B-cell acute lymphoblastic leukemia, pediatric
Section editor | |
---|---|
David Noyd, MD, MPH University of Washington Seattle, WA, USA |
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
- NCCN does not have guidelines at this granular level; please see NCCN Guidelines - Pediatric Acute Lymphoblastic Leukemia.
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
- Pegaspargase (Oncaspar) 2,500 units/m2 IV once over 1 to 2 hours on day 4
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
Glucocorticoid therapy
- Dexamethasone (Decadron) 3 mg/m2 IV or PO twice per day on days 1 to 28
CNS therapy, prophylaxis
- Cytarabine (Ara-C) IT once on day 0
Age in years, rounded to the nearest hundredth | Initial Dose |
---|---|
1.00 to 1.99 | 30 mg |
2.00 to 2.99 | 50 mg |
3.00 or older | 70 mg |
CNS2 Patients will receive an additional dose of cytarabine IT on either day 4, 5, or 6, followed by Methotrexate (MTX) IT on day 8 and then another dose of cytarabine IT on either day 11 or 12 according to the following dosing.
Age in years, rounded to the nearest hundredth | Subsequent Doses |
---|---|
1.00 to 1.99 | 20 mg |
2.00 to 2.99 | 30 mg |
3.00 or older | 40 mg |
- Methotrexate (MTX) IT once per day on days 8, 29
Age in years, rounded to the nearest hundredth | Dose |
---|---|
1.00 to 1.99 | 8 mg |
2.00 to 2.99 | 10 mg |
3.00 to 8.99 | 12 mg |
9.00 or older | 15 mg |
Supportive therapy, DS Arm
- Leucovorin (Folinic acid) 5 mg/m2 PO x 2 doses given 48 and 60 hours after the lumbar puncture on days 10, 11, 31, 32
35-day course
Subsequent treatment
- COG AALL0331, M2 marrow or M1 marrow with MRD of at least 1% at day 29: Extended induction
- COG AALL0932: 6-MP & Vincristine consolidation
Consolidation, Mercaptopurine & Vincristine
For AR B-ALL patients, LR-C Arm, and B-LLy
Preceding treatment
- Pegaspargase, Vincristine, Dexamethasone induction
Chemotherapy
- Mercaptopurine (6-MP) 75 mg/m2/day PO on days 1 to 28
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once on day 1
CNS therapy, prophylaxis
- Methotrexate (MTX) IT once per day on days 1, 8, 15
Age in years, rounded to the nearest hundredth | Dose |
---|---|
1.00 to 1.99 | 8 mg |
2.00 to 2.99 | 10 mg |
3.00 to 8.99 | 12 mg |
9.00 or older | 15 mg |
Supportive therapy, DS Arm
- Leucovorin (Folinic acid) 5 mg/m2 PO x 2 doses given 48 and 60 hours after the lumbar puncture on days 3, 4, 10, 11, 17, 18.
28-day course
Subsequent treatment
- MTX & Vincristine interim maintenance
Interim Maintenance, I (Methotrexate & Vincristine)
For AR B-ALL patients, LR-C Arm, and B-LLy
Preceding treatment
- COG AALL0932: 6-MP & Vincristine consolidation
Chemotherapy
- Methotrexate (MTX) 100 mg/m2 IV once on day 1, then 150 mg/m2 IV once on day 11, then 200 mg/m2 IV once on day 21, then 250 mg/m2 IV once on day 31, then 300 mg/m2 IV once on day 41
- Given over 2 to 5 minutes (undiluted) or over 10 to 15 minutes (diluted).
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 11, 21, 31, 41
CNS therapy, prophylaxis
- Methotrexate (MTX) IT once on day 31
Age in years, rounded to the nearest hundredth | Dose |
---|---|
1.00 to 1.99 | 8 mg |
2.00 to 2.99 | 10 mg |
3.00 to 8.99 | 12 mg |
9.00 or older | 15 mg |
Supportive therapy, DS Arm
- Leucovorin (Folinic acid) 5 mg/m2 PO x 2 doses given 48 and 60 hours after the lumbar puncture on days 33, 34
8-week course, followed by:
Delayed Intensification
For AR B-ALL patients, LR-C Arm, and B-LLy
Preceding treatment
- MTX & Vincristine interim maintenance
Chemotherapy
- Cyclophosphamide (Cytoxan) 1000 mg/m2 IV over 30 to 60 minutes once on day 29
- Cytarabine (Ara-C) 75 mg/m2 SC or IV over 1 to 30 minutes on days 29 to 32, 36 to 39
- Doxorubicin (Adriamycin) 25 mg/m2 IV push/infusion over 1 to 15 minutes once per day on days 1, 8, 15
- Pegaspargase (Oncaspar) 2,500 units/m2 IV over 1 to 2 hours once on day 4
- Thioguanine (Tabloid) 60 mg/m2 PO once per day on days 29 to 42
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 8, 15
Glucocorticoid therapy
- Dexamethasone (Decadron) 5 mg/m2/dose PO twice per day on days 1 to 7, 15 to 21 (10 mg/m2/day)
CNS therapy, prophylaxis
- Methotrexate (MTX) IT once per day on days 1 & 29
Age in years, rounded to the nearest hundredth | Dose |
---|---|
1.00 to 1.99 | 8 mg |
2.00 to 2.99 | 10 mg |
3.00 to 8.99 | 12 mg |
9.00 or older | 15 mg |
Supportive therapy, DS Arm
- Leucovorin (Folinic acid) 5 mg/m2 PO x 2 doses given 48 and 60 hours after the lumbar puncture on days 3 to 4, 31 to 32
8-week course
Subsequent treatment
- MTX & Vincristine interim maintenance II
Interim Maintenance, II (Methotrexate & Vincristine)
For AR B-ALL patients, LR-C Arm, and B-LLy
Preceding treatment
- COG AALL0932: 6-MP & Vincristine consolidation
Chemotherapy
- Methotrexate (MTX) 100 mg/m2 IV once on day 1, then 150 mg/m2 IV once on day 11, then 200 mg/m2 IV once on day 21, then 250 mg/m2 IV once on day 31, then 300 mg/m2 IV once on day 41
- Given over 2 to 5 minutes (undiluted) or over 10 to 15 minutes (diluted)
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 11, 21, 31, 41
CNS therapy, prophylaxis
- Methotrexate (MTX) IT once on day 31
Age in years, rounded to the nearest hundredth | Dose |
---|---|
1.00 to 1.99 | 8 mg |
2.00 to 2.99 | 10 mg |
3.00 to 8.99 | 12 mg |
9.00 or older | 15 mg |
Supportive therapy, DS Arm
- Leucovorin (Folinic acid) 5 mg/m2 PO x 2 doses given 48 and 60 hours after the lumbar puncture on days 3 to 4, 33 to 34
8-week course
Subsequent treatment
- COG AALL0932: AALL0932 delayed intensification
Maintenance, Arm A and C (Vincristine/Dexamethasone Pulses)
For AR B-ALL patients, and LR-C Arm
Preceding treatment
- COG AALL0932: MTX & Vincristine interim maintenance
Chemotherapy
- Methotrexate (MTX) 20 mg/m2 PO once per day on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 29, 57
- Mercaptopurine (6-MP) 75 mg/m2 PO once per day on days 1 to 84
Glucocorticoid therapy
- Dexamethasone (Decadron) 3 mg/m2 PO twice per day on days 1 to 5, 29 to 33, 57 to 61 (6 mg/m2/day)
CNS therapy, prophylaxis
- Methotrexate (MTX) IT once on day 1
Age in years, rounded to the nearest hundredth | Dose |
---|---|
1.00 to 1.99 | 8 mg |
2.00 to 2.99 | 10 mg |
3.00 to 8.99 | 12 mg |
9.00 or older | 15 mg |
12-week cycles until total duration of therapy is 2 years for female and 3 years for male from the start of Interim I
Maintenance, Arm B and D (Vincristine/Dexamethasone Pulses)
Preceding treatment
- COG AALL0932: MTX & Vincristine interim maintenance
Chemotherapy
- Currently maintenance arm B and D are also treated with Methotrexate (MTX) PO at 20 mg/m2 (decreased from the starting dose of 40 mg/m2) on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 29, 57
- Mercaptopurine (6-MP) 75 mg/m2 PO once per day on days 1 to 84
Glucocorticoid therapy
- Dexamethasone (Decadron) 3 mg/m2 PO twice per day on days 1 to 5, 29 to 33, 57 to 61
CNS therapy, prophylaxis
- Methotrexate (MTX) IT once on day 1
Age in years, rounded to the nearest hundredth | Dose |
---|---|
1.00 to 1.99 | 8 mg |
2.00 to 2.99 | 10 mg |
3.00 to 8.99 | 12 mg |
9.00 or older | 15 mg |
12-week cycles until total duration of therapy is 2 years for female and 3 years for male from the start of Interim I
Maintenance, Arm DS (Vincristine/Dexamethasone)
For DS AR B-ALL patients and DS B-LLy
Preceding treatment
- COG AALL0932: MTX & Vincristine interim maintenance
Chemotherapy
- Methotrexate (MTX) 20 mg/m2 PO once per day on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1
- Mercaptopurine (6-MP) 75 mg/m2 PO once per day on days 1 to 84
Glucocorticoid therapy
- Dexamethasone (Decadron) 3 mg/m2 IV or PO twice per day on days 1 to 5 (DO NOT TAPER)
CNS therapy, prophylaxis
- Methotrexate (MTX) IT once on day 1
Age in years, rounded to the nearest hundredth | Dose |
---|---|
1.00 to 1.99 | 8 mg |
2.00 to 2.99 | 10 mg |
3.00 to 8.99 | 12 mg |
9.00 or older | 15 mg |
12-week cycles until total duration of therapy is 2 years for female and 3 years for male from the start of Interim I
Consolidation, Arm LR-M
Chemotherapy
- Methotrexate (MTX) 1000 mg/m2 IV on days 8, 29, 50, 71, 92, 113
Given as a 200 mg/m2 bolus over 20 to 30 minutes followed by 800 mg/m2 over 23.5 hours (initial bolus of 30 minutes) or 23.67 hours (if initial bolus was over 20 minutes)
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 15, 22, 78, 85
- Mercaptopurine (6-MP) 50 mg/m2 PO once per day on days 1 to 33
Glucocorticoid therapy
- Dexamethasone (Decadron) 3 mg/m2 IV or PO twice per day on days 15 to 21, 78 to 84
Supportive therapy
- Leucovorin (Folinic acid) 10 mg/m2 x 2 doses PO or IV (given 48 and 60 hours after the START of methotrexate infusion, continuing until methotrexate level less than 0.2 μM) on days 9, 10, 30, 31, 51, 52, 72, 73, 93, 94, 114, 115
CNS therapy, prophylaxis
- Methotrexate (MTX) IT once on days 8, 29, 50, 71, 92, 113 (To be delivered within 6 hours of the beginning of the IV methotrexate infusion, -6hr to + 6 hr)
Age in years, rounded to the nearest hundredth | Dose |
---|---|
1.00 to 1.99 | 8 mg |
2.00 to 2.99 | 10 mg |
3.00 to 8.99 | 12 mg |
9.00 or older | 15 mg |
19-week cycle
Maintenance, Arm LR-M
Chemotherapy
- Methotrexate (MTX) as follows:
- Cycles 1 to 4: 20 mg/m2/day PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, 92, 99, 106
- Cycles 2 & 5: 20 mg/m2/day PO on days 1, 8, 15, 22, 29, 36, 43, 50, 64, 71, 78, 85, 92, 99, 106
- Cycles 3 & 6: 20 mg/m2/day PO on days 1, 8, 15, 22, 36, 43, 50, 57, 64, 71, 78, 85, 92, 99, 106
- Cycle 7: 20 mg/m2/day PO on days 1, 8, 15, 29, 22, 36, 43, 50, 57, 64
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1 & 8
- Mercaptopurine (6-MP) 75 mg/m2 PO once per day on days 1 to 112 (NOTE: Higher 6-MP dose than in consolidation)
Glucocorticoid therapy
- Dexamethasone (Decadron) 3 mg/m2 PO twice per day on days 1 to 7 (6 mg/m2/day, do not taper)
CNS therapy, prophylaxis
- Methotrexate (MTX) as follows:
- Cycles 1 to 4: IT once on day 1, 85
- Cycles 2 & 5: IT once on day 57
- Cycles 3 & 6: IT once on day 29
Age in years, rounded to the nearest hundredth | Dose |
---|---|
1.00 to 1.99 | 8 mg |
2.00 to 2.99 | 10 mg |
3.00 to 8.99 | 12 mg |
9.00 or older | 15 mg |
16-week cycles until a total duration of therapy of 2.5 years from the date of diagnosis is reached for both boys and girls.
Maintenance, Arm LLy (Vincristine/Dexamethasone)
Preceding treatment
- COG AALL0932: MTX & Vincristine interim maintenance
Chemotherapy
- Methotrexate (MTX) 20 mg/m2 PO once per day on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 29, 57 (4 Week Intervals)
- Mercaptopurine (6-MP) 75 mg/m2 PO once per day on days 1 to 84
Glucocorticoid therapy
- Dexamethasone (Decadron) 3 mg/m2 PO twice per day on days 1 to 5, 29 to 33, 57 to 61 (6 mg/m2/day) (DO NOT TAPER)
CNS therapy, prophylaxis
- Methotrexate (MTX) IT once on day 1
Age in years, rounded to the nearest hundredth | Dose |
---|---|
1.00 to 1.99 | 8 mg |
2.00 to 2.99 | 10 mg |
3.00 to 8.99 | 12 mg |
9.00 or older | 15 mg |
12-week cycles until total duration of therapy is 2 years for female and 3 years for male from the start of Interim I
References
- COG CCG-1991: Matloub Y, Bostrom BC, Hunger SP, Stork LC, Angiolillo A, Sather H, La M, Gastier-Foster JM, Heerema NA, Sailer S, Buckley PJ, Thomson B, Cole C, Nachman JB, Reaman G, Winick N, Carroll WL, Devidas M, Gaynon PS. Escalating intravenous methotrexate improves event-free survival in children with standard-risk acute lymphoblastic leukemia: a report from the Children's Oncology Group. Blood. 2011 Jul 14;118(2):243-51. Epub 2011 May 11. link to original article link to PMC article PubMed NCT00005945
- COG AALL0331: Maloney KW, Devidas M, Wang C, Mattano LA, Friedmann AM, Buckley P, Borowitz MJ, Carroll AJ, Gastier-Foster JM, Heerema NA, Kadan-Lottick N, Loh ML, Matloub YH, Marshall DT, Stork LC, Raetz EA, Wood B, Hunger SP, Carroll WL, Winick NJ. Outcome in Children With Standard-Risk B-Cell Acute Lymphoblastic Leukemia: Results of Children's Oncology Group Trial AALL0331. J Clin Oncol. 2020 Feb 20;38(6):602-612. Epub 2019 Dec 11. link to original article link to PMC article PubMed
- 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
- Daunorubicin (Cerubidine) 25 mg/m2 IV over 1 to 15 minutes once per day on days 1, 8, 15, 22
- Pegaspargase (Oncaspar) 2,500 units/m2 IV over 1 to 2 hours once on day 4
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
Glucocorticoid therapy
- Dexamethasone (Decadron) by the following age-based criteria:
- Younger than 10 years old: 5 mg/m2 IV or PO twice per day on days 1 to 14
- 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
- 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
- Cyclophosphamide (Cytoxan) 1000 mg/m2 IV over 30 to 60 minutes once on days 1, 29
- Cytarabine (Ara-C) 75 mg/m2 SC or IV over 1 to 30 minutes on days 1 to 4, 8 to 11, 29 to 32, 36 to 39
- Pegaspargase (Oncaspar) 2,500 units/m2 IV over 1 to 2 hours once on days 15, 43
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 15, 22, 43, 50
- Mercaptopurine (6-MP) 60 mg/m2 PO once per day on days 1 to 14, 29 to 42
CNS therapy, prophylaxis
- Methotrexate (MTX) IT once per day on days 1, 8, 15, 22
Age in years, rounded to the nearest hundredth | Dose |
---|---|
1.00 to 1.99 | 8 mg |
2.00 to 2.99 | 10 mg |
3.00 to 8.99 | 12 mg |
9.00 or older | 15 mg |
56-day course
Interim Maintenance, with HD MTX
Chemotherapy
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 15, 29, 43
- Mercaptopurine (6-MP) 25 mg/m2 PO once per day on days 1 to 56
- High Dose Methotrexate (MTX) 500 mg/m2 IV over 30 minutes once per day on days 1, 15, 29, 43, then 4500 mg/m2 IV continuous infusion over 23.5 hours, started on days 1, 15, 29, 43
- ANC must be at least 750/µL and platelets must be at least 75,000/µL prior to each dose of high dose MTX
Supportive therapy
- Leucovorin (Folinic acid) 15 mg/m2 x a minimum of 3 doses PO or IV (given at 42, 48, and 54 hours after the START of high dose methotrexate infusion) on days 3 to 4, 17 to 18, 31 to 32, 45 to 46
CNS therapy, prophylaxis
- Methotrexate (MTX) IT once per day on days 1, 29
Age in years, rounded to the nearest hundredth | Dose |
---|---|
1.00 to 1.99 | 8 mg |
2.00 to 2.99 | 10 mg |
3.00 to 8.99 | 12 mg |
9.00 or older | 15 mg |
When IT methotrexate therapy and high dose methotrexate are scheduled for the same day, deliver the IT methotrexate within 6 hours of the beginning of the IV methotrexate infusion. (hour -6 or +6, with 0 being the start of the methotrexate bolus).
63-day course
Delayed Intensification
Chemotherapy
- Doxorubicin (Adriamycin) 25 mg/m2 IV push over 1 to 15 minutes once per day on days 1, 8, 15
- Pegaspargase (Oncaspar) 2,500 units/m2 IV over 1 to 2 hours once on days 4, 43
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 43, 50
- Cyclophosphamide (Cytoxan) 1000 mg/m2 IV over 30 to 60 minutes once on day 29 ONLY
- Cytarabine (Ara-C) 75 mg/m2 SC or IV over 1 to 30 minutes on days 29 to 32, 36 to 39
- Thioguanine (Tabloid) 60 mg/m2 PO once per day on days 29 to 42
Glucocorticoid therapy
- Dexamethasone (Decadron) 5 mg/m2 IV or PO twice per day on days 1 to 7, 15 to 21
CNS therapy, prophylaxis
- Methotrexate (MTX) IT once per day on days 1, 29, 36
Age in years, rounded to the nearest hundredth | Dose |
---|---|
1.00 to 1.99 | 8 mg |
2.00 to 2.99 | 10 mg |
3.00 to 8.99 | 12 mg |
9.00 or older | 15 mg |
56-day course
Maintenance, HR B-ALL
Chemotherapy
- Mercaptopurine (6-MP) as follows:
- Cycles 1 to 4: 75 mg/m2 PO once per day on days 1 to 84
- Vincristine (Oncovin) as follows:
- Cycles 1 to 4: 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 29, 57
- Methotrexate (MTX) as follows:
- Cycles 1 to 4: 20 mg/m2 PO once per day on days 8, 15, 22, 36, 43, 50, 57, 64, 71, 78
- Cycle 5 onwards: 20 mg/m2 PO once per day on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78
Glucocorticoid therapy
- Prednisone (Sterapred) 20 mg/m2 PO or IV (methylprednisolone given at 80% of the oral dose) twice per day on days 1 to 5, 29 to 33, 57 to 61
CNS therapy, prophylaxis
- Methotrexate (MTX) as follows:
- Cycles 1 to 4: IT once per day on days 1, 29
- Cycle 5 onwards: IT once per day on day 1
Age in years, rounded to the nearest hundredth | Dose |
---|---|
1.00 to 1.99 | 8 mg |
2.00 to 2.99 | 10 mg |
3.00 to 8.99 | 12 mg |
9.00 or older | 15 mg |
12-week cycles repeated until the total duration of therapy is 2 years for female patients and 3 years for male patients from the start of interim maintenance.
References
- COG AALL1131: Burke MJ, Salzer WL, Devidas M, Dai Y, Gore L, Hilden JM, Larsen E, Rabin KR, Zweidler-McKay PA, Borowitz MJ, Wood B, Heerema NA, Carroll AJ, Winick N, Carroll WL, Raetz EA, Loh ML, Hunger SP. Replacing cyclophosphamide/cytarabine/mercaptopurine with cyclophosphamide/etoposide during consolidation/delayed intensification does not improve outcomes for pediatric B-cell acute lymphoblastic leukemia: a report from the COG. Haematologica. 2019 May;104(5):986-992. Epub 2018 Dec 13. link to original article link to PMC article 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
- Pegaspargase (Oncaspar) 2,500 units/m2 IV over 1 to 2 hours once on day 15, 43
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 15, 22, 43, 50
- Cyclophosphamide (Cytoxan) 1000 mg/m2 IV over 30 to 60 minutes once on day 1, 29
- Cytarabine (Ara-C) 75 mg/m2 SC or IV over 1 to 30 minutes once per day on days 1 to 4, 8 to 11, 29 to 32, 36 to 39
- Mercaptopurine (6-MP) 60 mg/m2 PO once per day on days 1 to 14, 29 to 42
CNS therapy, prophylaxis
- Methotrexate (MTX) IT once per day on days 1, 8, 15, 22 (Omit days 15 and 22 for CNS3 Patients)
Age in years, rounded to the nearest hundredth | Dose |
---|---|
1.00 to 1.99 | 8 mg |
2.00 to 2.99 | 10 mg |
3.00 to 8.99 | 12 mg |
9.00 or older | 15 mg |
56-day course
Interim Maintenance, I with HD MTX
Chemotherapy
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 15, 29, 43
- Mercaptopurine (6-MP) 60 mg/m2 PO once per day on days 1 to 56
- High Dose Methotrexate (MTX) 500 mg/m2 IV over 30 minutes once per day on days 1, 15, 29, 43, then 4500 mg/m2 IV continuous infusion over 23.5 hours, started on days 1, 15, 29, 43
- ANC must be at least 750/µL and platelets must be at least 75,000/µL prior to each dose of high dose MTX
Supportive therapy
- Leucovorin (Folinic acid) 15 mg/m2 x a minimum of 3 doses PO or IV (given at 42, 48, and 54 hours after the START of HD MTX infusion) on days 3 to 4, 17 to 18, 31 to 32, 45 to 46
CNS therapy, prophylaxis
- Methotrexate (MTX) IT once per day on days 1, 29
Age in years, rounded to the nearest hundredth | Dose |
---|---|
1.00 to 1.99 | 8 mg |
2.00 to 2.99 | 10 mg |
3.00 to 8.99 | 12 mg |
9.00 or older | 15 mg |
28-day course
Delayed Intensification
Chemotherapy
- Doxorubicin (Adriamycin) 25 mg/m2 IV push over 1 to 15 minutes once per day on days 1, 8, 15
- Pegaspargase (Oncaspar) 2,500 units/m2 IV over 1 to 2 hours once on day 4, 43
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 43, 50
- Cyclophosphamide (Cytoxan) 1000 mg/m2 IV over 30 to 60 minutes once on day 29 ONLY
- Cytarabine (Ara-C) 75 mg/m2 SC or IV over 1 to 30 minutes on days 29 to 32, 36 to 39
- Thioguanine (Tabloid) 60 mg/m2 PO once per day on days 29 to 42
Glucocorticoid therapy
- Dexamethasone (Decadron) 5 mg/m2 IV or PO twice per day on days 1 to 7, 15 to 21
CNS therapy, prophylaxis
- Methotrexate (MTX) IT once per day on day 1, 29, 36
Age in years, rounded to the nearest hundredth | Dose |
---|---|
1.00 to 1.99 | 8 mg |
2.00 to 2.99 | 10 mg |
3.00 to 8.99 | 12 mg |
9.00 or older | 15 mg |
56-day course
Interim Maintenance, II with Capizzi MTX
Chemotherapy
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on day 1, 11, 21, 31, 41
- Methotrexate (MTX) 100 mg/m2 IV over 2 to 5 minutes (undiluted) or over 10 to 15 minutes (diluted) on days 1, 150 mg/m2 on day 11, 200 mg/m2 on day 21, 250 mg/m2 on day 31, and 300 mg/m2 on day 41
- Pegaspargase (Oncaspar) 2,500 units/m2 IV over 1 to 2 hours once on day 2, 22
CNS therapy, prophylaxis
- Methotrexate (MTX) IT once per day on days 1, 31
Age in years, rounded to the nearest hundredth | Dose |
---|---|
1.00 to 1.99 | 8 mg |
2.00 to 2.99 | 10 mg |
3.00 to 8.99 | 12 mg |
9.00 or older | 15 mg |
56-day course
Maintenance, VHR Arm
Radiotherapy
- Total body irradiation (TBI) by the following risk-based criteria:
- CNS3: 1800 cGy in 10 fractions, during the first 4 weeks of Maintenance therapy and should be completed by day 29 of Maintenance
Chemotherapy
- Mercaptopurine (6-MP) 75 mg/m2 PO once per day on days 1 to 84
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 29, 57
- Methotrexate (MTX) 20 mg/m2 PO once per day on days 8, 15, 22, (29), 36, 43, 50, 57, 64, 71, 78 (OMIT DAY 29 WHEN CNS RADIATION IS GIVEN, DUE TO IT MTX)
Glucocorticoid therapy
- Prednisone (Sterapred) 20 mg/m2 PO or IV (methylprednisolone given at 80% of the oral dose) twice per day on days 1 to 5, 29 to 33, 57 to 61
CNS therapy, prophylaxis
- Methotrexate (MTX) IT once per day on day 1 (also Day 29 of cycles 1 and 2, for patients who did NOT receive CNS Radiation)
Age in years, rounded to the nearest hundredth | Dose |
---|---|
1.00 to 1.99 | 8 mg |
2.00 to 2.99 | 10 mg |
3.00 to 8.99 | 12 mg |
9.00 or older | 15 mg |
12-week cycles repeated until total duration of therapy is 2 years for female patients and 3 years for male patients from the start of interim maintenance.
References
- COG AALL1131: Burke MJ, Salzer WL, Devidas M, Dai Y, Gore L, Hilden JM, Larsen E, Rabin KR, Zweidler-McKay PA, Borowitz MJ, Wood B, Heerema NA, Carroll AJ, Winick N, Carroll WL, Raetz EA, Loh ML, Hunger SP. Replacing cyclophosphamide/cytarabine/mercaptopurine with cyclophosphamide/etoposide during consolidation/delayed intensification does not improve outcomes for pediatric B-cell acute lymphoblastic leukemia: a report from the COG. Haematologica. 2019 May;104(5):986-992. Epub 2018 Dec 13. link to original article link to PMC article 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
- Cyclophosphamide (Cytoxan) 1000 mg/m2 IV over 30 to 60 minutes once on days 1, 29
- Cytarabine (Ara-C) 75 mg/m2 SC or IV over 1 to 30 minutes once per day on days 1 to 4, 8 to 11, 29 to 32, 36 to 39
- Pegaspargase (Oncaspar) 2,500 units/m2 IV over 1 to 2 hours once on days 15, 43
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 15, 22, 43, 50
- Mercaptopurine (6-MP) 60 mg/m2 PO once per day on days 1 to 14, 29 to 42
Targeted therapy
- Dasatinib (Sprycel) 60 mg/m2 (rounded to the nearest 5 mg, maximum dose of 140 mg/day) PO once per day on days 1 to 56
CNS therapy, prophylaxis
- Methotrexate (MTX) IT once per day on days 1, 8, 15, 22
Age in years, rounded to the nearest hundredth | Dose |
---|---|
1.00 to 1.99 | 8 mg |
2.00 to 2.99 | 10 mg |
3.00 to 8.99 | 12 mg |
9.00 or older | 15 mg |
56-day course
Interim Maintenance, with HD MTX
Chemotherapy
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 15, 29, 43
- Mercaptopurine (6-MP) 25 mg/m2 PO once per day on days 1 to 56.
- High Dose Methotrexate (MTX) 500 mg/m2 IV over 30 minutes once per day on days 1, 15, 29, 43, then 4500 mg/m2 IV continuous infusion over 23.5 hours, started on days 1, 15, 29, 43
- ANC must be at least 750/µL and platelets must be at least 75,000/µL prior to each dose of high dose MTX
Targeted therapy
- Dasatinib (Sprycel) 60 mg/m2 (rounded to the nearest 5 mg, maximum dose of 140 mg/day) PO once per day on days 1 to 63
Supportive therapy
- Leucovorin (Folinic acid) 15 mg/m2 for a minimum of 3 doses PO or IV (given at 42, 48, and 54 hours after the START of high dose methotrexate infusion) on days 3, 4, 17, 18, 31, 32, 45, 46
CNS therapy, prophylaxis
- Methotrexate (MTX) IT once per day on days 1, 29
Age in years, rounded to the nearest hundredth | Dose |
---|---|
1.00 to 1.99 | 8 mg |
2.00 to 2.99 | 10 mg |
3.00 to 8.99 | 12 mg |
9.00 or older | 15 mg |
When IT methotrexate therapy and high dose methotrexate are scheduled for the same day, deliver the IT therapy within 6 hours of the beginning of the IV methotrexate infusion. (hour -6 or +6, with 0 being the start of the methotrexate bolus).
63-day course
Delayed Intensification
Chemotherapy
- Doxorubicin (Adriamycin) 25 mg/m2 IV push over 1 to 15 minutes once per day on days 1, 8, 15
- Pegaspargase (Oncaspar) 2,500 units/m2 IV over 1 to 2 hours once on days 4, 43
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 43, 50
- Cyclophosphamide (Cytoxan) 1000 mg/m2 IV over 30 to 60 minutes once on day 29 ONLY
- Cytarabine (Ara-C) 75 mg/m2 SC or IV over 1 to 30 minutes on days 29 to 32, 36 to 39
- Thioguanine (Tabloid) 60 mg/m2 PO once per day on days 29 to 42
Targeted therapy
- Dasatinib (Sprycel) 60 mg/m2 (rounded to the nearest 5 mg, maximum dose of 140 mg/day) PO once per day on days 1 to 56
Glucocorticoid therapy
- Dexamethasone (Decadron) 5 mg/m2 IV or PO twice per day on days 1 to 7, 15 to 21
CNS therapy, prophylaxis
- Methotrexate (MTX) IT once per day on days 1, 29, 36
Age in years, rounded to the nearest hundredth | Dose |
---|---|
1.00 to 1.99 | 8 mg |
2.00 to 2.99 | 10 mg |
3.00 to 8.99 | 12 mg |
9.00 or older | 15 mg |
56-day course
Interim Maintenance, II with Capizzi MTX
Chemotherapy
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on day 1, 11, 21, 31, 41
- Methotrexate (MTX) 100 mg/m2 IV over 2 to 5 minutes (undiluted) or over 10 to 15 minutes (diluted) on days 1, 150 mg/m2 on day 11, 200 mg/m2 on day 21, 250 mg/m2 on day 31, and 300 mg/m2 on day 41
- Pegaspargase (Oncaspar) 2,500 units/m2 IV over 1 to 2 hours once on day 2, 22
Targeted therapy
- Dasatinib (Sprycel) 60 mg/m2 (rounded to the nearest 5 mg, maximum dose of 140 mg/day) PO once per day on days 1 to 56
CNS therapy, prophylaxis
- Methotrexate (MTX) IT once per day on days 1, 31
Age in years, rounded to the nearest hundredth | Dose |
---|---|
1.00 to 1.99 | 8 mg |
2.00 to 2.99 | 10 mg |
3.00 to 8.99 | 12 mg |
9.00 or older | 15 mg |
56-day course
Maintenance
Radiotherapy
- Total body irradiation (TBI) by the following risk-based criteria:
- CNS3: 1800 cGy in 10 fractions, during the first 4 weeks of Maintenance therapy and should be completed by day 29 of Maintenance
Chemotherapy
- Mercaptopurine (6-MP) 75 mg/m2 PO once per day on days 1 to 84
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 29, 57
- Methotrexate (MTX) 20 mg/m2 PO once per day on days 8, 15, 22, (29), 36, 43, 50, 57, 64, 71, 78 (OMIT DAY 29 WHEN CNS RADIATION IS GIVEN, DUE TO IT MTX)
Glucocorticoid therapy
- Prednisone (Sterapred) 20 mg/m2 PO or IV (methylprednisolone given at 80% of the oral dose) twice per day on days 1 to 5, 29 to 33, 57 to 61
Targeted therapy
- Dasatinib (Sprycel) 60 mg/m2 (rounded to the nearest 5 mg, maximum of 140 mg/day) PO once per day on days 1 to 84
CNS therapy, prophylaxis
- Methotrexate (MTX) IT once per day on day 1 (also Day 29 of cycles 1 and 2, for patients who did NOT receive CNS Radiation)
Age in years, rounded to the nearest hundredth | Dose |
---|---|
1.00 to 1.99 | 8 mg |
2.00 to 2.99 | 10 mg |
3.00 to 8.99 | 12 mg |
9.00 or older | 15 mg |
12-week cycles repeated until total duration of therapy is 2 years for female patients and 3 years for male patients from the start of interim maintenance.
References
- COG AALL1131: Burke MJ, Salzer WL, Devidas M, Dai Y, Gore L, Hilden JM, Larsen E, Rabin KR, Zweidler-McKay PA, Borowitz MJ, Wood B, Heerema NA, Carroll AJ, Winick N, Carroll WL, Raetz EA, Loh ML, Hunger SP. Replacing cyclophosphamide/cytarabine/mercaptopurine with cyclophosphamide/etoposide during consolidation/delayed intensification does not improve outcome for pediatric B-cell acute lymphoblastic leukemia: a report from the COG. Haematologica. 2019 May;104(5):986-992. Epub 2018 Dec 13. link to original article link to PMC article 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
- Pegaspargase (Oncaspar) 2,500 units/m2 IV over 1 to 2 hours once on day 4
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
RER - M1 Marrow at Day 15
- Add Daunorubicin (Cerubidine) 50 mg/m2 IV over 1 to 15 minutes once on days 15
Glucocorticoid therapy
- Dexamethasone (Decadron) by the following age-based criteria:
- Younger than 10 years old: 3 mg/m2 IV or PO twice per day on days 1 to 28 (DO NOT TAPER)
- 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
- Cyclophosphamide (Cytoxan) 1000 mg/m2 IV over 30 to 60 minutes once on days 1, 29
- Cytarabine (Ara-C) 75 mg/m2 SC or IV over 1 to 30 minutes on days 1 to 4, 8 to 11, 29 to 32, 36 to 39
- Pegaspargase (Oncaspar) 2,500 units/m2 IV over 1 to 2 hours once on days 15, 43
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 15, 22, 43, 50
- Mercaptopurine (6-MP) 60 mg/m2 PO once per day on days 1 to 14, 29 to 42
CNS therapy, prophylaxis
- Methotrexate (MTX) IT once per day on days 1, 8, 15, 22
Age in years, rounded to the nearest hundredth | Dose |
---|---|
1.00 to 1.99 | 8 mg |
2.00 to 2.99 | 10 mg |
3.00 to 8.99 | 12 mg |
9.00 or older | 15 mg |
DS Arm
Supportive therapy
- Leucovorin (Folinic acid) 5 mg/m2 x 2 doses PO (given at 48 and 60 hours after the lumbar puncture) on days 3, 4, 10, 11, 17, 18, 24, 25
56-day course
Interim Maintenance, with ID MTX
Chemotherapy
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 15, 29, 43
- Mercaptopurine (6-MP) 25 mg/m2/dose PO once per day on days 1 to 56
- Intermediate Dose Methotrexate (MTX) 200 mg/m2 IV over 30 minutes once per day on days 1, 15, 29, 43, then 1800 mg/m2 IV continuous infusion over 23.5 hours, started on days 1, 15, 29, 43
- ANC must be at least 750/µL and platelets must be at least 75,000/µL prior to each dose of high dose MTX
Supportive therapy
- Leucovorin (Folinic acid) 15 mg/m2 x a minimum of 5 doses PO or IV (given at 30, 36, 42, 48, and 54 hours after the START of intermediate dose methotrexate infusion) on days 2, 3, 17, 18, 31, 32, 45, 46
CNS therapy, prophylaxis
- Methotrexate (MTX) IT once per day on days 1, 29
Age in years, rounded to the nearest hundredth | Dose |
---|---|
1.00 to 1.99 | 8 mg |
2.00 to 2.99 | 10 mg |
3.00 to 8.99 | 12 mg |
9.00 or older | 15 mg |
When IT methotrexate therapy and high dose methotrexate are scheduled for the same day, deliver the IT therapy within 6 hours of the beginning of the IV methotrexate infusion. (hour -6 or +6, with 0 being the start of the methotrexate bolus).
63-day course
Delayed Intensification
Chemotherapy
- Doxorubicin (Adriamycin) 25 mg/m2 IV push over 1 to 15 minutes once per day on days 1, 8, 15
- Pegaspargase (Oncaspar) 2,500 units/m2 IV over 1 to 2 hours once on days 4, 43
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 43, 50
- Cyclophosphamide (Cytoxan) 1000 mg/m2 IV over 30 to 60 minutes once on day 29 ONLY
- Cytarabine (Ara-C) 75 mg/m2 SC or IV over 1 to 30 minutes on days 29 to 32, 36 to 39
- Thioguanine (Tabloid) 60 mg/m2 PO once per day on days 29 to 42
Glucocorticoid therapy
- Dexamethasone (Decadron) 5 mg/m2 IV or PO twice per day on days 1 to 7, 15 to 21
Supportive therapy
- Leucovorin (Folinic acid) 5 mg/m2 x 2 doses PO or IV (given at 48, and 60 hours after the lumbar puncture) on days 3, 4, 31, 32, 38, 39
CNS therapy, prophylaxis
- Methotrexate (MTX) IT once per day on days 1, 29, 36
Age in years, rounded to the nearest hundredth | Dose |
---|---|
1.00 to 1.99 | 8 mg |
2.00 to 2.99 | 10 mg |
3.00 to 8.99 | 12 mg |
9.00 or older | 15 mg |
56-day course
Maintenance, DS HR Arm
Radiotherapy
- Total body irradiation (TBI) by the following risk-based criteria:
- CNS3: 1800 cGy in 10 fractions, during the first 4 weeks of Maintenance therapy and should be completed by day 29 of Maintenance
Chemotherapy
- Mercaptopurine (6-MP) 75 mg/m2 PO once per day on days 1 to 84
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once on day 1
- Methotrexate (MTX) 20 mg/m2 PO once per day on days 8, 15, 22, (29), 36, 43, 50, 57, 64, 71, 78 (OMIT DAY 29 WHEN CNS RADIATION IS GIVEN, DUE TO IT MTX)
Glucocorticoid therapy
- Prednisone (Sterapred) 20 mg/m2 PO or IV (methylprednisolone given at 80% of the oral dose) twice per day on days 1 to 5
CNS therapy, prophylaxis
- Methotrexate (MTX) IT once per day on day 1 (also Day 29 of cycles 1 and 2, for patients who did NOT receive CNS Radiation)
Age in years, rounded to the nearest hundredth | Dose |
---|---|
1.00 to 1.99 | 8 mg |
2.00 to 2.99 | 10 mg |
3.00 to 8.99 | 12 mg |
9.00 or older | 15 mg |
12-week cycles repeated until total duration of therapy is 2 years for female patients and 3 years for male patients from the start of interim maintenance.
References
- COG AALL1131: Burke MJ, Salzer WL, Devidas M, Dai Y, Gore L, Hilden JM, Larsen E, Rabin KR, Zweidler-McKay PA, Borowitz MJ, Wood B, Heerema NA, Carroll AJ, Winick N, Carroll WL, Raetz EA, Loh ML, Hunger SP. Replacing cyclophosphamide/cytarabine/mercaptopurine with cyclophosphamide/etoposide during consolidation/delayed intensification does not improve outcome for pediatric B-cell acute lymphoblastic leukemia: a report from the COG. Haematologica. 2019 May;104(5):986-992. Epub 2018 Dec 13. link to original article link to PMC article 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
- Methylprednisolone (Solumedrol) 8 mg/m2 IV three times per day on days 1 to 3
3-day course
Subsequent treatment
- DFCI 05-001: Doxorubicin, L-asparaginase, Methotrexate, Vincristine, Methylprednisolone versus Doxorubicin, Methotrexate, Pegaspargase, Vincristine, Methylprednisolone induction
- DFCI 11-001: Calaspargase, Doxorubicin, Methotrexate, Vincristine, Methylprednisolone versus Doxorubicin, Methotrexate, Pegaspargase, Vincristine, Methylprednisolone induction
References
- DFCI 05-001: Place AE, Stevenson KE, Vrooman LM, Harris MH, Hunt SK, O'Brien JE, Supko JG, Asselin BL, Athale UH, Clavell LA, Cole PD, Kelly KM, Laverdiere C, Leclerc JM, Michon B, Schorin MA, Welch JJ, Lipshultz SE, Kutok JL, Blonquist TM, Neuberg DS, Sallan SE, Silverman LB. Intravenous pegylated asparaginase versus intramuscular native Escherichia coli L-asparaginase in newly diagnosed childhood acute lymphoblastic leukaemia (DFCI 05-001): a randomised, open-label phase 3 trial. Lancet Oncol. 2015 Dec;16(16):1677-90. Epub 2015 Nov 6. link to original article PubMed NCT00400946
- Pooled update: Burns MA, Place AE, Stevenson KE, Gutiérrez A, Forrest S, Pikman Y, Vrooman LM, Harris MH, Hunt SK, O'Brien JE, Asselin BL, Athale UH, Clavell LA, Cole PD, Gennarini LM, Kahn JM, Kelly KM, Laverdiere C, Leclerc JM, Michon B, Schorin MA, Sulis ML, Welch JJG, Neuberg DS, Sallan SE, Silverman LB. Identification of prognostic factors in childhood T-cell acute lymphoblastic leukemia: Results from DFCI ALL Consortium Protocols 05-001 and 11-001. Pediatr Blood Cancer. 2021 Jan;68(1):e28719. Epub 2020 Oct 7. Erratum in: Pediatr Blood Cancer. 2021 Mar;68(3):e28885. link to original article contains dosing details in supplement link to PMC article PubMed
- 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
- 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
- Prednisone (Sterapred) 60 mg/m2/day PO on days 1 to 7
CNS therapy, prophylaxis
- Methotrexate (MTX) 15 mg IT once on day 1
7-day course
Subsequent treatment
References
- AIEOP-BFM ALL 2000: Möricke A, Zimmermann M, Valsecchi MG, Stanulla M, Biondi A, Mann G, Locatelli F, Cazzaniga G, Niggli F, Aricò M, Bartram CR, Attarbaschi A, Silvestri D, Beier R, Basso G, Ratei R, Kulozik AE, Lo Nigro L, Kremens B, Greiner J, Parasole R, Harbott J, Caruso R, von Stackelberg A, Barisone E, Rössig C, Conter V, Schrappe M. Dexamethasone vs prednisone in induction treatment of pediatric ALL: results of the randomized trial AIEOP-BFM ALL 2000. Blood. 2016 Apr 28;127(17):2101-12. Epub 2016 Feb 17. link to original article 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
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 8, 15
Glucocorticoid therapy
- Prednisone (Sterapred) 40 mg/m2/day PO on days 1 to 21
21-day course
References
- Sallan SE, Cammita BM, Cassady JR, Nathan DG, Frei E 3rd. Intermittent combination chemotherapy with adriamycin for childhood acute lymphoblastic leukemia: clinical results. Blood. 1978 Mar;51(3):425-33. link to original article 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
- Calaspargase (Asparlas) 2500 units/m2 IV once on day 4
- Daunorubicin (Cerubidine) 25 mg/m2 IV once per day on days 1, 8, 15, 22
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
Glucocorticoid therapy
- Prednisone (Sterapred) 30 mg/m2 PO twice per day on days 1 to 28
5-week course
Subsequent treatment
- See protocol for details of treatment beyond induction
References
- COG AALL07P4: Angiolillo AL, Schore RJ, Devidas M, Borowitz MJ, Carroll AJ, Gastier-Foster JM, Heerema NA, Keilani T, Lane AR, Loh ML, Reaman GH, Adamson PC, Wood B, Wood C, Zheng HW, Raetz EA, Winick NJ, Carroll WL, Hunger SP. Pharmacokinetic and pharmacodynamic properties of calaspargase pegol Escherichia coli L-asparaginase in the treatment of patients with acute lymphoblastic leukemia: results from Children's Oncology Group Study AALL07P4. J Clin Oncol. 2014 Dec 1;32(34):3874-82. Epub 2014 Oct 27. link to original article link to PMC article 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
- Daunorubicin (Cerubidine) 25 mg/m2 IV over 1 to 15 minutes once per day on days 1, 8, 15, 22
- Pegaspargase (Oncaspar) 2500 units/m2 IV over 1 to 2 hours once on day 4
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
Glucocorticoid therapy
- Dexamethasone (Decadron) 5 mg/m2 IV or PO twice per day on days 1 to 14
CNS therapy, prophylaxis
- Cytarabine (Ara-C) by the following age-based criteria:
- 1 to 1.99 years old: 30 mg IT once on day 1
- 2 to 2.99 years old: 50 mg IT once on day 1
- 3 years old or older: 70 mg IT once on day 1
- Methotrexate (MTX) by the following age-based criteria:
- 1 to 1.99 years old: 8 mg IT once per day on days 8 & 29
- 2 to 2.99 years old: 10 mg IT once per day on days 8 & 29
- 3 to 8.99 years old: 12 mg IT once per day on days 8 & 29
- 9 years old or older: 15 mg IT once per day on days 8 & 29
4-week course
Subsequent treatment
- See protocol for details of treatment beyond induction
References
- COG AALL1131: Burke MJ, Salzer WL, Devidas M, Dai Y, Gore L, Hilden JM, Larsen E, Rabin KR, Zweidler-McKay PA, Borowitz MJ, Wood B, Heerema NA, Carroll AJ, Winick N, Carroll WL, Raetz EA, Loh ML, Hunger SP. Replacing cyclophosphamide/cytarabine/mercaptopurine with cyclophosphamide/etoposide during consolidation/delayed intensification does not improve outcome for pediatric B-cell acute lymphoblastic leukemia: a report from the COG. Haematologica. 2019 May;104(5):986-992. Epub 2018 Dec 13. link to original article link to PMC article 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
- Daunorubicin (Cerubidine) 25 mg/m2 IV once per day on days 1, 8, 15, 22
- Pegaspargase (Oncaspar) 2500 units/m2 IV once on day 4
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
Glucocorticoid therapy
- Prednisone (Sterapred) 30 mg/m2 PO twice per day on days 1 to 28
5-week course
Subsequent treatment
- See protocol for details of treatment beyond induction
References
- COG AALL07P4: Angiolillo AL, Schore RJ, Devidas M, Borowitz MJ, Carroll AJ, Gastier-Foster JM, Heerema NA, Keilani T, Lane AR, Loh ML, Reaman GH, Adamson PC, Wood B, Wood C, Zheng HW, Raetz EA, Winick NJ, Carroll WL, Hunger SP. Pharmacokinetic and pharmacodynamic properties of calaspargase pegol Escherichia coli L-asparaginase in the treatment of patients with acute lymphoblastic leukemia: results from Children's Oncology Group Study AALL07P4. J Clin Oncol. 2014 Dec 1;32(34):3874-82. Epub 2014 Oct 27. link to original article link to PMC article 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
- Daunorubicin (Cerubidine) 25 mg/m2 IV once per day on days 0, 7, 14, 21
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 0, 7, 14, 21
- Asparaginase (Elspar) 6000 units/m2 IM once per day on days 3, 5, 7, 10, 12, 14, 17, 19, 21
Glucocorticoid therapy
- Prednisone (Sterapred) 60 mg/m2/day PO on days 0 to 27, then tapered from days 28 to 38 (see note)
CNS therapy
- Cytarabine (Ara-C) by the following age-based criteria:
- 1 to 1.99 years old: 30 mg IT once on day 0
- 2 to 2.99 years old: 50 mg IT once on day 0
- 3 years old or older: 70 mg IT once on day 0
- Methotrexate (MTX) by the following age-based criteria:
- 1 to 1.99 years old: 8 mg IT once per day on days 7 & 28
- 2 to 2.99 years old: 10 mg IT once per day on days 7 & 28
- 3 years old or older: 12 mg IT once per day on days 7 & 28
5-week course
Subsequent treatment
- COG CCG-1961: Standard versus increased intensity post-remission therapy (see paper for details)
- COG A5971: Consolidation (see paper for details)
Regimen variant #2, 30/1.5/5000/60 ("Phase A" of ALL-BFM 95; "Phase 1" of ALL IC-BFM 2002; "Phase IA" of ALL IC-BFM 2009)
Study | Dates of enrollment | Evidence |
---|---|---|
Möricke et al. 2008 (ALL-BFM 95) | 1995-2000 | Non-randomized |
Stary et al. 2013 (ALL IC-BFM 2002) | 2002-2007 | Non-randomized part of phase 3 RCT |
Campbell et al. 2023 (ALL IC-BFM 2009) | 2010-06 to 2018-03 | Non-randomized part of phase 3 RCT |
Note: see papers for details on dose adjustments based on risk. For example, in ALL IC-BFM 2002, days 22 & 29 of daunorubicin were omitted for standard risk B-cell precursor acute lymphoblastic leukemia.
Chemotherapy
- Daunorubicin (Cerubidine) 30 mg/m2 IV over 60 minutes once per day on days 8, 15, 22, 29
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 8, 15, 22, 29
- Asparaginase (Elspar) 5000 units IV over 60 minutes once per day on days 12, 15, 18, 21, 24, 27, 30, 33
Glucocorticoid therapy
- Prednisone (Sterapred) 60 mg/m2/day PO on days 1 to 28, tapered over 9 days
CNS therapy
- Methotrexate (MTX) 12 mg IT once per day on days 1, 12, 33
5-week course
Subsequent treatment
- ALL-BFM 95 & ALL IC-BFM 2002: See papers for details
- ALL IC-BFM 2009, SR: Induction phase IB
- ALL IC-BFM 2009, IR/HR: Induction phase IB versus induction phase augmented IB
Regimen variant #3, 30/1.5/10,000/60 ("Protocol I")
Study | 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
Glucocorticoid therapy
- Prednisone (Sterapred) 60 mg/m2/day PO on days 1 to 28
CNS therapy
- Methotrexate (MTX) 12 mg IT once per day on days 1, 15, 29
5-week course
Subsequent treatment
- See papers for details
Regimen variant #4, 40/1.5/10,000/60 ("Induction Protocol I" of ALL-BFM 86)
Study | Dates of enrollment | Evidence |
---|---|---|
Reiter et al. 1994 (ALL-BFM 86) | 1986-10 to 1990-03 | Non-randomized part of RCT |
Kamps et al. 1999 (DCLSG ALL-7) | 1988-07 to 1991-10 | Non-randomized part of RCT |
Chemotherapy
- Daunorubicin (Cerubidine) 40 mg/m2 IV once per day on days 8, 15, 22, 29
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 8, 15, 22, 29
- Asparaginase (Elspar) 10,000 units/m2 IV once per day on days 19, 22, 25, 28, 31, 34, 37, 40
Glucocorticoid therapy
- Prednisone (Sterapred) 60 mg/m2/day PO on days 1 to 28
6-week course
Subsequent treatment
- ALL-BFM 86 & DCLSG ALL-7, standard-risk group (SRG) and risk group (RG): 6-MP & MTX consolidation
- ALL-BFM 86 & DCLSG ALL-7, experimental group (EG): Cytarabine, Ifosfamide, MTX, Mitoxantrone, Prednisone consolidation
References
- ALL-BFM 86: Reiter A, Schrappe M, Ludwig WD, Hiddemann W, Sauter S, Henze G, Zimmermann M, Lampert F, Havers W, Niethammer D, Odenwald E, Ritter J, Mann G, Welte K, Gadner H, Riehm H. Chemotherapy in 998 unselected childhood acute lymphoblastic leukemia patients: results and conclusions of the multicenter trial ALL-BFM 86. Blood. 1994 Nov 1;84(9):3122-33. link to original article contains dosing details in manuscript PubMed
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- Daunorubicin (Cerubidine) 30 mg/m2 IV once per day on days 8, 15, 22, 29
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 8, 15, 22, 29
- Asparaginase (Elspar) 10,000 units (route not specified) once per day on days 12, 15, 18, 22, 25, 29, 32, 35
Glucocorticoid therapy
- Prednisolone (Millipred) 60 mg/m2/day PO on days 1 to 28, then tapered over 9 days
5-week course
Subsequent treatment
- See paper for details
Regimen variant #2, 45/6000/1.5/40
Study | 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
- Daunorubicin (Cerubidine) 45 mg/m2 IV once per day on days 1 & 2
- Vincristine (Oncovin) 1.5 mg/m2 IV once per day on days 1, 8, 15, 22, 29
- Asparaginase (Elspar) 6000 units/m2 SC once per day on days 3, 5, 7, 10, 12, 14, 17, 19, 21
Glucocorticoid therapy
- Prednisolone (Millipred) 40 mg/m2/day PO on days 1 to 28
29-day course
Subsequent treatment
- Intensification (randomized) or Cy/TBI with allo HSCT, depending on donor availability
References
- UK MRC ALLX: Chessells JM, Bailey C, Wheeler K, Richards SM. Bone marrow transplantation for high-risk childhood lymphoblastic leukaemia in first remission: experience in MRC UKALL X. Lancet. 1992 Sep 5;340(8819):565-8. link to original article contains dosing details in manuscript PubMed
- 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
- 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
- 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
- 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
- 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
- Methylprednisolone pre-phase
Chemotherapy
- Doxorubicin (Adriamycin) 30 mg/m2 IV once per day on days 4 & 5
- Methotrexate (MTX) 40 mg/m2 IV once on day 6
- Pegaspargase (Oncaspar) 2500 units/m2 IV once on day 7
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 4, 11, 18, 25
Glucocorticoid therapy
- Methylprednisolone (Solumedrol) 8 mg/m2 IV three times per day on days 4 to 32
Supportive therapy
- Dexrazoxane (Zinecard) 300 mg/m2 IV once per day on days 4 & 5
28-day course
CNS therapy, prophylaxis
- Cytarabine (Ara-C) IT once per day on days 1 & 18
- Day 18 dose is admixed with MTX and HC
- Methotrexate (MTX) IT once per day on days 18 & 32
- Day 18 dose is admixed with Ara-C and HC
- Hydrocortisone (Cortef) IT once on day 18, admixed with Ara-C and MTX
Subsequent treatment
- Doxorubicin, Mercaptopurine, Methotrexate, Vincristine consolidation (IA)
References
- DFCI 05-001: Place AE, Stevenson KE, Vrooman LM, Harris MH, Hunt SK, O'Brien JE, Supko JG, Asselin BL, Athale UH, Clavell LA, Cole PD, Kelly KM, Laverdiere C, Leclerc JM, Michon B, Schorin MA, Welch JJ, Lipshultz SE, Kutok JL, Blonquist TM, Neuberg DS, Sallan SE, Silverman LB. Intravenous pegylated asparaginase versus intramuscular native Escherichia coli L-asparaginase in newly diagnosed childhood acute lymphoblastic leukaemia (DFCI 05-001): a randomised, open-label phase 3 trial. Lancet Oncol. 2015 Dec;16(16):1677-90. Epub 2015 Nov 6. link to original article PubMed NCT00400946
- Pooled update: Burns MA, Place AE, Stevenson KE, Gutiérrez A, Forrest S, Pikman Y, Vrooman LM, Harris MH, Hunt SK, O'Brien JE, Asselin BL, Athale UH, Clavell LA, Cole PD, Gennarini LM, Kahn JM, Kelly KM, Laverdiere C, Leclerc JM, Michon B, Schorin MA, Sulis ML, Welch JJG, Neuberg DS, Sallan SE, Silverman LB. Identification of prognostic factors in childhood T-cell acute lymphoblastic leukemia: Results from DFCI ALL Consortium Protocols 05-001 and 11-001. Pediatr Blood Cancer. 2021 Jan;68(1):e28719. Epub 2020 Oct 7. Erratum in: Pediatr Blood Cancer. 2021 Mar;68(3):e28885. link to original article contains dosing details in supplement link to PMC article PubMed
- 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
- 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
- Pegaspargase (Oncaspar) 2500 units/m2 IV once on day 4
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
Glucocorticoid therapy
- Dexamethasone (Decadron) 3 mg/m2 PO twice per day on days 1 to 28
CNS therapy, prophylaxis
- Cytarabine (Ara-C) IT once at some point between days -2 and 1
- Methotrexate (MTX) IT once per day on days 8 & 29
35-day course
Subsequent treatment
- COG AALL0331, M2 marrow or M1 marrow with MRD of at least 1% at day 29: Extended induction
- COG AALL0932: 6-MP & Vincristine consolidation
References
- COG AALL0331: Maloney KW, Devidas M, Wang C, Mattano LA, Friedmann AM, Buckley P, Borowitz MJ, Carroll AJ, Gastier-Foster JM, Heerema NA, Kadan-Lottick N, Loh ML, Matloub YH, Marshall DT, Stork LC, Raetz EA, Wood B, Hunger SP, Carroll WL, Winick NJ. Outcome in Children With Standard-Risk B-Cell Acute Lymphoblastic Leukemia: Results of Children's Oncology Group Trial AALL0331. J Clin Oncol. 2020 Feb 20;38(6):602-612. Epub 2019 Dec 11. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00103285
- COG AALL0932: Angiolillo AL, Schore RJ, Kairalla JA, Devidas M, Rabin KR, Zweidler-McKay P, Borowitz MJ, Wood B, Carroll AJ, Heerema NA, Relling MV, Hitzler J, Lane AR, Maloney KW, Wang C, Bassal M, Carroll WL, Winick NJ, Raetz EA, Loh ML, Hunger SP. Excellent Outcomes With Reduced Frequency of Vincristine and Dexamethasone Pulses in Standard-Risk B-Lymphoblastic Leukemia: Results From Children's Oncology Group AALL0932. J Clin Oncol. 2021 May 1;39(13):1437-1447. Epub 2021 Jan 7. link to original article 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
- 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
- POG 9005: L-asparaginase, Vincristine, Prednisone induction
- POG 9006: DOLP induction
Chemotherapy
- Mercaptopurine (6-MP) 1000 mg/m2 IV over 6 hours once on day 1, then 50 mg/m2 PO once per day on days 8 to 14
- Methotrexate (MTX) 1000 mg/m2 IV continuous infusion over 24 hours, started on day 1, then 20 mg/m2 IM once on day 8
Supportive therapy
- Leucovorin (Folinic acid) 5 mg/m2 (route not specified) every 6 hours for at least 5 doses, started 48 hours after start of methotrexate and continued until methotrexate level less than 0.1 Lmol/L
14-day cycle for 12 cycles
Subsequent treatment
- POG 9005: 6-MP & MTX continuation
- POG 9006: 6-MP & MTX maintenance
References
- POG 9005: Mahoney DH Jr, Shuster J, Nitschke R, Lauer SJ, Winick N, Steuber CP, Camitta B. Intermediate-dose intravenous methotrexate with intravenous mercaptopurine is superior to repetitive low-dose oral methotrexate with intravenous mercaptopurine for children with lower-risk B-lineage acute lymphoblastic leukemia: a Pediatric Oncology Group phase III trial. J Clin Oncol. 1998 Jan;16(1):246-54. link to original article contains dosing details in manuscript PubMed
- 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
- Cyclophosphamide (Cytoxan) 1000 mg/m2 IV once per day on days 1 & 29
- Cytarabine (Ara-C) 75 mg/m2 IV or SC once per day on days 1 to 4, 8 to 11, 29 to 32, 36 to 39
- Mercaptopurine (6-MP) 60 mg/m2 PO once per day on days 1 to 14, 29 to 42
- Pegaspargase (Oncaspar) 2500 units/m2 IM or IV once per day on days 15 & 43
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 15, 22, 43, 50
50-day course
Subsequent treatment
- 6-MP, Capizzi MTX, Pegaspargase, Vincristine interim maintenance versus 6-MP, HD-MTX, Vincristine interim maintenance
References
- COG AALL0232: Larsen EC, Devidas M, Chen S, Salzer WL, Raetz EA, Loh ML, Mattano LA Jr, Cole C, Eicher A, Haugan M, Sorenson M, Heerema NA, Carroll AA, Gastier-Foster JM, Borowitz MJ, Wood BL, Willman CL, Winick NJ, Hunger SP, Carroll WL. Dexamethasone and high-dose methotrexate improve outcome for children and young adults with high-risk B-acute lymphoblastic leukemia: a report from Children's Oncology Group study AALL0232. J Clin Oncol. 2016 Jul 10;34(20):2380-8. Epub 2016 Apr 25. link to original article link to PMC article 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.
References
- Nachman JB, Sather HN, Sensel MG, Trigg ME, Cherlow JM, Lukens JN, Wolff L, Uckun FM, Gaynon PS. Augmented post-induction therapy for children with high-risk acute lymphoblastic leukemia and a slow response to initial therapy. N Engl J Med. 1998 Jun 4;338(23):1663-71. link to original article 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
- 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: 4.5 Gy once per day on days -5 & -4 (9 Gy total)
- Other studies: 10 to 12 Gy total
Immunotherapy
- Allogeneic stem cells transfused on day 0
References
- Thomas ED, Sanders JE, Flournoy N, Johnson FL, Buckner CD, Clift RA, Fefer A, Goodell BW, Storb R, Weiden PL. Marrow transplantation for patients with acute lymphoblastic leukemia in remission. Blood. 1979 Aug;54(2):468-76. link to original article 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
- 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 10 Gy (total dose: 1200 cGy)
Immunotherapy
- Allogeneic stem cells transfused on day 0
References
- Balduzzi A, Valsecchi MG, Uderzo C, De Lorenzo P, Klingebiel T, Peters C, Stary J, Felice MS, Magyarosy E, Conter V, Reiter A, Messina C, Gadner H, Schrappe M. Chemotherapy versus allogeneic transplantation for very-high-risk childhood acute lymphoblastic leukaemia in first complete remission: comparison by genetic randomisation in an international prospective study. Lancet. 2005 Aug 20-26;366(9486):635-42. link to original article contains dosing details in manuscript PubMed
- 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
- Pegaspargase, Vincristine, Dexamethasone induction
Chemotherapy
- Mercaptopurine (6-MP) 75 mg/m2/day PO on days 1 to 28
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once on day 1
CNS therapy, prophylaxis
- Methotrexate (MTX) IT once per day on days 1, 8, 15
28-day course
Subsequent treatment
- MTX & Vincristine interim maintenance
References
- COG AALL0932: Angiolillo AL, Schore RJ, Kairalla JA, Devidas M, Rabin KR, Zweidler-McKay P, Borowitz MJ, Wood B, Carroll AJ, Heerema NA, Relling MV, Hitzler J, Lane AR, Maloney KW, Wang C, Bassal M, Carroll WL, Winick NJ, Raetz EA, Loh ML, Hunger SP. Excellent Outcomes With Reduced Frequency of Vincristine and Dexamethasone Pulses in Standard-Risk B-Lymphoblastic Leukemia: Results From Children's Oncology Group AALL0932. J Clin Oncol. 2021 May 1;39(13):1437-1447. Epub 2021 Jan 7. link to original article 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
- Mercaptopurine (6-MP) 25 mg/m2 PO once per day on days 1 to 56
- Methotrexate (MTX) 5000 mg/m2 IV once per day on days 1, 15, 29, 43
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 15, 29, 43
CNS therapy
- Methotrexate (MTX) once per day on days 1 & 29
References
- COG AALL0232: Larsen EC, Devidas M, Chen S, Salzer WL, Raetz EA, Loh ML, Mattano LA Jr, Cole C, Eicher A, Haugan M, Sorenson M, Heerema NA, Carroll AA, Gastier-Foster JM, Borowitz MJ, Wood BL, Willman CL, Winick NJ, Hunger SP, Carroll WL. Dexamethasone and high-dose methotrexate improve outcome for children and young adults with high-risk B-acute lymphoblastic leukemia: a report from Children's Oncology Group study AALL0232. J Clin Oncol. 2016 Jul 10;34(20):2380-8. Epub 2016 Apr 25. link to original article link to PMC article 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
- COG AALL0932: 6-MP & Vincristine consolidation
Chemotherapy
- Methotrexate (MTX) 100 mg/m2 IV once on day 1, then 150 mg/m2 IV once on day 11, then 200 mg/m2 IV once on day 21, then 250 mg/m2 IV once on day 31, then 300 mg/m2 IV once on day 41
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 11, 21, 31, 41
CNS therapy, prophylaxis
- Methotrexate (MTX) IT once on day 31
8-week course
Subsequent treatment
- COG AALL0932: AALL0932 delayed intensification
References
- COG CCG-1991: Matloub Y, Bostrom BC, Hunger SP, Stork LC, Angiolillo A, Sather H, La M, Gastier-Foster JM, Heerema NA, Sailer S, Buckley PJ, Thomson B, Cole C, Nachman JB, Reaman G, Winick N, Carroll WL, Devidas M, Gaynon PS. Escalating intravenous methotrexate improves event-free survival in children with standard-risk acute lymphoblastic leukemia: a report from the Children's Oncology Group. Blood. 2011 Jul 14;118(2):243-51. Epub 2011 May 11. link to original article link to PMC article PubMed NCT00005945
- COG AALL0932: Angiolillo AL, Schore RJ, Kairalla JA, Devidas M, Rabin KR, Zweidler-McKay P, Borowitz MJ, Wood B, Carroll AJ, Heerema NA, Relling MV, Hitzler J, Lane AR, Maloney KW, Wang C, Bassal M, Carroll WL, Winick NJ, Raetz EA, Loh ML, Hunger SP. Excellent Outcomes With Reduced Frequency of Vincristine and Dexamethasone Pulses in Standard-Risk B-Lymphoblastic Leukemia: Results From Children's Oncology Group AALL0932. J Clin Oncol. 2021 May 1;39(13):1437-1447. Epub 2021 Jan 7. link to original article 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
- MTX & Vincristine interim maintenance
Chemotherapy
- Cyclophosphamide (Cytoxan) 1000 mg/m2 IV once on day 29
- Cytarabine (Ara-C) 75 mg/m2/day SC or IV on days 29 to 32, 36 to 39
- Doxorubicin (Adriamycin) 25 mg/m2 IV once per day on days 1, 8, 15
- Pegaspargase (Oncaspar) 2500 units/m2 IV once on day 4
- Thioguanine (Tabloid) 60 mg/m2/day PO on days 29 to 42
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 8, 15
Glucocorticoid therapy
- Dexamethasone (Decadron) 10 mg/m2/day PO on days 1 to 7, 15 to 21
CNS therapy, prophylaxis
- Methotrexate (MTX) IT once per day on days 1 & 29
8-week course
Subsequent treatment
- MTX & Vincristine interim maintenance II
References
- COG AALL0932: Angiolillo AL, Schore RJ, Kairalla JA, Devidas M, Rabin KR, Zweidler-McKay P, Borowitz MJ, Wood B, Carroll AJ, Heerema NA, Relling MV, Hitzler J, Lane AR, Maloney KW, Wang C, Bassal M, Carroll WL, Winick NJ, Raetz EA, Loh ML, Hunger SP. Excellent Outcomes With Reduced Frequency of Vincristine and Dexamethasone Pulses in Standard-Risk B-Lymphoblastic Leukemia: Results From Children's Oncology Group AALL0932. J Clin Oncol. 2021 May 1;39(13):1437-1447. Epub 2021 Jan 7. link to original article 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
- Methotrexate (MTX) IT once per day on days 1 & 31
8-week course
Subsequent treatment
- Randomization to one of four maintenance arms; see paper for details.
References
- COG AALL0932: Angiolillo AL, Schore RJ, Kairalla JA, Devidas M, Rabin KR, Zweidler-McKay P, Borowitz MJ, Wood B, Carroll AJ, Heerema NA, Relling MV, Hitzler J, Lane AR, Maloney KW, Wang C, Bassal M, Carroll WL, Winick NJ, Raetz EA, Loh ML, Hunger SP. Excellent Outcomes With Reduced Frequency of Vincristine and Dexamethasone Pulses in Standard-Risk B-Lymphoblastic Leukemia: Results From Children's Oncology Group AALL0932. J Clin Oncol. 2021 May 1;39(13):1437-1447. Epub 2021 Jan 7. link to original article 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
- Mercaptopurine (6-MP) 50 mg/m2 PO once per day
- Methotrexate (MTX) 20 mg/m2 PO once on day 1
7-day cycle for 74 cycles or a total of 2 years from start of treatment
References
- EORTC 58881: Millot F, Suciu S, Philippe N, Benoit Y, Mazingue F, Uyttebroeck A, Lutz P, Mechinaud F, Robert A, Boutard P, Marguerite G, Ferster A, Plouvier E, Rialland X, Behard C, Plantaz D, Dresse MF, Philippet P, Norton L, Thyss A, Dastugue N, Waterkeyn C, Vilmer E, Otten J; Children's Leukemia Cooperative Group of the European Organiztaion for Research and Treatment of Cancer. Value of high-dose cytarabine during interval therapy of a Berlin-Frankfurt-Munster-based protocol in increased-risk children with acute lymphoblastic leukemia and lymphoblastic lymphoma: results of the European Organisation for Research and Treatment of Cancer 58881 randomized phase III trial. J Clin Oncol. 2001 Apr 1;19(7):1935-42. link to original article PubMed
- 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
- 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
- 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
- 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
- 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
- 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
- Clofarabine (Clolar) 40 mg/m2 IV over 2 hours once per day on days 1 to 5, given first
- Cyclophosphamide (Cytoxan) 400 mg/m2 IV over 60 minutes once per day on days 1 to 5
- Etoposide (Vepesid) 150 mg/m2 IV over 2 hours once per day on days 1 to 5
Supportive therapy
- Prophylactic steroids used for patients with greater than 30 x 109 blasts/L in the peripheral blood prior to treatment
5-day course 2 out of 25 patients received a second course of CCE as consolidation therapy. Responding patients were given allogeneic HSCT if a suitable donor was immediately available or were given consolidation courses of chemotherapy including multiple agents active against ALL cells, chosen according to the treating physician's preference."
References
- Locatelli F, Testi AM, Bernardo ME, Rizzari C, Bertaina A, Merli P, Pession A, Giraldi E, Parasole R, Barberi W, Zecca M. Clofarabine, cyclophosphamide and etoposide as single-course re-induction therapy for children with refractory/multiple relapsed acute lymphoblastic leukaemia. Br J Haematol. 2009 Nov;147(3):371-8. Epub 2009 Aug 29. link to original article 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
- Clofarabine (Clolar) 52 mg/m2 IV over 2 hours once per day on days 1 to 5
2- to 6-week cycles, depending on response count recovery
References
- Jeha S, Gandhi V, Chan KW, McDonald L, Ramirez I, Madden R, Rytting M, Brandt M, Keating M, Plunkett W, Kantarjian H. Clofarabine, a novel nucleoside analog, is active in pediatric patients with advanced leukemia. Blood. 2004 Feb 1;103(3):784-9. Epub 2003 Oct 9. link to original article PubMed
- 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
- 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
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
- Pegaspargase (Oncaspar) 2500 units/m2 IM once per day on days 2, 9, 16, 23
- Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
Glucocorticoid therapy
- Prednisone (Sterapred) 40 mg/m2/day PO on days 1 to 29
CNS therapy, prophylaxis (CNS-)
- Methotrexate (MTX) once per day on days 8 & 29
CNS therapy, treatment (CNS+)
5-week course
Subsequent treatment
- See papers for details of treatment beyond induction block 1
References
- POG 9310: Abshire TC, Pollock BH, Billett AL, Bradley P, Buchanan GR. Weekly polyethylene glycol conjugated L-asparaginase compared with biweekly dosing produces superior induction remission rates in childhood relapsed acute lymphoblastic leukemia: a Pediatric Oncology Group Study. Blood. 2000 Sep 1;96(5):1709-15. link to original article PubMed
- 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
- 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
- Inotuzumab ozogamicin (Besponsa) 0.8 mg/m2 IV once on day 1, then 0.5 mg/m2 IV once per day on days 8 & 15
21-day course, then 28-day cycle for up to 5 cycles
Dose and schedule modifications
- If patients achieved a CR or CRi, the day 1 dose was reduced to 0.5 mg/m2 for all subsequent cycles.
References
- MDACC 2009-0872: Kantarjian H, Thomas D, Jorgensen J, Jabbour E, Kebriaei P, Rytting M, York S, Ravandi F, Kwari M, Faderl S, Rios MB, Cortes J, Fayad L, Tarnai R, Wang SA, Champlin R, Advani A, O'Brien S. Inotuzumab ozogamicin, an anti-CD22-calecheamicin conjugate, for refractory and relapsed acute lymphocytic leukaemia: a phase 2 study. Lancet Oncol. 2012 Apr;13(4):403-11. Epub 2012 Feb 21. link to original article 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
- Mitoxantrone (Novantrone) 10 mg/m2 IV once per day on days 1 & 8
- Asparaginase Erwinia chrysanthemi (Erwinaze) 20,000 units IM once per day on days 3, 5, 7, 9, 11, 13, 18, 20, 22, 24, 26, 28
- Vincristine (Oncovin) 1.5 mg/m2 IV once per day on days 3, 10, 17, 24
Glucocorticoid therapy
- Dexamethasone (Decadron) 20 mg/m2 PO once per day on days 1 to 5, 15 to 19
CNS therapy, prophylaxis
- Methotrexate (MTX) by the following age-based criteria:
- Younger than 2 years old: 8 mg IT once per day on days 1 & 8
- 2 years old: 10 mg IT once per day on days 1 & 8
- Older than 2 years old: 12 mg IT once per day on days 1 & 8
4-week course
Subsequent treatment
- See paper for details of treatment beyond induction
References
- CCLG ALL R3: Parker C, Waters R, Leighton C, Hancock J, Sutton R, Moorman AV, Ancliff P, Morgan M, Masurekar A, Goulden N, Green N, Révész T, Darbyshire P, Love S, Saha V. Effect of mitoxantrone on outcome of children with first relapse of acute lymphoblastic leukaemia (ALL R3): an open-label randomised trial. Lancet. 2010 Dec 11;376(9757):2009-17. Epub 2010 Dec 3. link to original article 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
- Mitoxantrone (Novantrone) 10 mg/m2 IV once per day on days 1 & 8
- Pegaspargase (Oncaspar) 1000 units/m2 IM once per day on days 3 & 18
- Vincristine (Oncovin) 1.5 mg/m2 IV once per day on days 3, 10, 17, 24
Glucocorticoid therapy
- Dexamethasone (Decadron) 20 mg/m2 PO once per day on days 1 to 5, 15 to 19
CNS therapy, prophylaxis
- Methotrexate (MTX) by the following age-based criteria:
- Younger than 2 years old: 8 mg IT once per day on days 1 & 8
- 2 years old: 10 mg IT once per day on days 1 & 8
- Older than 2 years old: 12 mg IT once per day on days 1 & 8
4-week course
Subsequent treatment
- See paper for details of treatment beyond induction
References
- CCLG ALL R3: Parker C, Waters R, Leighton C, Hancock J, Sutton R, Moorman AV, Ancliff P, Morgan M, Masurekar A, Goulden N, Green N, Révész T, Darbyshire P, Love S, Saha V. Effect of mitoxantrone on outcome of children with first relapse of acute lymphoblastic leukaemia (ALL R3): an open-label randomised trial. Lancet. 2010 Dec 11;376(9757):2009-17. Epub 2010 Dec 3. link to original article 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.
Immunotherapy
- Tisagenlecleucel (Kymriah) by the following weight-based criteria:
- Up to 50 kg: 2 to 5 x 106 CTL019 transduced viable T-cells per kg body weight IV once on day 0
- More than 50 kg: 1.0 to 2.5 x 108 CTL019 transduced viable T-cells IV once on day 0
One course
References
- Pedi CART19: Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, Teachey DT, Chew A, Hauck B, Wright JF, Milone MC, Levine BL, June CH. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med. 2013 Apr 18;368(16):1509-1518. Epub 2013 Mar 25. Erratum in: N Engl J Med. 2016 Mar 10;374(10):998. link to original article link to PMC article PubMed NCT01626495
- UPCC04409: Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, Chew A, Gonzalez VE, Zheng Z, Lacey SF, Mahnke YD, Melenhorst JJ, Rheingold SR, Shen A, Teachey DT, Levine BL, June CH, Porter DL, Grupp SA. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014 Oct 16;371(16):1507-17. Erratum in: N Engl J Med. 2016 Mar 10;374(10):998. link to original article link to PMC article PubMed NCT01029366
- ELIANA: Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, Bader P, Verneris MR, Stefanski HE, Myers GD, Qayed M, De Moerloose B, Hiramatsu H, Schlis K, Davis KL, Martin PL, Nemecek ER, Yanik GA, Peters C, Baruchel A, Boissel N, Mechinaud F, Balduzzi A, Krueger J, June CH, Levine BL, Wood P, Taran T, Leung M, Mueller KT, Zhang Y, Sen K, Lebwohl D, Pulsipher MA, Grupp SA. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018 Feb 1;378(5):439-448. link to original article link to supplementary protocol contains dosing details in supplement link to PMC article PubMed NCT02435849
- Update: Laetsch TW, Maude SL, Rives S, Hiramatsu H, Bittencourt H, Bader P, Baruchel A, Boyer M, De Moerloose B, Qayed M, Buechner J, Pulsipher MA, Myers GD, Stefanski HE, Martin PL, Nemecek E, Peters C, Yanik G, Khaw SL, Davis KL, Krueger J, Balduzzi A, Boissel N, Tiwari R, O'Donovan D, Grupp SA. Three-Year Update of Tisagenlecleucel in Pediatric and Young Adult Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia in the ELIANA Trial. J Clin Oncol. 2023 Mar 20;41(9):1664-1669. Epub 2022 Nov 18. link to original article link to PMC article 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
- UKALLR3 salvage re-induction
Immunotherapy
Subsequent treatment
References
- COG AALL1331: Brown PA, Ji L, Xu X, Devidas M, Hogan LE, Borowitz MJ, Raetz EA, Zugmaier G, Sharon E, Bernhardt MB, Terezakis SA, Gore L, Whitlock JA, Pulsipher MA, Hunger SP, Loh ML. Effect of Postreinduction Therapy Consolidation With Blinatumomab vs Chemotherapy on Disease-Free Survival in Children, Adolescents, and Young Adults With First Relapse of B-Cell Acute Lymphoblastic Leukemia: A Randomized Clinical Trial. JAMA. 2021 Mar 2;325(9):833-842. link to original article link to PMC article PubMed NCT02101853
- Amgen 20120215: Locatelli F, Zugmaier G, Rizzari C, Morris JD, Gruhn B, Klingebiel T, Parasole R, Linderkamp C, Flotho C, Petit A, Micalizzi C, Mergen N, Mohammad A, Kormany WN, Eckert C, Möricke A, Sartor M, Hrusak O, Peters C, Saha V, Vinti L, von Stackelberg A. Effect of Blinatumomab vs Chemotherapy on Event-Free Survival Among Children With High-risk First-Relapse B-Cell Acute Lymphoblastic Leukemia: A Randomized Clinical Trial. JAMA. 2021 Mar 2;325(9):843-854. link to original article contains dosing details in abstract link to PMC article PubMed NCT02393859
- COG AALL1331 LR relapse: Hogan LE, Brown PA, Ji L, Xu X, Devidas M, Bhatla T, Borowitz MJ, Raetz EA, Carroll A, Heerema NA, Zugmaier G, Sharon E, Bernhardt MB, Terezakis SA, Gore L, Whitlock JA, Hunger SP, Loh ML. Children's Oncology Group AALL1331: Phase III Trial of Blinatumomab in Children, Adolescents, and Young Adults With Low-Risk B-Cell ALL in First Relapse. J Clin Oncol. 2023 Sep 1;41(25):4118-4129. Epub 2023 May 31. link to original article 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
- 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: 4.5 Gy once per day on days -5 & -4 (9 Gy total)
- Other studies: 10 to 12 Gy total
Immunotherapy
- Allogeneic stem cells transfused on day 0
References
- Johnson FL, Thomas ED, Clark BS, Chard RL, Hartmann JR, Storb R. A comparison of marrow transplantation with chemotherapy for children with acute lymphoblastic leukemia in second or subsequent remission. N Engl J Med. 1981 Oct 8;305(15):846-51. link to original article PubMed
- 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