1.00 to 1.99 8 mg
2.00 to 2.99 10 mg
3.00 to 8.99 12 mg
9.00 or older 15 mg

56-day course


Maintenance

Radiotherapy

  • Total body irradiation (TBI) by the following risk-based criteria:
    • CNS3: 1800 cGy in 10 fractions, during the first 4 weeks of Maintenance therapy and should be completed by day 29 of Maintenance

Chemotherapy

  • Mercaptopurine (6-MP) 75 mg/m2 PO once per day on days 1 to 84
  • Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 29, 57
  • Methotrexate (MTX) 20 mg/m2 PO once per day on days 8, 15, 22, (29), 36, 43, 50, 57, 64, 71, 78 (OMIT DAY 29 WHEN CNS RADIATION IS GIVEN, DUE TO IT MTX)

Glucocorticoid therapy

  • Prednisone (Sterapred) 20 mg/m2 PO or IV (methylprednisolone given at 80% of the oral dose) twice per day on days 1 to 5, 29 to 33, 57 to 61

Targeted therapy

  • Dasatinib (Sprycel) 60 mg/m2 (rounded to the nearest 5 mg, maximum of 140 mg/day) PO once per day on days 1 to 84

CNS therapy, prophylaxis

  • Methotrexate (MTX) IT once per day on day 1 (also Day 29 of cycles 1 and 2, for patients who did NOT receive CNS Radiation)
Age in years, rounded to the nearest hundredth Dose
1.00 to 1.99 8 mg
2.00 to 2.99 10 mg
3.00 to 8.99 12 mg
9.00 or older 15 mg

12-week cycles repeated until total duration of therapy is 2 years for female patients and 3 years for male patients from the start of interim maintenance.

References

  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

COG AALL1131 protocol for DS HR B-ALL

Study Evidence
Burke et al. 2019 (COG AALL1131) Non-randomized part of phase 3 RCT

Note: the referenced publication does not specifically focus on induction; the full regimen is available as a protocol. Per the protocol, it is intended only for patients less than 10 years old.

Induction, Daunorubicin, Pegaspargase, Vincristine, Dexamethasone

Chemotherapy

RER - M1 Marrow at Day 15

Glucocorticoid therapy

  • Dexamethasone (Decadron) by the following age-based criteria:
    • Younger than 10 years old: 3 mg/m2 IV or PO twice per day on days 1 to 28 (DO NOT TAPER)
    • 10 years old or older: Not given
  • Prednisone (Sterapred) by the following age-based criteria:
    • Younger than 10 years old: Not given
    • 10 years old or older: 30 mg/m2 PO twice per day on days 1 to 28 (DO NOT TAPER)

Supportive therapy

  • Leucovorin (Folinic acid) 5 mg/m2 x 2 doses PO (given at 48 and 60 hours after the lumbar puncture) on days 10, 11, 31, 32 (CNS3 also on days 17, 18, 24, 25)

CNS therapy, prophylaxis

  • Cytarabine (Ara-C) by the following age-based criteria:
    • 1 to 1.99 years old: 30 mg IT once on day 1
    • 2 to 2.99 years old: 50 mg IT once on day 1
    • 3 years old or older: 70 mg IT once on day 1
  • Methotrexate (MTX) by the following age-based criteria:
    • 1 to 1.99 years old: 8 mg IT once per day on days 8 and 29 (CNS 3 also on days 15 and 22)
    • 2 to 2.99 years old: 10 mg IT once per day on days 8 and 29 (CNS 3 also on days 15 and 22)
    • 3 to 8.99 years old: 12 mg IT once per day on days 8 and 29 (CNS 3 also on days 15 and 22)
    • 9 years old or older: 15 mg IT once per day on days 8 and 29 (CNS 3 also on days 15 and 22)

4-week course

Subsequent treatment

  • See protocol for details of treatment beyond induction

Consolidation

Chemotherapy

CNS therapy, prophylaxis

Age in years, rounded to the nearest hundredth Dose
1.00 to 1.99 8 mg
2.00 to 2.99 10 mg
3.00 to 8.99 12 mg
9.00 or older 15 mg 
DS Arm

Supportive therapy

  • Leucovorin (Folinic acid) 5 mg/m2 x 2 doses PO (given at 48 and 60 hours after the lumbar puncture) on days 3, 4, 10, 11, 17, 18, 24, 25

56-day course


Interim Maintenance, with ID MTX

Chemotherapy

  • Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 15, 29, 43
  • Mercaptopurine (6-MP) 25 mg/m2/dose PO once per day on days 1 to 56
  • Intermediate Dose Methotrexate (MTX) 200 mg/m2 IV over 30 minutes once per day on days 1, 15, 29, 43, then 1800 mg/m2 IV continuous infusion over 23.5 hours, started on days 1, 15, 29, 43
    • ANC must be at least 750/µL and platelets must be at least 75,000/µL prior to each dose of high dose MTX

Supportive therapy

  • Leucovorin (Folinic acid) 15 mg/m2 x a minimum of 5 doses PO or IV (given at 30, 36, 42, 48, and 54 hours after the START of intermediate dose methotrexate infusion) on days 2, 3, 17, 18, 31, 32, 45, 46

CNS therapy, prophylaxis

Age in years, rounded to the nearest hundredth Dose
1.00 to 1.99 8 mg
2.00 to 2.99 10 mg
3.00 to 8.99 12 mg
9.00 or older 15 mg 
When IT methotrexate therapy and high dose methotrexate are scheduled for the same day, deliver the IT therapy within 6 hours of the beginning of the IV methotrexate infusion. (hour -6 or +6, with 0 being the start of the methotrexate bolus).

63-day course


Delayed Intensification

Chemotherapy

Glucocorticoid therapy

Supportive therapy

  • Leucovorin (Folinic acid) 5 mg/m2 x 2 doses PO or IV (given at 48, and 60 hours after the lumbar puncture) on days 3, 4, 31, 32, 38, 39

CNS therapy, prophylaxis

Age in years, rounded to the nearest hundredth Dose
1.00 to 1.99 8 mg
2.00 to 2.99 10 mg
3.00 to 8.99 12 mg
9.00 or older 15 mg

56-day course


Maintenance, DS HR Arm

Radiotherapy

  • Total body irradiation (TBI) by the following risk-based criteria:
    • CNS3: 1800 cGy in 10 fractions, during the first 4 weeks of Maintenance therapy and should be completed by day 29 of Maintenance

Chemotherapy

Glucocorticoid therapy

  • Prednisone (Sterapred) 20 mg/m2 PO or IV (methylprednisolone given at 80% of the oral dose) twice per day on days 1 to 5

CNS therapy, prophylaxis

  • Methotrexate (MTX) IT once per day on day 1 (also Day 29 of cycles 1 and 2, for patients who did NOT receive CNS Radiation)
Age in years, rounded to the nearest hundredth Dose
1.00 to 1.99 8 mg
2.00 to 2.99 10 mg
3.00 to 8.99 12 mg
9.00 or older 15 mg

12-week cycles repeated until total duration of therapy is 2 years for female patients and 3 years for male patients from the start of interim maintenance.

References

  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

Pre-phase

Methylprednisolone monotherapy

Regimen

Study Dates of enrollment Evidence
Place et al. 2015 (DFCI 05-001) 2005-2011 Non-randomized part of phase 3 RCT
Burns et al. 2020 (DFCI 11-001) 2012-2015 Non-randomized part of phase 3 RCT

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

Glucocorticoid therapy

3-day course

Subsequent treatment

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 dosing details in supplement link to PMC article 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 dosing details in supplement link to PMC article PubMed NCT01574274
    1. Update: Vrooman LM, Blonquist TM, Stevenson KE, Supko JG, Hunt SK, Cronholm SM, Koch V, Kay-Green S, Athale UH, Clavell LA, Cole PD, Harris MH, Kelly KM, Laverdiere C, Leclerc JM, Michon B, Place AE, Schorin MA, Welch JJG, Neuberg DS, Sallan SE, Silverman LB. Efficacy and Toxicity of Pegaspargase and Calaspargase Pegol in Childhood Acute Lymphoblastic Leukemia: Results of DFCI 11-001. J Clin Oncol. 2021 Nov 1;39(31):3496-3505. Epub 2021 Jul 6. link to original article PubMed

Prednisone monotherapy

Regimen

Study Dates of enrollment Evidence
Möricke et al. 2016 (AIEOP-BFM ALL 2000) 2000-2006 Non-randomized part of phase 3 RCT

Glucocorticoid therapy

CNS therapy, prophylaxis

7-day course

Subsequent treatment

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 dosing details in supplement PubMed NCT00430118; NCT00613457

Vincristine & Prednisone

VP: Vincristine & Prednisone

Regimen

Study Dates of enrollment Evidence
Sallan et al. 1978 1973-1977 Non-randomized

Note: this regimen is of historic interest as an induction regimen; it is still occasionally used as pre-phase in patients too ill to get cytotoxic chemotherapy at time of diagnosis.

Chemotherapy

Glucocorticoid therapy

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 dosing details in manuscript PubMed

Upfront induction therapy

Calaspargase, Daunorubicin, Vincristine, Prednisone

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Angiolillo et al. 2014 (COG AALL07P4) 2008-2010 Randomized (E-RT-switch-ic) Daunorubicin, Pegaspargase, Vincristine, Prednisone Longer half-life (primary endpoint)

Chemotherapy

Glucocorticoid therapy

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 dosing details in manuscript PubMed NCT00671034

Daunorubicin, Pegaspargase, Vincristine, Dexamethasone

Regimen

Study Evidence
Burke et al. 2019 (COG AALL1131) Non-randomized part of phase 3 RCT

Note: the referenced publication does not specifically focus on induction; the full regimen is available as a protocol. Per the protocol, it is intended only for patients less than 10 years old.

Chemotherapy

Glucocorticoid therapy

CNS therapy, prophylaxis

  • Cytarabine (Ara-C) by the following age-based criteria:
    • 1 to 1.99 years old: 30 mg IT once on day 1
    • 2 to 2.99 years old: 50 mg IT once on day 1
    • 3 years old or older: 70 mg IT once on day 1
  • Methotrexate (MTX) by the following age-based criteria:
    • 1 to 1.99 years old: 8 mg IT once per day on days 8 & 29
    • 2 to 2.99 years old: 10 mg IT once per day on days 8 & 29
    • 3 to 8.99 years old: 12 mg IT once per day on days 8 & 29
    • 9 years old or older: 15 mg IT once per day on days 8 & 29

4-week course

Subsequent treatment

  • See protocol for details of treatment beyond induction

References

  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

Daunorubicin, Pegaspargase, Vincristine, Prednisone

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Angiolillo et al. 2014 (COG AALL07P4) 2008-2010 Randomized (C) Calaspargase, Daunorubicin, Vincristine, Prednisone Shorter half-life (primary endpoint)

Chemotherapy

Glucocorticoid therapy

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 dosing details in manuscript PubMed NCT00671034

DOLP

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

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

Study Dates of enrollment Evidence
Seibel et al. 2007 (COG CCG-1961) 1996-2002 Non-randomized part of phase 3 RCT
Termuhlen et al. 2012 (COG A5971) 2000-2005 Non-randomized part of phase 3 RCT

Note: COG A5971 was intended for patients with localized lymphoblastic lymphoma, of which 75% had B-cell immunophenotype. Exact days were not specified for the L-asparaginase; suggested days are similar to those used in other protocols. COG CCG-1961 did not specify a tapering schedule for prednisone, and did not cap vincristine.

Chemotherapy

Glucocorticoid therapy

CNS therapy

  • Cytarabine (Ara-C) by the following age-based criteria:
    • 1 to 1.99 years old: 30 mg IT once on day 0
    • 2 to 2.99 years old: 50 mg IT once on day 0
    • 3 years old or older: 70 mg IT once on day 0
  • Methotrexate (MTX) by the following age-based criteria:
    • 1 to 1.99 years old: 8 mg IT once per day on days 7 & 28
    • 2 to 2.99 years old: 10 mg IT once per day on days 7 & 28
    • 3 years old or older: 12 mg IT once per day on days 7 & 28

5-week course

Subsequent treatment

  • COG CCG-1961: Standard versus increased intensity post-remission therapy (see paper for details)
  • COG A5971: Consolidation (see paper for details)


Regimen variant #2, 30/1.5/5000/60 ("Phase A" of ALL-BFM 95; "Phase 1" of ALL IC-BFM 2002; "Phase IA" of ALL IC-BFM 2009)

Study Dates of enrollment Evidence
Möricke et al. 2008 (ALL-BFM 95) 1995-2000 Non-randomized
Stary et al. 2013 (ALL IC-BFM 2002) 2002-2007 Non-randomized part of phase 3 RCT
Campbell et al. 2023 (ALL IC-BFM 2009) 2010-06 to 2018-03 Non-randomized part of phase 3 RCT

Note: see papers for details on dose adjustments based on risk. For example, in ALL IC-BFM 2002, days 22 & 29 of daunorubicin were omitted for standard risk B-cell precursor acute lymphoblastic leukemia.

Chemotherapy

Glucocorticoid therapy

CNS therapy

5-week course

Subsequent treatment


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

Glucocorticoid therapy

CNS therapy

5-week course

Subsequent treatment

  • See papers for details


Regimen variant #4, 40/1.5/10,000/60 ("Induction Protocol I" of ALL-BFM 86)

Study Dates of enrollment Evidence
Reiter et al. 1994 (ALL-BFM 86) 1986-10 to 1990-03 Non-randomized part of RCT
Kamps et al. 1999 (DCLSG ALL-7) 1988-07 to 1991-10 Non-randomized part of RCT

Chemotherapy

Glucocorticoid therapy

6-week course

Subsequent treatment

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 dosing details in manuscript 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 dosing details in manuscript 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. Epub 2007 Nov 26. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00002812
  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 dosing details in manuscript 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
  7. COG A5971: Termuhlen AM, Smith LM, Perkins SL, Lones M, Finlay JL, Weinstein H, Gross TG, Abromowitch M. Outcome of newly diagnosed children and adolescents with localized lymphoblastic lymphoma treated on Children's Oncology Group trial A5971: a report from the Children's Oncology Group. Pediatr Blood Cancer. 2012 Dec 15;59(7):1229-33. Epub 2012 Apr 5. link to original article contains dosing details in supplement PubMed NCT00004228
  8. ALL IC-BFM 2002: Stary J, Zimmermann M, Campbell M, Castillo L, Dibar E, Donska S, Gonzalez A, Izraeli S, Janic D, Jazbec J, Konja J, Kaiserova E, Kowalczyk J, Kovacs G, Li CK, Magyarosy E, Popa A, Stark B, Jabali Y, Trka J, Hrusak O, Riehm H, Masera G, Schrappe M. Intensive chemotherapy for childhood acute lymphoblastic leukemia: results of the randomized intercontinental trial ALL IC-BFM 2002. J Clin Oncol. 2014 Jan 20;32(3):174-84. Epub 2013 Dec 16. link to original article contains dosing details in manuscript PubMed NCT00764907
  9. ALL IC-BFM 2009: Campbell M, Kiss C, Zimmermann M, Riccheri C, Kowalczyk J, Felice MS, Kuzmanovic M, Kovacs G, Kosmidis H, Gonzalez A, Bilic E, Castillo L, Kolenova A, Jazbec J, Popa A, Konstantinov D, Kappelmayer J, Szczepanski T, Dworzak M, Buldini B, Gaipa G, Marinov N, Rossi J, Nagy A, Gaspar I, Stary J, Schrappe M. Childhood Acute Lymphoblastic Leukemia: Results of the Randomized Acute Lymphoblastic Leukemia Intercontinental-Berlin-Frankfurt-Münster 2009 Trial. J Clin Oncol. 2023 Jul 1;41(19):3499-3511. Epub 2023 May 4. link to original article contains dosing details in manuscript PubMed EudraCT 2010-019722-13

DOLP (Prednisolone)

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

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

Study Dates of enrollment Evidence Comparator Comparative Efficacy
de Moerloose et al. 2010 (EORTC CLG 58951) 1999-2002 Phase 3 (C) Daunorubicin, L-Asparaginase, Vincristine, Dexamethasone Did not meet primary endpoint of EFS

Note: see paper for details on CNS therapy and dose adjustments based on risk; these instructions include a 7-day pre-phase and are for AR1 patients.

Chemotherapy

Glucocorticoid therapy

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 part of RCT

Note: exact days for L-asparaginase were not specified in the protocol.

Chemotherapy

Glucocorticoid therapy

29-day course

Subsequent treatment

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 dosing details in manuscript 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 dosing details in manuscript 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

Regimen

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

Note: See protocol for initiation dependencies of 6-MP and pegaspargase.

Chemotherapy

  • Doxorubicin (Adriamycin) 40 mg/m2 IV over 4 hours once per day on days 1 & 22
  • Mercaptopurine (6-MP) 25 mg/m2 PO once per day on days 30 to 35
  • Pegaspargase (Oncaspar) 1000 units/m2 IM once on day 30
  • Vincristine (Oncovin) by the following age-based criteria:
    • Younger than 18 years old: 2 mg/m2 (maximum dose of 2.5 mg) IV once per day on days 1, 8, 15, 22, 29
    • 18 years old or older: 2 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22, 29

Glucocorticoid therapy

  • Prednisolone (Millipred) 20 mg/m2 PO three times per day on days 1 to 29, then 10 mg/m2 PO three times per day on days 30 to 32, then 5 mg/m2 PO three times per day on days 33 to 35, then 2.5 mg/m2 PO three times per day on days 36 to 38

CNS therapy, prophylaxis

  • Methotrexate (MTX) by the following age-based criteria:
    • 1 to 1.9 years old: 8 mg IT once per day on days 1, 8, 15, 29
    • 2 to 2.9 years old: 10 mg IT once per day on days 1, 8, 15, 29
    • 3 years old or older: 12 mg IT once per day on days 1, 8, 15, 29

5-week course

Subsequent treatment

  • See protocol for details of treatment beyond induction

References

  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 dosing details in supplement PubMed NCT00819351

Doxorubicin, Methotrexate, Pegaspargase, Vincristine, Methylprednisolone

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Place et al. 2015 (DFCI 05-001) 2005-2011 Phase 3 (E-switch-ic) Doxorubicin, L-asparaginase, Methotrexate, Vincristine, Methylprednisolone Did not meet secondary endpoint of DFS Less anxiety
Burns et al. 2020 (DFCI 11-001) 2012-2015 Phase 3 (C) Calaspargase, Doxorubicin, Methotrexate, Vincristine, Methylprednisolone Not reported

Note: Burns et al. 2020 is both an update of DFCI 05-001 and the primary publication of DFCI 11-001. Day numbering takes into account the pre-phase.

Preceding treatment

Chemotherapy

Glucocorticoid therapy

Supportive therapy

28-day course

CNS therapy, prophylaxis

Subsequent treatment

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 dosing details in supplement link to PMC article 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 dosing details in supplement link to PMC article PubMed NCT01574274
    1. Update: Vrooman LM, Blonquist TM, Stevenson KE, Supko JG, Hunt SK, Cronholm SM, Koch V, Kay-Green S, Athale UH, Clavell LA, Cole PD, Harris MH, Kelly KM, Laverdiere C, Leclerc JM, Michon B, Place AE, Schorin MA, Welch JJG, Neuberg DS, Sallan SE, Silverman LB. Efficacy and Toxicity of Pegaspargase and Calaspargase Pegol in Childhood Acute Lymphoblastic Leukemia: Results of DFCI 11-001. J Clin Oncol. 2021 Nov 1;39(31):3496-3505. Epub 2021 Jul 6. link to original article PubMed

Pegaspargase, Vincristine, Dexamethasone

Regimen

Study Dates of enrollment Evidence
Maloney et al. 2019 (COG AALL0331) 2005-2010 Non-randomized part of phase 3 RCT
Angiolillo et al. 2021 (COG AALL0932) 2010-2018 Non-randomized part of phase 3 RCT

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

Chemotherapy

Glucocorticoid therapy

CNS therapy, prophylaxis

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 dosing details in manuscript 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 dosing details in manuscript link to PMC article PubMed NCT01190930

Pegaspargase, Vincristine, Prednisone

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Avramis et al. 2002 (CCG 1962) 1997-1998 Randomized (E-RT-switch-ic) L-Asparaginase, Vincristine, Prednisone Did not meet secondary endpoint of EFS

Note: the primary endpoint of CCG 1962 was incidence of high-titer ASNase antibodies in the first dose intensification, which is neither an efficacy nor a toxicity endpoint.

Chemotherapy

Glucocorticoid therapy

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

Mercaptopurine & Methotrexate

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Mahoney et al. 1998 (POG 9005) 1991-1993 Phase 3 (E-switch-ic) 6-MP & MTX; LDMTX/IVMP Seems to have superior CCR
Lauer et al. 2001 (POG 9006) 1991-1994 Phase 3 (C) Intensive chemotherapy Might have inferior EFS

Preceding treatment

Chemotherapy

  • Mercaptopurine (6-MP) 1000 mg/m2 IV over 6 hours once on day 1, then 50 mg/m2 PO once per day on days 8 to 14
  • Methotrexate (MTX) 1000 mg/m2 IV continuous infusion over 24 hours, started on day 1, then 20 mg/m2 IM once on day 8

Supportive therapy

  • Leucovorin (Folinic acid) 5 mg/m2 (route not specified) every 6 hours for at least 5 doses, started 48 hours after start of methotrexate and continued until methotrexate level less than 0.1 Lmol/L

14-day cycle for 12 cycles

Subsequent treatment

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 contains dosing details in manuscript 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

Regimen

Study Dates of enrollment Evidence
Larsen et al. 2016 (COG AALL0232) 2004-2011 Non-randomized part of phase 3 RCT

Chemotherapy

50-day course

Subsequent treatment

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 dosing details in manuscript PubMed NCT00075725

Augmented BFM consolidation

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Nachman et al. 1998 1991-1995 Phase 3 (E-esc) Standard BFM consolidation Seems to have superior OS

Note: Unlikely to be completed, but of historic interest.

Chemotherapy

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

Cy/TBI: Cyclophosphamide & Total Body Irradiation

Regimen

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

Details in most of the manuscripts are limited.

Chemotherapy

Radiotherapy

  • Total body irradiation by the following study-specific criteria:
    • Zhang et al. 2023: 4.5 Gy once per day on days -5 & -4 (9 Gy total)
    • Other studies: 10 to 12 Gy total

Immunotherapy

References

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

Etoposide & TBI, then allo HSCT

Regimen

Study Dates 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

Radiotherapy

Immunotherapy

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 dosing details in manuscript 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 NCT01423747

Mercaptopurine & Vincristine

Regimen

Study Dates of enrollment Evidence
Angiolillo et al. 2021 (COG AALL0932) 2010-2018 Non-randomized part of phase 3 RCT

Preceding treatment

Chemotherapy

CNS therapy, prophylaxis

28-day course

Subsequent treatment

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 dosing details in manuscript link to PMC article PubMed NCT01190930

Interim maintenance

Mercaptopurine, Methotrexate, Vincristine

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Larsen et al. 2016 (COG AALL0232) 2004-2011 Phase 3 (E-switch-ic) 6-MP, Capizzi MTX, Pegaspargase, Vincristine Superior EFS (primary endpoint)

Chemotherapy

CNS therapy

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 dosing details in manuscript PubMed NCT00075725

Methotrexate & Vincristine

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Matloub et al. 2011 (COG CCG-1991) 2000-2005 Phase 3 (E-de-esc) 6-MP, MTX, Vincristine, Dexamethasone Superior EFS (co-primary endpoint)
Angiolillo et al. 2021 (COG AALL0932) 2010-2018 Non-randomized part of phase 3 RCT

Preceding treatment

Chemotherapy

  • Methotrexate (MTX) 100 mg/m2 IV once on day 1, then 150 mg/m2 IV once on day 11, then 200 mg/m2 IV once on day 21, then 250 mg/m2 IV once on day 31, then 300 mg/m2 IV once on day 41
  • Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 11, 21, 31, 41

CNS therapy, prophylaxis

8-week course

Subsequent treatment

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 dosing details in manuscript link to PMC article PubMed NCT01190930

Delayed intensification

AALL0932 delayed intensification

Regimen

Study Dates of enrollment Evidence
Angiolillo et al. 2021 (COG AALL0932) 2010-2018 Non-randomized part of phase 3 RCT

Preceding treatment

Chemotherapy

Glucocorticoid therapy

CNS therapy, prophylaxis

8-week course

Subsequent treatment

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 dosing details in manuscript link to PMC article PubMed NCT01190930

Interim maintenance II

Methotrexate & Vincristine

Regimen

Study Dates of enrollment Evidence
Angiolillo et al. 2021 (COG AALL0932) 2010-2018 Non-randomized part of phase 3 RCT

Note: starting dose of the systemic MTX is 2/3 of the MTD from interim maintenance I; dosage below assumes that the final maximum dose was tolerated.

Preceding treatment

Chemotherapy

  • Methotrexate (MTX) 200 mg/m2 IV once on day 1, then 250 mg/m2 IV once on day 11, then 300 mg/m2 IV once on day 21, then 350 mg/m2 IV once on day 31, then 400 mg/m2 IV once on day 41
  • Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 11, 21, 31, 41

CNS therapy, prophylaxis

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 dosing details in manuscript link to PMC article PubMed NCT01190930

Maintenance after upfront therapy

Mercaptopurine & Methotrexate

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Millot et al. 2001 (EORTC 58881) 1990-1996 Phase 3 (C) 6-MP & MTX; IV 6-MP & PO MTX Superior DFS1
Conter et al. 2007 (I-BFM-SG IR ALL) 1995-2000 Phase 3 (C) D-OMP Did not meet primary endpoint of DFS
Qiu et al. 2023 (GD-ALL-2008) 2008-02-28 to 2016-06-30 Phase 3 (C) 6-MP & MTX with Vincristine & Dexamethasone pulses Did not meet primary endpoint of EFS120a

1Reported efficacy for EORTC 58881 is based on the 2005 update.
aThe subgroup with high-risk (HR) ALL randomized to this arm had inferior EFS; see paper for details.

Preceding treatment

  • I-BFM-SG IR ALL: BFM re-induction

Chemotherapy

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 dosing details in manuscript PubMed NCT00411541
  3. GD-ALL-2008: Qiu KY, Wang JY, Huang LB, Li CG, Xu LH, Liu RY, Chen HQ, Ruan YS, Zhen ZJ, Li CK, Fang JP. Vincristine and dexamethasone pulses in addition to maintenance therapy among pediatric acute lymphoblastic leukemia (GD-ALL-2008): An open-label, multicentre, randomized, phase III clinical trial. Am J Hematol. 2023 Jun;98(6):869-880. Epub 2023 Mar 17. link to original article contains dosing details in manuscript PubMed NCT00846703

Observation

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Yang et al. 2021 (CCCG-ALL-2015) 2015-2020 Phase 3 (E-de-esc) Vincristine & Dexamethasone Non-inferior EFS60 (primary endpoint)

No active maintenance treatment beyond 1 year. Patients in this study were required to be in continuous remission for 1 year after initial treatment.

References

  1. CCCG-ALL-2015: Yang W, Cai J, Shen S, Gao J, Yu J, Hu S, Jiang H, Fang Y, Liang C, Ju X, Wu X, Zhai X, Tian X, Wang N, Liu A, Jiang H, Jin R, Sun L, Yang M, Leung AWK, Pan K, Zhang Y, Chen J, Zhu Y, Zhang H, Li C, Yang JJ, Cheng C, Li CK, Tang J, Zhu X, Pui CH. Pulse therapy with vincristine and dexamethasone for childhood acute lymphoblastic leukaemia (CCCG-ALL-2015): an open-label, multicentre, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2021 Sep;22(9):1322-1332. Epub 2021 Jul 27. link to original article link to PMC article PubMed ChiCTR-IPR-14005706

Relapsed or refractory

Blinatumomab monotherapy

Regimen

Study Dates of enrollment Evidence
von Stackelberg et al. 2016 (MT103-205) 2012-2014 Phase 1/2 (RT)

Note: this is the MTD of a phase 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. Epub 2016 Oct 31. link to original article contains dosing details in manuscript PubMed NCT01471782

CCE

CCE: Clofarabine, Cyclophosphamide, Etoposide

Regimen

Study Evidence
Locatelli et al. 2009 Non-randomized

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

Chemotherapy

Supportive therapy

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

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

References

  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 dosing details in manuscript PubMed

Clofarabine monotherapy

Regimen

Study Dates of enrollment Evidence
Jeha et al. 2003 2000-2002 Phase 1, fewer than 20 pts (RT)
Jeha et al. 2006 (CLO212) 2002-2004 Phase 2 (RT)

Note: this dose was the MTD in Jeha et al. 2003.

Chemotherapy

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

References

  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. CLO212: Jeha S, Gaynon PS, Razzouk BI, Franklin J, Kadota R, Shen V, Luchtman-Jones L, Rytting M, Bomgaars LR, Rheingold S, Ritchey K, Albano E, Arceci RJ, Goldman S, Griffin T, Altman A, Gordon B, Steinherz L, Weitman S, Steinherz P. Phase II study of clofarabine in pediatric patients with refractory or relapsed acute lymphoblastic leukemia. J Clin Oncol. 2006 Apr 20;24(12):1917-23. link to original article contains dosing details in abstract PubMed NCT00042341

DOLP

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

Regimen

Study Evidence
Rivera et al. 1986 Non-randomized

Chemotherapy

Glucocorticoid therapy

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

Regimen

Study Dates 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 part of phase 2 RCT
Lew et al. 2021 (COG AALL0433) 2007-2013 Phase 3 (C) Doxorubicin, Pegaspargase, Vincristine, Prednisone; high-dose vincristine Not reported

Note: This is "Block 1" of re-induction. Randomization in COG AALL0433 was discontinued early due to high rates of neuropathy in the experimental arm.

Chemotherapy

Glucocorticoid therapy

CNS therapy, prophylaxis (CNS-)

CNS therapy, treatment (CNS+)

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 dosing details in manuscript PubMed NCT00049569
  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 dosing details PubMed NCT00381680

Inotuzumab ozogamicin monotherapy

Regimen

Study Dates of enrollment Evidence
Kantarjian et al. 2012 (MDACC 2009-0872) 2010-2011 Phase 2

Antibody-drug conjugate therapy

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

Dose and schedule modifications

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

References

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

Mitoxantrone, Asparaginase Erwinia chrysanthemi, Vincristine, Dexamethasone

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Parker et al. 2010 (CCLG ALL R3) 2003-2007 Phase 3 (E-switch-ic) 1a. Idarubicin, Asparaginase Erwinia chrysanthemi, Vincristine, Dexamethasone
1b. Idarubicin, Pegaspargase, Vincristine, Dexamethasone 		Superior OS (secondary endpoint)
OS36: 69% vs 45.2%
(HR 0.56, 95% CI 0.36-0.87)

Note: per the protocol, this regimen is intended only for patients 18 and younger. This regimen is for patients allergic to pegaspargase.

Chemotherapy

Glucocorticoid therapy

CNS therapy, prophylaxis

  • Methotrexate (MTX) by the following age-based criteria:
    • Younger than 2 years old: 8 mg IT once per day on days 1 & 8
    • 2 years old: 10 mg IT once per day on days 1 & 8
    • Older than 2 years old: 12 mg IT once per day on days 1 & 8

4-week course

Subsequent treatment

  • See paper for details of treatment beyond induction

References

  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 dosing details in manuscript link to PMC article PubMed NCT00967057

Mitoxantrone, Pegaspargase, Vincristine, Dexamethasone

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Parker et al. 2010 (CCLG ALL R3) 2003-2007 Phase 3 (E-switch-ic) 1a. Idarubicin, Asparaginase Erwinia chrysanthemi, Vincristine, Dexamethasone
1b. Idarubicin, Pegaspargase, Vincristine, Dexamethasone 		Superior OS (secondary endpoint)
OS36: 69% vs 45.2%
(HR 0.56, 95% CI 0.36-0.87)

Note: per the protocol, this regimen is intended only for patients 18 and younger.

Chemotherapy

Glucocorticoid therapy

CNS therapy, prophylaxis

  • Methotrexate (MTX) by the following age-based criteria:
    • Younger than 2 years old: 8 mg IT once per day on days 1 & 8
    • 2 years old: 10 mg IT once per day on days 1 & 8
    • Older than 2 years old: 12 mg IT once per day on days 1 & 8

4-week course

Subsequent treatment

  • See paper for details of treatment beyond induction

References

  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 dosing details in manuscript link to PMC article PubMed NCT00967057

Tisagenlecleucel monotherapy

Regimen

Study Dates of enrollment Evidence Efficacy
Grupp et al. 2013 (Pedi CART19) 2011-NR Pilot
Maude et al. 2014 (UPCC04409) 2012-2014 Phase 1/2a
Maude et al. 2018 (ELIANA) 2015-2017 Phase 2 (RT) ORR: 81%

Note: dosing instructions are based on ELIANA.

Preceding treatment

  • Lymphodepleting therapy with FC or CYVE

Immunotherapy

  • Tisagenlecleucel (Kymriah) by the following weight-based criteria:
    • Up to 50 kg: 2 to 5 x 106 CTL019 transduced viable T-cells per kg body weight IV once on day 0
    • More than 50 kg: 1.0 to 2.5 x 108 CTL019 transduced viable T-cells IV once on day 0

One course

References

  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 dosing details in supplement link to PMC article PubMed NCT02435849
    1. Update: Laetsch TW, Maude SL, Rives S, Hiramatsu H, Bittencourt H, Bader P, Baruchel A, Boyer M, De Moerloose B, Qayed M, Buechner J, Pulsipher MA, Myers GD, Stefanski HE, Martin PL, Nemecek E, Peters C, Yanik G, Khaw SL, Davis KL, Krueger J, Balduzzi A, Boissel N, Tiwari R, O'Donovan D, Grupp SA. Three-Year Update of Tisagenlecleucel in Pediatric and Young Adult Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia in the ELIANA Trial. J Clin Oncol. 2023 Mar 20;41(9):1664-1669. Epub 2022 Nov 18. link to original article link to PMC article PubMed

Consolidation after salvage therapy

Blinatumomab monotherapy

Regimen variant #1, 1 cycle

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Locatelli et al. 2021 (Amgen 20120215) 2015-2019 Phase 3 (E-RT-switch-ooc) Standard salvage consolidation chemotherapy Superior EFS (primary endpoint)
EFS24: 66.2% vs 27.1%
(HR 0.33, 95% CI 0.18-0.61)

Immunotherapy

  • Blinatumomab (Blincyto) 15 mcg/m2/day IV continuous infusion over 28 days, started on day 1 (total dose: 420 mcg/m2)

42-day course

Subsequent treatment


Regimen variant #2, 2 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Brown et al. 2021 (COG AALL1331) 2014-2019 Phase 3 (E-RT-switch-ooc) Standard salvage consolidation chemotherapy Might have superior DFS (primary endpoint)
DFS24: 54.4% vs 39%
(HR 0.70, 95% CI 0.47-1.03)
Hogan et al. 2023 (COG AALL1331 LR relapse) 2014-01 to 2019-09 Phase 3 (E-switch-ooc) Standard salvage consolidation chemotherapy Did not meet primary endpoint of DFS

Note: pediatric dosing information is not available in the body of the manuscript.

Preceding treatment

Immunotherapy

Subsequent treatment

References

  1. COG AALL1331: Brown PA, Ji L, Xu X, Devidas M, Hogan LE, Borowitz MJ, Raetz EA, Zugmaier G, Sharon E, Bernhardt MB, Terezakis SA, Gore L, Whitlock JA, Pulsipher MA, Hunger SP, Loh ML. Effect of Postreinduction Therapy Consolidation With Blinatumomab vs Chemotherapy on Disease-Free Survival in Children, Adolescents, and Young Adults With First Relapse of B-Cell Acute Lymphoblastic Leukemia: A Randomized Clinical Trial. JAMA. 2021 Mar 2;325(9):833-842. link to original article link to PMC article 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 dosing details in abstract link to PMC article PubMed NCT02393859
  3. COG AALL1331 LR relapse: Hogan LE, Brown PA, Ji L, Xu X, Devidas M, Bhatla T, Borowitz MJ, Raetz EA, Carroll A, Heerema NA, Zugmaier G, Sharon E, Bernhardt MB, Terezakis SA, Gore L, Whitlock JA, Hunger SP, Loh ML. Children's Oncology Group AALL1331: Phase III Trial of Blinatumomab in Children, Adolescents, and Young Adults With Low-Risk B-Cell ALL in First Relapse. J Clin Oncol. 2023 Sep 1;41(25):4118-4129. Epub 2023 May 31. link to original article PubMed NCT02101853

Cyclophosphamide & TBI, then allo HSCT

Cy/TBI: Cyclophosphamide & Total Body Irradiation

Regimen

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

Details in most of the manuscripts are limited.

Chemotherapy

Radiotherapy

  • Total body irradiation by the following study-specific criteria:
    • Zhang et al. 2023: 4.5 Gy once per day on days -5 & -4 (9 Gy total)
    • Other studies: 10 to 12 Gy total

Immunotherapy

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
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