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	David Noyd, MD, MPH University of Washington Seattle, WA, USA LinkedIn

This page contains studies that are specific to pediatric populations. For the more general B-cell acute lymphoblastic leukemia page, including regimens for adolescents and young adults, follow this link.
Are you looking for a regimen but can't find it here? It is possible that we've moved it to the historical regimens page. For placebo or observational studies in this condition, please visit this page.
Note: certain regimens are to be found on dedicated pages:

Pediatric B-cell ALL, Ph-positive

Infant ALL

34 regimens on this page 40 variants on this page

Guidelines

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

NCCN

NCCN does not currently have guidelines at this granular level; please see NCCN Guidelines - Pediatric Acute Lymphoblastic Leukemia.

Upfront therapy

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

63-day course

Delayed Intensification

Chemotherapy

Doxorubicin (Adriamycin) 25 mg/m² IV push over 1 to 15 minutes once per day on days 1, 8, 15
Pegaspargase (Oncaspar) 2,500 units/m² IV over 1 to 2 hours once on day 4, 43
Vincristine (Oncovin) 1.5 mg/m² (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 43, 50
Cyclophosphamide (Cytoxan) 1000 mg/m² IV over 30 to 60 minutes once on day 29 ONLY
Cytarabine (Ara-C) 75 mg/m² SC or IV over 1 to 30 minutes on days 29 to 32, 36 to 39
Thioguanine (Tabloid) 60 mg/m² PO once per day on days 29 to 42

Glucocorticoid therapy

Dexamethasone (Decadron) 5 mg/m² IV or PO twice per day on days 1 to 7, 15 to 21

CNS therapy, prophylaxis

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

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

56-day course

Interim Maintenance, II with Capizzi MTX

Chemotherapy

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

CNS therapy, prophylaxis

Methotrexate (MTX) IT once per day on days 1, 31

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

56-day course

Maintenance, VHR Arm

Radiotherapy

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

Chemotherapy

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

Glucocorticoid therapy

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

CNS therapy, prophylaxis

Methotrexate (MTX) IT once per day on day 1 (also Day 29 of cycles 1 and 2, for patients who did NOT receive CNS Radiation)

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

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

References

COG AALL1131: Burke MJ, Salzer WL, Devidas M, Dai Y, Gore L, Hilden JM, Larsen E, Rabin KR, Zweidler-McKay PA, Borowitz MJ, Wood B, Heerema NA, Carroll AJ, Winick N, Carroll WL, Raetz EA, Loh ML, Hunger SP. Replacing cyclophosphamide/cytarabine/mercaptopurine with cyclophosphamide/etoposide during consolidation/delayed intensification does not improve outcomes for pediatric B-cell acute lymphoblastic leukemia: a report from the COG. Haematologica. 2019 May;104(5):986-992. Epub 2018 Dec 13. link to original article link to PMC article 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
1. Pooled update: Burns MA, Place AE, Stevenson KE, Gutiérrez A, Forrest S, Pikman Y, Vrooman LM, Harris MH, Hunt SK, O'Brien JE, Asselin BL, Athale UH, Clavell LA, Cole PD, Gennarini LM, Kahn JM, Kelly KM, Laverdiere C, Leclerc JM, Michon B, Schorin MA, Sulis ML, Welch JJG, Neuberg DS, Sallan SE, Silverman LB. Identification of prognostic factors in childhood T-cell acute lymphoblastic leukemia: Results from DFCI ALL Consortium Protocols 05-001 and 11-001. Pediatr Blood Cancer. 2021 Jan;68(1):e28719. Epub 2020 Oct 7. Erratum in: Pediatr Blood Cancer. 2021 Mar;68(3):e28885. link to original article contains dosing details in supplement link to PMC article PubMed
DFCI 11-001: Burns MA, Place AE, Stevenson KE, Gutiérrez A, Forrest S, Pikman Y, Vrooman LM, Harris MH, Hunt SK, O'Brien JE, Asselin BL, Athale UH, Clavell LA, Cole PD, Gennarini LM, Kahn JM, Kelly KM, Laverdiere C, Leclerc JM, Michon B, Schorin MA, Sulis ML, Welch JJG, Neuberg DS, Sallan SE, Silverman LB. Identification of prognostic factors in childhood T-cell acute lymphoblastic leukemia: Results from DFCI ALL Consortium Protocols 05-001 and 11-001. Pediatr Blood Cancer. 2021 Jan;68(1):e28719. Epub 2020 Oct 7. Erratum in: Pediatr Blood Cancer. 2021 Mar;68(3):e28885. link to original article contains dosing details in supplement link to PMC article PubMed NCT01574274
1. Update: Vrooman LM, Blonquist TM, Stevenson KE, Supko JG, Hunt SK, Cronholm SM, Koch V, Kay-Green S, Athale UH, Clavell LA, Cole PD, Harris MH, Kelly KM, Laverdiere C, Leclerc JM, Michon B, Place AE, Schorin MA, Welch JJG, Neuberg DS, Sallan SE, Silverman LB. Efficacy and Toxicity of Pegaspargase and Calaspargase Pegol in Childhood Acute Lymphoblastic Leukemia: Results of DFCI 11-001. J Clin Oncol. 2021 Nov 1;39(31):3496-3505. Epub 2021 Jul 6. link to original article PubMed

Prednisone monotherapy

Regimen

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

Glucocorticoid therapy

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

CNS therapy, prophylaxis

Methotrexate (MTX) 15 mg IT once on day 1

7-day course

Subsequent treatment

Daunorubicin, L-Asparaginase, Vincristine, Prednisone versus Daunorubicin, L-Asparaginase, Vincristine, Dexamethasone induction

References

AIEOP-BFM ALL 2000: Möricke A, Zimmermann M, Valsecchi MG, Stanulla M, Biondi A, Mann G, Locatelli F, Cazzaniga G, Niggli F, Aricò M, Bartram CR, Attarbaschi A, Silvestri D, Beier R, Basso G, Ratei R, Kulozik AE, Lo Nigro L, Kremens B, Greiner J, Parasole R, Harbott J, Caruso R, von Stackelberg A, Barisone E, Rössig C, Conter V, Schrappe M. Dexamethasone vs prednisone in induction treatment of pediatric ALL: results of the randomized trial AIEOP-BFM ALL 2000. Blood. 2016 Apr 28;127(17):2101-12. Epub 2016 Feb 17. link to original article 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	Dates of enrollment	Evidence
Schrappe et al. 2000 (ALL-BFM 90)	1990-04-01 to 1995-03-31	Non-randomized
Kamps et al. 2002 (DCLSG ALL-8)	1991-10 to 1996-12	Non-randomized

Note: see papers for details on dose adjustments based on risk.

Chemotherapy

Daunorubicin (Cerubidine) 30 mg/m² IV over 60 minutes once per day on days 8, 15, 22, 29
Vincristine (Oncovin) 1.5 mg/m² (maximum dose of 2 mg) IV once per day on days 8, 15, 22, 29
Asparaginase (Elspar) 10,000 units IV over 60 minutes once per day on days 12, 15, 18, 21, 24, 27, 30, 33

Glucocorticoid therapy

Prednisone (Sterapred) 60 mg/m²/day PO on days 1 to 28

CNS therapy

Methotrexate (MTX) 12 mg IT once per day on days 1, 15, 29

5-week course

Subsequent treatment

See papers for details

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

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

Chemotherapy

Daunorubicin (Cerubidine) 40 mg/m² IV once per day on days 8, 15, 22, 29
Vincristine (Oncovin) 1.5 mg/m² (maximum dose of 2 mg) IV once per day on days 8, 15, 22, 29
Asparaginase (Elspar) 10,000 units/m² IV once per day on days 19, 22, 25, 28, 31, 34, 37, 40

Glucocorticoid therapy

Prednisone (Sterapred) 60 mg/m²/day PO on days 1 to 28

6-week course

Subsequent treatment

ALL-BFM 86 & DCLSG ALL-7, standard-risk group (SRG) and risk group (RG): 6-MP & MTX consolidation
ALL-BFM 86 & DCLSG ALL-7, experimental group (EG): Cytarabine, Ifosfamide, MTX, Mitoxantrone, Prednisone consolidation

References

ALL-BFM 86: Reiter A, Schrappe M, Ludwig WD, Hiddemann W, Sauter S, Henze G, Zimmermann M, Lampert F, Havers W, Niethammer D, Odenwald E, Ritter J, Mann G, Welte K, Gadner H, Riehm H. Chemotherapy in 998 unselected childhood acute lymphoblastic leukemia patients: results and conclusions of the multicenter trial ALL-BFM 86. Blood. 1994 Nov 1;84(9):3122-33. link to original article 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
1. Pooled subgroup analysis: Schrauder A, Reiter A, Gadner H, Niethammer D, Klingebiel T, Kremens B, Peters C, Ebell W, Zimmermann M, Niggli F, Ludwig WD, Riehm H, Welte K, Schrappe M. Superiority of allogeneic hematopoietic stem-cell transplantation compared with chemotherapy alone in high-risk childhood T-cell acute lymphoblastic leukemia: results from ALL-BFM 90 and 95. J Clin Oncol. 2006 Dec 20;24(36):5742-9. link to original article PubMed
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
1. Pooled subgroup analysis: Schrauder A, Reiter A, Gadner H, Niethammer D, Klingebiel T, Kremens B, Peters C, Ebell W, Zimmermann M, Niggli F, Ludwig WD, Riehm H, Welte K, Schrappe M. Superiority of allogeneic hematopoietic stem-cell transplantation compared with chemotherapy alone in high-risk childhood T-cell acute lymphoblastic leukemia: results from ALL-BFM 90 and 95. J Clin Oncol. 2006 Dec 20;24(36):5742-9. link to original article PubMed
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
1. Update: Conter V, Valsecchi MG, Cario G, Zimmermann M, Attarbaschi A, Stary J, Niggli F, Dalla Pozza L, Elitzur S, Silvestri D, Locatelli F, Möricke A, Engstler G, Smisek P, Bodmer N, Barbaric D, Izraeli S, Rizzari C, Boos J, Buldini B, Zucchetti M, von Stackelberg A, Matteo C, Lehrnbecher T, Lanvers-Kaminsky C, Cazzaniga G, Gruhn B, Biondi A, Schrappe M. Four Additional Doses of PEG-L-Asparaginase During the Consolidation Phase in the AIEOP-BFM ALL 2009 Protocol Do Not Improve Outcome and Increase Toxicity in High-Risk ALL: Results of a Randomized Study. J Clin Oncol. 2024 Mar 10;42(8):915-926. Epub 2023 Dec 14. link to original article PubMed

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
1. Update: Chessells JM, Bailey C, Richards SM; Medical Research Council Working Party on Childhood Leukaemia. Intensification of treatment and survival in all children with lymphoblastic leukaemia: results of UK Medical Research Council trial UKALL X. Lancet. 1995 Jan 21;345(8943):143-8. link to original article PubMed
EORTC CLG 58951: De Moerloose B, Suciu S, Bertrand Y, Mazingue F, Robert A, Uyttebroeck A, Yakouben K, Ferster A, Margueritte G, Lutz P, Munzer M, Sirvent N, Norton L, Boutard P, Plantaz D, Millot F, Philippet P, Baila L, Benoit Y, Otten J; Children's Leukemia Group of the European Organisation for Research and Treatment of Cancer. Improved outcome with pulses of vincristine and corticosteroids in continuation therapy of children with average risk acute lymphoblastic leukemia (ALL) and lymphoblastic non-Hodgkin lymphoma (NHL): report of the EORTC randomized phase 3 trial 58951. Blood. 2010 Jul 8;116(1):36-44. Epub 2010 Apr 20. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00003728
1. Update: Domenech C, Suciu S, De Moerloose B, Mazingue F, Plat G, Ferster A, Uyttebroeck A, Sirvent N, Lutz P, Yakouben K, Munzer M, Röhrlich P, Plantaz D, Millot F, Philippet P, Dastugue N, Girard S, Cavé H, Benoit Y, Bertrand Y; Children's Leukemia Group (CLG) of European Organisation for Research and Treatment of Cancer. Dexamethasone (6 mg/m²/day) and prednisolone (60 mg/m²/day) were equally effective as induction therapy for childhood acute lymphoblastic leukemia in the EORTC CLG 58951 randomized trial. Haematologica. 2014 Jul;99(7):1220-7. Epub 2014 Apr 11. link to original article link to PMC article PubMed
2. Update: Mondelaers V, Suciu S, De Moerloose B, Ferster A, Mazingue F, Plat G, Yakouben K, Uyttebroeck A, Lutz P, Costa V, Sirvent N, Plouvier E, Munzer M, Poirée M, Minckes O, Millot F, Plantaz D, Maes P, Hoyoux C, Cavé H, Rohrlich P, Bertrand Y, Benoit Y; Children's Leukemia Group (CLG) of the European Organisation for Research and Treatment of Cancer. Prolonged versus standard native E coli asparaginase therapy in childhood acute lymphoblastic leukemia and non-Hodgkin lymphoma: final results of the EORTC-CLG randomized phase III trial 58951. Haematologica. 2017 Oct;102(10):1727-1738. Epub 2017 Jul 27. link to original article link to PMC article PubMed

Doxorubicin, Mercaptopurine, Pegaspargase, Vincristine, Prednisolone

Regimen

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

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

Chemotherapy

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

Glucocorticoid therapy

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

CNS therapy, prophylaxis

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

5-week course

Subsequent treatment

See protocol for details of treatment beyond induction

References

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
1. Pooled update: Burns MA, Place AE, Stevenson KE, Gutiérrez A, Forrest S, Pikman Y, Vrooman LM, Harris MH, Hunt SK, O'Brien JE, Asselin BL, Athale UH, Clavell LA, Cole PD, Gennarini LM, Kahn JM, Kelly KM, Laverdiere C, Leclerc JM, Michon B, Schorin MA, Sulis ML, Welch JJG, Neuberg DS, Sallan SE, Silverman LB. Identification of prognostic factors in childhood T-cell acute lymphoblastic leukemia: Results from DFCI ALL Consortium Protocols 05-001 and 11-001. Pediatr Blood Cancer. 2021 Jan;68(1):e28719. Epub 2020 Oct 7. Erratum in: Pediatr Blood Cancer. 2021 Mar;68(3):e28885. link to original article contains dosing details in supplement link to PMC article PubMed
DFCI 11-001: Burns MA, Place AE, Stevenson KE, Gutiérrez A, Forrest S, Pikman Y, Vrooman LM, Harris MH, Hunt SK, O'Brien JE, Asselin BL, Athale UH, Clavell LA, Cole PD, Gennarini LM, Kahn JM, Kelly KM, Laverdiere C, Leclerc JM, Michon B, Schorin MA, Sulis ML, Welch JJG, Neuberg DS, Sallan SE, Silverman LB. Identification of prognostic factors in childhood T-cell acute lymphoblastic leukemia: Results from DFCI ALL Consortium Protocols 05-001 and 11-001. Pediatr Blood Cancer. 2021 Jan;68(1):e28719. Epub 2020 Oct 7. Erratum in: Pediatr Blood Cancer. 2021 Mar;68(3):e28885. link to original article contains dosing details in supplement link to PMC article PubMed NCT01574274
1. Update: Vrooman LM, Blonquist TM, Stevenson KE, Supko JG, Hunt SK, Cronholm SM, Koch V, Kay-Green S, Athale UH, Clavell LA, Cole PD, Harris MH, Kelly KM, Laverdiere C, Leclerc JM, Michon B, Place AE, Schorin MA, Welch JJG, Neuberg DS, Sallan SE, Silverman LB. Efficacy and Toxicity of Pegaspargase and Calaspargase Pegol in Childhood Acute Lymphoblastic Leukemia: Results of DFCI 11-001. J Clin Oncol. 2021 Nov 1;39(31):3496-3505. Epub 2021 Jul 6. link to original article PubMed

Pegaspargase, Vincristine, Dexamethasone

Regimen

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

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

Chemotherapy

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

Pegaspargase (Oncaspar) 2500 IU/m² IM once on day 3
Vincristine (Oncovin) 1.5 mg/m² IV once per day on days 0, 7, 14, 21

Glucocorticoid therapy

Prednisone (Sterapred) 40 mg/m²/day PO on days 0 to 28, then tapered off over 10 days

CNS prophylaxis

Cytarabine (Ara-C) IT once on day 0
Methotrexate (MTX) IT once per day on days 7 & 28

4-week course

Subsequent treatment

See protocol for details of treatment beyond induction

References

CCG 1962: Avramis VI, Sencer S, Periclou AP, Sather H, Bostrom BC, Cohen LJ, Ettinger AG, Ettinger LJ, Franklin J, Gaynon PS, Hilden JM, Lange B, Majlessipour F, Mathew P, Needle M, Neglia J, Reaman G, Holcenberg JS, Stork L. A randomized comparison of native Escherichia coli asparaginase and polyethylene glycol conjugated asparaginase for treatment of children with newly diagnosed standard-risk acute lymphoblastic leukemia: a Children's Cancer Group study. Blood. 2002 Mar 15;99(6):1986-94. Erratum in: Blood 2002 Sep 1;100(5):1531. link to original article contains dosing details in manuscript 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

Preceding treatment

BFM induction

Chemotherapy

Cyclophosphamide (Cytoxan) 1000 mg/m² IV once per day on days 0 & 28
Cytarabine (Ara-C) 75 mg/m² SC or IV once per day on days 1 to 4, 8 to 11, 29 to 32, 36 to 39
Mercaptopurine (6-MP) 60 mg/m²/day PO on days 0 to 13, 28 to 41
Vincristine (Oncovin) 1.5 mg/m² IV once per day on days 14, 21, 42, 49
Asparaginase (Elspar) 6000 units/m² IM once per day on days 14, 16, 18, 21, 23, 25, 42, 44, 46, 49, 51, 53

CNS prophylaxis

Methotrexate (MTX) IT once per day on days 1, 8, 15, 22
Craniocaudal and testicular irradiation

9-week course

Subsequent treatment

Interim maintenance I

References

Nachman JB, Sather HN, Sensel MG, Trigg ME, Cherlow JM, Lukens JN, Wolff L, Uckun FM, Gaynon PS. Augmented post-induction therapy for children with high-risk acute lymphoblastic leukemia and a slow response to initial therapy. N Engl J Med. 1998 Jun 4;338(23):1663-71. link to original article contains dosing details in manuscript 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: 450 cGy once per day on days -5 & -4 (900 cGy total)
- Other studies: 10 to 1200 cGy total

Immunotherapy

Allogeneic stem cells transfused on day 0

One course

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 variant #1, weight-based

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 1000 cGy (total dose: 1200 cGy)

Immunotherapy

Allogeneic stem cells transfused on day 0

One course

Regimen variant #2, BSA-based

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Peters et al. 2020 (FORUM)	2013-2018	Phase 3 (C)	1a. Busulfan, Fludarabine, Thiotepa 1b. Fludarabine, Thiotepa, Treosulfan	Superior OS (primary endpoint)

Chemotherapy

Etoposide (Vepesid) 1800 mg/m² (maximum dose of 3600 mg) IV once on day -3

Radiotherapy

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

Immunotherapy

Allogeneic stem cells transfused on day 0

One course

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
FORUM: Peters C, Dalle JH, Locatelli F, Poetschger U, Sedlacek P, Buechner J, Shaw PJ, Staciuk R, Ifversen M, Pichler H, Vettenranta K, Svec P, Aleinikova O, Stein J, Güngör T, Toporski J, Truong TH, Diaz-de-Heredia C, Bierings M, Ariffin H, Essa M, Burkhardt B, Schultz K, Meisel R, Lankester A, Ansari M, Schrappe M, von Stackelberg A, Balduzzi A, Corbacioglu S, Bader P; IBFM Study Group; IntReALL Study Group; I-BFM SCT Study Group; EBMT Paediatric Diseases Working Party. Total Body Irradiation or Chemotherapy Conditioning in Childhood ALL: A Multinational, Randomized, Noninferiority Phase III Study. J Clin Oncol. 2021 Feb 1;39(4):295-307. Epub 2020 Dec 17. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01949129

Mercaptopurine & Vincristine

Regimen

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

Preceding treatment

Pegaspargase, Vincristine, Dexamethasone induction

Chemotherapy

Mercaptopurine (6-MP) 75 mg/m²/day PO on days 1 to 28
Vincristine (Oncovin) 1.5 mg/m² (maximum dose of 2 mg) IV once on day 1

CNS therapy, prophylaxis

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

28-day course

Subsequent treatment

MTX & Vincristine interim maintenance

References

COG AALL0932: Angiolillo AL, Schore RJ, Kairalla JA, Devidas M, Rabin KR, Zweidler-McKay P, Borowitz MJ, Wood B, Carroll AJ, Heerema NA, Relling MV, Hitzler J, Lane AR, Maloney KW, Wang C, Bassal M, Carroll WL, Winick NJ, Raetz EA, Loh ML, Hunger SP. Excellent Outcomes With Reduced Frequency of Vincristine and Dexamethasone Pulses in Standard-Risk B-Lymphoblastic Leukemia: Results From Children's Oncology Group AALL0932. J Clin Oncol. 2021 May 1;39(13):1437-1447. Epub 2021 Jan 7. link to original article 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

AALL0932 delayed intensification

Chemotherapy

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

CNS therapy, prophylaxis

Methotrexate (MTX) IT once per day on days 1 & 31

8-week course

Subsequent treatment

Randomization to one of four maintenance arms; see paper for details.

References

COG AALL0932: Angiolillo AL, Schore RJ, Kairalla JA, Devidas M, Rabin KR, Zweidler-McKay P, Borowitz MJ, Wood B, Carroll AJ, Heerema NA, Relling MV, Hitzler J, Lane AR, Maloney KW, Wang C, Bassal M, Carroll WL, Winick NJ, Raetz EA, Loh ML, Hunger SP. Excellent Outcomes With Reduced Frequency of Vincristine and Dexamethasone Pulses in Standard-Risk B-Lymphoblastic Leukemia: Results From Children's Oncology Group AALL0932. J Clin Oncol. 2021 May 1;39(13):1437-1447. Epub 2021 Jan 7. link to original article 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 EFS120^a

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
1. Update: Duval M, Suciu S, Ferster A, Rialland X, Nelken B, Lutz P, Benoit Y, Robert A, Manel AM, Vilmer E, Otten J, Philippe N. Comparison of Escherichia coli-asparaginase with Erwinia-asparaginase in the treatment of childhood lymphoid malignancies: results of a randomized European Organisation for Research and Treatment of Cancer-Children's Leukemia Group phase 3 trial. Blood. 2002 Apr 15;99(8):2734-9. link to original article PubMed
2. Update: van der Werff Ten Bosch J, Suciu S, Thyss A, Bertrand Y, Norton L, Mazingue F, Uyttebroeck A, Lutz P, Robert A, Boutard P, Ferster A, Plouvier E, Maes P, Munzer M, Plantaz D, Dresse MF, Philippet P, Sirvent N, Waterkeyn C, Vilmer E, Philippe N, Otten J. Value of intravenous 6-mercaptopurine during continuation treatment in childhood acute lymphoblastic leukemia and non-Hodgkin's lymphoma: final results of a randomized phase III trial (58881) of the EORTC CLG. Leukemia. 2005 May;19(5):721-6. link to original article PubMed
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

Relapsed or refractory

Blinatumomab monotherapy

Regimen

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

Note: this is the MTD of a phase 1/2 trial enrolling children under the age of 18.

Immunotherapy

Blinatumomab (Blincyto) as follows:
- Cycle 1: 5 mcg/day IV continuous infusion over 7 days, started on day 1, then 15 mcg/day IV continuous infusion over 21 days, started on day 8 (total dose: 350 mcg)
- Cycles 2 to 5: 28 mcg/day IV continuous infusion over 28 days, started on day 1 (total dose per cycle: 784 mcg)

42-day cycle for up to 5 cycles

References

MT103-205: von Stackelberg A, Locatelli F, Zugmaier G, Handgretinger R, Trippett TM, Rizzari C, Bader P, O'Brien MM, Brethon B, Bhojwani D, Schlegel PG, Borkhardt A, Rheingold SR, Cooper TM, Zwaan CM, Barnette P, Messina C, Michel G, DuBois SG, Hu K, Zhu M, Whitlock JA, Gore L. Phase I/Phase II Study of Blinatumomab in Pediatric Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia. J Clin Oncol. 2016 Dec 20;34(36):4381-4389. Epub 2016 Oct 31. link to original article 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
PVDA: Prednisone, Vincristine, Daunorubicin, L-Asparaginase

Regimen

Study	Dates of enrollment	Evidence
Rivera et al. 1986	1982-01 to 1983-01	Non-randomized

Chemotherapy

Daunorubicin (Cerubidine) 25 mg/m² IV once per day on days 1, 8, 15, 22
Vincristine (Oncovin) 1.5 mg/m² IV once per day on days 1, 8, 15, 22
Asparaginase (Elspar) 10,000 IU/m² IM once per day on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, 26

Glucocorticoid therapy

Prednisone (Sterapred) 40 mg/m² PO once per day on days 1 to 28

4-week course

Subsequent treatment

Ara-C & Teniposide consolidation (see paper for details)

References

Rivera GK, Buchanan G, Boyett JM, Camitta B, Ochs J, Kalwinsky D, Amylon M, Vietti TJ, Crist WM; Pediatric Oncology Group. Intensive retreatment of childhood acute lymphoblastic leukemia in first bone marrow relapse: a Pediatric Oncology Group study. N Engl J Med. 1986 Jul 31;315(5):273-8. link to original article contains dosing details in manuscript 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.

Preceding treatment

Lymphodepleting therapy with FC or CYVE

Immunotherapy

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

One course

References

Pedi CART19: Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, Teachey DT, Chew A, Hauck B, Wright JF, Milone MC, Levine BL, June CH. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med. 2013 Apr 18;368(16):1509-1518. Epub 2013 Mar 25. Erratum in: N Engl J Med. 2016 Mar 10;374(10):998. link to original article link to PMC article 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
1. Update: Laetsch TW, Maude SL, Rives S, Hiramatsu H, Bittencourt H, Bader P, Baruchel A, Boyer M, De Moerloose B, Qayed M, Buechner J, Pulsipher MA, Myers GD, Stefanski HE, Martin PL, Nemecek E, Peters C, Yanik G, Khaw SL, Davis KL, Krueger J, Balduzzi A, Boissel N, Tiwari R, O'Donovan D, Grupp SA. Three-Year Update of Tisagenlecleucel in Pediatric and Young Adult Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia in the ELIANA Trial. J Clin Oncol. 2023 Mar 20;41(9):1664-1669. Epub 2022 Nov 18. link to original article link to PMC article PubMed

Consolidation after salvage therapy

Blinatumomab monotherapy

Regimen variant #1, 1 cycle

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

Immunotherapy

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

42-day course

Subsequent treatment

Allogeneic hematopoietic stem cell transplant consolidation

Regimen variant #2, 2 cycles

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Brown et al. 2021 (COG AALL1331)	2014-2019	Phase 3 (E-RT-switch-ooc)	Standard salvage consolidation chemotherapy	Might have 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

Blinatumomab (Blincyto)

Subsequent treatment

Allogeneic hematopoietic stem cell transplant consolidation

References

COG AALL1331: Brown PA, Ji L, Xu X, Devidas M, Hogan LE, Borowitz MJ, Raetz EA, Zugmaier G, Sharon E, Bernhardt MB, Terezakis SA, Gore L, Whitlock JA, Pulsipher MA, Hunger SP, Loh ML. Effect of Postreinduction Therapy Consolidation With Blinatumomab vs Chemotherapy on Disease-Free Survival in Children, Adolescents, and Young Adults With First Relapse of B-Cell Acute Lymphoblastic Leukemia: A Randomized Clinical Trial. JAMA. 2021 Mar 2;325(9):833-842. link to original article link to PMC article 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: 450 cGy once per day on days -5 & -4 (900 cGy total)
- Other studies: 10 to 1200 cGy total

Immunotherapy

Allogeneic stem cells transfused on day 0

One course

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

@@ Line 1: / Line 1: @@
-{| class="wikitable" style="text-align:center; width:50%;"
+<span id="BackToTop"></span>
-! colspan="2" align="center" style="color:white; font-size:125%; background-color:#4a1486" |'''Section editor'''
+<div class="noprint" style="background-color:LightGray; position:fixed; bottom:2%; right:0.25%; padding-left:5px; padding-right:5px; margin: 15px; opacity:0.8; border-style: solid; border-color:DarkGray; border-width: 1px">
-|-
+[[#top|Back to Top]]
-| style="background-color:#F0F0F0" |[[File:Liang.jpg|frameless|upright=0.3|center]]
+</div>
-|<big>[[User:Wayneliang|Wayne H. Liang, MD, MS, FAMIA]]<br>UAB<br>Birmingham, AL</big><br>[https://www.linkedin.com/in/wayneliang/ LinkedIn]<br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/WayneLiangMD WayneLiangMD]
+{{#lst:Editorial board transclusions|peds}}
-|-
-|}
 <big>''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 [[B-cell acute lymphoblastic leukemia|this link]].''</big>
+<br>''Are you looking for a regimen but can't find it here? It is possible that we've moved it to the [[B-cell acute lymphoblastic leukemia, pediatric - historical|historical regimens page]]. For placebo or observational studies in this condition, please visit [[B-cell acute lymphoblastic leukemia, pediatric - null regimens|this page]].''
+<br><big>'''Note: certain regimens are to be found on dedicated pages:
+*'''[[B-cell acute lymphoblastic leukemia,_Ph-positive,_pediatric|Pediatric B-cell ALL, Ph-positive]]
+*'''[[Acute lymphoblastic leukemia, infant|Infant ALL]]</big>
 {| class="wikitable" style="float:right; margin-right: 5px;"
 |-
@@ Line 12: / Line 14: @@
 <div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div>
 |}
-{{TOC limit|limit=3}}
+{{TOC limit|limit=4}}
 =Guidelines=
-=="How I Treat"==
+'''Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.'''
+==NCCN==
+*''NCCN does not currently have guidelines at this granular level; please see [https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1496 NCCN Guidelines - Pediatric Acute Lymphoblastic Leukemia]''.
-*'''2020:''' Hunger & Raetz. [https://doi.org/10.1182/blood.2019004043 How I treat relapsed acute lymphoblastic leukemia in the pediatric population]
+=Upfront therapy=
+==COG AALL0932 protocol for standard-risk==
-==[https://www.nccn.org/ NCCN]==
+<div class="toccolours" style="background-color:#c8a2c8">
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-*[https://www.nccn.org/professionals/physician_gls/pdf/ped_all.pdf NCCN Guidelines - Pediatric Acute Lymphoblastic Leukemia]
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
-=COG AALL0932=
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-'''For Standard Risk B-ALL'''
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-==Induction==
-===Pegaspargase, Vincristine, Dexamethasone {{#subobject:15hgu1|Regimen=1}}===
-{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[[#top|back to top]]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3138679/ Matloub et al. 2011 (COG CCG-1991)]
-|}
+|2000-2005
-====Regimen {{#subobject:e8uyt1|Variant=1}}====
+| style="background-color:#1a9851" |Phase 3 (E-de-esc)
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
+|[[#Mercaptopurine.2C_Methotrexate.2C_Vincristine.2C_Dexamethasone_888|Mercaptopurine, MTX, Vincristine, Dexamethasone]]
-! style="width: 33%" |Study
+| style="background-color:#1a9850" |Superior EFS (co-primary endpoint)
-! style="width: 33%" |Years of enrollment
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7030893/ Maloney et al. 2019 (COG AALL0331)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7030893/ Maloney et al. 2019 (COG AALL0331)]
 |2005-2010
-| style="background-color:#91cf61" |Non-randomized portion of RCT
+| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
+| style="background-color:#d3d3d3" |
+| style="background-color:#d3d3d3" |
 |-
-|[https://doi.org/10.1200/jco.20.00494 Angiolillo et al. 2021 (COG AALL0932)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274746/ Angiolillo et al. 2021 (COG AALL0932)]
 |2010-2018
-| style="background-color:#91cf61" |Non-randomized portion of RCT
+| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
+| style="background-color:#d3d3d3" |
+| style="background-color:#d3d3d3" |
 |-
 |}
 ''Note: there are very minor differences in timing between protocols; see papers for details.''
-=====Chemotherapy=====
+<div class="toccolours" style="background-color:#eeeeee">
+===Induction, Pegaspargase, Vincristine, Dexamethasone {{#subobject:15hgu1|Regimen=1}}===
-*[[Pegaspargase (Oncaspar)]] 2500 units/m<sup>2</sup> IV once over 1 - 2 hours on day 4
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Pegaspargase (Oncaspar)]] 2,500 units/m<sup>2</sup> IV once over 1 to 2 hours on day 4
 *[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
+====Glucocorticoid therapy====
 *[[Dexamethasone (Decadron)]] 3 mg/m<sup>2</sup> IV or PO twice per day on days 1 to 28
+====CNS therapy, prophylaxis====
-=====CNS prophylaxis=====
 *[[Cytarabine (Ara-C)]] IT once on day 0
 {| class="wikitable" style="width: 40%; text-align:center;"
-! style="width: 25%" |Age
+! style="width: 25%" |Age in years, rounded to the nearest hundredth
 ! style="width: 25%" |Initial Dose
 |-
-|1 - 1.99 years
+|1.00 to 1.99
 |30 mg
 |-
-|2 - 2.99 years
+|2.00 to 2.99
 |50 mg
 |-
-|≥ 3 years
+|3.00 or older
 |70 mg
 |}
-  CNS2 Patients will receive an additional dose of [[Cytarabine (Ara-C)]] IT on either day 4, 5, or 6, followed by [[Methotrexate (MTX)]] IT on day 8 and then another dose of [[Cytarabine (Ara-C)]] IT on either day 11 or 12 according to the following dosing.
+  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.
 {| class="wikitable" style="width: 40%; text-align:center;"
-! style="width: 25%" |Age
+! style="width: 25%" |Age in years, rounded to the nearest hundredth
 ! style="width: 25%" |Subsequent Doses
 |-
-|1 - 1.99
+|1.00 to 1.99
 |20 mg
 |-
-|2 - 2.99
+|2.00 to 2.99
 |30 mg
 |-
-|≥ 3
+|3.00 or older
 |40 mg
 |}
+*[[Methotrexate (MTX)]] IT once per day on days 8, 29
-*[[Methotrexate (MTX)]] IT once per day on days 8 & 29
+{| class="wikitable" style="width: 40%; text-align:center;"
+! style="width: 25%" |Age in years, rounded to the nearest hundredth
-{| class="wikitable" style="width: 40%; text-align:center;"
-! style="width: 25%" |Age
 ! style="width: 25%" |Dose
 |-
-|1 - 1.99
+|1.00 to 1.99
 |8 mg
 |-
-|2 - 2.99
+|2.00 to 2.99
 |10 mg
 |-
-|3 - 8.99
+|3.00 to 8.99
 |12 mg
 |-
-|≥ 9
+|9.00 or older
 |15 mg
 |}
+====Supportive therapy, DS Arm====
-=====DS Arm=====
+*[[Leucovorin (Folinic acid)]] 5 mg/m<sup>2</sup> PO x 2 doses given 48 and 60 hours after the lumbar puncture on days 10, 11, 31, 32
-*[[Folinic acid (Leucovorin)]] 5 mg/m<sup>2</sup> x 2 doses given 48 and 60 hours after the lumbar puncture on days 10-11 and 31-32
 '''35-day course'''
+</div>
-=====Subsequent treatment=====
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
 *COG AALL0331, M2 marrow or M1 marrow with MRD of at least 1% at day 29: Extended induction
-*COG AALL0932: [[#Mercaptopurine_.26_Vincristine|6-MP & Vincristine consolidation]]
+*COG AALL0932: [[#Mercaptopurine_.26_Vincristine|6-MP & Vincristine]] consolidation
+</div></div><br>
-====References====
+<div class="toccolours" style="background-color:#eeeeee">
+===Consolidation, Mercaptopurine & Vincristine {{#subobject:171gc1|Regimen=1}}===
-#'''COG AALL0331:''' Maloney KW, Devidas M, Wang C, Mattano LA, Friedmann AM, Buckley P, Borowitz MJ, Carroll AJ, Gastier-Foster JM, Heerema NA, Kadan-Lottick N, Loh ML, Matloub YH, Marshall DT, Stork LC, Raetz EA, Wood B, Hunger SP, Carroll WL, Winick NJ. Outcome in Children With Standard-Risk B-Cell Acute Lymphoblastic Leukemia: Results of Children's Oncology Group Trial AALL0331. J Clin Oncol. 2020 Feb 20;38(6):602-612. Epub 2019 Dec 11. [https://doi.org/10.1200/jco.19.01086 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7030893/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/31825704/ 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. [https://doi.org/10.1200/jco.20.00494 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33411585/ PubMed] NCT01190930
-==Consolidation==
 '''For AR B-ALL patients, LR-C Arm, and B-LLy'''
-===Mercaptopurine & Vincristine {{#subobject:171gc1|Regimen=1}}===
+<div class="toccolours" style="background-color:#cbd5e8">
-{| class="wikitable" style="float:right; margin-left: 5px;"
+====Preceding treatment====
+*[[#Pegaspargase.2C_Vincristine.2C_Dexamethasone|Pegaspargase, Vincristine, Dexamethasone]] induction
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup>/day PO on days 1 to 28
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1
+====CNS therapy, prophylaxis====
+*[[Methotrexate (MTX)]] IT once per day on days 1, 8, 15
+{| class="wikitable" style="width: 40%; text-align:center;"
+! style="width: 25%" |Age in years, rounded to the nearest hundredth
+! style="width: 25%" |Dose
 |-
-|[[#top|back to top]]
+|1.00 to 1.99
-|}
+|8 mg
-====Regimen {{#subobject:1ygvt1|Variant=1}}====
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
-! style="width: 33%" |Study
-! style="width: 33%" |Years of enrollment
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://doi.org/10.1200/jco.20.00494 Angiolillo et al. 2021 (COG AALL0932)]
+|2.00 to 2.99
-|2010-2018
+|10 mg
-| style="background-color:#91cf61" |Non-randomized portion of RCT
 |-
+|3.00 to 8.99
+|12 mg
+|-
+|9.00 or older
+|15 mg
 |}
-=====Preceding treatment=====
+====Supportive therapy, DS Arm====
+*[[Leucovorin (Folinic acid)]] 5 mg/m<sup>2</sup> PO x 2 doses given 48 and 60 hours after the lumbar puncture on days 3, 4, 10, 11, 17, 18.
-*[[#Pegaspargase.2C_Vincristine.2C_Dexamethasone|Pegaspargase, Vincristine, Dexamethasone induction]]
+'''28-day course'''
+</div>
-=====Chemotherapy=====
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
-*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup>/day PO on days 1 to 28
+*[[#Methotrexate_.26_Vincristine|MTX & Vincristine]] interim maintenance
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
-=====CNS prophylaxis=====
+===Interim Maintenance, I (Methotrexate & Vincristine) {{#subobject:0ae09f|Regimen=1}}===
+'''For AR B-ALL patients, LR-C Arm, and B-LLy'''
-*[[Methotrexate (MTX)]] IT once per day on days 1, 8, 15
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*COG AALL0932: [[#Mercaptopurine_.26_Vincristine|6-MP & Vincristine]] consolidation
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Methotrexate (MTX)]] 100 mg/m<sup>2</sup> IV once on day 1, then 150 mg/m<sup>2</sup> IV once on day 11, then 200 mg/m<sup>2</sup> IV once on day 21, then 250 mg/m<sup>2</sup> IV once on day 31, then 300 mg/m<sup>2</sup> IV once on day 41
+**Given over 2 to 5 minutes (undiluted) or over 10 to 15 minutes (diluted).
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (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
 {| class="wikitable" style="width: 40%; text-align:center;"
-! style="width: 25%" |Age
+! style="width: 25%" |Age in years, rounded to the nearest hundredth
 ! style="width: 25%" |Dose
 |-
-|1 - 1.99
+|1.00 to 1.99
 |8 mg
 |-
-|2 - 2.99
+|2.00 to 2.99
 |10 mg
 |-
-|3 - 8.99
+|3.00 to 8.99
 |12 mg
 |-
-|≥ 9
+|9.00 or older
 |15 mg
 |}
+====Supportive therapy, DS Arm====
-=====DS Arm=====
+*[[Leucovorin (Folinic acid)]] 5 mg/m<sup>2</sup> PO x 2 doses given 48 and 60 hours after the lumbar puncture on days 33, 34
+'''8-week course, followed by:'''
-*[[Folinic acid (Leucovorin)]] 5 mg/m<sup>2</sup> x 2 doses given 48 and 60 hours after the lumbar puncture on days 3-4, 10-11, and 17-18.
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Delayed Intensification {{#subobject:17185g|Regimen=1}}===
-'''28-day course'''
+'''For AR B-ALL patients, LR-C Arm, and B-LLy'''
+<div class="toccolours" style="background-color:#cbd5e8">
-=====Subsequent treatment=====
+====Preceding treatment====
+*[[#Methotrexate_.26_Vincristine|MTX & Vincristine]] interim maintenance
-*[[#Methotrexate_.26_Vincristine|MTX & Vincristine interim maintenance]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
-====References====
+====Chemotherapy====
+*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV over 30 to 60 minutes once on day 29
-#'''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. [https://doi.org/10.1200/jco.20.00494 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33411585/ PubMed] NCT01190930
+*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> SC or IV over 1 to 30 minutes on days 29 to 32, 36 to 39
+*[[Doxorubicin (Adriamycin)]] 25 mg/m<sup>2</sup> IV push/infusion over 1 to 15 minutes once per day on days 1, 8, 15
-==Interim Maintenance I==
+*[[Pegaspargase (Oncaspar)]] 2,500 units/m<sup>2</sup> IV over 1 to 2 hours once on day 4
-'''For AR B-ALL patients, LR-C Arm, and B-LLy'''
+*[[Thioguanine (Tabloid)]] 60 mg/m<sup>2</sup> PO once per day on days 29 to 42
-===Methotrexate & Vincristine {{#subobject:0ae09f|Regimen=1}}===
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15
-{| class="wikitable" style="float:right; margin-left: 5px;"
+====Glucocorticoid therapy====
+*[[Dexamethasone (Decadron)]] 5 mg/m<sup>2</sup>/dose PO twice per day on days 1 to 7, 15 to 21 (10 mg/m<sup>2</sup>/day)
+====CNS therapy, prophylaxis====
+*[[Methotrexate (MTX)]] IT once per day on days 1 & 29
+{| class="wikitable" style="width: 40%; text-align:center;"
+! style="width: 25%" |Age in years, rounded to the nearest hundredth
+! style="width: 25%" |Dose
 |-
-|[[#top|back to top]]
+|1.00 to 1.99
-|}
+|8 mg
-====Regimen {{#subobject:57f39d|Variant=1}}====
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3138679/ Matloub et al. 2011 (COG CCG-1991)]
+|2.00 to 2.99
-|2000-2005
+|10 mg
-| style="background-color:#1a9851" |Phase III (E-de-esc)
-|Mercaptopurine, MTX, Vincristine, Dexamethasone
-| style="background-color:#1a9850" |Superior EFS
 |-
-|[https://doi.org/10.1200/jco.20.00494 Angiolillo et al. 2021 (COG AALL0932)]
+|3.00 to 8.99
-|2010-2018
+|12 mg
-| style="background-color:#91cf61" |Non-randomized portion of RCT
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
 |-
+|9.00 or older
+|15 mg
 |}
-=====Preceding treatment=====
+====Supportive therapy, DS Arm====
+*[[Leucovorin (Folinic acid)]] 5 mg/m<sup>2</sup> PO x 2 doses given 48 and 60 hours after the lumbar puncture on days 3 to 4, 31 to 32
-*COG AALL0932: [[#Mercaptopurine_.26_Vincristine|6-MP & Vincristine consolidation]]
+'''8-week course'''
+</div>
-=====Chemotherapy=====
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*[[#Methotrexate_.26_Vincristine_2|MTX & Vincristine]] interim maintenance II
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Interim Maintenance, II (Methotrexate & Vincristine) {{#subobject:0ae09f|Regimen=1}}===
+'''For AR B-ALL patients, LR-C Arm, and B-LLy'''
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*COG AALL0932: [[#Mercaptopurine_.26_Vincristine|6-MP & Vincristine]] consolidation
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
 *[[Methotrexate (MTX)]] 100 mg/m<sup>2</sup> IV once on day 1, then 150 mg/m<sup>2</sup> IV once on day 11, then 200 mg/m<sup>2</sup> IV once on day 21, then 250 mg/m<sup>2</sup> IV once on day 31, then 300 mg/m<sup>2</sup> IV once on day 41
-**Given over 2 - 5 minutes (undiluted) or over 10 - 15 minutes (diluted).
+**Given over 2 to 5 minutes (undiluted) or over 10 to 15 minutes (diluted)
 *[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 11, 21, 31, 41
+====CNS therapy, prophylaxis====
-=====CNS prophylaxis=====
 *[[Methotrexate (MTX)]] IT once on day 31
 {| class="wikitable" style="width: 40%; text-align:center;"
-! style="width: 25%" |Age
+! style="width: 25%" |Age in years, rounded to the nearest hundredth
 ! style="width: 25%" |Dose
 |-
-|1 - 1.99
+|1.00 to 1.99
 |8 mg
 |-
-|2 - 2.99
+|2.00 to 2.99
 |10 mg
 |-
-|3 - 8.99
+|3.00 to 8.99
 |12 mg
 |-
-|≥ 9
+|9.00 or older
 |15 mg
 |}
+====Supportive therapy, DS Arm====
-=====DS Arm=====
+*[[Leucovorin (Folinic acid)]] 5 mg/m<sup>2</sup> PO x 2 doses given 48 and 60 hours after the lumbar puncture on days 3 to 4, 33 to 34
-*[[Folinic acid (Leucovorin)]] 5 mg/m<sup>2</sup> x 2 doses given 48 and 60 hours after the lumbar puncture on days 33-34
 '''8-week course'''
+</div>
-=====Subsequent treatment=====
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
-*COG AALL0932: [[#AALL0932_delayed_intensification|AALL0932 delayed intensification]]
+*COG AALL0932: [[#AALL0932_delayed_intensification|AALL0932]] delayed intensification
+</div></div><br>
-====References====
+<div class="toccolours" style="background-color:#eeeeee">
+===Maintenance, Arm A and C (Vincristine/Dexamethasone Pulses) {{#subobject:0ae09f|Regimen=1}}===
-#'''COG CCG-1991:''' Matloub Y, Bostrom BC, Hunger SP, Stork LC, Angiolillo A, Sather H, La M, Gastier-Foster JM, Heerema NA, Sailer S, Buckley PJ, Thomson B, Cole C, Nachman JB, Reaman G, Winick N, Carroll WL, Devidas M, Gaynon PS. Escalating intravenous methotrexate improves event-free survival in children with standard-risk acute lymphoblastic leukemia: a report from the Children's Oncology Group. Blood. 2011 Jul 14;118(2):243-51. Epub 2011 May 11. [http://www.bloodjournal.org/content/118/2/243.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3138679/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21562038 PubMed] NCT00005945
+'''For AR B-ALL patients, and LR-C Arm'''
-#'''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. [https://doi.org/10.1200/jco.20.00494 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33411585/ PubMed] NCT01190930
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
-==Delayed Intensification==
+*COG AALL0932: [[#Methotrexate_.26_Vincristine|MTX & Vincristine]] interim maintenance
-'''For AR B-ALL patients, LR-C Arm, and B-LLy'''
+</div>
-===AALL0932 delayed intensification {{#subobject:17185g|Regimen=1}}===
+<div class="toccolours" style="background-color:#b3e2cd">
-{| class="wikitable" style="float:right; margin-left: 5px;"
+====Chemotherapy====
+*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> PO once per day on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 29, 57
+*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup> PO once per day on days 1 to 84
+====Glucocorticoid therapy====
+*[[Dexamethasone (Decadron)]] 3 mg/m<sup>2</sup> PO twice per day on days 1 to 5, 29 to 33, 57 to 61 (6 mg/m<sup>2</sup>/day)
+====CNS therapy, prophylaxis====
+*[[Methotrexate (MTX)]] IT once on day 1
+{| class="wikitable" style="width: 40%; text-align:center;"
+! style="width: 25%" |Age in years, rounded to the nearest hundredth
+! style="width: 25%" |Dose
+|-
+|1.00 to 1.99
+|8 mg
 |-
-|[[#top|back to top]]
+|2.00 to 2.99
-|}
+|10 mg
-====Regimen {{#subobject:1y47gc|Variant=1}}====
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
-! style="width: 33%" |Study
-! style="width: 33%" |Years of enrollment
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://doi.org/10.1200/jco.20.00494 Angiolillo et al. 2021 (COG AALL0932)]
+|3.00 to 8.99
-|2010-2018
+|12 mg
-| style="background-color:#91cf61" |Non-randomized portion of RCT
 |-
+|9.00 or older
+|15 mg
 |}
-=====Preceding treatment=====
+'''12-week cycles until total duration of therapy is 2 years for female and 3 years for male from the start of Interim I'''
+</div></div><br>
-*[[#Methotrexate_.26_Vincristine|MTX & Vincristine interim maintenance]]
+<div class="toccolours" style="background-color:#eeeeee">
+===Maintenance, Arm B and D (Vincristine/Dexamethasone Pulses) {{#subobject:0ae09f|Regimen=1}}===
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*COG AALL0932: [[#Methotrexate_.26_Vincristine|MTX & Vincristine]] interim maintenance
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*Currently maintenance arm B and D are also treated with [[Methotrexate (MTX)]] PO at 20 mg/m<sup>2</sup> (decreased from the starting dose of 40 mg/m<sup>2</sup>) on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78
-*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV over 30 - 60 minutes once on day 29
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 29, 57
-*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup>/day SC or IV over 1 - 30 minutes on days 29 to 32, 36 to 39
+*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup> PO once per day on days 1 to 84
-*[[Doxorubicin (Adriamycin)]] 25 mg/m<sup>2</sup> IV push/infusion over 1 - 15 minutes once per day on days 1, 8, 15
+====Glucocorticoid therapy====
-*[[Pegaspargase (Oncaspar)]] 2500 units/m<sup>2</sup> IV over 1 - 2 hours once on day 4
+*[[Dexamethasone (Decadron)]] 3 mg/m<sup>2</sup> PO twice per day on days 1 to 5, 29 to 33, 57 to 61
-*[[Thioguanine (Tabloid)]] 60 mg/m<sup>2</sup>/day PO once per day on days 29 to 42
+====CNS therapy, prophylaxis====
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15
+*[[Methotrexate (MTX)]] IT once on day 1
-*[[Dexamethasone (Decadron)]] 5 mg/m<sup>2</sup>/dose PO twice daily on days 1 to 7, 15 to 21 (10 mg/m<sup>2</sup>/day)
-=====CNS prophylaxis=====
-*[[Methotrexate (MTX)]] IT once per day on days 1 & 29
 {| class="wikitable" style="width: 40%; text-align:center;"
-! style="width: 25%" |Age
+! style="width: 25%" |Age in years, rounded to the nearest hundredth
 ! style="width: 25%" |Dose
 |-
-|1 - 1.99
+|1.00 to 1.99
 |8 mg
 |-
-|2 - 2.99
+|2.00 to 2.99
 |10 mg
 |-
-|3 - 8.99
+|3.00 to 8.99
 |12 mg
 |-
-|≥ 9
+|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'''
-=====DS Arm=====
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
-*[[Folinic acid (Leucovorin)]] 5 mg/m<sup>2</sup> x 2 doses given 48 and 60 hours after the lumbar puncture on days 3-4 and 31-32.
+===Maintenance, Arm DS (Vincristine/Dexamethasone) {{#subobject:0ae09f|Regimen=1}}===
+'''For DS AR B-ALL patients and DS B-LLy'''
+<div class="toccolours" style="background-color:#cbd5e8">
-'''8-week course'''
+====Preceding treatment====
+*COG AALL0932: [[#Methotrexate_.26_Vincristine|MTX & Vincristine]] interim maintenance
-=====Subsequent treatment=====
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
-*[[#Methotrexate_.26_Vincristine_2|MTX & Vincristine interim maintenance II]]
+====Chemotherapy====
+*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> PO once per day on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78
-====References====
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1
+*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup> PO once per day on days 1 to 84
-#'''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. [https://doi.org/10.1200/jco.20.00494 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33411585/ PubMed] NCT01190930
+====Glucocorticoid therapy====
+*[[Dexamethasone (Decadron)]] 3 mg/m<sup>2</sup> IV or PO twice per day on days 1 to 5 (DO NOT TAPER)
-==Interim Maintenance II==
+====CNS therapy, prophylaxis====
-'''For AR B-ALL patients, LR-C Arm, and B-LLy'''
+*[[Methotrexate (MTX)]] IT once on day 1
-===Methotrexate & Vincristine {{#subobject:0ae09f|Regimen=1}}===
+{| class="wikitable" style="width: 40%; text-align:center;"
-{| class="wikitable" style="float:right; margin-left: 5px;"
+! style="width: 25%" |Age in years, rounded to the nearest hundredth
+! style="width: 25%" |Dose
 |-
-|[[#top|back to top]]
+|1.00 to 1.99
-|}
+|8 mg
-====Regimen {{#subobject:57f39d|Variant=1}}====
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3138679/ Matloub et al. 2011 (COG CCG-1991)]
+|2.00 to 2.99
-|2000-2005
+|10 mg
-| style="background-color:#1a9851" |Phase III (E-de-esc)
-|Mercaptopurine, MTX, Vincristine, Dexamethasone
-| style="background-color:#1a9850" |Superior EFS
 |-
-|[https://doi.org/10.1200/jco.20.00494 Angiolillo et al. 2021 (COG AALL0932)]
+|3.00 to 8.99
-|2010-2018
+|12 mg
-| style="background-color:#91cf61" |Non-randomized portion of RCT
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
 |-
+|9.00 or older
+|15 mg
 |}
-=====Preceding treatment=====
+'''12-week cycles until total duration of therapy is 2 years for female and 3 years for male from the start of Interim I'''
+</div></div><br>
-*COG AALL0932: [[#Mercaptopurine_.26_Vincristine|6-MP & Vincristine consolidation]]
+<div class="toccolours" style="background-color:#eeeeee">
+===Consolidation, Arm LR-M {{#subobject:0ae09f|Regimen=1}}===
-=====Chemotherapy=====
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
-*[[Methotrexate (MTX)]] 100 mg/m<sup>2</sup> IV once on day 1, then 150 mg/m<sup>2</sup> IV once on day 11, then 200 mg/m<sup>2</sup> IV once on day 21, then 250 mg/m<sup>2</sup> IV once on day 31, then 300 mg/m<sup>2</sup> IV once on day 41
+*[[Methotrexate (MTX)]] 1000 mg/m<sup>2</sup> IV on days 8, 29, 50, 71, 92, 113
-**Given over 2 - 5 minutes (undiluted) or over 10 - 15 minutes (diluted).
+ Given as a 200 mg/m<sup>2</sup> bolus over 20 to 30 minutes followed by 800 mg/m<sup>2</sup> 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/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 11, 21, 31, 41
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 15, 22, 78, 85
+*[[Mercaptopurine (6-MP)]] 50 mg/m<sup>2</sup> PO once per day on days 1 to 33
-=====CNS prophylaxis=====
+====Glucocorticoid therapy====
+*[[Dexamethasone (Decadron)]] 3 mg/m<sup>2</sup> IV or PO twice per day on days 15 to 21, 78 to 84
-*[[Methotrexate (MTX)]] IT once on day 31
+====Supportive therapy====
+*[[Leucovorin (Folinic acid)]] 10 mg/m<sup>2</sup> 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)
+{| class="wikitable" style="width: 40%; text-align:center;"
+! style="width: 25%" |Age in years, rounded to the nearest hundredth
+! style="width: 25%" |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'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Maintenance, Arm LR-M {{#subobject:0ae09f|Regimen=1}}===
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Methotrexate (MTX)]] as follows:
+**Cycles 1 to 4: 20 mg/m<sup>2</sup>/day PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, 92, 99, 106
+**Cycles 2 & 5: 20 mg/m<sup>2</sup>/day PO on days 1, 8, 15, 22, 29, 36, 43, 50, 64, 71, 78, 85, 92, 99, 106
+**Cycles 3 & 6: 20 mg/m<sup>2</sup>/day PO on days 1, 8, 15, 22, 36, 43, 50, 57, 64, 71, 78, 85, 92, 99, 106
+**Cycle 7: 20 mg/m<sup>2</sup>/day PO on days 1, 8, 15, 29, 22, 36, 43, 50, 57, 64
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1 & 8
+*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup> PO once per day on days 1 to 112 (NOTE: Higher 6-MP dose than in consolidation)
+====Glucocorticoid therapy====
+*[[Dexamethasone (Decadron)]] 3 mg/m<sup>2</sup> PO twice per day on days 1 to 7 (6 mg/m<sup>2</sup>/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
 {| class="wikitable" style="width: 40%; text-align:center;"
-! style="width: 25%" |Age
+! style="width: 25%" |Age in years, rounded to the nearest hundredth
 ! style="width: 25%" |Dose
 |-
-|1 - 1.99
+|1.00 to 1.99
 |8 mg
 |-
-|2 - 2.99
+|2.00 to 2.99
 |10 mg
 |-
-|3 - 8.99
+|3.00 to 8.99
 |12 mg
 |-
-|≥ 9
+|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.'''
-=====DS Arm=====
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
-*[[Folinic acid (Leucovorin)]] 5 mg/m<sup>2</sup> x 2 doses given 48 and 60 hours after the lumbar puncture on days 3-4 and 33-34.
+===Maintenance, Arm LLy (Vincristine/Dexamethasone) {{#subobject:0ae09f|Regimen=1}}===
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
-'''8-week course'''
+*COG AALL0932: [[#Methotrexate_.26_Vincristine|MTX & Vincristine]] interim maintenance
+</div>
-=====Subsequent treatment=====
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
-*COG AALL0932: [[#AALL0932_delayed_intensification|AALL0932 delayed intensification]]
+*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> PO once per day on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 29, 57 (4 Week Intervals)
-====References====
+*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup> PO once per day on days 1 to 84
+====Glucocorticoid therapy====
-#'''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. [http://www.bloodjournal.org/content/118/2/243.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3138679/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21562038 PubMed] NCT00005945
+*[[Dexamethasone (Decadron)]] 3 mg/m<sup>2</sup> PO twice per day on days 1 to 5, 29 to 33, 57 to 61 (6 mg/m<sup>2</sup>/day) (DO NOT TAPER)
-#'''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. [https://doi.org/10.1200/jco.20.00494 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33411585/ PubMed] NCT01190930
+====CNS therapy, prophylaxis====
-==Maintenance Arm A and C==
-'''For AR B-ALL patients, and LR-C Arm'''
-===Vincristine/Dexamethasone Pulses {{#subobject:0ae09f|Regimen=1}}===
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-====Regimen {{#subobject:1y47gc|Variant=1}}====
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
-! style="width: 33%" |Study
-! style="width: 33%" |Years of enrollment
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://doi.org/10.1200/jco.20.00494 Angiolillo et al. 2021 (COG AALL0932)]
-|2010-2018
-| style="background-color:#91cf61" |Randomized portion of RCT
-|-
-|}
-=====Preceding treatment=====
-*COG AALL0932: [[#Methotrexate_.26_Vincristine|MTX & Vincristine interim maintenance]]
-=====Chemotherapy=====
-*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> PO once on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71 and 78.
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 29, and 57
-*[[Dexamethasone (Decadron)]] 3 mg/m<sup>2</sup>/dose PO twice daily on days 1 to 5, 29 - 33, and 578 - 61 (6 mg/m<sup>2</sup>/day)
-*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup>/dose PO once per day on days 1 to 84
-=====CNS prophylaxis=====
 *[[Methotrexate (MTX)]] IT once on day 1
 {| class="wikitable" style="width: 40%; text-align:center;"
-! style="width: 25%" |Age
+! style="width: 25%" |Age in years, rounded to the nearest hundredth
 ! style="width: 25%" |Dose
 |-
-|1 - 1.99
+|1.00 to 1.99
 |8 mg
 |-
-|2 - 2.99
+|2.00 to 2.99
 |10 mg
 |-
-|3 - 8.99
+|3.00 to 8.99
 |12 mg
 |-
-|≥ 9
+|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'''
+</div></div></div>
+===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. [https://doi.org/10.1182/blood-2010-12-322909 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3138679/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21562038/ PubMed] [https://clinicaltrials.gov/study/NCT00005945 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. [https://doi.org/10.1200/jco.19.01086 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7030893/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31825704/ 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. [https://doi.org/10.1200/jco.20.00494 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274746/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33411585/ PubMed] [https://clinicaltrials.gov/study/NCT01190930 NCT01190930]
-====References====
+==COG AALL1131 protocol==
+<div class="toccolours" style="background-color:#eeeeee">
-#'''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. [http://www.bloodjournal.org/content/118/2/243.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3138679/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21562038 PubMed] NCT00005945
+===Induction, Daunorubicin, Pegaspargase, Vincristine, Dexamethasone {{#subobject:98346f|Variant=1}}===
-#'''COG AALL0932:''' Angiolillo AL, Schore RJ, Kairalla JA, Devidas M, Rabin KR, Zweidler-McKay P, Borowitz MJ, Wood B, Carroll AJ, Heerema NA, Relling MV, Hitzler J, Lane AR, Maloney KW, Wang C, Bassal M, Carroll WL, Winick NJ, Raetz EA, Loh ML, Hunger SP. Excellent Outcomes With Reduced Frequency of Vincristine and Dexamethasone Pulses in Standard-Risk B-Lymphoblastic Leukemia: Results From Children's Oncology Group AALL0932. J Clin Oncol. 2021 May 1;39(13):1437-1447. Epub 2021 Jan 7. [https://doi.org/10.1200/jco.20.00494 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33411585/ PubMed] NCT01190930
+{| class="wikitable" style="width: 40%; text-align:center;"
+! style="width: 25%" |Study
-==Maintenance Arm B and D==
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-===Vincristine/Dexamethasone Pulses {{#subobject:0ae09f|Regimen=1}}===
+|-
-{| class="wikitable" style="float:right; margin-left: 5px;"
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ Burke et al. 2019 (COG AALL1131)]
+| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
 |-
-|[[#top|back to top]]
 |}
-====Regimen {{#subobject:1y47gc|Variant=1}}====
+''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.''
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
+<div class="toccolours" style="background-color:#b3e2cd">
-! style="width: 33%" |Study
+====Chemotherapy====
-! style="width: 33%" |Years of enrollment
+*[[Daunorubicin (Cerubidine)]] 25 mg/m<sup>2</sup> IV over 1 to 15 minutes once per day on days 1, 8, 15, 22
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
+*[[Pegaspargase (Oncaspar)]] 2,500 units/m<sup>2</sup> IV over 1 to 2 hours once on day 4
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (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/m<sup>2</sup> 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/m<sup>2</sup> 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'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*See protocol for details of treatment beyond induction
+</div></div>
+===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. [https://doi.org/10.3324/haematol.2018.204545 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30545921/ PubMed] [https://clinicaltrials.gov/study/NCT02883049 NCT02883049]
+==COG AALL1131 protocol for HR B-ALL==
+<div class="toccolours" style="background-color:#c8a2c8">
+{| class="wikitable" style="width: 40%; text-align:center;"
+! style="width: 25%" |Study
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://doi.org/10.1200/jco.20.00494 Angiolillo et al. 2021 (COG AALL0932)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ Burke et al. 2019 (COG AALL1131)]
-|2010-2018
+| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
-| style="background-color:#91cf61" |Randomized portion of RCT
 |-
 |}
+<div class="toccolours" style="background-color:#eeeeee">
-=====Preceding treatment=====
+===Consolidation, Cyclophosphamide, Cytarabine, Mercaptopurine, Pegaspargase, Vincristine {{#subobject:98346f|Variant=1}}===
+<div class="toccolours" style="background-color:#b3e2cd">
-*COG AALL0932: [[#Methotrexate_.26_Vincristine|MTX & Vincristine interim maintenance]]
+====Chemotherapy====
+*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV over 30 to 60 minutes once on days 1, 29
-=====Chemotherapy=====
+*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> 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/m<sup>2</sup> IV over 1 to 2 hours once on days 15, 43
-*Currently maintenance arm B and D are also treated with [[Methotrexate (MTX)]] PO at 20 mg/m<sup>2</sup> (decreased from the starting dose of 40 mg/m<sup>2</sup>) on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71 and 78.
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 15, 22, 43, 50
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 29, and 57
+*[[Mercaptopurine (6-MP)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 14, 29 to 42
-*[[Dexamethasone (Decadron)]] 3 mg/m<sup>2</sup>/dose PO twice daily on days 1 to 5, 29 - 33, and 57 - 61 (6 mg/m<sup>2</sup>/day)
+====CNS therapy, prophylaxis====
-*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup>/dose PO once per day on days 1 to 84
+*[[Methotrexate (MTX)]] IT once per day on days 1, 8, 15, 22
+{| class="wikitable" style="width: 40%; text-align:center;"
-=====CNS prophylaxis=====
+! style="width: 25%" |Age in years, rounded to the nearest hundredth
-*[[Methotrexate (MTX)]] IT once on day 1
-{| class="wikitable" style="width: 40%; text-align:center;"
-! style="width: 25%" |Age
 ! style="width: 25%" |Dose
 |-
-|1 - 1.99
+|1.00 to 1.99
 |8 mg
 |-
-|2 - 2.99
+|2.00 to 2.99
 |10 mg
 |-
-|3 - 8.99
+|3.00 to 8.99
 |12 mg
 |-
-|≥ 9
+|9.00 or older
 |15 mg
 |}
+'''56-day course'''
-'''12-week cycles until total duration of therapy is 2 years for female and 3 years for male from the start of Interim I'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
-====References====
+===Interim Maintenance, with HD MTX {{#subobject:98346f|Variant=1}}===
+<div class="toccolours" style="background-color:#b3e2cd">
-#'''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. [http://www.bloodjournal.org/content/118/2/243.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3138679/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21562038 PubMed] NCT00005945
+====Chemotherapy====
-#'''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. [https://doi.org/10.1200/jco.20.00494 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33411585/ PubMed] NCT01190930
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 15, 29, 43
+*[[Mercaptopurine (6-MP)]] 25 mg/m<sup>2</sup> PO once per day on days 1 to 56
-==Maintenance Arm DS==
+*High Dose [[Methotrexate (MTX)]] 500 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 15, 29, 43, then 4500 mg/m<sup>2</sup> IV continuous infusion over 23.5 hours, started on days 1, 15, 29, 43
-'''For DS AR B-ALL patients and DS B-LLy'''
+**ANC must be at least 750/µL and platelets must be at least 75,000/µL prior to each dose of high dose MTX
-===Vincristine/Dexamethasone {{#subobject:0ae09f|Regimen=1}}===
+====Supportive therapy====
-{| class="wikitable" style="float:right; margin-left: 5px;"
+*[[Leucovorin (Folinic acid)]] 15 mg/m<sup>2</sup> 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
+{| class="wikitable" style="width: 40%; text-align:center;"
+! style="width: 25%" |Age in years, rounded to the nearest hundredth
+! style="width: 25%" |Dose
+|-
+|1.00 to 1.99
+|8 mg
 |-
-|[[#top|back to top]]
+|2.00 to 2.99
-|}
+|10 mg
-====Regimen {{#subobject:1y47gc|Variant=1}}====
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
-! style="width: 33%" |Study
-! style="width: 33%" |Years of enrollment
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://doi.org/10.1200/jco.20.00494 Angiolillo et al. 2021 (COG AALL0932)]
+|3.00 to 8.99
-|2010-2018
+|12 mg
-| style="background-color:#91cf61" |Randomized portion of RCT
 |-
+|9.00 or older
+|15 mg
 |}
-=====Preceding treatment=====
+ 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'''
-*COG AALL0932: [[#Methotrexate_.26_Vincristine|MTX & Vincristine interim maintenance]]
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
-=====Chemotherapy=====
+===Delayed Intensification {{#subobject:98346f|Variant=1}}===
+<div class="toccolours" style="background-color:#b3e2cd">
-*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> PO once on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71 and 78.
+====Chemotherapy====
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1
+*[[Doxorubicin (Adriamycin)]] 25 mg/m<sup>2</sup> IV push over 1 to 15 minutes once per day on days 1, 8, 15
-*[[Dexamethasone (Decadron)]] 3 mg/m<sup>2</sup>/dose IV or PO twice daily on days 1 to 5 (6 mg/m<sup>2</sup>/day) (DO NOT TAPER)
+*[[Pegaspargase (Oncaspar)]] 2,500 units/m<sup>2</sup> IV over 1 to 2 hours once on days 4, 43
-*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup>/dose PO once per day on days 1 to 84
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 43, 50
+*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV over 30 to 60 minutes once on day 29 ONLY
-=====CNS prophylaxis=====
+*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> SC or IV over 1 to 30 minutes on days 29 to 32, 36 to 39
+*[[Thioguanine (Tabloid)]] 60 mg/m<sup>2</sup> PO once per day on days 29 to 42
-*[[Methotrexate (MTX)]] IT once on day 1
+====Glucocorticoid therapy====
+*[[Dexamethasone (Decadron)]] 5 mg/m<sup>2</sup> IV or PO twice per day on days 1 to 7, 15 to 21
-{| class="wikitable" style="width: 40%; text-align:center;"
+====CNS therapy, prophylaxis====
-! style="width: 25%" |Age
+*[[Methotrexate (MTX)]] IT once per day on days 1, 29, 36
+{| class="wikitable" style="width: 40%; text-align:center;"
+! style="width: 25%" |Age in years, rounded to the nearest hundredth
 ! style="width: 25%" |Dose
 |-
-|1 - 1.99
+|1.00 to 1.99
 |8 mg
 |-
-|2 - 2.99
+|2.00 to 2.99
 |10 mg
 |-
-|3 - 8.99
+|3.00 to 8.99
 |12 mg
 |-
-|≥ 9
+|9.00 or older
 |15 mg
 |}
+'''56-day course'''
-'''12-week cycles until total duration of therapy is 2 years for female and 3 years for male from the start of Interim I'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
-====References====
+===Maintenance, HR B-ALL {{#subobject:98346f|Variant=1}}===
+<div class="toccolours" style="background-color:#b3e2cd">
-#'''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. [http://www.bloodjournal.org/content/118/2/243.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3138679/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21562038 PubMed] NCT00005945
+====Chemotherapy====
-#'''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. [https://doi.org/10.1200/jco.20.00494 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33411585/ PubMed] NCT01190930
+*[[Mercaptopurine (6-MP)]] as follows:
+**Cycles 1 to 4: 75 mg/m<sup>2</sup> PO once per day on days 1 to 84
-==Arm LR-M==
+*[[Vincristine (Oncovin)]] as follows:
-===Consolidation {{#subobject:0ae09f|Regimen=1}}===
+**Cycles 1 to 4: 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 29, 57
-{| class="wikitable" style="float:right; margin-left: 5px;"
+*[[Methotrexate (MTX)]] as follows:
+**Cycles 1 to 4: 20 mg/m<sup>2</sup> PO once per day on days 8, 15, 22, 36, 43, 50, 57, 64, 71, 78
+**Cycle 5 onwards: 20 mg/m<sup>2</sup> PO once per day on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78
+====Glucocorticoid therapy====
+*[[Prednisone (Sterapred)]] 20 mg/m<sup>2</sup> 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
+{| class="wikitable" style="width: 40%; text-align:center;"
+! style="width: 25%" |Age in years, rounded to the nearest hundredth
+! style="width: 25%" |Dose
 |-
-|[[#top|back to top]]
+|1.00 to 1.99
-|}
+|8 mg
-====Regimen {{#subobject:1y47gc|Variant=1}}====
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
-! style="width: 33%" |Study
-! style="width: 33%" |Years of enrollment
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://doi.org/10.1200/jco.20.00494 Angiolillo et al. 2021 (COG AALL0932)]
+|2.00 to 2.99
-|2010-2018
+|10 mg
-| style="background-color:#91cf61" |Randomized portion of RCT
 |-
-|}
+|3.00 to 8.99
+|12 mg
-=====Chemotherapy=====
+|-
+|9.00 or older
-*[[Methotrexate (MTX)]] IV at 1000 mg/m<sup>2</sup> on days 8, 29, 50, 71, 92, and 113.
+|15 mg
+|}
- Given as a 200 mg/m<sup>2</sup> bolus over 20 - 30 minutes followed by 800 mg/m<sup>2</sup> over 23.5 hours (initial bolus of 30 minutes) or 23 hours and 40 minutes (if initial bolus was over 20 minutes)
+'''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.'''
+</div></div></div>
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 15, 22, 78, and 85.
+===References===
-*[[Dexamethasone (Decadron)]] 3 mg/m<sup>2</sup>/dose IV or PO twice daily on days 15 - 21, and 78 - 84. (6 mg/m<sup>2</sup>/day)
+#'''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. [https://doi.org/10.3324/haematol.2018.204545 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30545921/ PubMed] [https://clinicaltrials.gov/study/NCT02883049 NCT02883049]
-*[[Mercaptopurine (6-MP)]] 50 mg/m<sup>2</sup>/dose PO once per day on days 1 to 33
+==COG AALL1131 protocol for VHR B-ALL==
-*[[Folinic acid (Leucovorin)]] 10 mg/m<sup>2</sup> x 2 doses PO or IV (given 48 and 60 hours after the START of MTX infusion, continuing until MTX level < 0.2 μM) on days 9 - 10, 30 - 31, 51 - 52, 72 - 73, 93 - 94, and 114 - 115.
+<div class="toccolours" style="background-color:#c8a2c8">
+{| class="wikitable" style="width: 40%; text-align:center;"
-=====CNS prophylaxis=====
+! style="width: 25%" |Study
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-*[[Methotrexate (MTX)]] IT once on day 8, 29, 50, 71, 92, and 113 (To be delivered within 6 hours of the beginning of the IV MTX infusion, -6hr to + 6 hr)
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ Burke et al. 2019 (COG AALL1131)]
+| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
+|-
+|}
+<div class="toccolours" style="background-color:#eeeeee">
+===Consolidation {{#subobject:98346f|Variant=1}}===
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Pegaspargase (Oncaspar)]] 2,500 units/m<sup>2</sup> IV over 1 to 2 hours once on day 15, 43
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 15, 22, 43, 50
+*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV over 30 to 60 minutes once on day 1, 29
+*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> 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/m<sup>2</sup> 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)
 {| class="wikitable" style="width: 40%; text-align:center;"
-! style="width: 25%" |Age
+! style="width: 25%" |Age in years, rounded to the nearest hundredth
 ! style="width: 25%" |Dose
 |-
-|1 - 1.99
+|1.00 to 1.99
 |8 mg
 |-
-|2 - 2.99
+|2.00 to 2.99
 |10 mg
 |-
-|3 - 8.99
+|3.00 to 8.99
 |12 mg
 |-
-|≥ 9
+|9.00 or older
 |15 mg
 |}
+'''56-day course'''
-'''19-week cycle'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
-====References====
+===Interim Maintenance, I with HD MTX {{#subobject:98346f|Variant=1}}===
+<div class="toccolours" style="background-color:#b3e2cd">
-#'''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. [http://www.bloodjournal.org/content/118/2/243.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3138679/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21562038 PubMed] NCT00005945
+====Chemotherapy====
-#'''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. [https://doi.org/10.1200/jco.20.00494 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33411585/ PubMed] NCT01190930
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 15, 29, 43
+*[[Mercaptopurine (6-MP)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 56
-===Maintenance {{#subobject:0ae09f|Regimen=1}}===
+*High Dose [[Methotrexate (MTX)]] 500 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 15, 29, 43, then 4500 mg/m<sup>2</sup> IV continuous infusion over 23.5 hours, started on days 1, 15, 29, 43
-{| class="wikitable" style="float:right; margin-left: 5px;"
+**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/m<sup>2</sup> 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
+{| class="wikitable" style="width: 40%; text-align:center;"
+! style="width: 25%" |Age in years, rounded to the nearest hundredth
+! style="width: 25%" |Dose
+|-
+|1.00 to 1.99
+|8 mg
 |-
-|[[#top|back to top]]
+|2.00 to 2.99
-|}
+|10 mg
-====Regimen {{#subobject:1y47gc|Variant=1}}====
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
-! style="width: 33%" |Study
-! style="width: 33%" |Years of enrollment
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://doi.org/10.1200/jco.20.00494 Angiolillo et al. 2021 (COG AALL0932)]
+|3.00 to 8.99
-|2010-2018
+|12 mg
-| style="background-color:#91cf61" |Randomized portion of RCT
 |-
+|9.00 or older
+|15 mg
 |}
+'''63-day course'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
-=====Chemotherapy=====
+===Delayed Intensification {{#subobject:98346f|Variant=1}}===
+<div class="toccolours" style="background-color:#b3e2cd">
-MTX DATES CHANGE DEPENDING ON CYCLE NUMBER
+====Chemotherapy====
+*[[Doxorubicin (Adriamycin)]] 25 mg/m<sup>2</sup> IV push over 1 to 15 minutes once per day on days 1, 8, 15
-Cycles 1 and 4:
+*[[Pegaspargase (Oncaspar)]] 2,500 units/m<sup>2</sup> IV over 1 to 2 hours once on day 4, 43
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 43, 50
-*[[Methotrexate (MTX)]] PO at 20 mg/m<sup>2</sup> on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, 92, 99, and 106.
+*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV over 30 to 60 minutes once on day 29 ONLY
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1 and 8.
+*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> SC or IV over 1 to 30 minutes on days 29 to 32, 36 to 39
-*[[Dexamethasone (Decadron)]] 3 mg/m<sup>2</sup>/dose PO twice daily on days 1 - 7. (6 mg/m<sup>2</sup>/day, do not taper)
+*[[Thioguanine (Tabloid)]] 60 mg/m<sup>2</sup> PO once per day on days 29 to 42
-*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup>/dose PO once per day on days 1 - 112. (NOTE: Higher 6-MP dose than in consolidation)
+====Glucocorticoid therapy====
+*[[Dexamethasone (Decadron)]] 5 mg/m<sup>2</sup> IV or PO twice per day on days 1 to 7, 15 to 21
-Cycles 2 and 5:
+====CNS therapy, prophylaxis====
+*[[Methotrexate (MTX)]] IT once per day on day 1, 29, 36
-*[[Methotrexate (MTX)]] PO at 20 mg/m<sup>2</sup> on days 1, 8, 15, 22, 29, 36, 43, 50, 64, 71, 78, 85, 92, 99, and 106.
+{| class="wikitable" style="width: 40%; text-align:center;"
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1 and 8.
+! style="width: 25%" |Age in years, rounded to the nearest hundredth
-*[[Dexamethasone (Decadron)]] 3 mg/m<sup>2</sup>/dose PO twice daily on days 1 - 7. (6 mg/m<sup>2</sup>/day, do not taper)
+! style="width: 25%" |Dose
-*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup>/dose PO once per day on days 1 - 112. (NOTE: Higher 6-MP dose than in consolidation)
+|-
+|1.00 to 1.99
-Cycles 3 and 6:
+|8 mg
+|-
-*[[Methotrexate (MTX)]] PO at 20 mg/m<sup>2</sup> on days 1, 8, 15, 22, 36, 43, 50, 57, 64, 71, 78, 85, 92, 99, and 106.
+|2.00 to 2.99
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1 and 8.
+|10 mg
-*[[Dexamethasone (Decadron)]] 3 mg/m<sup>2</sup>/dose PO twice daily on days 1 - 7. (6 mg/m<sup>2</sup>/day, do not taper)
+|-
-*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup>/dose PO once per day on days 1 - 112. (NOTE: Higher 6-MP dose than in consolidation)
+|3.00 to 8.99
+|12 mg
-Cycle 7:
+|-
+|9.00 or older
-*[[Methotrexate (MTX)]] PO at 20 mg/m<sup>2</sup> on days 1, 8, 15, 29, 22, 36, 43, 50, 57, and 64
+|15 mg
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1 and 8.
+|}
-*[[Dexamethasone (Decadron)]] 3 mg/m<sup>2</sup>/dose PO twice daily on days 1 - 7. (6 mg/m<sup>2</sup>/day, do not taper)
+'''56-day course'''
-*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup>/dose PO once per day on days 1 - 70. (NOTE: Higher 6-MP dose than in consolidation)
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Interim Maintenance, II with Capizzi MTX {{#subobject:98346f|Variant=1}}===
-=====CNS prophylaxis=====
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
-DATES CHANGE DEPENDING ON CYCLE NUMBER
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on day 1, 11, 21, 31, 41
+*[[Methotrexate (MTX)]] 100 mg/m<sup>2</sup> IV over 2 to 5 minutes (undiluted) or over 10 to 15 minutes (diluted) on days 1, 150 mg/m<sup>2</sup> on day 11, 200 mg/m<sup>2</sup> on day 21, 250 mg/m<sup>2</sup> on day 31, and 300 mg/m<sup>2</sup> on day 41
-Cycles 1 and 4:
+*[[Pegaspargase (Oncaspar)]] 2,500 units/m<sup>2</sup> IV over 1 to 2 hours once on day 2, 22
+====CNS therapy, prophylaxis====
-*[[Methotrexate (MTX)]] IT once on day 1 and 85.
+*[[Methotrexate (MTX)]] IT once per day on days 1, 31
-Cycles 2 and 5:
-*[[Methotrexate (MTX)]] IT once on day 57.
-Cycles 3 and 6:
-*[[Methotrexate (MTX)]] IT once on day 29.
-Cycle 7:
-NO MTX IT on Cycle 7
 {| class="wikitable" style="width: 40%; text-align:center;"
-! style="width: 25%" |Age
+! style="width: 25%" |Age in years, rounded to the nearest hundredth
 ! style="width: 25%" |Dose
 |-
-|1 - 1.99
+|1.00 to 1.99
 |8 mg
 |-
-|2 - 2.99
+|2.00 to 2.99
 |10 mg
 |-
-|3 - 8.99
+|3.00 to 8.99
 |12 mg
 |-
-|≥ 9
+|9.00 or older
 |15 mg
 |}
+'''56-day course'''
-'''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.'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
-====References====
+===Maintenance, VHR Arm {{#subobject:98346f|Variant=1}}===
+<div class="toccolours" style="background-color:#b3e2cd">
-#'''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. [http://www.bloodjournal.org/content/118/2/243.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3138679/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21562038 PubMed] NCT00005945
+====Radiotherapy====
-#'''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. [https://doi.org/10.1200/jco.20.00494 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33411585/ PubMed] NCT01190930
+*[[External_beam_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
-==Maintenance Arm LLy==
+====Chemotherapy====
-===Vincristine/Dexamethasone {{#subobject:0ae09f|Regimen=1}}===
+*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup> PO once per day on days 1 to 84
-{| class="wikitable" style="float:right; margin-left: 5px;"
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 29, 57
+*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> 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/m<sup>2</sup> 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)
+{| class="wikitable" style="width: 40%; text-align:center;"
+! style="width: 25%" |Age in years, rounded to the nearest hundredth
+! style="width: 25%" |Dose
 |-
-|[[#top|back to top]]
+|1.00 to 1.99
-|}
+|8 mg
-====Regimen {{#subobject:1y47gc|Variant=1}}====
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
-! style="width: 33%" |Study
-! style="width: 33%" |Years of enrollment
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://doi.org/10.1200/jco.20.00494 Angiolillo et al. 2021 (COG AALL0932)]
-|2010-2018
-| style="background-color:#91cf61" |Randomized portion of RCT
-|-
-|}
-=====Preceding treatment=====
-*COG AALL0932: [[#Methotrexate_.26_Vincristine|MTX & Vincristine interim maintenance]]
-=====Chemotherapy=====
-*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> PO once on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71 and 78.
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 29, and 57. (4 Week Intervals)
-*[[Dexamethasone (Decadron)]] 3 mg/m<sup>2</sup>/dose PO twice daily on days 1 - 5, 29 - 33, and 57 - 61. (6 mg/m<sup>2</sup>/day) (DO NOT TAPER)
-*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup>/dose PO once per day on days 1 to 84.
-=====CNS prophylaxis=====
-*[[Methotrexate (MTX)]] IT once on day 1
-{| class="wikitable" style="width: 40%; text-align:center;"
-! style="width: 25%" |Age
-! style="width: 25%" |Dose
-|-
-|1 - 1.99
-|8 mg
 |-
-|2 - 2.99
+|2.00 to 2.99
 |10 mg
 |-
-|3 - 8.99
+|3.00 to 8.99
 |12 mg
 |-
-|≥ 9
+|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.'''
-'''12-week cycles until total duration of therapy is 2 years for female and 3 years for male from the start of Interim I'''
+</div></div></div>
+===References===
-====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. [https://doi.org/10.3324/haematol.2018.204545 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30545921/ PubMed] [https://clinicaltrials.gov/study/NCT02883049 NCT02883049]
+==COG AALL1131 protocol for Ph-like B-ALL (Dasatinib Arm)==
-#'''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. [http://www.bloodjournal.org/content/118/2/243.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3138679/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21562038 PubMed] NCT00005945
+<div class="toccolours" style="background-color:#c8a2c8">
-#'''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. [https://doi.org/10.1200/jco.20.00494 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33411585/ PubMed] NCT01190930
-=AALL1131=
-==Induction==
-===Daunorubicin, Pegaspargase, Vincristine, Dexamethasone {{#subobject:088146|Regimen=1}}===
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-====Regimen {{#subobject:98346f|Variant=1}}====
 {| class="wikitable" style="width: 40%; text-align:center;"
 ! style="width: 25%" |Study
@@ Line 792: / Line 829: @@
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ Burke et al. 2019 (COG AALL1131)]
-| style="background-color:#91cf61" |Non-randomized portion of RCT
+| style="background-color:#91cf61" |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.''
+<div class="toccolours" style="background-color:#eeeeee">
+===Consolidation {{#subobject:98346f|Variant=1}}===
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV over 30 to 60 minutes once on days 1, 29
-*[[Daunorubicin (Cerubidine)]] 25 mg/m<sup>2</sup> IV over 1 to 15 minutes once per day on days 1, 8, 15, 22
+*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> 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)]] 2500 units/m<sup>2</sup> IV over 1 to 2 hours once on day 4
+*[[Pegaspargase (Oncaspar)]] 2,500 units/m<sup>2</sup> IV over 1 to 2 hours once on days 15, 43
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 15, 22, 43, 50
+*[[Mercaptopurine (6-MP)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 14, 29 to 42
- Patients < 10 years ONLY:
+====Targeted therapy====
+*[[Dasatinib (Sprycel)]] 60 mg/m<sup>2</sup> (rounded to the nearest 5 mg, maximum dose of 140 mg/day) PO once per day on days 1 to 56
-*[[Dexamethasone (Decadron)]] 5 mg/m<sup>2</sup> IV or PO twice per day on days 1 to 14
+====CNS therapy, prophylaxis====
+*[[Methotrexate (MTX)]] IT once per day on days 1, 8, 15, 22
- Patients ≥ 10 years ONLY:
-*[[Prednisone (Sterapred)]] 30 mg/m<sup>2</sup>/dose PO twice per day on days 1 to 28
-=====CNS prophylaxis=====
-*[[Cytarabine (Ara-C)]] as follows:
-**Ages 1 to 1.99: 30 mg IT once on day 1
-**Ages 2 to 2.99: 50 mg IT once on day 1
-**Age 3 and older: 70 mg IT once on day 1
- CNS2 Patients will receive an additional dose of [[Cytarabine (Ara-C)]] IT on either day 4, 5, or 6, and then another dose of [[Cytarabine (Ara-C)]] IT on either day 11 or 12 according to the following dosing.
-*[[Cytarabine (Ara-C)]] as follows:
-**Ages 1 to 1.99: 20 mg IT once
-**Ages 2 to 2.99: 30 mg IT once
-**Age 3 and older: 40 mg IT once
-*[[Methotrexate (MTX)]] as follows: (CNS3 also on Days 15 and 22)
-**Ages 1 to 1.99: 8 mg IT once per day on days 8 & 29
-**Ages 2 to 2.99: 10 mg IT once per day on days 8 & 29
-**Ages 3 to 8.99: 12 mg IT once per day on days 8 & 29
-**Age 9 and older: 15 mg IT once per day on days 8 & 29
-'''4-week course'''
-=====Subsequent treatment=====
-*See protocol for details of treatment beyond induction
-===References===
-#'''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. [http://www.haematologica.org/content/104/5/986.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30545921 PubMed] NCT02883049
-==HR B-ALL==
-===Consolidation===
-====Regimen {{#subobject:98346f|Variant=1}}====
 {| class="wikitable" style="width: 40%; text-align:center;"
-! style="width: 25%" |Study
+! style="width: 25%" |Age in years, rounded to the nearest hundredth
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |Dose
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ Burke et al. 2019 (COG AALL1131)]
+|1.00 to 1.99
-| style="background-color:#91cf61" |Randomized portion of RCT
+|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'''
-=====Chemotherapy=====
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
-*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV over 30 - 60 minutes once on days 1 and 29
+===Interim Maintenance, with HD MTX {{#subobject:98346f|Variant=1}}===
-*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup>/day SC or IV over 1 - 30 minutes on days 1 - 4, 8 - 11, 29 - 32, 36 - 39.
+<div class="toccolours" style="background-color:#b3e2cd">
-*[[Pegaspargase (Oncaspar)]] 2500 units/m<sup>2</sup> IV over 1 - 2 hours once on days 15, and 43.
+====Chemotherapy====
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 15, 22, 43, and 50.
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 15, 29, 43
-*[[Mercaptopurine (6-MP)]] 60 mg/m<sup>2</sup>/dose PO once per day on days 1 - 14, and 29 - 42.
+*[[Mercaptopurine (6-MP)]] 25 mg/m<sup>2</sup> PO once per day on days 1 to 56.
+*High Dose [[Methotrexate (MTX)]] 500 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 15, 29, 43, then 4500 mg/m<sup>2</sup> IV continuous infusion over 23.5 hours, started on days 1, 15, 29, 43
-======CNS prophylaxis======
+**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====
-*[[Methotrexate (MTX)]] IT once per day on days 1, 8, 15, and 22.
+*[[Dasatinib (Sprycel)]] 60 mg/m<sup>2</sup> (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/m<sup>2</sup> 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
 {| class="wikitable" style="width: 40%; text-align:center;"
-! style="width: 25%" |Age
+! style="width: 25%" |Age in years, rounded to the nearest hundredth
 ! style="width: 25%" |Dose
 |-
-|1 - 1.99
+|1.00 to 1.99
 |8 mg
 |-
-|2 - 2.99
+|2.00 to 2.99
 |10 mg
 |-
-|3 - 8.99
+|3.00 to 8.99
 |12 mg
 |-
-|≥ 9
+|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).
-'''56-Day Course'''
+'''63-day course'''
+</div></div><br>
-====References====
+<div class="toccolours" style="background-color:#eeeeee">
+===Delayed Intensification {{#subobject:98346f|Variant=1}}===
-#'''COG AALL1131:''' Burke MJ, Salzer WL, Devidas M, Dai Y, Gore L, Hilden JM, Larsen E, Rabin KR, Zweidler-McKay PA, Borowitz MJ, Wood B, Heerema NA, Carroll AJ, Winick N, Carroll WL, Raetz EA, Loh ML, Hunger SP. Replacing cyclophosphamide/cytarabine/mercaptopurine with cyclophosphamide/etoposide during consolidation/delayed intensification does not improve outcome for pediatric B-cell acute lymphoblastic leukemia: a report from the COG. Haematologica. 2019 May;104(5):986-992. Epub 2018 Dec 13. [http://www.haematologica.org/content/104/5/986.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30545921 PubMed] NCT02883049
+<div class="toccolours" style="background-color:#b3e2cd">
-#'''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. [https://doi.org/10.1200/jco.20.00494 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33411585/ PubMed] NCT01190930
+====Chemotherapy====
+*[[Doxorubicin (Adriamycin)]] 25 mg/m<sup>2</sup> IV push over 1 to 15 minutes once per day on days 1, 8, 15
-===Interim Maintenance with HD MTX===
+*[[Pegaspargase (Oncaspar)]] 2,500 units/m<sup>2</sup> IV over 1 to 2 hours once on days 4, 43
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 43, 50
-====Regimen {{#subobject:98346f|Variant=1}}====
+*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV over 30 to 60 minutes once on day 29 ONLY
+*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> SC or IV over 1 to 30 minutes on days 29 to 32, 36 to 39
+*[[Thioguanine (Tabloid)]] 60 mg/m<sup>2</sup> PO once per day on days 29 to 42
+====Targeted therapy====
+*[[Dasatinib (Sprycel)]] 60 mg/m<sup>2</sup> (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/m<sup>2</sup> 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
 {| class="wikitable" style="width: 40%; text-align:center;"
-! style="width: 25%" |Study
+! style="width: 25%" |Age in years, rounded to the nearest hundredth
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |Dose
+|-
+|1.00 to 1.99
+|8 mg
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ Burke et al. 2019 (COG AALL1131)]
+|2.00 to 2.99
-| style="background-color:#91cf61" |Randomized portion of RCT
+|10 mg
 |-
-|}
+|3.00 to 8.99
+|12 mg
-=====Chemotherapy=====
+|-
+|9.00 or older
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 15, 29, and 43.
+|15 mg
-*[[Mercaptopurine (6-MP)]] 25 mg/m<sup>2</sup>/dose PO once per day on days 1 - 56.
+|}
-*High Dose [[Methotrexate (MTX)]] 5000 mg/m<sup>2</sup> IV over 24 hours on days 1, 15, 29, and 43.
+'''56-day course'''
-**MTX 500 mg/m<sup>2</sup> IV infused over 30 minutes. This is followed, immediately, by MTX 4500 mg/m<sup>2</sup> given by continuous IV infusion over 23.5 hours.
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
- ANC must be ≥ 750/µL and platelets must be ≥ 75,000/µL prior to each dose of HD MTX
+===Interim Maintenance, II with Capizzi MTX {{#subobject:98346f|Variant=1}}===
+<div class="toccolours" style="background-color:#b3e2cd">
-*[[Folinic acid (Leucovorin)]] 15 mg/m<sup>2</sup> x a minimum of 3 doses PO or IV (given at 42, 48, and 54 hours after the START of HD MTX infusion) on days 3 - 4, 17 - 18, 31 - 32, and 45 - 46.
+====Chemotherapy====
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on day 1, 11, 21, 31, 41
-======CNS prophylaxis======
+*[[Methotrexate (MTX)]] 100 mg/m<sup>2</sup> IV over 2 to 5 minutes (undiluted) or over 10 to 15 minutes (diluted) on days 1, 150 mg/m<sup>2</sup> on day 11, 200 mg/m<sup>2</sup> on day 21, 250 mg/m<sup>2</sup> on day 31, and 300 mg/m<sup>2</sup> on day 41
+*[[Pegaspargase (Oncaspar)]] 2,500 units/m<sup>2</sup> IV over 1 to 2 hours once on day 2, 22
-*[[Methotrexate (MTX)]] IT once per day on days 1 and 29.
+====Targeted therapy====
+*[[Dasatinib (Sprycel)]] 60 mg/m<sup>2</sup> (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
 {| class="wikitable" style="width: 40%; text-align:center;"
-! style="width: 25%" |Age
+! style="width: 25%" |Age in years, rounded to the nearest hundredth
 ! style="width: 25%" |Dose
 |-
-|1 - 1.99
+|1.00 to 1.99
 |8 mg
 |-
-|2 - 2.99
+|2.00 to 2.99
 |10 mg
 |-
-|3 - 8.99
+|3.00 to 8.99
 |12 mg
 |-
-|≥ 9
+|9.00 or older
 |15 mg
 |}
+'''56-day course'''
- When IT therapy and HD MTX are scheduled for the same day, deliver the IT therapy within 6 hours of the beginning of the IV MTX infusion. (hour -6 or +6, with 0 being the start of the MTX bolus).
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Maintenance {{#subobject:98346f|Variant=1}}===
+<div class="toccolours" style="background-color:#b3e2cd">
-'''63-Day Course'''
+====Radiotherapy====
+*[[External_beam_radiotherapy|Total body irradiation (TBI)]] by the following risk-based criteria:
-====References====
+**CNS3: 1800 cGy in 10 fractions, during the first 4 weeks of Maintenance therapy and should be completed by day 29 of Maintenance
+====Chemotherapy====
-#'''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. [http://www.haematologica.org/content/104/5/986.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30545921 PubMed] NCT02883049
+*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup> PO once per day on days 1 to 84
-#'''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. [https://doi.org/10.1200/jco.20.00494 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33411585/ PubMed] NCT01190930
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 29, 57
+*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> 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)
-===Delayed Intensification===
+====Glucocorticoid therapy====
+*[[Prednisone (Sterapred)]] 20 mg/m<sup>2</sup> 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
-====Regimen {{#subobject:98346f|Variant=1}}====
+====Targeted therapy====
+*[[Dasatinib (Sprycel)]] 60 mg/m<sup>2</sup> (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)
 {| class="wikitable" style="width: 40%; text-align:center;"
-! style="width: 25%" |Study
+! style="width: 25%" |Age in years, rounded to the nearest hundredth
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |Dose
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ Burke et al. 2019 (COG AALL1131)]
+|1.00 to 1.99
-| style="background-color:#91cf61" |Randomized portion of RCT
+|8 mg
 |-
-|}
+|2.00 to 2.99
+|10 mg
-====Chemotherapy====
-*[[Doxorubicin (Adriamycin)]] 25 mg/m<sup>2</sup> IV push over 1 to 15 minutes once per day on days 1, 8, and 15.
-*[[Pegaspargase (Oncaspar)]] 2500 units/m<sup>2</sup> IV over 1 to 2 hours once on days 4 and 43.
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 43, and 50.
-*[[Dexamethasone (Decadron)]] 5 mg/m<sup>2</sup> IV or PO twice per day on days 1 - 7 and 15 - 21.
-*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV over 30 - 60 minutes once on day 29 ONLY.
-*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup>/day SC or IV over 1 - 30 minutes on days 29 - 32 and 36 - 39.
-*[[Thioguanine (Tabloid)]] 60 mg/m<sup>2</sup>/day PO once per day on days 29 to 42.
-=====CNS prophylaxis=====
-*[[Methotrexate (MTX)]] IT once per day on days 1, 29, and 36.
-{| class="wikitable" style="width: 40%; text-align:center;"
-! style="width: 25%" |Age
-! style="width: 25%" |Dose
-|-
-|1 - 1.99
-|8 mg
-|-
-|2 - 2.99
-|10 mg
 |-
-|3 - 8.99
+|3.00 to 8.99
 |12 mg
 |-
-|≥ 9
+|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.'''
+</div></div></div>
-'''56-Day course'''
 ===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. [https://doi.org/10.3324/haematol.2018.204545 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30545921/ PubMed] [https://clinicaltrials.gov/study/NCT02883049 NCT02883049]
-#'''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. [http://www.haematologica.org/content/104/5/986.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30545921 PubMed] NCT02883049
+==COG AALL1131 protocol for DS HR B-ALL {{#subobject:088146|Regimen=1}}==
+<div class="toccolours" style="background-color:#c8a2c8">
-===Maintenance HR B-ALL===
-====Regimen {{#subobject:98346f|Variant=1}}====
 {| class="wikitable" style="width: 40%; text-align:center;"
 ! style="width: 25%" |Study
@@ Line 1,003: / Line 1,003: @@
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ Burke et al. 2019 (COG AALL1131)]
-| style="background-color:#91cf61" |Randomized portion of RCT
+| style="background-color:#91cf61" |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.''
+<div class="toccolours" style="background-color:#eeeeee">
+===Induction, Daunorubicin, Pegaspargase, Vincristine, Dexamethasone {{#subobject:98346f|Variant=1}}===
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
- Cycles 1-4
+*[[Pegaspargase (Oncaspar)]] 2,500 units/m<sup>2</sup> IV over 1 to 2 hours once on day 4
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
-*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup>/dose PO once per day on days 1 - 84.
+ RER - M1 Marrow at Day 15
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 29, and 57.
+*Add [[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV over 1 to 15 minutes once on days 15
-*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> PO once on days 8, 15, 22, 36, 43, 50, 57, 64, 71 and 78.
+====Glucocorticoid therapy====
-*[[Prednisone (Sterapred)]] 20 mg/m<sup>2</sup>/dose PO or IV (methylprednisolone given at 80% of the oral dose) twice per day on days 1 - 5, 29 - 33, and 57 - 61.
+*[[Dexamethasone (Decadron)]] by the following age-based criteria:
+**Younger than 10 years old: 3 mg/m<sup>2</sup> IV or PO twice per day on days 1 to 28 (DO NOT TAPER)
- Cycles 5 and Later
+**10 years old or older: Not given
+*[[Prednisone (Sterapred)]] by the following age-based criteria:
-*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup>/dose PO once per day on days 1 - 84.
+**Younger than 10 years old: Not given
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 29, and 57.
+**10 years old or older: 30 mg/m<sup>2</sup> PO twice per day on days 1 to 28 (DO NOT TAPER)
-*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> PO once on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71 and 78.
+====Supportive therapy====
-*[[Prednisone (Sterapred)]] 20 mg/m<sup>2</sup>/dose PO or IV (methylprednisolone given at 80% of the oral dose) twice per day on days 1 - 5, 29 - 33, and 57 - 61.
+*[[Leucovorin (Folinic acid)]] 5 mg/m<sup>2</sup> 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====
-=====CNS prophylaxis=====
+*[[Cytarabine (Ara-C)]] by the following age-based criteria:
- Cycles 1-4
+**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
-*[[Methotrexate (MTX)]] IT once per day on days 1 and 29.
+**3 years old or older: 70 mg IT once on day 1
+*[[Methotrexate (MTX)]] by the following age-based criteria:
- Cycles 5 and Later
+**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)
-*[[Methotrexate (MTX)]] IT once per day on day 1.
+**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'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*See protocol for details of treatment beyond induction
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Consolidation {{#subobject:98346f|Variant=1}}===
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV over 30 to 60 minutes once on days 1, 29
+*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> 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/m<sup>2</sup> IV over 1 to 2 hours once on days 15, 43
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 15, 22, 43, 50
+*[[Mercaptopurine (6-MP)]] 60 mg/m<sup>2</sup> 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
 {| class="wikitable" style="width: 40%; text-align:center;"
-! style="width: 25%" |Age
+! style="width: 25%" |Age in years, rounded to the nearest hundredth
 ! style="width: 25%" |Dose
 |-
-|1 - 1.99
+|1.00 to 1.99
 |8 mg
 |-
-|2 - 2.99
+|2.00 to 2.99
 |10 mg
 |-
-|3 - 8.99
+|3.00 to 8.99
 |12 mg
 |-
-|≥ 9
+|9.00 or older
 |15 mg
 |}
+ DS Arm
-'''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.'''
+====Supportive therapy====
+*[[Leucovorin (Folinic acid)]] 5 mg/m<sup>2</sup> x 2 doses PO (given at 48 and 60 hours after the lumbar puncture) on days 3, 4, 10, 11, 17, 18, 24, 25
-===References===
+'''56-day course'''
+</div></div><br>
-#'''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. [http://www.haematologica.org/content/104/5/986.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30545921 PubMed] NCT02883049
+<div class="toccolours" style="background-color:#eeeeee">
+===Interim Maintenance, with ID MTX {{#subobject:98346f|Variant=1}}===
-==VHR B-ALL==
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
-===Consolidation===
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 15, 29, 43
+*[[Mercaptopurine (6-MP)]] 25 mg/m<sup>2</sup>/dose PO once per day on days 1 to 56
-====Regimen {{#subobject:98346f|Variant=1}}====
+*Intermediate Dose [[Methotrexate (MTX)]] 200 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 15, 29, 43, then 1800 mg/m<sup>2</sup> 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/m<sup>2</sup> 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
 {| class="wikitable" style="width: 40%; text-align:center;"
-! style="width: 25%" |Study
+! style="width: 25%" |Age in years, rounded to the nearest hundredth
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |Dose
+|-
+|1.00 to 1.99
+|8 mg
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ Burke et al. 2019 (COG AALL1131)]
+|2.00 to 2.99
-| style="background-color:#91cf61" |Randomized portion of RCT
+|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'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Delayed Intensification {{#subobject:98346f|Variant=1}}===
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Doxorubicin (Adriamycin)]] 25 mg/m<sup>2</sup> IV push over 1 to 15 minutes once per day on days 1, 8, 15
-*[[Pegaspargase (Oncaspar)]] 2500 units/m<sup>2</sup> IV over 1 to 2 hours once on day 15 and 43.
+*[[Pegaspargase (Oncaspar)]] 2,500 units/m<sup>2</sup> IV over 1 to 2 hours once on days 4, 43
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 15, 22, 43, and 50.
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 43, 50
-*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV over 30 - 60 minutes once on day 1 and 29.
+*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV over 30 to 60 minutes once on day 29 ONLY
-*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup>/day SC or IV over 1 - 30 minutes on days 1 - 4, 8 - 11, 29 - 32, and 36 - 39.
+*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> SC or IV over 1 to 30 minutes on days 29 to 32, 36 to 39
-*[[Mercaptopurine (6-MP)]] 60 mg/m<sup>2</sup>/dose PO once per day on days 1 - 14 and 29 - 42.
+*[[Thioguanine (Tabloid)]] 60 mg/m<sup>2</sup> PO once per day on days 29 to 42
+====Glucocorticoid therapy====
-=====CNS prophylaxis=====
+*[[Dexamethasone (Decadron)]] 5 mg/m<sup>2</sup> IV or PO twice per day on days 1 to 7, 15 to 21
+====Supportive therapy====
-*[[Methotrexate (MTX)]] IT once per day on days 1, 8, 15, and 22. (Omit days 15 and 22 for CNS3 Patients)
+*[[Leucovorin (Folinic acid)]] 5 mg/m<sup>2</sup> 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
 {| class="wikitable" style="width: 40%; text-align:center;"
-! style="width: 25%" |Age
+! style="width: 25%" |Age in years, rounded to the nearest hundredth
 ! style="width: 25%" |Dose
 |-
-|1 - 1.99
+|1.00 to 1.99
 |8 mg
 |-
-|2 - 2.99
+|2.00 to 2.99
 |10 mg
 |-
-|3 - 8.99
+|3.00 to 8.99
 |12 mg
 |-
-|≥ 9
+|9.00 or older
 |15 mg
 |}
+'''56-day course'''
-'''56-Day course'''
+</div></div><br>
-===References===
+<div class="toccolours" style="background-color:#eeeeee">
+===Maintenance, DS HR Arm {{#subobject:98346f|Variant=1}}===
-#'''COG AALL1131:''' Burke MJ, Salzer WL, Devidas M, Dai Y, Gore L, Hilden JM, Larsen E, Rabin KR, Zweidler-McKay PA, Borowitz MJ, Wood B, Heerema NA, Carroll AJ, Winick N, Carroll WL, Raetz EA, Loh ML, Hunger SP. Replacing cyclophosphamide/cytarabine/mercaptopurine with cyclophosphamide/etoposide during consolidation/delayed intensification does not improve outcome for pediatric B-cell acute lymphoblastic leukemia: a report from the COG. Haematologica. 2019 May;104(5):986-992. Epub 2018 Dec 13. [http://www.haematologica.org/content/104/5/986.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30545921 PubMed] NCT02883049
+<div class="toccolours" style="background-color:#b3e2cd">
+====Radiotherapy====
-===Interim Maintenance I with HD MTX===
+*[[External_beam_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
-====Regimen {{#subobject:98346f|Variant=1}}====
+====Chemotherapy====
+*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup> PO once per day on days 1 to 84
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1
+*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> 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/m<sup>2</sup> 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)
 {| class="wikitable" style="width: 40%; text-align:center;"
-! style="width: 25%" |Study
+! style="width: 25%" |Age in years, rounded to the nearest hundredth
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 25%" |Dose
+|-
+|1.00 to 1.99
+|8 mg
+|-
+|2.00 to 2.99
+|10 mg
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ Burke et al. 2019 (COG AALL1131)]
+|3.00 to 8.99
-| style="background-color:#91cf61" |Randomized portion of RCT
+|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.'''
+</div></div></div>
+===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. [https://doi.org/10.3324/haematol.2018.204545 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30545921/ PubMed] [https://clinicaltrials.gov/study/NCT02883049 NCT02883049]
-====Chemotherapy====
+=Pre-phase=
+==Methylprednisolone monotherapy {{#subobject:5gh1bb|Regimen=1}}==
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 15, 29, and 43.
+<div class="toccolours" style="background-color:#eeeeee">
-*[[Mercaptopurine (6-MP)]] 60 mg/m<sup>2</sup>/dose PO once per day on days 1 - 56.
+===Regimen {{#subobject:88fgh7|Variant=1}}===
-*High Dose [[Methotrexate (MTX)]] 5000 mg/m<sup>2</sup> IV over 24 hours on days 1, 15, 29, and 43.
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
-**MTX 500 mg/m<sup>2</sup> IV infused over 30 minutes. This is followed, immediately, by MTX 4500 mg/m<sup>2</sup> given by continuous IV infusion over 23.5 hours.
+! style="width: 33%" |Study
+! style="width: 33%" |Dates of enrollment
- ANC must be ≥ 750/µL and platelets must be ≥ 75,000/µL prior to each dose of HD MTX
+! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
-*[[Folinic acid (Leucovorin)]] 15 mg/m<sup>2</sup> x a minimum of 3 doses PO or IV (given at 42, 48, and 54 hours after the START of HD MTX infusion) on days 3 - 4, 17 - 18, 31 - 32, and 45 - 46.
-=====CNS prophylaxis=====
-*[[Methotrexate (MTX)]] IT once per day on days 1 and 29.
-{| class="wikitable" style="width: 40%; text-align:center;"
-! style="width: 25%" |Age
-! style="width: 25%" |Dose
 |-
-|1 - 1.99
+|[https://doi.org/10.1016/s1470-2045(15)00363-0 Place et al. 2015 (DFCI 05-001)]
-|8 mg
+|2005-2011
+| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
 |-
-|2 - 2.99
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8369809/ Burns et al. 2020 (DFCI 11-001)]
-|10 mg
+|2012-2015
+| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
 |-
-|3 - 8.99
-|12 mg
-|-
-|≥ 9
-|15 mg
 |}
+''Note: Burns et al. 2020 is both an update of DFCI 05-001 and the primary publication of DFCI 11-001.''
-'''28-Day course'''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Glucocorticoid therapy====
+*[[Methylprednisolone (Solumedrol)]] 8 mg/m<sup>2</sup> IV three times per day on days 1 to 3
+'''3-day course'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*DFCI 05-001: [[#Doxorubicin.2C_L-Asparaginase.2C_Methotrexate.2C_Vincristine.2C_Methylprednisolone_888|Doxorubicin, L-asparaginase, Methotrexate, Vincristine, Methylprednisolone]] versus [[#Doxorubicin.2C_Methotrexate.2C_Pegaspargase.2C_Vincristine.2C_Methylprednisolone|Doxorubicin, Methotrexate, Pegaspargase, Vincristine, Methylprednisolone]] induction
+*DFCI 11-001: [[#Calaspargase.2C_Doxorubicin.2C_Methotrexate.2C_Vincristine.2C_Methylprednisolone_888|Calaspargase, Doxorubicin, Methotrexate, Vincristine, Methylprednisolone]] versus [[#Doxorubicin.2C_Methotrexate.2C_Pegaspargase.2C_Vincristine.2C_Methylprednisolone|Doxorubicin, Methotrexate, Pegaspargase, Vincristine, Methylprednisolone]] induction
+</div></div>
 ===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. [https://doi.org/10.1016/s1470-2045(15)00363-0 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26549586/ PubMed] [https://clinicaltrials.gov/study/NCT00400946 NCT00400946]
-#'''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. [http://www.haematologica.org/content/104/5/986.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30545921 PubMed] NCT02883049
+##'''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. [https://doi.org/10.1002/pbc.28719 link to original article] '''contains dosing details in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8369809/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33026184/ 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. [https://doi.org/10.1002/pbc.28719 link to original article] '''contains dosing details in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8369809/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33026184/ PubMed] [https://clinicaltrials.gov/study/NCT01574274 NCT01574274]
-===Delayed Intensification===
+## '''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. [https://doi.org/10.1200/jco.20.03692 link to original article] [https://pubmed.ncbi.nlm.nih.gov/34228505/ PubMed]
+==Prednisone monotherapy {{#subobject:8ca13b|Regimen=1}}==
-====Regimen {{#subobject:98346f|Variant=1}}====
+<div class="toccolours" style="background-color:#eeeeee">
-{| class="wikitable" style="width: 40%; text-align:center;"
+===Regimen {{#subobject:2fd1d7|Variant=1}}===
-! style="width: 25%" |Study
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 33%" |Study
+! style="width: 33%" |Dates of enrollment
+! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ Burke et al. 2019 (COG AALL1131)]
+|[https://doi.org/10.1182/blood-2015-09-670729 Möricke et al. 2016 (AIEOP-BFM ALL 2000)]
-| style="background-color:#91cf61" |Randomized portion of RCT
+|2000-2006
+| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
-====Chemotherapy====
+====Glucocorticoid therapy====
+*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup>/day PO on days 1 to 7
-*[[Doxorubicin (Adriamycin)]] 25 mg/m<sup>2</sup> IV push over 1 to 15 minutes once per day on days 1, 8, and 15.
+====CNS therapy, prophylaxis====
-*[[Pegaspargase (Oncaspar)]] 2500 units/m<sup>2</sup> IV over 1 to 2 hours once on day 4 and 43.
+*[[Methotrexate (MTX)]] 15 mg IT once on day 1
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 43, and 50.
+'''7-day course'''
-*[[Dexamethasone (Decadron)]] 5 mg/m<sup>2</sup> IV or PO twice per day on days 1 - 7 and 15 - 21.
+</div>
-*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV over 30 - 60 minutes once on day 29 ONLY.
+<div class="toccolours" style="background-color:#cbd5e7">
-*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup>/day SC or IV over 1 - 30 minutes on days 29 - 32 and 36 - 39.
+====Subsequent treatment====
-*[[Thioguanine (Tabloid)]] 60 mg/m<sup>2</sup>/day PO once per day on days 29 to 42.
+*[[#DOLP|Daunorubicin, L-Asparaginase, Vincristine, Prednisone]] versus [[#Daunorubicin.2C_L-Asparaginase.2C_Vincristine.2C_Dexamethasone_999|Daunorubicin, L-Asparaginase, Vincristine, Dexamethasone]] induction
+</div></div>
-=====CNS prophylaxis=====
+===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. [https://doi.org/10.1182/blood-2015-09-670729 link to original article] '''contains dosing details in supplement''' [https://pubmed.ncbi.nlm.nih.gov/26888258/ PubMed] [https://clinicaltrials.gov/study/NCT00430118 NCT00430118]; [https://clinicaltrials.gov/study/NCT00613457 NCT00613457]
-*[[Methotrexate (MTX)]] IT once per day on day 1, 29, and 36.
+==Vincristine & Prednisone {{#subobject:663781|Regimen=1}}==
+VP: '''<u>V</u>'''incristine & '''<u>P</u>'''rednisone
-{| class="wikitable" style="width: 40%; text-align:center;"
+<div class="toccolours" style="background-color:#eeeeee">
-! style="width: 25%" |Age
+===Regimen {{#subobject:79fc67|Variant=1}}===
-! style="width: 25%" |Dose
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+! style="width: 33%" |Study
+! style="width: 33%" |Dates of enrollment
+! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|1 - 1.99
+|[https://doi.org/10.1182/blood.V51.3.425.425 Sallan et al. 1978]
-|8 mg
+|1973-1977
-|-
+| style="background-color:#91cf61" |Non-randomized
-|2 - 2.99
-|10 mg
-|-
-|3 - 8.99
-|12 mg
 |-
-|≥ 9
-|15 mg
 |}
+''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.''
-'''56-Day course'''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15
+====Glucocorticoid therapy====
+*[[Prednisone (Sterapred)]] 40 mg/m<sup>2</sup>/day PO on days 1 to 21
+'''21-day course'''
+</div></div>
 ===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. [https://doi.org/10.1182/blood.V51.3.425.425 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/272207/ PubMed]
-#'''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. [http://www.haematologica.org/content/104/5/986.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30545921 PubMed] NCT02883049
+=Upfront induction therapy=
+==Calaspargase, Daunorubicin, Vincristine, Prednisone {{#subobject:1abca2|Regimen=1}}==
-===Interim Maintenance II with Capizzi MTX===
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:cf26ce|Variant=1}}===
-====Regimen {{#subobject:98346f|Variant=1}}====
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-{| class="wikitable" style="width: 40%; text-align:center;"
+! style="width: 20%" |Study
-! style="width: 25%" |Study
+! style="width: 20%" |Dates of enrollment
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ Burke et al. 2019 (COG AALL1131)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239306/ Angiolillo et al. 2014 (COG AALL07P4)]
-| style="background-color:#91cf61" |Randomized portion of RCT
+|2008-2010
+| style="background-color:#1a9851" |Randomized (E-RT-switch-ic)
+|[[#Daunorubicin.2C_Pegaspargase.2C_Vincristine.2C_Prednisone|Daunorubicin, Pegaspargase, Vincristine, Prednisone]]
+| style="background-color:#1a9850" |Longer half-life (primary endpoint)
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Calaspargase (Asparlas)]] 2500 units/m<sup>2</sup> IV once on day 4
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on day 1, 11, 21, 31, and 41.
+*[[Daunorubicin (Cerubidine)]] 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
-*[[Methotrexate (MTX)]] 100 mg/m<sup>2</sup> IV over 2 - 5 minutes (undiluted) or over 10 - 15 minutes (diluted) on days 1, 150 mg/m<sup>2</sup> on day 11, 200 mg/m<sup>2</sup> on day 21, 250 mg/m<sup>2</sup> on day 31, and 300 mg/m<sup>2</sup> on day 41.
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
-*[[Pegaspargase (Oncaspar)]] 2500 units/m<sup>2</sup> IV over 1 to 2 hours once on day 2 and 22.
+====Glucocorticoid therapy====
+*[[Prednisone (Sterapred)]] 30 mg/m<sup>2</sup> PO twice per day on days 1 to 28
-=====CNS prophylaxis=====
+'''5-week course'''
+</div>
-*[[Methotrexate (MTX)]] IT once per day on days 1 and 31.
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*See protocol for details of treatment beyond induction
+</div></div>
+===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. [https://doi.org/10.1200/JCO.2014.55.5763 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239306/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25348002/ PubMed] [https://clinicaltrials.gov/study/NCT00671034 NCT00671034]
+==Daunorubicin, Pegaspargase, Vincristine, Dexamethasone {{#subobject:088146|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:98346f|Variant=1}}===
 {| class="wikitable" style="width: 40%; text-align:center;"
-! style="width: 25%" |Age
+! style="width: 25%" |Study
-! style="width: 25%" |Dose
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|1 - 1.99
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ Burke et al. 2019 (COG AALL1131)]
-|8 mg
+| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
 |-
-|2 - 2.99
+|}
-|10 mg
+''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.''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Daunorubicin (Cerubidine)]] 25 mg/m<sup>2</sup> IV over 1 to 15 minutes once per day on days 1, 8, 15, 22
+*[[Pegaspargase (Oncaspar)]] 2500 units/m<sup>2</sup> IV over 1 to 2 hours once on day 4
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
+====Glucocorticoid therapy====
+*[[Dexamethasone (Decadron)]] 5 mg/m<sup>2</sup> 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'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*See protocol for details of treatment beyond induction
+</div></div>
+===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. [https://doi.org/10.3324/haematol.2018.204545 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30545921/ PubMed] [https://clinicaltrials.gov/study/NCT02883049 NCT02883049]
+==Daunorubicin, Pegaspargase, Vincristine, Prednisone {{#subobject:1apea2|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:cfgace|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|3 - 8.99
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239306/ Angiolillo et al. 2014 (COG AALL07P4)]
-|12 mg
+|2008-2010
+| style="background-color:#1a9851" |Randomized (C)
+|[[#Calaspargase.2C_Daunorubicin.2C_Vincristine.2C_Prednisone|Calaspargase, Daunorubicin, Vincristine, Prednisone]]
+| style="background-color:#d73027" |Shorter half-life (primary endpoint)
 |-
-|≥ 9
-|15 mg
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
-'''56-Day course'''
+====Chemotherapy====
+*[[Daunorubicin (Cerubidine)]] 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
-===References===
+*[[Pegaspargase (Oncaspar)]] 2500 units/m<sup>2</sup> IV once on day 4
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
-#'''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. [http://www.haematologica.org/content/104/5/986.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30545921 PubMed] NCT02883049
+====Glucocorticoid therapy====
+*[[Prednisone (Sterapred)]] 30 mg/m<sup>2</sup> PO twice per day on days 1 to 28
-===VHR Arm Maintenance===
+'''5-week course'''
+</div>
-====Regimen {{#subobject:98346f|Variant=1}}====
+<div class="toccolours" style="background-color:#cbd5e7">
-{| class="wikitable" style="width: 40%; text-align:center;"
+====Subsequent treatment====
-! style="width: 25%" |Study
+*See protocol for details of treatment beyond induction
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+</div></div>
+===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. [https://doi.org/10.1200/JCO.2014.55.5763 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239306/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25348002/ PubMed] [https://clinicaltrials.gov/study/NCT00671034 NCT00671034]
+==DOLP {{#subobject:3c9897|Regimen=1}}==
+DOLP: '''<u>D</u>'''aunorubicin, '''<u>O</u>'''ncovin (Vincristine), '''<u>L</u>'''-Asparaginase, '''<u>P</u>'''rednisone
+<br>DVPA: '''<u>D</u>'''aunorubicin, '''<u>V</u>'''incristine, '''<u>P</u>'''rednisone, '''<u>A</u>'''sparaginase
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1, 25/1.5/6000/60 {{#subobject:3fe1a2|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2254538/ Seibel et al. 2007 (COG CCG-1961)]
+|1996-2002
+| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ Burke et al. 2019 (COG AALL1131)]
+|[https://doi.org/10.1002/pbc.24149 Termuhlen et al. 2012 (COG A5971)]
-| style="background-color:#91cf61" |Randomized portion of RCT
+|2000-2005
+| style="background-color:#91cf61" |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.''
-====Radiotherapy====
+<div class="toccolours" style="background-color:#b3e2cd">
- For Patients with CNS3 Disease
-*[[External_beam_radiotherapy|Total body irradiation (TBI)]] 1800 cGy in 10 fractions, during the first 4 weeks of Maintenance therapy and should be completed by day 29 of Maintenance.
 ====Chemotherapy====
+*[[Daunorubicin (Cerubidine)]] 25 mg/m<sup>2</sup> IV once per day on days 0, 7, 14, 21
-*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup>/dose PO once per day on days 1 - 84.
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 0, 7, 14, 21
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 29, and 57.
+*[[Asparaginase (Elspar)]] 6000 units/m<sup>2</sup> IM once per day on days 3, 5, 7, 10, 12, 14, 17, 19, 21
-*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> PO once on days 8, 15, 22, (29), 36, 43, 50, 57, 64, 71 and 78. (OMIT DAY 29 WHEN CNS RADIATION IS GIVEN, DUE TO IT MTX).
+====Glucocorticoid therapy====
-*[[Prednisone (Sterapred)]] 20 mg/m<sup>2</sup>/dose PO or IV (methylprednisolone given at 80% of the oral dose) twice per day on days 1 - 5, 29 - 33, and 57 - 61.
+*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup>/day PO on days 0 to 27, then tapered from days 28 to 38 (see note)
+====CNS therapy====
-=====CNS prophylaxis=====
+*[[Cytarabine (Ara-C)]] by the following age-based criteria:
+**1 to 1.99 years old: 30 mg IT once on day 0
-*[[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).
+**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
-{| class="wikitable" style="width: 40%; text-align:center;"
+*[[Methotrexate (MTX)]] by the following age-based criteria:
-! style="width: 25%" |Age
+**1 to 1.99 years old: 8 mg IT once per day on days 7 & 28
-! style="width: 25%" |Dose
+**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'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*COG CCG-1961: Standard versus increased intensity post-remission therapy (see paper for details)
+*COG A5971: Consolidation (see paper for details)
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===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) {{#subobject:020017|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|1 - 1.99
+|[https://doi.org/10.1182/blood-2007-09-112920 Möricke et al. 2008 (ALL-BFM 95)]
-|8 mg
+|1995-2000
+| style="background-color:#91cf61" |Non-randomized
 |-
-|2 - 2.99
+|[https://doi.org/10.1200/jco.2013.48.6522 Stary et al. 2013 (ALL IC-BFM 2002)]
-|10 mg
+|2002-2007
+| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
 |-
-|3 - 8.99
+|[https://doi.org/10.1200/jco.22.01760 Campbell et al. 2023 (ALL IC-BFM 2009)]
-|12 mg
+|2010-06 to 2018-03
+| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
 |-
-|≥ 9
-|15 mg
 |}
+''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.''
-'''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.'''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
-===References===
+*[[Daunorubicin (Cerubidine)]] 30 mg/m<sup>2</sup> IV over 60 minutes once per day on days 8, 15, 22, 29
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 8, 15, 22, 29
-#'''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. [http://www.haematologica.org/content/104/5/986.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30545921 PubMed] NCT02883049
+*[[Asparaginase (Elspar)]] 5000 units IV over 60 minutes once per day on days 12, 15, 18, 21, 24, 27, 30, 33
+====Glucocorticoid therapy====
-==Ph-Like B-ALL (Dasatinib Arm)==
+*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup>/day PO on days 1 to 28, tapered over 9 days
+====CNS therapy====
-===Consolidation (Dasatinib Arm)===
+*[[Methotrexate (MTX)]] 12 mg IT once per day on days 1, 12, 33
+'''5-week course'''
-====Regimen {{#subobject:98346f|Variant=1}}====
+</div>
-{| class="wikitable" style="width: 40%; text-align:center;"
+<div class="toccolours" style="background-color:#cbd5e7">
-! style="width: 25%" |Study
+====Subsequent treatment====
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+*ALL-BFM 95 & ALL IC-BFM 2002: See papers for details
+*ALL IC-BFM 2009, SR: [[#Cytarabine.2C_Cyclophosphamide.2C_Mercaptopurine_888|Induction phase IB]]
+*ALL IC-BFM 2009, IR/HR: [[#Cytarabine.2C_Cyclophosphamide.2C_Mercaptopurine_888|Induction phase IB]] versus induction phase augmented IB
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #3, 30/1.5/10,000/60 ("Protocol I") {{#subobject:0ccc82|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ Burke et al. 2019 (COG AALL1131)]
+|[https://doi.org/10.1182/blood.V95.11.3310 Schrappe et al. 2000 (ALL-BFM 90)]
-| style="background-color:#91cf61" |Randomized portion of RCT
+|1990-04-01 to 1995-03-31
+| style="background-color:#91cf61" |Non-randomized
+|-
+|[https://doi.org/10.1038/sj.leu.2402489 Kamps et al. 2002 (DCLSG ALL-8)]
+|1991-10 to 1996-12
+| style="background-color:#91cf61" |Non-randomized
 |-
 |}
+''Note: see papers for details on dose adjustments based on risk.''
-=====Chemotherapy=====
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
-*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV over 30 - 60 minutes once on days 1 and 29
+*[[Daunorubicin (Cerubidine)]] 30 mg/m<sup>2</sup> IV over 60 minutes once per day on days 8, 15, 22, 29
-*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup>/day SC or IV over 1 - 30 minutes on days 1 - 4, 8 - 11, 29 - 32, 36 - 39.
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 8, 15, 22, 29
-*[[Pegaspargase (Oncaspar)]] 2500 units/m<sup>2</sup> IV over 1 - 2 hours once on days 15, and 43.
+*[[Asparaginase (Elspar)]] 10,000 units IV over 60 minutes once per day on days 12, 15, 18, 21, 24, 27, 30, 33
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 15, 22, 43, and 50.
+====Glucocorticoid therapy====
-*[[Mercaptopurine (6-MP)]] 60 mg/m<sup>2</sup>/dose PO once per day on days 1 - 14, and 29 - 42.
+*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup>/day PO on days 1 to 28
-*[[Dasatinib (Sprycel)]] 60 mg (rounded to the nearest 5 mg, max of 140 mg/day) PO once daily on days 1 to 56.
+====CNS therapy====
+*[[Methotrexate (MTX)]] 12 mg IT once per day on days 1, 15, 29
-======CNS prophylaxis======
+'''5-week course'''
+</div>
-*[[Methotrexate (MTX)]] IT once per day on days 1, 8, 15, and 22.
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
-{| class="wikitable" style="width: 40%; text-align:center;"
+*See papers for details
-! style="width: 25%" |Age
+</div></div><br>
-! style="width: 25%" |Dose
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #4, 40/1.5/10,000/60 ("Induction Protocol I" of ALL-BFM 86) {{#subobject:6ad40d|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|1 - 1.99
+|[https://doi.org/10.1182/blood.V84.9.3122.3122 Reiter et al. 1994 (ALL-BFM 86)]
-|8 mg
+|1986-10 to 1990-03
+| style="background-color:#91cf61" |Non-randomized part of RCT
 |-
-|2 - 2.99
+|[https://doi.org/10.1182/blood.V94.4.1226 Kamps et al. 1999 (DCLSG ALL-7)]
-|10 mg
+|1988-07 to 1991-10
+| style="background-color:#91cf61" |Non-randomized part of RCT
 |-
-|3 - 8.99
+|}
-|12 mg
+<div class="toccolours" style="background-color:#b3e2cd">
-|-
+====Chemotherapy====
-|≥ 9
+*[[Daunorubicin (Cerubidine)]] 40 mg/m<sup>2</sup> IV once per day on days 8, 15, 22, 29
-|15 mg
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 8, 15, 22, 29
-|}
+*[[Asparaginase (Elspar)]] 10,000 units/m<sup>2</sup> IV once per day on days 19, 22, 25, 28, 31, 34, 37, 40
+====Glucocorticoid therapy====
+*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup>/day PO on days 1 to 28
+'''6-week course'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*ALL-BFM 86 & DCLSG ALL-7, standard-risk group (SRG) and risk group (RG): [[B-cell_acute_lymphoblastic_leukemia,_pediatric_-_historical#Mercaptopurine_.26_Methotrexate_2|6-MP & MTX]] consolidation
+*ALL-BFM 86 & DCLSG ALL-7, experimental group (EG): [[#Cytarabine.2C_Ifosfamide.2C_Methotrexate.2C_Mitoxantrone.2C_Prednisone_888|Cytarabine, Ifosfamide, MTX, Mitoxantrone, Prednisone]] consolidation
+</div></div>
-*[[Dasatinib (Sprycel)]] 60 mg (rounded to the nearest 5 mg, max of 140 mg/day) PO once daily on days 1 to 56.
+===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. [https://doi.org/10.1182/blood.V84.9.3122.3122 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/7949185/ 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. [https://doi.org/10.1182/blood.V94.4.1226 link to original article] [https://pubmed.ncbi.nlm.nih.gov/10438710/ 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. [https://doi.org/10.1182/blood.V95.11.3310 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/10828010/ 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. [https://doi.org/10.1200/JCO.2006.06.2679 link to original article] [https://pubmed.ncbi.nlm.nih.gov/17179108/ 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. [https://doi.org/10.1038/sj.leu.2402489 link to original article] '''refers to ALL-BFM 90 protocol''' [https://pubmed.ncbi.nlm.nih.gov/12040440/ 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. [https://doi.org/10.1182/blood-2007-02-070342 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2254538/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18039957/ PubMed] [https://clinicaltrials.gov/study/NCT00002812 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. [https://doi.org/10.1182/blood-2007-09-112920 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18285545/ 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. [https://doi.org/10.1200/JCO.2006.06.2679 link to original article] [https://pubmed.ncbi.nlm.nih.gov/17179108/ 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. [https://doi.org/10.1002/pbc.24149 link to original article] '''contains dosing details in supplement''' [https://pubmed.ncbi.nlm.nih.gov/22488718/ PubMed] [https://clinicaltrials.gov/study/NCT00004228 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. [https://doi.org/10.1200/jco.2013.48.6522 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/24344215/ PubMed] [https://clinicaltrials.gov/study/NCT00764907 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. [https://doi.org/10.1200/jco.22.01760 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/37141547/ PubMed] EudraCT 2010-019722-13
+##'''Update:''' Conter V, Valsecchi MG, Cario G, Zimmermann M, Attarbaschi A, Stary J, Niggli F, Dalla Pozza L, Elitzur S, Silvestri D, Locatelli F, Möricke A, Engstler G, Smisek P, Bodmer N, Barbaric D, Izraeli S, Rizzari C, Boos J, Buldini B, Zucchetti M, von Stackelberg A, Matteo C, Lehrnbecher T, Lanvers-Kaminsky C, Cazzaniga G, Gruhn B, Biondi A, Schrappe M. Four Additional Doses of PEG-L-Asparaginase During the Consolidation Phase in the AIEOP-BFM ALL 2009 Protocol Do Not Improve Outcome and Increase Toxicity in High-Risk ALL: Results of a Randomized Study. J Clin Oncol. 2024 Mar 10;42(8):915-926. Epub 2023 Dec 14. [https://doi.org/10.1200/jco.23.01388 link to original article] [https://pubmed.ncbi.nlm.nih.gov/38096462/ PubMed]
-'''56-Day Course'''
+==DOLP (Prednisolone) {{#subobject:3c7jg7|Regimen=1}}==
+DOLP: '''<u>D</u>'''aunorubicin, '''<u>O</u>'''ncovin (Vincristine), '''<u>L</u>'''-Asparaginase, '''<u>P</u>'''rednisolone
-====References====
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1, 30/10,000/1.5/60 {{#subobject:087cg2|Variant=1}}===
-#'''COG AALL1131:''' Burke MJ, Salzer WL, Devidas M, Dai Y, Gore L, Hilden JM, Larsen E, Rabin KR, Zweidler-McKay PA, Borowitz MJ, Wood B, Heerema NA, Carroll AJ, Winick N, Carroll WL, Raetz EA, Loh ML, Hunger SP. Replacing cyclophosphamide/cytarabine/mercaptopurine with cyclophosphamide/etoposide during consolidation/delayed intensification does not improve outcome for pediatric B-cell acute lymphoblastic leukemia: a report from the COG. Haematologica. 2019 May;104(5):986-992. Epub 2018 Dec 13. [http://www.haematologica.org/content/104/5/986.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30545921 PubMed] NCT02883049
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-#'''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. [https://doi.org/10.1200/jco.20.00494 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33411585/ PubMed] NCT01190930
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
-===Interim Maintenance with HD MTX (Dasatinib Arm)===
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
-====Regimen {{#subobject:98346f|Variant=1}}====
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-{| class="wikitable" style="width: 40%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ Burke et al. 2019 (COG AALL1131)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2904579/ de Moerloose et al. 2010 (EORTC CLG 58951)]
-| style="background-color:#91cf61" |Randomized portion of RCT
+|1999-2002
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Daunorubicin.2C_L-Asparaginase.2C_Vincristine.2C_Dexamethasone_999|Daunorubicin, L-Asparaginase, Vincristine, Dexamethasone]]
+| style="background-color:#ffffbf" |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=====
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 15, 29, and 43.
+*[[Daunorubicin (Cerubidine)]] 30 mg/m<sup>2</sup> IV once per day on days 8, 15, 22, 29
-*[[Mercaptopurine (6-MP)]] 25 mg/m<sup>2</sup>/dose PO once per day on days 1 - 56.
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 8, 15, 22, 29
-*High Dose [[Methotrexate (MTX)]] 5000 mg/m<sup>2</sup> IV over 24 hours on days 1, 15, 29, and 43.
+*[[Asparaginase (Elspar)]] 10,000 units (route not specified) once per day on days 12, 15, 18, 22, 25, 29, 32, 35
-**MTX 500 mg/m<sup>2</sup> IV infused over 30 minutes. This is followed, immediately, by MTX 4500 mg/m<sup>2</sup> given by continuous IV infusion over 23.5 hours.
+====Glucocorticoid therapy====
+*[[Prednisolone (Millipred)]] 60 mg/m<sup>2</sup>/day PO on days 1 to 28, then tapered over 9 days
- ANC must be ≥ 750/µL and platelets must be ≥ 75,000/µL prior to each dose of HD MTX
+'''5-week course'''
+</div>
-*[[Folinic acid (Leucovorin)]] 15 mg/m<sup>2</sup> x a minimum of 3 doses PO or IV (given at 42, 48, and 54 hours after the START of HD MTX infusion) on days 3 - 4, 17 - 18, 31 - 32, and 45 - 46.
+<div class="toccolours" style="background-color:#cbd5e7">
-*[[Dasatinib (Sprycel)]] 60 mg (rounded to the nearest 5 mg, max of 140 mg/day) PO once daily on days 1 to 63.
+====Subsequent treatment====
+*See paper for details
-======CNS prophylaxis======
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
-*[[Methotrexate (MTX)]] IT once per day on days 1 and 29.
+===Regimen variant #2, 45/6000/1.5/40 {{#subobject:b39731|Variant=1}}===
 {| class="wikitable" style="width: 40%; text-align:center;"
-! style="width: 25%" |Age
+! style="width: 25%" |Study
-! style="width: 25%" |Dose
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|1 - 1.99
-|8 mg
 |-
-|2 - 2.99
+|[https://doi.org/10.1016/0140-6736(92)92103-m Chessells et al. 1992 (UK MRC ALLX)]
-|10 mg
+| style="background-color:#91cf61" |Non-randomized part of RCT
 |-
-|3 - 8.99
-|12 mg
-|-
-|≥ 9
-|15 mg
 |}
+''Note: exact days for L-asparaginase were not specified in the protocol.''
- When IT therapy and HD MTX are scheduled for the same day, deliver the IT therapy within 6 hours of the beginning of the IV MTX infusion. (hour -6 or +6, with 0 being the start of the MTX bolus).
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Daunorubicin (Cerubidine)]] 45 mg/m<sup>2</sup> IV once per day on days 1 & 2
-'''63-Day Course'''
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29
+*[[Asparaginase (Elspar)]] 6000 units/m<sup>2</sup> SC once per day on days 3, 5, 7, 10, 12, 14, 17, 19, 21
-====References====
+====Glucocorticoid therapy====
+*[[Prednisolone (Millipred)]] 40 mg/m<sup>2</sup>/day PO on days 1 to 28
-#'''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. [http://www.haematologica.org/content/104/5/986.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30545921 PubMed] NCT02883049
+'''29-day course'''
-#'''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. [https://doi.org/10.1200/jco.20.00494 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33411585/ PubMed] NCT01190930
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
-===Delayed Intensification (Dasatinib Arm)===
+====Subsequent treatment====
+*Intensification (randomized) or [[#Cyclophosphamide_.26_TBI.2C_then_allo_HSCT|Cy/TBI with allo HSCT]], depending on donor availability
-====Regimen {{#subobject:98346f|Variant=1}}====
+</div></div>
-{| class="wikitable" style="width: 40%; text-align:center;"
+===References===
-! style="width: 25%" |Study
+#'''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. [https://doi.org/10.1016/0140-6736(92)92103-m link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/1355153/ PubMed]
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+##'''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. [https://doi.org/10.1016/s0140-6736(95)90164-7 link to original article] [https://pubmed.ncbi.nlm.nih.gov/7823668/ 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. [https://doi.org/10.1182/blood-2009-10-247965 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2904579/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20407035/ PubMed] [https://clinicaltrials.gov/study/NCT00003728 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/m<sup>2</sup>/day) and prednisolone (60 mg/m<sup>2</sup>/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. [https://doi.org/10.3324/haematol.2014.103507 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4077084/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24727815/ 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. [https://doi.org/10.3324/haematol.2017.165845 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5622857/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28751566/ PubMed]
+==Doxorubicin, Mercaptopurine, Pegaspargase, Vincristine, Prednisolone {{#subobject:127ca2|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:nc303e|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+! style="width: 33%" |Study
+! style="width: 33%" |Dates of enrollment
+! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ Burke et al. 2019 (COG AALL1131)]
+|[https://doi.org/10.1200/JCO.18.01877 Albertsen et al. 2019 (NOPHO ALL2008)]
-| style="background-color:#91cf61" |Randomized portion of RCT
+|2008-2016
+| style="background-color:#91cf61" |Non-randomized part of RCT
 |-
 |}
+''Note: See protocol for initiation dependencies of 6-MP and pegaspargase.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Doxorubicin (Adriamycin)]] 40 mg/m<sup>2</sup> IV over 4 hours once per day on days 1 & 22
+*[[Mercaptopurine (6-MP)]] 25 mg/m<sup>2</sup> PO once per day on days 30 to 35
+*[[Pegaspargase (Oncaspar)]] 1000 units/m<sup>2</sup> IM once on day 30
+*[[Vincristine (Oncovin)]] by the following age-based criteria:
+**Younger than 18 years old: 2 mg/m<sup>2</sup> (maximum dose of 2.5 mg) IV once per day on days 1, 8, 15, 22, 29
+**18 years old or older: 2 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22, 29
+====Glucocorticoid therapy====
+*[[Prednisolone (Millipred)]] 20 mg/m<sup>2</sup> PO three times per day on days 1 to 29, then 10 mg/m<sup>2</sup> PO three times per day on days 30 to 32, then 5 mg/m<sup>2</sup> PO three times per day on days 33 to 35, then 2.5 mg/m<sup>2</sup> 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'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
-*[[Doxorubicin (Adriamycin)]] 25 mg/m<sup>2</sup> IV push over 1 to 15 minutes once per day on days 1, 8, and 15.
+====Subsequent treatment====
-*[[Pegaspargase (Oncaspar)]] 2500 units/m<sup>2</sup> IV over 1 to 2 hours once on days 4 and 43.
+*See protocol for details of treatment beyond induction
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 43, and 50.
+</div></div>
-*[[Dexamethasone (Decadron)]] 5 mg/m<sup>2</sup> IV or PO twice per day on days 1 - 7 and 15 - 21.
+===References===
-*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV over 30 - 60 minutes once on day 29 ONLY.
+#'''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. [https://doi.org/10.1200/JCO.18.01877 link to original article] '''contains dosing details in supplement''' [https://pubmed.ncbi.nlm.nih.gov/30978155/ PubMed] [https://clinicaltrials.gov/study/NCT00819351 NCT00819351]
-*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup>/day SC or IV over 1 - 30 minutes on days 29 - 32 and 36 - 39.
-*[[Thioguanine (Tabloid)]] 60 mg/m<sup>2</sup>/day PO once per day on days 29 to 42.
-*[[Dasatinib (Sprycel)]] 60 mg (rounded to the nearest 5 mg, max of 140 mg/day) PO once daily on days 1 to 56.
+==Doxorubicin, Methotrexate, Pegaspargase, Vincristine, Methylprednisolone {{#subobject:h1gtbb|Regimen=1}}==
-=====CNS prophylaxis=====
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:hgu1h7|Variant=1}}===
-*[[Methotrexate (MTX)]] IT once per day on days 1, 29, and 36.
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 17%" |Study
-{| class="wikitable" style="width: 40%; text-align:center;"
+! style="width: 15%" |Dates of enrollment
-! style="width: 25%" |Age
+! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Dose
+! style="width: 17%" |Comparator
+! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 |-
-|1 - 1.99
+|[https://doi.org/10.1016/s1470-2045(15)00363-0 Place et al. 2015 (DFCI 05-001)]
-|8 mg
+|2005-2011
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
+|[[#Doxorubicin.2C_L-Asparaginase.2C_Methotrexate.2C_Vincristine.2C_Methylprednisolone_888|Doxorubicin, L-asparaginase, Methotrexate, Vincristine, Methylprednisolone]]
+| style="background-color:#ffffbf" |Did not meet secondary endpoint of DFS
+| style="background-color:#1a9850" |Less anxiety
 |-
-|2 - 2.99
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8369809/ Burns et al. 2020 (DFCI 11-001)]
-|10 mg
+|2012-2015
-|-
+| style="background-color:#1a9851" |Phase 3 (C)
-|3 - 8.99
+|[[#Calaspargase.2C_Doxorubicin.2C_Methotrexate.2C_Vincristine.2C_Methylprednisolone_999|Calaspargase, Doxorubicin, Methotrexate, Vincristine, Methylprednisolone]]
-|12 mg
+| style="background-color:#d3d3d3" |Not reported
+|
 |-
-|≥ 9
-|15 mg
 |}
+''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.''
+<div class="toccolours" style="background-color:#cbd5e8">
-'''56-Day course'''
+====Preceding treatment====
+*[[#Methylprednisolone_monotherapy|Methylprednisolone]] pre-phase
-====References====
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
-#'''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. [http://www.haematologica.org/content/104/5/986.long link to original article]
-===Interim Maintenance II with Capizzi MTX (Dasatinib Arm)===
-====Regimen {{#subobject:98346f|Variant=1}}====
-{| class="wikitable" style="width: 40%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ Burke et al. 2019 (COG AALL1131)]
-| style="background-color:#91cf61" |Randomized portion of RCT
-|-
-|}
 ====Chemotherapy====
+*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once per day on days 4 & 5
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on day 1, 11, 21, 31, and 41.
+*[[Methotrexate (MTX)]] 40 mg/m<sup>2</sup> IV once on day 6
-*[[Methotrexate (MTX)]] 100 mg/m<sup>2</sup> IV over 2 - 5 minutes (undiluted) or over 10 - 15 minutes (diluted) on days 1, 150 mg/m<sup>2</sup> on day 11, 200 mg/m<sup>2</sup> on day 21, 250 mg/m<sup>2</sup> on day 31, and 300 mg/m<sup>2</sup> on day 41.
+*[[Pegaspargase (Oncaspar)]] 2500 units/m<sup>2</sup> IV once on day 7
-*[[Pegaspargase (Oncaspar)]] 2500 units/m<sup>2</sup> IV over 1 to 2 hours once on day 2 and 22.
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 4, 11, 18, 25
-*[[Dasatinib (Sprycel)]] 60 mg (rounded to the nearest 5 mg, max of 140 mg/day) PO once daily on days 1 to 56.
+====Glucocorticoid therapy====
+*[[Methylprednisolone (Solumedrol)]] 8 mg/m<sup>2</sup> IV three times per day on days 4 to 32
-=====CNS prophylaxis=====
+====Supportive therapy====
+*[[Dexrazoxane (Zinecard)]] 300 mg/m<sup>2</sup> IV once per day on days 4 & 5
-*[[Methotrexate (MTX)]] IT once per day on days 1 and 31.
+'''28-day course'''
+====CNS therapy, prophylaxis====
-{| class="wikitable" style="width: 40%; text-align:center;"
+*[[Cytarabine (Ara-C)]] IT once per day on days 1 & 18
-! style="width: 25%" |Age
+**Day 18 dose is admixed with MTX and HC
-! style="width: 25%" |Dose
+*[[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
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*[[#Doxorubicin.2C_Mercaptopurine.2C_Methotrexate.2C_Vincristine|Doxorubicin, Mercaptopurine, Methotrexate, Vincristine]] consolidation (IA)
+</div></div>
+===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. [https://doi.org/10.1016/s1470-2045(15)00363-0 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26549586/ PubMed] [https://clinicaltrials.gov/study/NCT00400946 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. [https://doi.org/10.1002/pbc.28719 link to original article] '''contains dosing details in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8369809/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33026184/ 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. [https://doi.org/10.1002/pbc.28719 link to original article] '''contains dosing details in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8369809/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33026184/ PubMed] [https://clinicaltrials.gov/study/NCT01574274 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. [https://doi.org/10.1200/jco.20.03692 link to original article] [https://pubmed.ncbi.nlm.nih.gov/34228505/ PubMed]
+==Pegaspargase, Vincristine, Dexamethasone {{#subobject:15hgu1|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:e8uyt1|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+! style="width: 33%" |Study
+! style="width: 33%" |Dates of enrollment
+! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|1 - 1.99
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7030893/ Maloney et al. 2019 (COG AALL0331)]
-|8 mg
+|2005-2010
+| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
 |-
-|2 - 2.99
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274746/ Angiolillo et al. 2021 (COG AALL0932)]
-|10 mg
+|2010-2018
-|-
+| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
-|3 - 8.99
-|12 mg
 |-
-|≥ 9
-|15 mg
 |}
+''Note: there are very minor differences in timing between protocols; see papers for details.''
-'''56-Day course'''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Pegaspargase (Oncaspar)]] 2500 units/m<sup>2</sup> IV once on day 4
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
+====Glucocorticoid therapy====
+*[[Dexamethasone (Decadron)]] 3 mg/m<sup>2</sup> 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'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*COG AALL0331, M2 marrow or M1 marrow with MRD of at least 1% at day 29: Extended induction
+*COG AALL0932: [[#Mercaptopurine_.26_Vincristine|6-MP & Vincristine]] consolidation
+</div></div>
 ===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. [https://doi.org/10.1200/jco.19.01086 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7030893/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/31825704/ PubMed] [https://clinicaltrials.gov/study/NCT00103285 NCT00103285]
-#'''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. [http://www.haematologica.org/content/104/5/986.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30545921 PubMed] NCT02883049
+#'''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. [https://doi.org/10.1200/jco.20.00494 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274746/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33411585/ PubMed] [https://clinicaltrials.gov/study/NCT01190930 NCT01190930]
+==Pegaspargase, Vincristine, Prednisone {{#subobject:158722|Regimen=1}}==
-===Maintenance (Dasatinib Arm)===
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:e8uhb3|Variant=1}}===
-====Regimen {{#subobject:98346f|Variant=1}}====
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-{| class="wikitable" style="width: 40%; text-align:center;"
+! style="width: 20%" |Study
-! style="width: 25%" |Study
+! style="width: 20%" |Dates of enrollment
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ Burke et al. 2019 (COG AALL1131)]
+|[https://doi.org/10.1182/blood.v99.6.1986 Avramis et al. 2002 (CCG 1962)]
-| style="background-color:#91cf61" |Randomized portion of RCT
+|1997-1998
+| style="background-color:#1a9851" |Randomized (E-RT-switch-ic)
+|[[B-cell_acute_lymphoblastic_leukemia_-_historical#L-Asparaginase.2C_Vincristine.2C_Prednisone|L-Asparaginase, Vincristine, Prednisone]]
+| style="background-color:#ffffbf" |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.''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Pegaspargase (Oncaspar)]] 2500 IU/m<sup>2</sup> IM once on day 3
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once per day on days 0, 7, 14, 21
+====Glucocorticoid therapy====
+*[[Prednisone (Sterapred)]] 40 mg/m<sup>2</sup>/day PO on days 0 to 28, then tapered off over 10 days
+====CNS prophylaxis====
+*[[Cytarabine (Ara-C)]] IT once on day 0
+*[[Methotrexate (MTX)]] IT once per day on days 7 & 28
+'''4-week course'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*See protocol for details of treatment beyond induction
+</div></div>
+===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. [https://doi.org/10.1182/blood.v99.6.1986 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11877270/ PubMed]
-====Radiotherapy====
+=Early intensification therapy=
- For Patients with CNS3 Disease
+==Mercaptopurine & Methotrexate {{#subobject:6ad6d6|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-*[[External_beam_radiotherapy|Total body irradiation (TBI)]] 1800 cGy in 10 fractions, during the first 4 weeks of Maintenance therapy and should be completed by day 29 of Maintenance.
+===Regimen {{#subobject:5b0ec9|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-====Chemotherapy====
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
-*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup>/dose PO once per day on days 1 - 84.
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 29, and 57.
+! style="width: 20%" |Comparator
-*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> PO once on days 8, 15, 22, (29), 36, 43, 50, 57, 64, 71 and 78. (OMIT DAY 29 WHEN CNS RADIATION IS GIVEN, DUE TO IT MTX).
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-*[[Prednisone (Sterapred)]] 20 mg/m<sup>2</sup>/dose PO or IV (methylprednisolone given at 80% of the oral dose) twice per day on days 1 - 5, 29 - 33, and 57 - 61.
-*[[Dasatinib (Sprycel)]] 60 mg (rounded to the nearest 5 mg, max of 140 mg/day) PO once daily on days 1 to 84.
-=====CNS prophylaxis=====
-*[[Methotrexate (MTX)]] IT once per day on day 1 (also Day 29 of cycles 1 and 2, for patients who did NOT receive CNS Radiation).
-{| class="wikitable" style="width: 40%; text-align:center;"
-! style="width: 25%" |Age
-! style="width: 25%" |Dose
 |-
-|1 - 1.99
+|[https://doi.org/10.1200/JCO.1998.16.1.246 Mahoney et al. 1998 (POG 9005)]
-|8 mg
+|1991-1993
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
+|[[#Mercaptopurine_.26_Methotrexate|6-MP & MTX]]; LDMTX/IVMP
+| style="background-color:#91cf60" |Seems to have superior CCR
 |-
-|2 - 2.99
+|[https://doi.org/10.1038/sj.leu.2402132 Lauer et al. 2001 (POG 9006)]
-|10 mg
+|1991-1994
+| style="background-color:#1a9851" |Phase 3 (C)
+|Intensive chemotherapy
+| style="background-color:#fee08b" |Might have inferior EFS
 |-
-|3 - 8.99
-|12 mg
-|-
-|≥ 9
-|15 mg
 |}
+<div class="toccolours" style="background-color:#cbd5e8">
-'''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.'''
+====Preceding treatment====
+*POG 9005: [[B-cell_acute_lymphoblastic_leukemia,_pediatric_-_historical#L-Asparaginase.2C_Vincristine.2C_Prednisone|L-asparaginase, Vincristine, Prednisone]] induction
+*POG 9006: [[#DOLP|DOLP]] induction
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Mercaptopurine (6-MP)]] 1000 mg/m<sup>2</sup> IV over 6 hours once on day 1, then 50 mg/m<sup>2</sup> PO once per day on days 8 to 14
+*[[Methotrexate (MTX)]] 1000 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 1, then 20 mg/m<sup>2</sup> IM once on day 8
+====Supportive therapy====
+*[[Leucovorin (Folinic acid)]] 5 mg/m<sup>2</sup> (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'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*POG 9005: [[#Mercaptopurine_.26_Methotrexate_2|6-MP & MTX]] continuation
+*POG 9006: [[#Mercaptopurine_.26_Methotrexate_2|6-MP & MTX]] maintenance
+</div></div>
 ===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. [https://doi.org/10.1200/JCO.1998.16.1.246 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/9440749/ 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. [https://doi.org/10.1038/sj.leu.2402132 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11455971/ PubMed]
-#'''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. [http://www.haematologica.org/content/104/5/986.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30545921 PubMed] NCT02883049
+=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.''
-==DS HR B-ALL==
+==AALL0232 consolidation {{#subobject:065gg9|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-===Induction===
+===Regimen {{#subobject:342b6d|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
-====Daunorubicin, Pegaspargase, Vincristine, Dexamethasone {{#subobject:088146|Regimen=1}}====
+!style="width: 33%"|Study
-{| class="wikitable" style="float:right; margin-left: 5px;"
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[[#top|back to top]]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4981974/ Larsen et al. 2016 (COG AALL0232)]
-|}
+|2004-2011
-====Regimen {{#subobject:98346f|Variant=1}}====
+| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
-{| class="wikitable" style="width: 40%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ Burke et al. 2019 (COG AALL1131)]
-| style="background-color:#91cf61" |Randomized portion of RCT
 |-
 |}
-''Note: the referenced publication does not specifically focus on induction; the full regimen is available as a protocol. Per the protocol, it is intended only for patients less than 10 years old.''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 29
+*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> 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/m<sup>2</sup> PO once per day on days 1 to 14, 29 to 42
+*[[Pegaspargase (Oncaspar)]] 2500 units/m<sup>2</sup> IM or IV once per day on days 15 & 43
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 15, 22, 43, 50
+'''50-day course'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*6-MP, Capizzi MTX, Pegaspargase, Vincristine interim maintenance versus [[#Mercaptopurine.2C_Methotrexate.2C_Vincristine_2|6-MP, HD-MTX, Vincristine interim]] maintenance
+</div></div>
+===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. [https://doi.org/10.1200/JCO.2015.62.4544 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4981974/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/27114587/ PubMed] [https://clinicaltrials.gov/study/NCT00075725 NCT00075725]
+==Augmented BFM consolidation {{#subobject:065ff9|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:687b6d|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1056/NEJM199806043382304 Nachman et al. 1998]
+|1991-1995
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|Standard BFM consolidation
+| style="background-color:#91cf60" |Seems to have superior OS
+|-
+|}
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*BFM induction
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV once per day on days 0 & 28
+*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> SC or IV once per day on days 1 to 4, 8 to 11, 29 to 32, 36 to 39
+*[[Mercaptopurine (6-MP)]] 60 mg/m<sup>2</sup>/day PO on days 0 to 13, 28 to 41
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once per day on days 14, 21, 42, 49
+*[[Asparaginase (Elspar)]] 6000 units/m<sup>2</sup> IM once per day on days 14, 16, 18, 21, 23, 25, 42, 44, 46, 49, 51, 53
+====CNS prophylaxis====
+*[[Methotrexate (MTX)]] IT once per day on days 1, 8, 15, 22
+*[[External beam radiotherapy|Craniocaudal and testicular irradiation]]
+'''9-week course'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e8">
+====Subsequent treatment====
+*Interim maintenance I
+</div></div>
+===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. [https://doi.org/10.1056/NEJM199806043382304 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/9614257/ PubMed]
-*[[Pegaspargase (Oncaspar)]] 2500 units/m<sup>2</sup> IV over 1 to 2 hours once on day 4
+==Cyclophosphamide & TBI, then allo HSCT {{#subobject:a9f7e8|Regimen=1}}==
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15, and 22
+Cy/TBI: '''<u>Cy</u>'''clophosphamide & '''<u>T</u>'''otal '''<u>B</u>'''ody '''<u>I</u>'''rradiation
+<div class="toccolours" style="background-color:#eeeeee">
- Patients < 10 years ONLY:
+===Regimen {{#subobject:6ca28d|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
-*[[Dexamethasone (Decadron)]] 3 mg/m<sup>2</sup> IV or PO twice per day on days 1 to 28 (DO NOT TAPER)
+! style="width: 33%" |Study
+! style="width: 33%" |Dates of enrollment
- Patients ≥ 10 years ONLY:
+! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
+|-
-*[[Prednisone (Sterapred)]] 30 mg/m<sup>2</sup>/dose PO twice per day on days 1 to 28 (DO NOT TAPER)
+|[https://doi.org/10.1182/blood.V54.2.468.468 Thomas et al. 1979]
-*[[Folinic acid (Leucovorin)]] 5 mg/m<sup>2</sup> x 2 doses PO (given at 48 and 60 hours after the lumbar puncture) on days 10 - 11 and 31 - 32. (CNS3 also on days 17 - 18  and 24 - 25).
+|1976-1977
+| style="background-color:#91cf61" |Non-randomized
- RER - M1 Marrow at Day 15
+|-
+|}
-*Add [[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV over 1 to 15 minutes once on days 15.
+{{#lst:Allogeneic HSCT|6ca28d}}
+</div></div>
-=====CNS prophylaxis=====
-*[[Cytarabine (Ara-C)]] as follows:
-**Ages 1 to 1.99: 30 mg IT once on day 1
-**Ages 2 to 2.99: 50 mg IT once on day 1
-**Age 3 and older: 70 mg IT once on day 1
-*[[Methotrexate (MTX)]] as follows:
-**Ages 1 to 1.99: 8 mg IT once per day on days 8 and 29 (CNS 3 also on days 15 and 22)
-**Ages 2 to 2.99: 10 mg IT once per day on days 8 and 29 (CNS 3 also on days 15 and 22)
-**Ages 3 to 8.99: 12 mg IT once per day on days 8 and 29 (CNS 3 also on days 15 and 22)
-**Age 9 and older: 15 mg IT once per day on days 8 and 29 (CNS 3 also on days 15 and 22)
-'''4-week course'''
-=====Subsequent treatment=====
-*See protocol for details of treatment beyond induction
 ===References===
+#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. [https://doi.org/10.1182/blood.V54.2.468.468 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/378292/ PubMed]
-#'''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. [http://www.haematologica.org/content/104/5/986.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30545921 PubMed] NCT02883049
+==Etoposide & TBI, then allo HSCT {{#subobject:b389e1|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-===Consolidation===
+===Regimen variant #1, weight-based {{#subobject:45f841|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-====Regimen {{#subobject:98346f|Variant=1}}====
+! style="width: 20%" |Study
-{| class="wikitable" style="width: 40%; text-align:center;"
+! style="width: 20%" |Dates of enrollment
-! style="width: 25%" |Study
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1016/s0140-6736(05)66998-x Balduzzi et al. 2005]
+|1995-2000
+| style="background-color:#1a9851" |Quasi-randomized
+|Chemotherapy
+| style="background-color:#91cf60" |Seems to have superior DFS
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ Burke et al. 2019 (COG AALL1131)]
+|[https://doi.org/10.1200/jco.2014.58.9747 Peters et al. 2015 (ALL-SCT-BFM 2003)]
-| style="background-color:#91cf61" |Randomized portion of RCT
+|2003-2011
+| style="background-color:#91cf61" |Non-randomized
+| style="background-color:#d3d3d3" |
+| style="background-color:#d3d3d3" |
 |-
 |}
+{{#lst:Allogeneic HSCT|45f841}}
-=====Chemotherapy=====
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
-*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV over 30 - 60 minutes once on days 1 and 29
+===Regimen variant #2, BSA-based {{#subobject:45bs41|Variant=1}}===
-*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup>/day SC or IV over 1 - 30 minutes on days 1 - 4, 8 - 11, 29 - 32, 36 - 39.
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-*[[Pegaspargase (Oncaspar)]] 2500 units/m<sup>2</sup> IV over 1 - 2 hours once on days 15, and 43.
+! style="width: 20%" |Study
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 15, 22, 43, and 50.
+! style="width: 20%" |Dates of enrollment
-*[[Mercaptopurine (6-MP)]] 60 mg/m<sup>2</sup>/dose PO once per day on days 1 - 14, and 29 - 42.
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
-======CNS prophylaxis======
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-*[[Methotrexate (MTX)]] IT once per day on days 1, 8, 15, and 22.
-{| class="wikitable" style="width: 40%; text-align:center;"
-! style="width: 25%" |Age
-! style="width: 25%" |Dose
 |-
-|1 - 1.99
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8078415/ Peters et al. 2020 (FORUM)]
-|8 mg
+|2013-2018
+| style="background-color:#1a9851" |Phase 3 (C)
+|1a. [[#Busulfan.2C_Fludarabine.2C_Thiotepa_999|Busulfan, Fludarabine, Thiotepa]]<br>1b. [[#Fludarabine.2C_Thiotepa.2C_Treosulfan_999|Fludarabine, Thiotepa, Treosulfan]]
+| style="background-color:#1a9850" |Superior OS (primary endpoint)
 |-
-|2 - 2.99
+|}
-|10 mg
+{{#lst:Allogeneic HSCT|45u7g1}}
+</div></div>
+===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. [https://doi.org/10.1016/s0140-6736(05)66998-x link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16112299/ 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. [https://doi.org/10.1200/jco.2014.58.9747 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25753432/ PubMed] [https://clinicaltrials.gov/study/NCT01423747 NCT01423747]
+#'''FORUM:''' Peters C, Dalle JH, Locatelli F, Poetschger U, Sedlacek P, Buechner J, Shaw PJ, Staciuk R, Ifversen M, Pichler H, Vettenranta K, Svec P, Aleinikova O, Stein J, Güngör T, Toporski J, Truong TH, Diaz-de-Heredia C, Bierings M, Ariffin H, Essa M, Burkhardt B, Schultz K, Meisel R, Lankester A, Ansari M, Schrappe M, von Stackelberg A, Balduzzi A, Corbacioglu S, Bader P; IBFM Study Group; IntReALL Study Group; I-BFM SCT Study Group; EBMT Paediatric Diseases Working Party. Total Body Irradiation or Chemotherapy Conditioning in Childhood ALL: A Multinational, Randomized, Noninferiority Phase III Study. J Clin Oncol. 2021 Feb 1;39(4):295-307. Epub 2020 Dec 17. [https://doi.org/10.1200/jco.20.02529 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8078415/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33332189/ PubMed] [https://clinicaltrials.gov/study/NCT01949129 NCT01949129]
+==Mercaptopurine & Vincristine {{#subobject:171gc1|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:1ygvt1|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+! style="width: 33%" |Study
+! style="width: 33%" |Dates of enrollment
+! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|3 - 8.99
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274746/ Angiolillo et al. 2021 (COG AALL0932)]
-|12 mg
+|2010-2018
+| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
 |-
-|≥ 9
-|15 mg
 |}
+<div class="toccolours" style="background-color:#cbd5e8">
- DS Arm
+====Preceding treatment====
+*[[#Pegaspargase.2C_Vincristine.2C_Dexamethasone|Pegaspargase, Vincristine, Dexamethasone]] induction
-*[[Folinic acid (Leucovorin)]] 5 mg/m<sup>2</sup> x 2 doses PO (given at 48 and 60 hours after the lumbar puncture) on days 3 - 4, 10 - 11, 17 - 18, and 24 - 25.
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
-'''56-Day Course'''
+====Chemotherapy====
+*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup>/day PO on days 1 to 28
-====References====
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1
+====CNS therapy, prophylaxis====
-#'''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. [http://www.haematologica.org/content/104/5/986.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30545921 PubMed] NCT02883049
+*[[Methotrexate (MTX)]] IT once per day on days 1, 8, 15
-#'''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. [https://doi.org/10.1200/jco.20.00494 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33411585/ PubMed] NCT01190930
+'''28-day course'''
+</div>
-===Interim Maintenance with ID MTX===
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
-====Regimen {{#subobject:98346f|Variant=1}}====
+*[[#Methotrexate_.26_Vincristine|MTX & Vincristine]] interim maintenance
-{| class="wikitable" style="width: 40%; text-align:center;"
+</div></div>
-! style="width: 25%" |Study
+===References===
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+#'''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. [https://doi.org/10.1200/jco.20.00494 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274746/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33411585/ PubMed] [https://clinicaltrials.gov/study/NCT01190930 NCT01190930]
+=Interim maintenance=
+==Mercaptopurine, Methotrexate, Vincristine {{#subobject:72025a|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:b9e09c|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ Burke et al. 2019 (COG AALL1131)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4981974/ Larsen et al. 2016 (COG AALL0232)]
-| style="background-color:#91cf61" |Randomized portion of RCT
+|2004-2011
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
+|[[#Mercaptopurine.2C_Methotrexate.2C_Pegaspargase.2C_Vincristine_888|6-MP, Capizzi MTX, Pegaspargase, Vincristine]]
+| style="background-color:#1a9850" |Superior EFS (primary endpoint)
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
-=====Chemotherapy=====
+====Chemotherapy====
+*[[Mercaptopurine (6-MP)]] 25 mg/m<sup>2</sup> PO once per day on days 1 to 56
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 15, 29, and 43.
+*[[Methotrexate (MTX)]] 5000 mg/m<sup>2</sup> IV once per day on days 1, 15, 29, 43
-*[[Mercaptopurine (6-MP)]] 25 mg/m<sup>2</sup>/dose PO once per day on days 1 - 56.
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 15, 29, 43
-*Intermediate Dose [[Methotrexate (MTX)]] 2000 mg/m<sup>2</sup> IV over 24 hours on days 1, 15, 29, and 43.
+====CNS therapy====
-**MTX 200 mg/m<sup>2</sup> IV infused over 30 minutes. This is followed, immediately, by MTX 1800 mg/m<sup>2</sup> given by continuous IV infusion over 23.5 hours.
+*[[Methotrexate (MTX)]] once per day on days 1 & 29
+</div></div>
- ANC must be ≥ 750/µL and platelets must be ≥ 75,000/µL prior to each dose of HD MTX
+===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. [https://doi.org/10.1200/JCO.2015.62.4544 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4981974/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/27114587/ PubMed] [https://clinicaltrials.gov/study/NCT00075725 NCT00075725]
-*[[Folinic acid (Leucovorin)]] 15 mg/m<sup>2</sup> x a minimum of 5 doses PO or IV (given at 30, 36, 42, 48, and 54 hours after the START of ID MTX infusion) on days 2 - 3, 17 - 18, 31 - 32, and 45 - 46.
+==Methotrexate & Vincristine {{#subobject:0ae09f|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-======CNS prophylaxis======
+===Regimen {{#subobject:57f39d|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-*[[Methotrexate (MTX)]] IT once per day on days 1 and 29.
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
-{| class="wikitable" style="width: 40%; text-align:center;"
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Age
+! style="width: 20%" |Comparator
-! style="width: 25%" |Dose
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|1 - 1.99
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3138679/ Matloub et al. 2011 (COG CCG-1991)]
-|8 mg
+|2000-2005
+| style="background-color:#1a9851" |Phase 3 (E-de-esc)
+|[[#Mercaptopurine.2C_Methotrexate.2C_Vincristine.2C_Dexamethasone_888|6-MP, MTX, Vincristine, Dexamethasone]]
+| style="background-color:#1a9850" |Superior EFS (co-primary endpoint)
 |-
-|2 - 2.99
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274746/ Angiolillo et al. 2021 (COG AALL0932)]
-|10 mg
+|2010-2018
+| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
+| style="background-color:#d3d3d3" |
+| style="background-color:#d3d3d3" |
 |-
-|3 - 8.99
-|12 mg
-|-
-|≥ 9
-|15 mg
 |}
+<div class="toccolours" style="background-color:#cbd5e8">
- When IT therapy and HD MTX are scheduled for the same day, deliver the IT therapy within 6 hours of the beginning of the IV MTX infusion. (hour -6 or +6, with 0 being the start of the MTX bolus).
+====Preceding treatment====
+*COG AALL0932: [[#Mercaptopurine_.26_Vincristine|6-MP & Vincristine]] consolidation
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
-'''63-Day Course'''
+====Chemotherapy====
+*[[Methotrexate (MTX)]] 100 mg/m<sup>2</sup> IV once on day 1, then 150 mg/m<sup>2</sup> IV once on day 11, then 200 mg/m<sup>2</sup> IV once on day 21, then 250 mg/m<sup>2</sup> IV once on day 31, then 300 mg/m<sup>2</sup> IV once on day 41
-====References====
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 11, 21, 31, 41
+====CNS therapy, prophylaxis====
-#'''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. [http://www.haematologica.org/content/104/5/986.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30545921 PubMed] NCT02883049
+*[[Methotrexate (MTX)]] IT once on day 31
-#'''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. [https://doi.org/10.1200/jco.20.00494 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33411585/ PubMed] NCT01190930
+'''8-week course'''
+</div>
-===Delayed Intensification===
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
-====Regimen {{#subobject:98346f|Variant=1}}====
+*COG AALL0932: [[#AALL0932_delayed_intensification|AALL0932]] delayed intensification
-{| class="wikitable" style="width: 40%; text-align:center;"
+</div></div>
-! style="width: 25%" |Study
+===References===
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+#'''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. [https://doi.org/10.1182/blood-2010-12-322909 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3138679/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21562038/ PubMed] [https://clinicaltrials.gov/study/NCT00005945 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. [https://doi.org/10.1200/jco.20.00494 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274746/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33411585/ PubMed] [https://clinicaltrials.gov/study/NCT01190930 NCT01190930]
+=Delayed intensification=
+==AALL0932 delayed intensification {{#subobject:17185g|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:1y47gc|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+! style="width: 33%" |Study
+! style="width: 33%" |Dates of enrollment
+! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ Burke et al. 2019 (COG AALL1131)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274746/ Angiolillo et al. 2021 (COG AALL0932)]
-| style="background-color:#91cf61" |Randomized portion of RCT
+|2010-2018
+| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
 |-
 |}
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*[[#Methotrexate_.26_Vincristine|MTX & Vincristine]] interim maintenance
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV once on day 29
-*[[Doxorubicin (Adriamycin)]] 25 mg/m<sup>2</sup> IV push over 1 to 15 minutes once per day on days 1, 8, and 15.
+*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup>/day SC or IV on days 29 to 32, 36 to 39
-*[[Pegaspargase (Oncaspar)]] 2500 units/m<sup>2</sup> IV over 1 to 2 hours once on days 4 and 43.
+*[[Doxorubicin (Adriamycin)]] 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 43, and 50.
+*[[Pegaspargase (Oncaspar)]] 2500 units/m<sup>2</sup> IV once on day 4
-*[[Dexamethasone (Decadron)]] 5 mg/m<sup>2</sup> IV or PO twice per day on days 1 - 7 and 15 - 21.
+*[[Thioguanine (Tabloid)]] 60 mg/m<sup>2</sup>/day PO on days 29 to 42
-*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV over 30 - 60 minutes once on day 29 ONLY.
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15
-*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup>/day SC or IV over 1 - 30 minutes on days 29 - 32 and 36 - 39.
+====Glucocorticoid therapy====
-*[[Thioguanine (Tabloid)]] 60 mg/m<sup>2</sup>/day PO once per day on days 29 to 42.
+*[[Dexamethasone (Decadron)]] 10 mg/m<sup>2</sup>/day PO on days 1 to 7, 15 to 21
-*[[Folinic acid (Leucovorin)]] 5 mg/m<sup>2</sup> x 2 doses PO or IV (given at 48, and 60 hours after the lumbar puncture) on days 3 - 4, 31 - 32, and 38 - 39.
+====CNS therapy, prophylaxis====
+*[[Methotrexate (MTX)]] IT once per day on days 1 & 29
-=====CNS prophylaxis=====
+'''8-week course'''
+</div>
-*[[Methotrexate (MTX)]] IT once per day on days 1, 29, and 36.
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
-{| class="wikitable" style="width: 40%; text-align:center;"
+*[[#Methotrexate_.26_Vincristine_2|MTX & Vincristine]] interim maintenance II
-! style="width: 25%" |Age
+</div></div>
-! style="width: 25%" |Dose
+===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. [https://doi.org/10.1200/jco.20.00494 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274746/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33411585/ PubMed] [https://clinicaltrials.gov/study/NCT01190930 NCT01190930]
+=Interim maintenance II=
+==Methotrexate & Vincristine {{#subobject:ajbz5g|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:18guaz|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+! style="width: 33%" |Study
+! style="width: 33%" |Dates of enrollment
+! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|1 - 1.99
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274746/ Angiolillo et al. 2021 (COG AALL0932)]
-|8 mg
+|2010-2018
+| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
 |-
-|2 - 2.99
+|}
-|10 mg
+''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.''
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*[[#AALL0932_delayed_intensification|AALL0932]] delayed intensification
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Methotrexate (MTX)]] 200 mg/m<sup>2</sup> IV once on day 1, then 250 mg/m<sup>2</sup> IV once on day 11, then 300 mg/m<sup>2</sup> IV once on day 21, then 350 mg/m<sup>2</sup> IV once on day 31, then 400 mg/m<sup>2</sup> IV once on day 41
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (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'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*Randomization to one of four maintenance arms; see paper for details.
+</div></div>
+===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. [https://doi.org/10.1200/jco.20.00494 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274746/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33411585/ PubMed] [https://clinicaltrials.gov/study/NCT01190930 NCT01190930]
+=Maintenance after upfront therapy=
+==Mercaptopurine & Methotrexate {{#subobject:6366a6|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:e46d92|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1200/JCO.2001.19.7.1935 Millot et al. 2001 (EORTC 58881)]
+|1990-1996
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Mercaptopurine_.26_Methotrexate_2|6-MP & MTX]]; IV 6-MP & PO MTX
+| style="background-color:#1a9850" |Superior DFS<sup>1</sup>
+|-
+|[https://doi.org/10.1016/S0140-6736(07)60073-7 Conter et al. 2007 (I-BFM-SG IR ALL)]
+|1995-2000
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#D-OMP_999|D-OMP]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 |-
-|3 - 8.99
+|[https://doi.org/10.1002/ajh.26910 Qiu et al. 2023 (GD-ALL-2008)]
-|12 mg
+|2008-02-28 to 2016-06-30
+| style="background-color:#1a9851" |Phase 3 (C)
+|6-MP & MTX with Vincristine & Dexamethasone pulses
+| style="background-color:#ffffbf" |Did not meet primary endpoint of EFS120<sup>a</sup>
 |-
-|≥ 9
-|15 mg
 |}
+''<sup>1</sup>Reported efficacy for EORTC 58881 is based on the 2005 update.''<br>
+''<sup>a</sup>The subgroup with high-risk (HR) ALL randomized to this arm had inferior EFS; see paper for details.''
-'''56-Day course'''
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*I-BFM-SG IR ALL: BFM re-induction
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Mercaptopurine (6-MP)]] 50 mg/m<sup>2</sup> PO once per day
+*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> PO once on day 1
+'''7-day cycle for 74 cycles or a total of 2 years from start of treatment'''
+</div></div>
 ===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. [https://doi.org/10.1200/JCO.2001.19.7.1935 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11283125/ 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. [https://doi.org/10.1182/blood.v99.8.2734 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11929760/ 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. [https://doi.org/10.1038/sj.leu.2403689 link to original article] [https://pubmed.ncbi.nlm.nih.gov/15744348/ 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. [https://doi.org/10.1016/S0140-6736(07)60073-7 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17223475/ PubMed] [https://clinicaltrials.gov/study/NCT00411541 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. [https://doi.org/10.1002/ajh.26910 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/36877527/ PubMed] [https://clinicaltrials.gov/study/NCT00846703 NCT00846703]
-#'''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. [http://www.haematologica.org/content/104/5/986.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30545921 PubMed] NCT02883049
+=Relapsed or refractory=
+==Blinatumomab monotherapy {{#subobject:e7b2c6|Regimen=1}}==
-===DS HR Arm Maintenance===
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:fd494b|Variant=1}}===
-====Regimen {{#subobject:98346f|Variant=1}}====
+{| class="wikitable" style="width: 60%; text-align:center;"
-{| class="wikitable" style="width: 40%; text-align:center;"
+! style="width: 33%" |Study
-! style="width: 25%" |Study
+! style="width: 33%" |Dates of enrollment
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ Burke et al. 2019 (COG AALL1131)]
+|[https://doi.org/10.1200/JCO.2016.67.3301 von Stackelberg et al. 2016 (MT103-205)]
-| style="background-color:#91cf61" |Randomized portion of RCT
+|2012-2014
+| style="background-color:#91cf61" |Phase 1/2 (RT)
 |-
 |}
+''Note: this is the MTD of a phase 1/2 trial enrolling children under the age of 18.''
+<div class="toccolours" style="background-color:#b3e2cd">
+====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'''
+</div></div>
+===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. [https://doi.org/10.1200/JCO.2016.67.3301 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/27998223/ PubMed] [https://clinicaltrials.gov/study/NCT01471782 NCT01471782]
-====Radiotherapy====
+==CCE {{#subobject:f74969|Regimen=1}}==
- For Patients with CNS3 Disease
+CCE: '''<u>C</u>'''lofarabine, '''<u>C</u>'''yclophosphamide, '''<u>E</u>'''toposide
+<div class="toccolours" style="background-color:#eeeeee">
-*[[External_beam_radiotherapy|Total body irradiation (TBI)]] 1800 cGy in 10 fractions, during the first 4 weeks of Maintenance therapy and should be completed by day 29 of Maintenance.
+===Regimen {{#subobject:24f55b|Variant=1}}===
-====Chemotherapy====
-*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup>/dose PO once per day on days 1 - 84.
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on day 1 ONLY.
-*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> PO once on days 8, 15, 22, (29), 36, 43, 50, 57, 64, 71 and 78. (OMIT DAY 29 WHEN CNS RADIATION IS GIVEN, DUE TO IT MTX).
-*[[Prednisone (Sterapred)]] 20 mg/m<sup>2</sup>/dose PO or IV (methylprednisolone given at 80% of the oral dose) twice per day on days 1 - 5.
-=====CNS prophylaxis=====
-*[[Methotrexate (MTX)]] IT once per day on day 1 (also Day 29 of cycles 1 and 2, for patients who did NOT receive CNS Radiation).
 {| class="wikitable" style="width: 40%; text-align:center;"
-! style="width: 25%" |Age
+! style="width: 25%" |Study
-! style="width: 25%" |Dose
+! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|1 - 1.99
+|[https://doi.org/10.1111/j.1365-2141.2009.07882.x Locatelli et al. 2009]
-|8 mg
+| style="background-color:#91cf61" |Non-randomized
-|-
-|2 - 2.99
-|10 mg
 |-
-|3 - 8.99
-|12 mg
-|-
-|≥ 9
-|15 mg
 |}
+''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.''
-'''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.'''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Clofarabine (Clolar)]] 40 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 to 5, given first
+*[[Cyclophosphamide (Cytoxan)]] 400 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5
+*[[Etoposide (Vepesid)]] 150 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 to 5
+====Supportive therapy====
+*Prophylactic [[:Category:Steroids|steroids]] used for patients with greater than 30 x 10<sup>9</sup> 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."''
+</div></div>
 ===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. [https://doi.org/10.1111/j.1365-2141.2009.07882.x link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19747360/ PubMed]
-#'''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. [http://www.haematologica.org/content/104/5/986.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30545921 PubMed] NCT02883049
+==Clofarabine monotherapy {{#subobject:6befdc|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-=Prephase=
+===Regimen {{#subobject:fc17b2|Variant=1}}===
-==Methylprednisolone monotherapy {{#subobject:5gh1bb|Regimen=1}}==
+{| class="wikitable" style="width: 60%; text-align:center;"
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:88fgh7|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
 ! style="width: 33%" |Study
-! style="width: 33%" |Years of enrollment
+! style="width: 33%" |Dates of enrollment
 ! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://doi.org/10.1016/s1470-2045(15)00363-0 Place et al. 2015 (DFCI 05-001)]
+|[https://doi.org/10.1182/blood-2003-06-2122 Jeha et al. 2003]
-|2005-2011
+|2000-2002
-| style="background-color:#91cf61" |Non-randomized portion of RCT
+| style="background-color:#ffffbe" |Phase 1, fewer than 20 pts (RT)
 |-
-|[https://doi.org/10.1002/pbc.28719 Burns et al. 2020 (DFCI 11-001)]
+|[https://doi.org/10.1200/JCO.2005.03.8554 Jeha et al. 2006 (CLO212)]
-|2012-2015
+|2002-2004
-| style="background-color:#91cf61" |Non-randomized portion of RCT
+| style="background-color:#91cf61" |Phase 2 (RT)
 |-
 |}
-''Note: Burns et al. 2020 is both an update of DFCI 05-001 and the primary publication of DFCI 11-001.''
+''Note: this dose was the MTD in Jeha et al. 2003.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Clofarabine (Clolar)]] 52 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 to 5
-*[[Methylprednisolone (Solumedrol)]] 8 mg/m<sup>2</sup> IV three times per day on days 1 to 3
+'''2- to 6-week cycles, depending on response count recovery'''
+</div></div>
-'''3-day course'''
-====Subsequent treatment====
-*DFCI 05-001: Doxorubicin, L-Asparaginase, Methotrexate, Vincristine, Methylprednisolone induction versus [[#Doxorubicin.2C_Methotrexate.2C_Pegaspargase.2C_Vincristine.2C_Methylprednisolone|Doxorubicin, Methotrexate, Pegaspargase, Vincristine, Methylprednisolone induction]]
-*DFCI 11-001: Calaspargase, Doxorubicin, Methotrexate, Vincristine, Methylprednisolone induction versus [[#Doxorubicin.2C_Methotrexate.2C_Pegaspargase.2C_Vincristine.2C_Methylprednisolone|Doxorubicin, Methotrexate, Pegaspargase, Vincristine, Methylprednisolone induction]]
 ===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. [https://doi.org/10.1182/blood-2003-06-2122 link to original article] [https://pubmed.ncbi.nlm.nih.gov/14551141/ PubMed]
-#'''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. [https://doi.org/10.1016/s1470-2045(15)00363-0 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26549586/ PubMed] NCT00400946
+#'''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. [https://doi.org/10.1200/JCO.2005.03.8554 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/16622268/ PubMed] [https://clinicaltrials.gov/study/NCT00042341 NCT00042341]
-##'''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. [https://doi.org/10.1002/pbc.28719 link to original article] '''contains verified protocol in supplement''' [https://pubmed.ncbi.nlm.nih.gov/33026184/ PubMed]
+==DOLP {{#subobject:8804f2|Regimen=1}}==
-#'''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. [https://doi.org/10.1002/pbc.28719 link to original article] '''contains verified protocol in supplement''' [https://pubmed.ncbi.nlm.nih.gov/33026184/ PubMed] NCT01574274
+DOLP: '''<u>D</u>'''aunorubicin, '''<u>O</u>'''ncovin (Vincristine), '''<u>L</u>'''-Asparaginase, '''<u>P</u>'''rednisone
+<br>PVDA: '''<u>P</u>'''rednisone, '''<u>V</u>'''incristine, '''<u>D</u>'''aunorubicin, L-'''<u>A</u>'''sparaginase
-==Prednisone monotherapy {{#subobject:8ca13b|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-{| class="wikitable" style="float:right; margin-left: 5px;"
+===Regimen {{#subobject:a6fef6|Variant=1}}===
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:2fd1d7|Variant=1}}===
 {| class="wikitable sortable" style="width: 60%; text-align:center;"
-! style="width: 33%" |Study
+!style="width: 33%"|Study
-! style="width: 33%" |Years of enrollment
+!style="width: 33%"|Dates of enrollment
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[http://www.bloodjournal.org/content/127/17/2101.long Möricke et al. 2016 (AIEOP-BFM ALL 2000)]
+|[https://doi.org/10.1056/NEJM198607313150501 Rivera et al. 1986]
-|2000-2006
+|1982-01 to 1983-01
-| style="background-color:#91cf61" |Non-randomized portion of RCT
+| style="background-color:#91cf61" |Non-randomized
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Daunorubicin (Cerubidine)]] 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
-*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup>/day PO on days 1 to 7
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
+*[[Asparaginase (Elspar)]] 10,000 IU/m<sup>2</sup> IM once per day on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, 26
-====CNS prophylaxis====
+====Glucocorticoid therapy====
+*[[Prednisone (Sterapred)]] 40 mg/m<sup>2</sup> PO once per day on days 1 to 28
-*[[Methotrexate (MTX)]] 15 mg IT once on day 1
+'''4-week course'''
+</div>
-'''7-day course'''
+<div class="toccolours" style="background-color:#cbd5e7">
 ====Subsequent treatment====
+*[[#Cytarabine_.26_Teniposide_888|Ara-C & Teniposide]] consolidation (see paper for details)
-*[[#DOLP|Daunorubicin, L-Asparaginase, Vincristine, Prednisone]] versus Daunorubicin, L-Asparaginase, Vincristine, Dexamethasone induction
+</div></div>
 ===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. [https://doi.org/10.1056/NEJM198607313150501 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/3523250/ PubMed]
-#'''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. [http://www.bloodjournal.org/content/127/17/2101.long link to original article] '''contains verified protocol in supplement''' [https://pubmed.ncbi.nlm.nih.gov/26888258 PubMed] NCT00430118; NCT00613457
+==Doxorubicin, Pegaspargase, Vincristine, Prednisone {{#subobject:1265yg|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-==Vincristine & Prednisone {{#subobject:663781|Regimen=1}}==
+===Regimen {{#subobject:3gt03e|Variant=1}}===
-{| class="wikitable" style="float:right; margin-left: 5px;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1182/blood.V96.5.1709 Abshire et al. 2000 (POG 9310)]
+|NR
+| style="background-color:#91cf61" |Non-randomized
+| style="background-color:#d3d3d3" |
+| style="background-color:#d3d3d3" |
 |-
-|[[#top|back to top]]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc2654313/ Raetz et al. 2008 (COG AALL01P2)]
-|}
+|2003-2005
-VP: '''<u>V</u>'''incristine & '''<u>P</u>'''rednisone
+| style="background-color:#91cf61" |Non-randomized part of phase 2 RCT
-===Regimen {{#subobject:79fc67|Variant=1}}===
+| style="background-color:#d3d3d3" |
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
+| style="background-color:#d3d3d3" |
-! style="width: 33%" |Study
-! style="width: 33%" |Years of enrollment
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[http://www.bloodjournal.org/content/51/3/425.long Sallan et al. 1978]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7776266/ Lew et al. 2021 (COG AALL0433)]
-|1973-1977
+|2007-2013
-| style="background-color:#91cf61" |Non-randomized
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Doxorubicin.2C_Pegaspargase.2C_Vincristine.2C_Prednisone|Doxorubicin, Pegaspargase, Vincristine, Prednisone]]; high-dose vincristine
+| style="background-color:#d3d3d3" |Not reported
 |-
 |}
-''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.''
+''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.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> IV once on day 1
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15
+*[[Pegaspargase (Oncaspar)]] 2500 units/m<sup>2</sup> IM once per day on days 2, 9, 16, 23
-*[[Prednisone (Sterapred)]] 40 mg/m<sup>2</sup>/day PO on days 1 to 21
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
+====Glucocorticoid therapy====
-'''21-day course'''
+*[[Prednisone (Sterapred)]] 40 mg/m<sup>2</sup>/day PO on days 1 to 29
+====CNS therapy, prophylaxis (CNS-)====
+*[[Methotrexate (MTX)]] once per day on days 8 & 29
+====CNS therapy, treatment (CNS+)====
+*[[Methotrexate (MTX)]]
+*[[Cytarabine (Ara-C)]]
+*[[Hydrocortisone (Cortef)]]
+'''5-week course'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*See papers for details of treatment beyond induction block 1
+</div></div>
 ===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. [https://doi.org/10.1182/blood.V96.5.1709 link to original article] [https://pubmed.ncbi.nlm.nih.gov/10961868/ PubMed]
-#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. [http://www.bloodjournal.org/content/51/3/425.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/272207 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. [https://doi.org/10.1200/jco.2008.16.1414 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc2654313/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18711187/ PubMed] [https://clinicaltrials.gov/study/NCT00049569 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. [https://doi.org/10.3324/haematol.2019.237230 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7776266/ link to PMC article] '''does not contain dosing details''' [https://pubmed.ncbi.nlm.nih.gov/32001530/ PubMed] [https://clinicaltrials.gov/study/NCT00381680 NCT00381680]
-=Upfront induction therapy=
+==Inotuzumab ozogamicin monotherapy {{#subobject:d90806|Regimen=1}}==
-==Calaspargase, Daunorubicin, Vincristine, Prednisone {{#subobject:1abca2|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-{| class="wikitable" style="float:right; margin-left: 5px;"
+===Regimen {{#subobject:8be9f9|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+! style="width: 33%" |Study
+! style="width: 33%" |Dates of enrollment
+! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
+|-
+|[https://doi.org/10.1016/S1470-2045(11)70386-2 Kantarjian et al. 2012 (MDACC 2009-0872)]
+|2010-2011
+| style="background-color:#91cf61" |Phase 2
 |-
-|[[#top|back to top]]
 |}
-===Regimen {{#subobject:cf26ce|Variant=1}}===
+<div class="toccolours" style="background-color:#b3e2cd">
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
+====Antibody-drug conjugate therapy====
+*[[Inotuzumab ozogamicin (Besponsa)]] 0.8 mg/m<sup>2</sup> IV once on day 1, then 0.5 mg/m<sup>2</sup> IV once per day on days 8 & 15
+'''21-day course, then 28-day cycle for up to 5 cycles'''
+</div>
+<div class="toccolours" style="background-color:#fff2ae">
+====Dose and schedule modifications====
+*If patients achieved a CR or CRi, the day 1 dose was reduced to 0.5 mg/m<sup>2</sup> for all subsequent cycles.
+</div></div>
+===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. [https://doi.org/10.1016/S1470-2045(11)70386-2 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/22357140/ PubMed] [https://clinicaltrials.gov/study/NCT01134575 NCT01134575]
+==Mitoxantrone, Asparaginase Erwinia chrysanthemi, Vincristine, Dexamethasone {{#subobject:910a81|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:ecb2e4|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239306/ Angiolillo et al. 2014 (COG AALL07P4)]
+|[https://doi.org/10.1016/S0140-6736(10)62002-8 Parker et al. 2010 (CCLG ALL R3)]
-|2008-2010
+|2003-2007
-| style="background-color:#1a9851" |Randomized (E-RT-switch-ic)
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
-|Daunorubicin, Pegaspargase, Vincristine, Prednisone
+|1a. [[#Idarubicin.2C_Asparaginase_Erwinia_chrysanthemi.2C_Vincristine.2C_Dexamethasone_888|Idarubicin, Asparaginase Erwinia chrysanthemi, Vincristine, Dexamethasone]]<br>1b. [[#Idarubicin.2C_Pegaspargase.2C_Vincristine.2C_Dexamethasone_888|Idarubicin, Pegaspargase, Vincristine, Dexamethasone]]
-| style="background-color:#1a9850" |Longer half-life
+| style="background-color:#1a9850" |Superior OS (secondary endpoint)<br>OS36: 69% vs 45.2%<br>(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.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Mitoxantrone (Novantrone)]] 10 mg/m<sup>2</sup> IV once per day on days 1 & 8
-*[[Calaspargase (Asparlas)]] 2500 units/m<sup>2</sup> IV once on day 4
+*[[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
-*[[Daunorubicin (Cerubidine)]] 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once per day on days 3, 10, 17, 24
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
+====Glucocorticoid therapy====
-*[[Prednisone (Sterapred)]] 30 mg/m<sup>2</sup> PO twice per day on days 1 to 28
+*[[Dexamethasone (Decadron)]] 20 mg/m<sup>2</sup> PO once per day on days 1 to 5, 15 to 19
+====CNS therapy, prophylaxis====
-'''5-week course'''
+*[[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'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
 ====Subsequent treatment====
+*See paper for details of treatment beyond induction
-*See protocol for details of treatment beyond induction
+</div></div>
 ===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. [https://doi.org/10.1016/S0140-6736(10)62002-8 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3010035/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21131038/ PubMed] [https://clinicaltrials.gov/study/NCT00967057 NCT00967057]
-#'''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. [https://doi.org/10.1200/JCO.2014.55.5763 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239306/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25348002 PubMed] NCT00671034
+==Mitoxantrone, Pegaspargase, Vincristine, Dexamethasone {{#subobject:910a79|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-==Daunorubicin, Pegaspargase, Vincristine, Dexamethasone {{#subobject:088146|Regimen=1}}==
+===Regimen {{#subobject:e3cbe4|Variant=1}}===
-{| class="wikitable" style="float:right; margin-left: 5px;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[[#top|back to top]]
+|[https://doi.org/10.1016/S0140-6736(10)62002-8 Parker et al. 2010 (CCLG ALL R3)]
-|}
+|2003-2007
-===Regimen {{#subobject:98346f|Variant=1}}===
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
-{| class="wikitable" style="width: 40%; text-align:center;"
+|1a. [[#Idarubicin.2C_Asparaginase_Erwinia_chrysanthemi.2C_Vincristine.2C_Dexamethasone_888|Idarubicin, Asparaginase Erwinia chrysanthemi, Vincristine, Dexamethasone]]<br>1b. [[#Idarubicin.2C_Pegaspargase.2C_Vincristine.2C_Dexamethasone_888|Idarubicin, Pegaspargase, Vincristine, Dexamethasone]]
-! style="width: 25%" |Study
+| style="background-color:#1a9850" |Superior OS (secondary endpoint)<br>OS36: 69% vs 45.2%<br>(HR 0.56, 95% CI 0.36-0.87)
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ Burke et al. 2019 (COG AALL1131)]
-| style="background-color:#91cf61" |Non-randomized portion of RCT
 |-
 |}
-''Note: the referenced publication does not specifically focus on induction; the full regimen is available as a protocol. Per the protocol, it is intended only for patients less than 10 years old.''
+''Note: per the protocol, this regimen is intended only for patients 18 and younger.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
+*[[Mitoxantrone (Novantrone)]] 10 mg/m<sup>2</sup> IV once per day on days 1 & 8
-*[[Daunorubicin (Cerubidine)]] 25 mg/m<sup>2</sup> IV over 1 to 15 minutes once per day on days 1, 8, 15, 22
+*[[Pegaspargase (Oncaspar)]] 1000 units/m<sup>2</sup> IM once per day on days 3 & 18
-*[[Pegaspargase (Oncaspar)]] 2500 units/m<sup>2</sup> IV over 1 to 2 hours once on day 4
+*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once per day on days 3, 10, 17, 24
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
+====Glucocorticoid therapy====
-*[[Dexamethasone (Decadron)]] 5 mg/m<sup>2</sup> IV or PO twice per day on days 1 to 14
+*[[Dexamethasone (Decadron)]] 20 mg/m<sup>2</sup> PO once per day on days 1 to 5, 15 to 19
+====CNS therapy, prophylaxis====
-====CNS prophylaxis====
+*[[Methotrexate (MTX)]] by the following age-based criteria:
+**Younger than 2 years old: 8 mg IT once per day on days 1 & 8
-*[[Cytarabine (Ara-C)]] as follows:
+**2 years old: 10 mg IT once per day on days 1 & 8
-**Ages 1 to 1.99: 30 mg IT once on day 1
+**Older than 2 years old: 12 mg IT once per day on days 1 & 8
-**Ages 2 to 2.99: 50 mg IT once on day 1
-**Age 3 and older: 70 mg IT once on day 1
-*[[Methotrexate (MTX)]] as follows:
-**Ages 1 to 1.99: 8 mg IT once per day on days 8 & 29
-**Ages 2 to 2.99: 10 mg IT once per day on days 8 & 29
-**Ages 3 to 8.99: 12 mg IT once per day on days 8 & 29
-**Age 9 and older: 15 mg IT once per day on days 8 & 29
 '''4-week course'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
 ====Subsequent treatment====
+*See paper for details of treatment beyond induction
-*See protocol for details of treatment beyond induction
+</div></div>
 ===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. [https://doi.org/10.1016/S0140-6736(10)62002-8 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3010035/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21131038/ PubMed] [https://clinicaltrials.gov/study/NCT00967057 NCT00967057]
-#'''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. [http://www.haematologica.org/content/104/5/986.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30545921 PubMed] NCT02883049
+==Tisagenlecleucel monotherapy {{#subobject:d68f14|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
-==DOLP {{#subobject:3c9897|Regimen=1}}==
+===Regimen {{#subobject:60fc19|Variant=1}}===
-{| class="wikitable" style="float:right; margin-left: 5px;"
+{| class="wikitable sortable" style="width: 80%; text-align:center;"
+!style="width: 25%"|Study
+!style="width: 25%"|Dates of enrollment
+!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[[#top|back to top]]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4058440/ Grupp et al. 2013 (Pedi CART19)]
-|}
+|2011-NR
-DOLP: '''<u>D</u>'''aunorubicin, '''<u>O</u>'''ncovin (Vincristine), '''<u>L</u>'''-Asparaginase, '''<u>P</u>'''rednisone
+| style="background-color:#ffffbe" |Pilot
-<br>DVPA: '''<u>D</u>'''aunorubicin, '''<u>V</u>'''incristine, '''<u>P</u>'''rednisone, '''<u>A</u>'''sparaginase
+|
-===Regimen variant #1, 25/6000/1.5/60 {{#subobject:3fe1a2|Variant=1}}===
-{| class="wikitable" style="width: 40%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2254538/ Seibel et al. 2008 (COG CCG-1961)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4267531/ Maude et al. 2014 (UPCC04409)]
-| style="background-color:#91cf61" |Non-randomized portion of RCT
+|2012-2014
+| style="background-color:#91cf61" |Phase 1/2a
+|
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5996391/ Maude et al. 2018 (ELIANA)]
+|2015-2017
+| style="background-color:#91cf61" |Phase 2 (RT)
+|ORR: 81%
 |-
 |}
-''Note: exact days were not specified for the L-asparaginase; suggested days are similar to those used in subsequent parts of the protocol.''
+''Note: dosing instructions are based on ELIANA.''
-====Chemotherapy====
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*Lymphodepleting therapy with [[Autologous_HSCT#Cyclophosphamide_.26_Fludarabine_.28FC.29|FC]] or [[Autologous_HSCT#Cytarabine_.26_Etoposide_.28CYVE.29|CYVE]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Immunotherapy====
+*[[Tisagenlecleucel (Kymriah)]] by the following weight-based criteria:
+**Up to 50 kg: 2 to 5 x 10<sup>6</sup> CTL019 transduced viable T-cells per kg body weight IV once on day 0
+**More than 50 kg: 1.0 to 2.5 x 10<sup>8</sup> CTL019 transduced viable T-cells IV once on day 0
+'''One course'''
+</div></div>
+===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. [https://doi.org/10.1056/NEJMoa1215134 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4058440/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23527958/ PubMed] [https://clinicaltrials.gov/study/NCT01626495 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. [https://doi.org/10.1056/NEJMoa1407222 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4267531/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25317870/ PubMed] [https://clinicaltrials.gov/study/NCT01029366 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. [https://doi.org/10.1056/NEJMoa1709866 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1709866/suppl_file/nejmoa1709866_protocol.pdf link to supplementary protocol] '''contains dosing details in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5996391/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29385370/ PubMed] [https://clinicaltrials.gov/study/NCT02435849 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. [https://doi.org/10.1200/jco.22.00642 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc10022844/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/36399695/ PubMed]
-*[[Daunorubicin (Cerubidine)]] 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
+=Consolidation after salvage therapy=
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
+==Blinatumomab monotherapy {{#subobject:e7bh86|Regimen=1}}==
-*[[Asparaginase (Elspar)]] 6000 units/m<sup>2</sup> IM once per day on days 3, 5, 7, 10, 12, 14, 17, 19, 21
+<div class="toccolours" style="background-color:#eeeeee">
-*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup>/day PO on days 1 to 28
+===Regimen variant #1, 1 cycle {{#subobject:2db26g|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-====CNS therapy====
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
-*[[Cytarabine (Ara-C)]] IT once on day 0 (dose not specified)
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-*[[Methotrexate (MTX)]] IT once per day on days 7 & 28 (dose not specified)
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-'''4-week course'''
-====Subsequent treatment====
-*Standard versus increased intensity post-remission therapy (see paper for details)
-===Regimen variant #2, 30/5000/1.5/60 ("Phase A" of ALL-BFM 95) {{#subobject:020017|Variant=1}}===
-{| class="wikitable" style="width: 40%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[http://www.bloodjournal.org/content/111/9/4477.long Möricke et al. 2008 (ALL-BFM 95)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7926287/ Locatelli et al. 2021 (Amgen 20120215)]
-| style="background-color:#91cf61" |Non-randomized
+|2015-2019
+| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
+|Standard salvage consolidation chemotherapy
+| style="background-color:#1a9850" |Superior EFS (primary endpoint)<br>EFS24: 66.2% vs 27.1%<br>(HR 0.33, 95% CI 0.18-0.61)
 |-
 |}
-''Note: see paper for details on dose adjustments based on risk.''
+<div class="toccolours" style="background-color:#b3e2cd">
-====Chemotherapy====
+====Immunotherapy====
+*[[Blinatumomab (Blincyto)]] 15 mcg/m<sup>2</sup>/day IV continuous infusion over 28 days, started on day 1 (total dose: 420 mcg/m<sup>2</sup>)
-*[[Daunorubicin (Cerubidine)]] 30 mg/m<sup>2</sup> IV over 60 minutes once per day on days 8, 15, 22, 29
+'''42-day course'''
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 8, 15, 22, 29
+</div>
-*[[Asparaginase (Elspar)]] 5000 units IV over 60 minutes once per day on days 12, 15, 18, 21, 24, 27, 30, 33
+<div class="toccolours" style="background-color:#cbd5e7">
-*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup>/day PO on days 1 to 28
-====CNS therapy====
-*[[Methotrexate (MTX)]] 12 mg IT once per day on days 1, 12, 33
-'''5-week course'''
 ====Subsequent treatment====
+*[[Regimen_classes#Allogeneic_HSCT|Allogeneic hematopoietic stem cell transplant]] consolidation
-*See paper for details
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #3, 30/10,000/1.5/60 ("Protocol I") {{#subobject:0ccc82|Variant=1}}===
+===Regimen variant #2, 2 cycles {{#subobject:2db2g7|Variant=1}}===
-{| class="wikitable" style="width: 40%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[http://www.bloodjournal.org/content/95/11/3310.long Schrappe et al. 2000 (ALL-BFM 90)]
-| style="background-color:#91cf61" |Non-randomized
-|-
-|[https://doi.org/10.1038/sj.leu.2402489 Kamps et al. 2002 (DCLSG ALL-8)]
-| style="background-color:#91cf61" |Non-randomized
-|-
-|}
-''Note: see papers for details on dose adjustments based on risk.''
-====Chemotherapy====
-*[[Daunorubicin (Cerubidine)]] 30 mg/m<sup>2</sup> IV over 60 minutes once per day on days 8, 15, 22, 29
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 8, 15, 22, 29
-*[[Asparaginase (Elspar)]] 10,000 units IV over 60 minutes once per day on days 12, 15, 18, 21, 24, 27, 30, 33
-*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup>/day PO on days 1 to 28
-====CNS therapy====
-*[[Methotrexate (MTX)]] 12 mg IT once per day on days 1, 15, 29
-'''5-week course'''
-====Subsequent treatment====
-*See papers for details
-===Regimen variant #4, 40/10,000/1.5/60 ("Induction Protocol I" of ALL-BFM 86) {{#subobject:6ad40d|Variant=1}}===
-{| class="wikitable" style="width: 40%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[http://www.bloodjournal.org/content/84/9/3122.long Reiter et al. 1994 (ALL-BFM 86)]
-| style="background-color:#91cf61" |Non-randomized portion of RCT
-|-
-|[http://www.bloodjournal.org/content/94/4/1226.long Kamps et al. 1999 (DCLSG ALL-7)]
-| style="background-color:#91cf61" |Non-randomized portion of RCT
-|-
-|}
-====Chemotherapy====
-*[[Daunorubicin (Cerubidine)]] 40 mg/m<sup>2</sup> IV once per day on days 8, 15, 22, 29
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 8, 15, 22, 29
-*[[Asparaginase (Elspar)|L-Asparaginase]] 10,000 units/m<sup>2</sup> IV once per day on days 19, 22, 25, 28, 31, 34, 37, 40
-*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup>/day PO on days 1 to 28
-'''6-week course'''
-====Subsequent treatment====
-*Induction phase II (see papers for details)
-===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. [http://www.bloodjournal.org/content/84/9/3122.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/7949185 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. [http://www.bloodjournal.org/content/94/4/1226.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/10438710 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. [http://www.bloodjournal.org/content/95/11/3310.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/10828010 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. [https://doi.org/10.1200/JCO.2006.06.2679 link to original article] [https://pubmed.ncbi.nlm.nih.gov/17179108 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. [https://doi.org/10.1038/sj.leu.2402489 link to original article] '''refers to ALL-BFM 90 protocol''' [https://pubmed.ncbi.nlm.nih.gov/12040440 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. [http://www.bloodjournal.org/content/111/5/2548.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2254538/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18039957 PubMed]
-#'''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. [http://www.bloodjournal.org/content/111/9/4477.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18285545 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. [https://doi.org/10.1200/JCO.2006.06.2679 link to original article] [https://pubmed.ncbi.nlm.nih.gov/17179108 PubMed]
-==DOLP (Prednisolone) {{#subobject:3c7jg7|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-DOLP: '''<u>D</u>'''aunorubicin, '''<u>O</u>'''ncovin (Vincristine), '''<u>L</u>'''-Asparaginase, '''<u>P</u>'''rednisolone
-===Regimen variant #1, 30/10,000/1.5/60 {{#subobject:087cg2|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2904579/ de Moerloose et al. 2010 (EORTC CLG 58951)]
-|1999-2002
-| style="background-color:#1a9851" |Phase III (C)
-|Daunorubicin, L-Asparaginase, Vincristine, Dexamethasone
-| style="background-color:#ffffbf" |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/m<sup>2</sup> IV once per day on days 8, 15, 22, 29
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 8, 15, 22, 29
-*[[Asparaginase (Elspar)]] 10,000 units (route not specified) once per day on days 12, 15, 18, 22, 25, 29, 32, 35
-*[[Prednisolone (Millipred)]] 60 mg/m<sup>2</sup>/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 {{#subobject:b39731|Variant=1}}===
-{| class="wikitable" style="width: 40%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://www.thelancet.com/journals/lancet/article/PII014067369292103M/fulltext Chessells et al. 1992 (UK MRC ALLX)]
-| style="background-color:#91cf61" |Non-randomized portion of RCT
-|-
-|}
-''Note: exact days for L-asparaginase were not specified in the protocol.''
-====Chemotherapy====
-*[[Daunorubicin (Cerubidine)]] 45 mg/m<sup>2</sup> IV once per day on days 1 & 2
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29
-*[[Asparaginase (Elspar)]] 6000 units/m<sup>2</sup> SC once per day on days 3, 5, 7, 10, 12, 14, 17, 19, 21
-*[[Prednisolone (Millipred)]] 40 mg/m<sup>2</sup>/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. [https://www.thelancet.com/journals/lancet/article/PII014067369292103M/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/1355153 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. [https://www.thelancet.com/journals/lancet/article/PIIS0140673695901647/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/7823668 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. [http://www.bloodjournal.org/content/116/1/36.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2904579/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20407035 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/m<sup>2</sup>/day) and prednisolone (60 mg/m<sup>2</sup>/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. [http://www.haematologica.org/content/99/7/1220.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4077084/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24727815 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. [http://www.haematologica.org/content/102/10/1727.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5622857/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28751566 PubMed]
-==Doxorubicin, Mercaptopurine, Pegaspargase, Vincristine, Prednisolone {{#subobject:127ca2|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:nc303e|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
-! style="width: 33%" |Study
-! style="width: 33%" |Years of enrollment
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://doi.org/10.1200/JCO.18.01877 Albertsen et al. 2019 (NOPHO ALL2008)]
-|2008-2016
-| style="background-color:#91cf61" |Non-randomized portion of RCT
-|-
-|}
-''See protocol for initiation dependencies of 6-MP and pegaspargase.''
-====Chemotherapy====
-*[[Doxorubicin (Adriamycin)]] 40 mg/m<sup>2</sup> IV over 4 hours once per day on days 1 & 22
-*[[Mercaptopurine (6-MP)]] 25 mg/m<sup>2</sup> PO once per day on days 30 to 35
-*[[Pegaspargase (Oncaspar)]] 1000 units/m<sup>2</sup> IM once on day 30
-*[[Vincristine (Oncovin)]] as follows:
-**Younger than 18: 2 mg/m<sup>2</sup> (maximum dose of 2.5 mg) IV once per day on days 1, 8, 15, 22, 29
-**18 or older: 2 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22, 29
-*[[Prednisolone (Millipred)]] 20 mg/m<sup>2</sup> PO three times per day on days 1 to 29, then 10 mg/m<sup>2</sup> PO three times per day on days 30 to 32, then 5 mg/m<sup>2</sup> PO three times per day on days 33 to 35, then 2.5 mg/m<sup>2</sup> PO three times per day on days 36 to 38
-====CNS prophylaxis====
-*[[Methotrexate (MTX)]] as follows:
-**Ages 1 to 1.9: 8 mg IT once per day on days 1, 8, 15, 29
-**Ages 2 to 2.9: 10 mg IT once per day on days 1, 8, 15, 29
-**Age 3 and older: 12 mg IT once per day on days 1, 8, 15, 29
-'''5-week course'''
-====Subsequent treatment====
-*See protocol for details of treatment beyond induction
-===References===
-#'''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. [https://doi.org/10.1200/JCO.18.01877 link to original article] '''contains verified protocol in supplement''' [https://pubmed.ncbi.nlm.nih.gov/30978155 PubMed] NCT00819351
-==Doxorubicin, Methotrexate, Pegaspargase, Vincristine, Methylprednisolone {{#subobject:h1gtbb|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:hgu1h7|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 17%" |Study
-! style="width: 15%" |Years of enrollment
-! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 17%" |Comparator
-! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
-|-
-|[https://doi.org/10.1016/s1470-2045(15)00363-0 Place et al. 2015 (DFCI 05-001)]
-|2005-2011
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|Doxorubicin, L-Asparaginase, Methotrexate, Vincristine, Methylprednisolone
-| style="background-color:#ffffbf" |Did not meet secondary endpoint of DFS
-| style="background-color:#1a9850" |Less anxiety
-|-
-|[https://doi.org/10.1002/pbc.28719 Burns et al. 2020 (DFCI 11-001)]
-|2012-2015
-| style="background-color:#1a9851" |Phase III (C)
-|Calaspargase, Doxorubicin, Methotrexate, Vincristine, Methylprednisolone
-| style="background-color:#d3d3d3" |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_monotherapy|Methylprednisolone pre-phase]]
-====Chemotherapy====
-*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once per day on days 4 & 5
-*[[Methotrexate (MTX)]] 40 mg/m<sup>2</sup> IV once on day 6
-*[[Pegaspargase (Oncaspar)]] 2500 units/m<sup>2</sup> IV once on day 7
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 4, 11, 18, 25
-*[[Methylprednisolone (Solumedrol)]] 8 mg/m<sup>2</sup> IV three times per day on days 4 to 32
-====Supportive medications====
-*[[Dexrazoxane (Zinecard)]] 300 mg/m<sup>2</sup> IV once per day on days 4 & 5
-'''28-day course'''
-====CNS prophylaxis====
-*[[Cytarabine (Ara-C)]] IT once per day on days 1 & 18
-**Day 18 dose is admixed with MTX and HC
-*[[Methotrexate (MTX)]] IT once per day on days 18 & 32
-**Day 18 dose is admixed with Ara-C and HC
-*[[Hydrocortisone (Cortef)]] IT once on day 18, admixed with Ara-C and MTX
-====Subsequent treatment====
-*[[#Doxorubicin.2C_Mercaptopurine.2C_Methotrexate.2C_Vincristin|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. [https://doi.org/10.1016/s1470-2045(15)00363-0 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26549586/ 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. [https://doi.org/10.1002/pbc.28719 link to original article] '''contains verified protocol in supplement''' [https://pubmed.ncbi.nlm.nih.gov/33026184/ 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. [https://doi.org/10.1002/pbc.28719 link to original article] '''contains verified protocol in supplement''' [https://pubmed.ncbi.nlm.nih.gov/33026184/ PubMed] NCT01574274
-==Pegaspargase, Vincristine, Dexamethasone {{#subobject:15hgu1|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:e8uyt1|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
-! style="width: 33%" |Study
-! style="width: 33%" |Years of enrollment
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7030893/ Maloney et al. 2019 (COG AALL0331)]
-|2005-2010
-| style="background-color:#91cf61" |Non-randomized portion of RCT
-|-
-|[https://doi.org/10.1200/jco.20.00494 Angiolillo et al. 2021 (COG AALL0932)]
-|2010-2018
-| style="background-color:#91cf61" |Non-randomized portion of RCT
-|-
-|}
-''Note: there are very minor differences in timing between protocols; see papers for details.''
-====Chemotherapy====
-*[[Pegaspargase (Oncaspar)]] 2500 units/m<sup>2</sup> IV once on day 4
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
-*[[Dexamethasone (Decadron)]] 3 mg/m<sup>2</sup> PO twice per day on days 1 to 28
-====CNS prophylaxis====
-*[[Cytarabine (Ara-C)]] IT once at some point between days -2 and 1
-*[[Methotrexate (MTX)]] IT once per day on days 8 & 29
-'''35-day course'''
-====Subsequent treatment====
-*COG AALL0331, M2 marrow or M1 marrow with MRD of at least 1% at day 29: Extended induction
-*COG AALL0932: [[#Mercaptopurine_.26_Vincristine|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. [https://doi.org/10.1200/jco.19.01086 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7030893/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/31825704/ 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. [https://doi.org/10.1200/jco.20.00494 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33411585/ PubMed] NCT01190930
-==Pegaspargase, Vincristine, Prednisone {{#subobject:158722|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:e8uhb3|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[http://www.bloodjournal.org/content/99/6/1986.long Avramis et al. 2002 (CCG 1962)]
-|1997-1998
-| style="background-color:#1a9851" |Randomized (E-RT-switch-ic)
-|L-Asparaginase, Vincristine, Prednisone
-| style="background-color:#ffffbf" |Did not meet secondary endpoint of EFS
-|-
-|}
-''Note: the primary endpoint of CCG 1962 was incidence of high-titer ASNase antibodies in the first dose intensification, which is neither an efficacy nor a toxicity endpoint.''
-====Chemotherapy====
-*[[Pegaspargase (Oncaspar)]]
-*[[Vincristine (Oncovin)]]
-*[[Prednisone (Sterapred)]]
-====Subsequent treatment====
-*See protocol for details of treatment beyond induction
-===References===
-#'''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. [http://www.bloodjournal.org/content/99/6/1986.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/11877270 PubMed]
-=Early intensification therapy=
-==Cyclophosphamide, Etoposide, Methotrexate {{#subobject:6ahzn6|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:16fxc9|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc5145261/ Dreyer et al. 2014 (COG P9407)]
-|2001-2006
-| style="background-color:#91cf61" |Non-randomized
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|-
-|[https://doi.org/10.1038/s41375-021-01177-6 Brown et al. 2021 (COG AALL0631)]
-|2008-2014
-| style="background-color:#1a9851" |Phase III (C)
-|Cyclophosphamide, Etoposide, Lestaurtinib, Methotrexate
-| style="background-color:#ffffbf" |Did not meet primary endpoint of EFS
-|-
-|}
-====Biomarker eligibility criteria====
-*COG AALL0631: KMT2A rearrangement
-====Preceding treatment====
-*Induction
-====Chemotherapy====
-*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> IV over 30 minutes once per day on days 15 to 19
-*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV over 2 hours once per day on days 15 to 19
-*[[Methotrexate (MTX)]] 200 mg/m<sup>2</sup> IV over 20 minutes, then 3800 mg/m<sup>2</sup> IV continuous infusion over 23 hours and 40 minutes on days 1 & 8 (total dose: 8000 mg/m<sup>2</sup>)
-====Subsequent treatment====
-*Reinduction
-===References===
-#'''COG P9407:''' Dreyer ZE, Hilden JM, Jones TL, Devidas M, Winick NJ, Willman CL, Harvey RC, Chen IM, Behm FG, Pullen J, Wood BL, Carroll AJ, Heerema NA, Felix CA, Robinson B, Reaman GH, Salzer WL, Hunger SP, Carroll WL, Camitta BM. Intensified chemotherapy without SCT in infant ALL: results from COG P9407 (Cohort 3). Pediatr Blood Cancer. 2015 Mar;62(3):419-26. Epub 2014 Nov 14. [https://doi.org/10.1002/pbc.25322 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc5145261/ link to PMC article]  [https://pubmed.ncbi.nlm.nih.gov/25399948/ PubMed] NCT00002756
-#'''COG AALL0631:''' Brown PA, Kairalla JA, Hilden JM, Dreyer ZE, Carroll AJ, Heerema NA, Wang C, Devidas M, Gore L, Salzer WL, Winick NJ, Carroll WL, Raetz EA, Borowitz MJ, Small D, Loh ML, Hunger SP. FLT3 inhibitor lestaurtinib plus chemotherapy for newly diagnosed KMT2A-rearranged infant acute lymphoblastic leukemia: Children's Oncology Group trial AALL0631. Leukemia. 2021 May;35(5):1279-1290. Epub 2021 Feb 23. Erratum in: Leukemia. 2021 Apr 12. [https://doi.org/10.1038/s41375-021-01177-6 link to original article] '''contains verified protocol in supplement''' [https://pubmed.ncbi.nlm.nih.gov/33623141/ PubMed] NCT00557193
-==Mercaptopurine & Methotrexate {{#subobject:6ad6d6|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:5b0ec9|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1200/JCO.1998.16.1.246 Mahoney et al. 1998 (POG 9005)]
-|1991-1993
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|LDMTX/IVMP
-| style="background-color:#91cf60" |Seems to have superior CCR
-|-
-|[https://www.nature.com/articles/2402132 Lauer et al. 2001 (POG 9006)]
-|1991-1994
-| style="background-color:#1a9851" |Phase III (C)
-|Intensive chemotherapy
-| style="background-color:#fee08b" |Might have inferior EFS
-|-
-|}
-====Preceding treatment====
-*POG 9006: [[#DOLP|DOLP induction]]
-====Chemotherapy====
-*[[Mercaptopurine (6-MP)]]
-*[[Methotrexate (MTX)]]
-====Subsequent treatment====
-*POG 9006: [[#Mercaptopurine_.26_Methotrexate_2|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. [https://doi.org/10.1200/JCO.1998.16.1.246 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9440749 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. [https://www.nature.com/articles/2402132 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11455971 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 {{#subobject:065gg9|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:342b6d|Variant=1}}===
-{| class="wikitable" style="width: 40%; text-align:center;"
-! style="width: 50%" |Study
-! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4981974/ Larsen et al. 2016 (COG AALL0232)]
-| style="background-color:#91cf61" |Non-randomized portion of RCT
-|-
-|}
-====Chemotherapy====
-*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 29
-*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> 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/m<sup>2</sup> PO once per day on days 1 to 14, 29 to 42
-*[[Pegaspargase (Oncaspar)]] 2500 units/m<sup>2</sup> IM or IV once per day on days 15 & 43
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (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 [[#Mercaptopurine.2C_Methotrexate.2C_Vincristine_2|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. [https://doi.org/10.1200/JCO.2015.62.4544 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4981974/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/27114587 PubMed] NCT00075725
-==Augmented BFM consolidation {{#subobject:065ff9|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:687b6d|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.nejm.org/doi/full/10.1056/NEJM199806043382304 Nachman et al. 1998]
-|1991-1995
-| style="background-color:#1a9851" |Phase III (E-esc)
-|Standard BFM consolidation
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-|}
-''Unlikely to be completed, but of historic interest.''
-====Chemotherapy====
-*[[Cyclophosphamide (Cytoxan)]]
-*[[Cytarabine (Ara-C)]]
-*[[Asparaginase (Elspar)]]
-*[[Mercaptopurine (6-MP)]]
-*[[Vincristine (Oncovin)]]
-===References===
-#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. [https://www.nejm.org/doi/full/10.1056/NEJM199806043382304 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9614257 PubMed]
-==Cyclophosphamide & TBI, then allo HSCT {{#subobject:a9f7e8|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-Cy/TBI: '''<u>Cy</u>'''clophosphamide & '''<u>T</u>'''otal '''<u>B</u>'''ody '''<u>I</u>'''rradiation
-===Regimen {{#subobject:6ca28d|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
-! style="width: 33%" |Study
-! style="width: 33%" |Years of enrollment
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[http://www.bloodjournal.org/content/54/2/468.long Thomas et al. 1979]
-|1976-1977
-| style="background-color:#91cf61" |Non-randomized
-|-
-|}
-{{#lst:Allogeneic HSCT|6ca28d}}
-====Immunotherapy====
-*[[Allogeneic stem cells]]
-'''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. [http://www.bloodjournal.org/content/54/2/468.long link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/378292 PubMed]
-==Etoposide & TBI, then allo HSCT {{#subobject:b389e1|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:45f841|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS014067360566998X/fulltext Balduzzi et al. 2005]
-|1995-2000
-| style="background-color:#1a9851" |Quasi-randomized
-|Chemotherapy
-| style="background-color:#91cf60" |Seems to have superior DFS
-|-
-|[https://doi.org/10.1200/jco.2014.58.9747 Peters et al. 2015 (ALL-SCT-BFM 2003)]
-|2003-2011
-| style="background-color:#91cf61" |Non-randomized
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|-
-|}
-{{#lst:Allogeneic HSCT|45f841}}
-====Immunotherapy====
-*[[Allogeneic stem cells]]
-'''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. [https://www.thelancet.com/journals/lancet/article/PIIS014067360566998X/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16112299 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. [https://doi.org/10.1200/jco.2014.58.9747 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25753432 PubMed]
-==Mercaptopurine & Vincristine {{#subobject:171gc1|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:1ygvt1|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
-! style="width: 33%" |Study
-! style="width: 33%" |Years of enrollment
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://doi.org/10.1200/jco.20.00494 Angiolillo et al. 2021 (COG AALL0932)]
-|2010-2018
-| style="background-color:#91cf61" |Non-randomized portion of RCT
-|-
-|}
-====Preceding treatment====
-*[[#Pegaspargase.2C_Vincristine.2C_Dexamethasone|Pegaspargase, Vincristine, Dexamethasone induction]]
-====Chemotherapy====
-*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup>/day PO on days 1 to 28
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1
-====CNS prophylaxis====
-*[[Methotrexate (MTX)]] IT once per day on days 1, 8, 15
-'''28-day course'''
-====Subsequent treatment====
-*[[#Methotrexate_.26_Vincristine|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. [https://doi.org/10.1200/jco.20.00494 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33411585/ PubMed] NCT01190930
-=Interim maintenance=
-==Mercaptopurine, Methotrexate, Vincristine {{#subobject:72025a|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:b9e09c|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4981974/ Larsen et al. 2016 (COG AALL0232)]
-|2004-2011
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|Mercaptopurine, Capizzi MTX, Pegaspargase, Vincristine
-| style="background-color:#1a9850" |Superior EFS
-|-
-|}
-====Chemotherapy====
-*[[Mercaptopurine (6-MP)]] 25 mg/m<sup>2</sup> PO once per day on days 1 to 56
-*[[Methotrexate (MTX)]] 5000 mg/m<sup>2</sup> IV once per day on days 1, 15, 29, 43
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 15, 29, 43
-====Intrathecal component====
-*[[Methotrexate (MTX)]] once per day on days 1 & 29
-===References===
-#'''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. [https://doi.org/10.1200/JCO.2015.62.4544 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4981974/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/27114587 PubMed] NCT00075725
-==Methotrexate & Vincristine {{#subobject:0ae09f|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:57f39d|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3138679/ Matloub et al. 2011 (COG CCG-1991)]
-|2000-2005
-| style="background-color:#1a9851" |Phase III (E-de-esc)
-|Mercaptopurine, MTX, Vincristine, Dexamethasone
-| style="background-color:#1a9850" |Superior EFS
-|-
-|[https://doi.org/10.1200/jco.20.00494 Angiolillo et al. 2021 (COG AALL0932)]
-|2010-2018
-| style="background-color:#91cf61" |Non-randomized portion of RCT
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|-
-|}
-====Preceding treatment====
-*COG AALL0932: [[#Mercaptopurine_.26_Vincristine|6-MP & Vincristine consolidation]]
-====Chemotherapy====
-*[[Methotrexate (MTX)]] 100 mg/m<sup>2</sup> IV once on day 1, then 150 mg/m<sup>2</sup> IV once on day 11, then 200 mg/m<sup>2</sup> IV once on day 21, then 250 mg/m<sup>2</sup> IV once on day 31, then 300 mg/m<sup>2</sup> IV once on day 41
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 11, 21, 31, 41
-====CNS prophylaxis====
-*[[Methotrexate (MTX)]] IT once on day 31
-'''8-week course'''
-====Subsequent treatment====
-*COG AALL0932: [[#AALL0932_delayed_intensification|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. [http://www.bloodjournal.org/content/118/2/243.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3138679/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21562038 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. [https://doi.org/10.1200/jco.20.00494 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33411585/ PubMed] NCT01190930
-=Delayed intensification=
-==AALL0932 delayed intensification {{#subobject:17185g|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:1y47gc|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
-! style="width: 33%" |Study
-! style="width: 33%" |Years of enrollment
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://doi.org/10.1200/jco.20.00494 Angiolillo et al. 2021 (COG AALL0932)]
-|2010-2018
-| style="background-color:#91cf61" |Non-randomized portion of RCT
-|-
-|}
-====Preceding treatment====
-*[[#Methotrexate_.26_Vincristine|MTX & Vincristine interim maintenance]]
-====Chemotherapy====
-*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV once on day 29
-*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup>/day SC or IV on days 29 to 32, 36 to 39
-*[[Doxorubicin (Adriamycin)]] 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
-*[[Pegaspargase (Oncaspar)]] 2500 units/m<sup>2</sup> IV once on day 4
-*[[Thioguanine (Tabloid)]] 60 mg/m<sup>2</sup>/day PO on days 29 to 42
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15
-*[[Dexamethasone (Decadron)]] 10 mg/m<sup>2</sup>/day PO on days 1 to 7, 15 to 21
-====CNS prophylaxis====
-*[[Methotrexate (MTX)]] IT once per day on days 1 & 29
-'''8-week course'''
-====Subsequent treatment====
-*[[#Methotrexate_.26_Vincristine_2|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. [https://doi.org/10.1200/jco.20.00494 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33411585/ PubMed] NCT01190930
-=Interim maintenance II=
-==Methotrexate & Vincristine {{#subobject:ajbz5g|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:18guaz|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
-! style="width: 33%" |Study
-! style="width: 33%" |Years of enrollment
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://doi.org/10.1200/jco.20.00494 Angiolillo et al. 2021 (COG AALL0932)]
-|2010-2018
-| style="background-color:#91cf61" |Non-randomized portion of RCT
-|-
-|}
-''Note: starting dose of the systemic MTX is 2/3 of the MTD from interim maintenance I; dosage below assumes that the final maximum dose was tolerated.''
-====Preceding treatment====
-*[[#AALL0932_delayed_intensification|AALL0932 delayed intensification]]
-====Chemotherapy====
-*[[Methotrexate (MTX)]] 200 mg/m<sup>2</sup> IV once on day 1, then 250 mg/m<sup>2</sup> IV once on day 11, then 300 mg/m<sup>2</sup> IV once on day 21, then 350 mg/m<sup>2</sup> IV once on day 31, then 400 mg/m<sup>2</sup> IV once on day 41
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 11, 21, 31, 41
-====CNS prophylaxis====
-*[[Methotrexate (MTX)]] IT once per day on days 1 & 31
-'''8-week course'''
-====Subsequent treatment====
-*Randomization to one of four maintenance arms; see paper for details.
-===References===
-#'''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. [https://doi.org/10.1200/jco.20.00494 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33411585/ PubMed] NCT01190930
-=Maintenance after upfront therapy=
-==Mercaptopurine & Methotrexate {{#subobject:6366a6|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:e46d92|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1200/JCO.2001.19.7.1935 Millot et al. 2001 (EORTC 58881)]
-|1990-1996
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Mercaptopurine_.26_Methotrexate_2|6-MP & MTX]]; IV 6-MP & PO MTX
-| style="background-color:#1a9850" |Superior DFS<sup>1</sup>
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(07)60073-7/fulltext Conter et al. 2007 (I-BFM-SG IR ALL)]
-|1995-2000
-| style="background-color:#1a9851" |Phase III (C)
-|D-OMP
-| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
-|-
-|}
-''<sup>1</sup>Reported efficacy for EORTC 58881 is based on the 2005 update.''
-====Preceding treatment====
-*I-BFM-SG IR ALL: BFM re-induction
-====Chemotherapy====
-*[[Mercaptopurine (6-MP)]] 50 mg/m<sup>2</sup> PO once per day
-*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> 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. [https://doi.org/10.1200/JCO.2001.19.7.1935 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11283125 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. [http://www.bloodjournal.org/content/99/8/2734.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/11929760 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. [https://www.nature.com/articles/2403689 link to original article] [https://pubmed.ncbi.nlm.nih.gov/15744348 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. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(07)60073-7/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17223475 PubMed] NCT00411541
-=Relapsed or refractory=
-==Blinatumomab monotherapy {{#subobject:e7b2c6|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:fd494b|Variant=1}}===
-{| class="wikitable" style="width: 60%; text-align:center;"
-! style="width: 33%" |Study
-! style="width: 33%" |Years of enrollment
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://doi.org/10.1200/JCO.2016.67.3301 von Stackelberg et al. 2016 (MT103-205)]
-|2012-2014
-| style="background-color:#91cf61" |Phase I/II (RT)
-|-
-|}
-''Note: this is the MTD of a phase I/II trial enrolling children under the age of 18.''
-====Immunotherapy====
-*[[Blinatumomab (Blincyto)]] as follows:
-**Cycle 1: 5 mcg/day IV continuous infusion over 7 days, started on day 1, then 15 mcg/day IV continuous infusion over 21 days, started on day 8 (total dose: 350 mcg)
-**Cycles 2 to 5: 28 mcg/day IV continuous infusion over 28 days, started on day 1 (total dose per cycle: 784 mcg)
-'''42-day cycle for up to 5 cycles'''
-===References===
-#'''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. [https://doi.org/10.1200/JCO.2016.67.3301 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/27998223 PubMed] NCT01471782
-==CCE {{#subobject:f74969|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-CCE: '''<u>C</u>'''lofarabine, '''<u>C</u>'''yclophosphamide, '''<u>E</u>'''toposide
-===Regimen {{#subobject:24f55b|Variant=1}}===
-{| class="wikitable" style="width: 40%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2009.07882.x/full Locatelli et al. 2009]
-| style="background-color:#91cf61" |Non-randomized
-|-
-|}
-''Patients in this study were pediatric: ≤ 15 years old at diagnosis and ≤ 21 years old at time of treatment. No patients had CNS disease at time of treatment, and no patients received CNS prophylaxis.''
-====Chemotherapy====
-*[[Clofarabine (Clolar)]] 40 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 to 5, given first
-*[[Cyclophosphamide (Cytoxan)]] 400 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5
-*[[Etoposide (Vepesid)]] 150 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 to 5
-====Supportive medications====
-*Prophylactic [[:Category:Steroids|steroids]] used for patients with greater than 30 x 10<sup>9</sup> 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. [https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2009.07882.x/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19747360 PubMed]
-==Clofarabine monotherapy {{#subobject:6befdc|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:fc17b2|Variant=1}}===
-{| class="wikitable" style="width: 60%; text-align:center;"
-! style="width: 33%" |Study
-! style="width: 33%" |Years of enrollment
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[http://www.bloodjournal.org/content/103/3/784.long Jeha et al. 2003]
-|2000-2002
-| style="background-color:#ffffbe" |Phase 1, <20 pts (RT)
-|-
-|[https://doi.org/10.1200/JCO.2005.03.8554 Jeha et al. 2006]
-|2002-2004
-| style="background-color:#91cf61" |Phase II (RT)
-|-
-|}
-''Note: this dose was the MTD in Jeha et al. 2003.''
-====Chemotherapy====
-*[[Clofarabine (Clolar)]] 52 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 to 5
-'''2- to 6-week cycles, depending on response count recovery'''
-===References===
-#'''Phase 1:''' Jeha S, Gandhi V, Chan KW, McDonald L, Ramirez I, Madden R, Rytting M, Brandt M, Keating M, Plunkett W, Kantarjian H. Clofarabine, a novel nucleoside analog, is active in pediatric patients with advanced leukemia. Blood. 2004 Feb 1;103(3):784-9. Epub 2003 Oct 9. [http://www.bloodjournal.org/content/103/3/784.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/14551141 PubMed]
-#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. [https://doi.org/10.1200/JCO.2005.03.8554 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16622268 PubMed]
-==DOLP {{#subobject:8804f2|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-DOLP: '''<u>D</u>'''aunorubicin, '''<u>O</u>'''ncovin (Vincristine), '''<u>L</u>'''-Asparaginase, '''<u>P</u>'''rednisone
-===Regimen {{#subobject:a6fef6|Variant=1}}===
-{| class="wikitable" style="width: 40%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://www.nejm.org/doi/full/10.1056/NEJM198607313150501 Rivera et al. 1986]
-| style="background-color:#91cf61" |Non-randomized
-|-
-|}
-====Chemotherapy====
-*[[Daunorubicin (Cerubidine)]]
-*[[Vincristine (Oncovin)]]
-*[[Asparaginase (Elspar)]]
-*[[Prednisone (Sterapred)]]
-'''4-week course'''
-====Subsequent treatment====
-*See paper for details of treatment beyond induction
-===References===
-#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. [https://www.nejm.org/doi/full/10.1056/NEJM198607313150501 link to original article] [https://pubmed.ncbi.nlm.nih.gov/3523250 PubMed]
-==Doxorubicin, Pegaspargase, Vincristine, Prednisone {{#subobject:1265yg|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:3gt03e|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1182/blood.V96.5.1709 Abshire et al. 2000 (POG 9310)]
-|NR
-| style="background-color:#91cf61" |Non-randomized
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|-
-|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc2654313/ Raetz et al. 2008 (COG AALL01P2)]
-|2003-2005
-| style="background-color:#91cf61" |Non-randomized portion of RCT
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|-
-|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7776266/ Lew et al. 2021 (COG AALL0433)]
-|2007-2013
-| style="background-color:#1a9851" |Phase III (C)
-|Doxorubicin, Pegaspargase, Vincristine, Prednisone; high-dose vincristine
-| style="background-color:#d3d3d3" |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/m<sup>2</sup> IV once on day 1
-*[[Pegaspargase (Oncaspar)]] 2500 units/m<sup>2</sup> IM once per day on days 2, 9, 16, 23
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
-*[[Prednisone (Sterapred)]] 40 mg/m<sup>2</sup>/day PO on days 1 to 29
-====CNS prophylaxis (CNS-)====
-*[[Methotrexate (MTX)]] once per day on days 8 & 29
-====CNS treatment (CNS+)====
-*[[Methotrexate (MTX)]]
-*[[Cytarabine (Ara-C)]]
-*[[Hydrocortisone (Cortef)]]
-'''5-week course'''
-====Subsequent treatment====
-*See papers for details of treatment beyond induction block 1
-===References===
-#'''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. [https://doi.org/10.1182/blood.V96.5.1709 link to original article] [https://pubmed.ncbi.nlm.nih.gov/10961868/ 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. [https://doi.org/10.1200/jco.2008.16.1414 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc2654313/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18711187/ PubMed]
-#'''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. [https://doi.org/10.3324/haematol.2019.237230 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7776266/ link to PMC article] '''does not contain protocol''' [https://pubmed.ncbi.nlm.nih.gov/32001530/ PubMed] NCT00381680
-==Inotuzumab ozogamicin monotherapy {{#subobject:d90806|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:8be9f9|Variant=1}}===
-{| class="wikitable sortable" style="width: 60%; text-align:center;"
-! style="width: 33%" |Study
-! style="width: 33%" |Years of enrollment
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70386-2/fulltext Kantarjian et al. 2012 (MDACC 2009-0872)]
-|2010-2011
-| style="background-color:#91cf61" |Phase II
-|-
-|}
-====Antibody-drug conjugate therapy====
-*[[Inotuzumab ozogamicin (Besponsa)]] 0.8 mg/m<sup>2</sup> IV once on day 1, then 0.5 mg/m<sup>2</sup> IV once per day on days 8 & 15
-**For patients achieving CR or CRi, day 1 dose was reduced to 0.5 mg/m<sup>2</sup>
-'''21-day cycle for 1 cycle, then 28-day cycle for up to 5 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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70386-2/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/22357140 PubMed] NCT01134575
-==Mitoxantrone, Asparaginase Erwinia chrysanthemi, Vincristine, Dexamethasone {{#subobject:910a81|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:ecb2e4|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)62002-8/fulltext Parker et al. 2010 (CCLG ALL R3)]
-|2003-2007
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|Idarubicin, Asparaginase Erwinia chrysanthemi, Vincristine, Dexamethasone
-| style="background-color:#1a9850" |Superior OS
-|-
-|}
-''Note: per the protocol, this regimen is intended only for patients 18 and younger. This regimen is for patients allergic to pegaspargase.''
-====Chemotherapy====
-*[[Mitoxantrone (Novantrone)]] 10 mg/m<sup>2</sup> 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/m<sup>2</sup> IV once per day on days 3, 10, 17, 24
-*[[Dexamethasone (Decadron)]] 20 mg/m<sup>2</sup> PO once per day on days 1 to 5, 15 to 19
-====CNS prophylaxis====
-*[[Methotrexate (MTX)]] as follows:
-**Age less than 2: 8 mg IT once per day on days 1 & 8
-**Age 2: 10 mg IT once per day on days 1 & 8
-**Age older than 2: 12 mg IT once per day on days 1 & 8
-'''4-week course'''
-====Subsequent treatment====
-*See paper for details of treatment beyond induction
-===References===
-#'''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. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)62002-8/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3010035/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21131038 PubMed] ISRCTN45724312
-==Mitoxantrone, Pegaspargase, Vincristine, Dexamethasone {{#subobject:910a79|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:e3cbe4|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)62002-8/fulltext Parker et al. 2010 (CCLG ALL R3)]
-|2003-2007
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|Idarubicin, Pegaspargase, Vincristine, Dexamethasone
-| style="background-color:#1a9850" |Superior OS
-|-
-|}
-''Note: per the protocol, this regimen is intended only for patients 18 and younger.''
-====Chemotherapy====
-*[[Mitoxantrone (Novantrone)]] 10 mg/m<sup>2</sup> IV once per day on days 1 & 8
-*[[Pegaspargase (Oncaspar)]] 1000 units/m<sup>2</sup> IM once per day on days 3 & 18
-*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once per day on days 3, 10, 17, 24
-*[[Dexamethasone (Decadron)]] 20 mg/m<sup>2</sup> PO once per day on days 1 to 5, 15 to 19
-====CNS prophylaxis====
-*[[Methotrexate (MTX)]] as follows:
-**Age less than 2: 8 mg IT once per day on days 1 & 8
-**Age 2: 10 mg IT once per day on days 1 & 8
-**Age older than 2: 12 mg IT once per day on days 1 & 8
-'''4-week course'''
-====Subsequent treatment====
-*See paper for details of treatment beyond induction
-===References===
-#'''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. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)62002-8/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3010035/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21131038 PubMed] ISRCTN45724312
-==Tisagenlecleucel monotherapy {{#subobject:d68f14|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:60fc19|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |Years of enrollment
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4058440/ Grupp et al. 2013 (Pedi CART19)]
-|2011-NR
-| style="background-color:#ffffbe" |Pilot
-|
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4267531/ Maude et al. 2014 (UPCC04409)]
-|2012-2014
-| style="background-color:#91cf61" |Phase I/IIa
-|
-|-
-|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc5996391/ Maude et al. 2018 (ELIANA)]
-|2015-2017
-| style="background-color:#91cf61" |Phase II (RT)
-|ORR: 81%
-|-
-|}
-''Note: dosing instructions are based on ELIANA.''
-====Preceding treatment====
-*Lymphodepleting therapy with [[Autologous_HSCT#FC|FC]] or [[Autologous_HSCT#CYVE|CYVE]]
-====Immunotherapy====
-*[[Tisagenlecleucel (Kymriah)]] as follows:
-**Up to 50 kg: 2 to 5 x 10<sup>6</sup> CTL019 transduced viable T-cells per kg body weight IV once on day 0
-**Greater than 50 kg: 1.0 to 2.5 x 10<sup>8</sup> 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. [https://www.nejm.org/doi/10.1056/NEJMoa1215134 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4058440/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23527958 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. [https://www.nejm.org/doi/10.1056/NEJMoa1407222 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4267531/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25317870 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. [https://www.nejm.org/doi/full/10.1056/NEJMoa1709866 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1709866/suppl_file/nejmoa1709866_protocol.pdf link to supplementary protocol] '''contains verified protocol in supplement''' [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc5996391/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29385370 PubMed] NCT02435849
-=Consolidation after salvage therapy=
-==Blinatumomab monotherapy {{#subobject:e7bh86|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen variant #1, 1 cycle {{#subobject:2db26g|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1001/jama.2021.0987 Locatelli et al. 2021 (Amgen 20120215)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7926290/ Brown et al. 2021 (COG AALL1331)]
-|2015-2019
+|2014-2019
-| style="background-color:#1a9851" |Phase III (E-switch-ooc)
+| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
+|Standard salvage consolidation chemotherapy
+| style="background-color:#d9ef8b" |Might have superior DFS (primary endpoint)<br>DFS24: 54.4% vs 39%<br>(HR 0.70, 95% CI 0.47-1.03)
+|-
+|[https://doi.org/10.1200/jco.22.02200 Hogan et al. 2023 (COG AALL1331 LR relapse)]
+|2014-01 to 2019-09
+| style="background-color:#1a9851" |Phase 3 (E-switch-ooc)
 |Standard salvage consolidation chemotherapy
-| style="background-color:#1a9850" |Superior EFS
+| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 |-
 |}
+''Note: pediatric dosing information is not available in the body of the manuscript.''
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*[[#Mitoxantrone.2C_Pegaspargase.2C_Vincristine.2C_Dexamethasone|UKALLR3]] salvage re-induction
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Immunotherapy====
-*[[Blinatumomab (Blincyto)]] 15 mcg/m<sup>2</sup>/day IV continuous infusion over 28 days, started on day 1 (total dose: 420 mcg/m<sup>2</sup>)
-'''42-day course'''
-====Subsequent treatment====
-*Allogeneic hematopoietic stem cell transplant
-===Regimen variant #2, 2 cycles {{#subobject:2db2g7|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://doi.org/10.1001/jama.2021.0669 Brown et al. 2021 (COG AALL1331)]
-|2014-2019
-| style="background-color:#1a9851" |Phase III (E-switch-ooc)
-|Standard salvage consolidation chemotherapy
-| style="background-color:#d9ef8b" |Might have superior DFS
-|-
-|}
-''Note: insufficient dosing information was present in the abstract.''
-====Immunotherapy====
 *[[Blinatumomab (Blincyto)]]
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
 ====Subsequent treatment====
+*[[Regimen_classes#Allogeneic_HSCT|Allogeneic hematopoietic stem cell transplant]] consolidation
-*Allogeneic hematopoietic stem cell transplant
+</div></div>
 ===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. [https://doi.org/10.1001/jama.2021.0669 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7926290/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33651090/ PubMed] [https://clinicaltrials.gov/study/NCT02101853 NCT02101853]
-#'''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. [https://doi.org/10.1001/jama.2021.0669 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33651090/ 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. [https://doi.org/10.1001/jama.2021.0987 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7926287/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33651091/ PubMed] [https://clinicaltrials.gov/study/NCT02393859 NCT02393859]
-#'''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. [https://doi.org/10.1001/jama.2021.0987 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/33651091/ 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. [https://doi.org/10.1200/jco.22.02200 link to original article] [https://pubmed.ncbi.nlm.nih.gov/37257143/ PubMed] [https://clinicaltrials.gov/study/NCT02101853 NCT02101853]
 ==Cyclophosphamide & TBI, then allo HSCT {{#subobject:a9e6e8|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
 Cy/TBI: '''<u>Cy</u>'''clophosphamide & '''<u>T</u>'''otal '''<u>B</u>'''ody '''<u>I</u>'''rradiation
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen {{#subobject:1ba28d|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJM198110083051502 Johnson et al. 1981]
+|[https://doi.org/10.1056/NEJM198110083051502 Johnson et al. 1981]
 |1976-1980
 | style="background-color:#91cf61" |Non-randomized
@@ Line 3,286: / Line 2,543: @@
 | style="background-color:#d3d3d3" |
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJM198708203170801 Kersey et al. 1987]
+|[https://doi.org/10.1056/NEJM198708203170801 Kersey et al. 1987]
 |1982-1985
 | style="background-color:#1a9851" |Quasi-randomized
@@ Line 3,294: / Line 2,551: @@
 |}
 {{#lst:Allogeneic HSCT|6ca28d}}
-====Immunotherapy====
+</div></div>
-*[[Allogeneic stem cells]]
-'''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. [https://doi.org/10.1056/NEJM198110083051502 link to original article] [https://pubmed.ncbi.nlm.nih.gov/7024804/ PubMed]
-#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. [https://www.nejm.org/doi/full/10.1056/NEJM198110083051502 link to original article] [https://pubmed.ncbi.nlm.nih.gov/7024804 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. [https://doi.org/10.1056/NEJM198708203170801 link to original article] [https://pubmed.ncbi.nlm.nih.gov/3302708/ 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. [https://www.nejm.org/doi/full/10.1056/NEJM198708203170801 link to original article] [https://pubmed.ncbi.nlm.nih.gov/3302708 PubMed]
-=Further notes=
-''Pediatric ALL regimens tend to be very complex. [http://www.ped-onc.org/diseases/ALLtrials/ALLtrials.html This list on ped-onc.org] appears to be fairly comprehensive and includes regimen details for some of the common regimens e.g. COG-AALL0232.'' For now we will try to include a list of references here and potentially build these regimens here, over time.
 [[Category:B-cell acute lymphoblastic leukemia regimens]]
 [[Category:Disease-specific pages]]
 [[Category:Acute lymphoblastic leukemias]]
 [[Category:Pediatric hematologic neoplasms]]

Difference between revisions of "B-cell acute lymphoblastic leukemia, pediatric"

Latest revision as of 18:31, 26 June 2024

Guidelines

NCCN

Upfront therapy

COG AALL0932 protocol for standard-risk

Induction, Pegaspargase, Vincristine, Dexamethasone

Chemotherapy

Glucocorticoid therapy

CNS therapy, prophylaxis

Supportive therapy, DS Arm

Subsequent treatment

Consolidation, Mercaptopurine & Vincristine

Preceding treatment

Chemotherapy

CNS therapy, prophylaxis

Supportive therapy, DS Arm

Subsequent treatment

Interim Maintenance, I (Methotrexate & Vincristine)

Preceding treatment

Chemotherapy

CNS therapy, prophylaxis

Supportive therapy, DS Arm

Delayed Intensification

Preceding treatment

Chemotherapy

Glucocorticoid therapy

CNS therapy, prophylaxis

Supportive therapy, DS Arm

Subsequent treatment

Interim Maintenance, II (Methotrexate & Vincristine)

Preceding treatment

Chemotherapy

CNS therapy, prophylaxis

Supportive therapy, DS Arm

Subsequent treatment

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

Preceding treatment

Chemotherapy

Glucocorticoid therapy

CNS therapy, prophylaxis

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

Preceding treatment

Chemotherapy

Glucocorticoid therapy

CNS therapy, prophylaxis

Maintenance, Arm DS (Vincristine/Dexamethasone)

Preceding treatment

Chemotherapy

Glucocorticoid therapy

CNS therapy, prophylaxis

Consolidation, Arm LR-M

Chemotherapy

Glucocorticoid therapy

Supportive therapy

CNS therapy, prophylaxis

Maintenance, Arm LR-M

Chemotherapy

Glucocorticoid therapy

CNS therapy, prophylaxis

Maintenance, Arm LLy (Vincristine/Dexamethasone)

Preceding treatment

Chemotherapy

Glucocorticoid therapy

CNS therapy, prophylaxis

References

COG AALL1131 protocol

Induction, Daunorubicin, Pegaspargase, Vincristine, Dexamethasone

Chemotherapy

Glucocorticoid therapy

CNS therapy, prophylaxis

Subsequent treatment

References

COG AALL1131 protocol for HR B-ALL

Consolidation, Cyclophosphamide, Cytarabine, Mercaptopurine, Pegaspargase, Vincristine

Chemotherapy

CNS therapy, prophylaxis

Interim Maintenance, with HD MTX

Chemotherapy

Supportive therapy