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

Michael J. Burke, Wanda L. Salzer, Meenakshi Devidas, Yunfeng Dai, Lia Gore, Joanne M. Hilden, Eric Larsen, Karen R. Rabin, Patrick A. Zweidler-McKay, Michael J. Borowitz, Brent Wood, Nyla A. Heerema, Andrew J. Carroll, Naomi J Winick, William L. Carroll, Elizabeth A. Raetz, Mignon L. Loh, Stephen P. Hunger

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

With modern chemotherapy, approximately 90% of patients with pediatric acute lymphoblastic leukemia are now cured. However, subsets of patients can be identified who remain at very high risk of relapse with expected 4-year disease-free survival rates <80%; such patients are appropriate candidates for intensive therapeutic strategies designed to improve survival. The AALL1131 trial was designed to determine, in a randomized fashion, whether substitution with cyclophosphamide/etoposide (experimental arm 1) would improve the 4-year disease-free survival of children, adolescents, and young adults with very high-risk B-cell acute lymphoblastic leukemia compared to a modified Berlin-Frankfurt-Münster regimen (control arm). Patients 1-30 years of age with newly diagnosed very high-risk B-cell acute lymphoblastic leukemia were randomized after induction in a 1:2 fashion to the control arm or experimental arm 1 in which they were given cyclophosphamide (440 mg/m2 days 1-5)/etoposide (100 mg/m2 days 1-5) during part 2 of consolidation and delayed intensification. Prospective interim monitoring rules for efficacy and futility were included where futility would be determined for a one-sided P-value ≥0.7664. The study was stopped for futility as the interim monitoring boundary was crossed [hazard ratio 0.606 (95% confidence interval: 0.297 - 1.237)] and the very high-risk arm of AALL1131 was closed in February 2017. Using data current as of December 31, 2017, 4-year disease-free survival rates were 85.5±6.8% (control arm) versus 72.3±6.3% (experimental arm 1) (P-value = 0.76). There were no significant differences in grade 3/4 adverse events between the two arms. Substitution of this therapy for very high-risk B-cell acute lymphoblastic leukemia patients on the Children's Oncology Group AALL1131 trial (NCT02883049) randomized to cyclophosphamide/etoposide during part 2 of consolidation and delayed intensification did not improve disease-free survival.

Original languageEnglish (US)
Pages (from-to)986-992
Number of pages7
JournalHaematologica
Volume104
Issue number5
DOIs
StatePublished - May 1 2019

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6-Mercaptopurine
Cytarabine
Etoposide
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Cyclophosphamide
Medical Futility
B-Lymphocytes
Disease-Free Survival
Pediatrics
Survival Rate
Berlin
Young Adult
Confidence Intervals
Recurrence
Drug Therapy
Survival
Therapeutics

ASJC Scopus subject areas

  • Hematology

Cite this

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. / Burke, Michael J.; Salzer, Wanda L.; Devidas, Meenakshi; Dai, Yunfeng; Gore, Lia; Hilden, Joanne M.; Larsen, Eric; Rabin, Karen R.; Zweidler-McKay, Patrick A.; Borowitz, Michael J.; Wood, Brent; Heerema, Nyla A.; Carroll, Andrew J.; Winick, Naomi J; Carroll, William L.; Raetz, Elizabeth A.; Loh, Mignon L.; Hunger, Stephen P.

In: Haematologica, Vol. 104, No. 5, 01.05.2019, p. 986-992.

Research output: Contribution to journalArticle

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, NJ, Carroll, WL, Raetz, EA, Loh, ML & Hunger, SP 2019, '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, vol. 104, no. 5, pp. 986-992. https://doi.org/10.3324/haematol.2018.204545
Burke, Michael J. ; Salzer, Wanda L. ; Devidas, Meenakshi ; Dai, Yunfeng ; Gore, Lia ; Hilden, Joanne M. ; Larsen, Eric ; Rabin, Karen R. ; Zweidler-McKay, Patrick A. ; Borowitz, Michael J. ; Wood, Brent ; Heerema, Nyla A. ; Carroll, Andrew J. ; Winick, Naomi J ; Carroll, William L. ; Raetz, Elizabeth A. ; Loh, Mignon L. ; Hunger, Stephen P. / 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. In: Haematologica. 2019 ; Vol. 104, No. 5. pp. 986-992.
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AU - Burke, Michael J.

AU - Salzer, Wanda L.

AU - Devidas, Meenakshi

AU - Dai, Yunfeng

AU - Gore, Lia

AU - Hilden, Joanne M.

AU - Larsen, Eric

AU - Rabin, Karen R.

AU - Zweidler-McKay, Patrick A.

AU - Borowitz, Michael J.

AU - Wood, Brent

AU - Heerema, Nyla A.

AU - Carroll, Andrew J.

AU - Winick, Naomi J

AU - Carroll, William L.

AU - Raetz, Elizabeth A.

AU - Loh, Mignon L.

AU - Hunger, Stephen P.

PY - 2019/5/1

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N2 - With modern chemotherapy, approximately 90% of patients with pediatric acute lymphoblastic leukemia are now cured. However, subsets of patients can be identified who remain at very high risk of relapse with expected 4-year disease-free survival rates <80%; such patients are appropriate candidates for intensive therapeutic strategies designed to improve survival. The AALL1131 trial was designed to determine, in a randomized fashion, whether substitution with cyclophosphamide/etoposide (experimental arm 1) would improve the 4-year disease-free survival of children, adolescents, and young adults with very high-risk B-cell acute lymphoblastic leukemia compared to a modified Berlin-Frankfurt-Münster regimen (control arm). Patients 1-30 years of age with newly diagnosed very high-risk B-cell acute lymphoblastic leukemia were randomized after induction in a 1:2 fashion to the control arm or experimental arm 1 in which they were given cyclophosphamide (440 mg/m2 days 1-5)/etoposide (100 mg/m2 days 1-5) during part 2 of consolidation and delayed intensification. Prospective interim monitoring rules for efficacy and futility were included where futility would be determined for a one-sided P-value ≥0.7664. The study was stopped for futility as the interim monitoring boundary was crossed [hazard ratio 0.606 (95% confidence interval: 0.297 - 1.237)] and the very high-risk arm of AALL1131 was closed in February 2017. Using data current as of December 31, 2017, 4-year disease-free survival rates were 85.5±6.8% (control arm) versus 72.3±6.3% (experimental arm 1) (P-value = 0.76). There were no significant differences in grade 3/4 adverse events between the two arms. Substitution of this therapy for very high-risk B-cell acute lymphoblastic leukemia patients on the Children's Oncology Group AALL1131 trial (NCT02883049) randomized to cyclophosphamide/etoposide during part 2 of consolidation and delayed intensification did not improve disease-free survival.

AB - With modern chemotherapy, approximately 90% of patients with pediatric acute lymphoblastic leukemia are now cured. However, subsets of patients can be identified who remain at very high risk of relapse with expected 4-year disease-free survival rates <80%; such patients are appropriate candidates for intensive therapeutic strategies designed to improve survival. The AALL1131 trial was designed to determine, in a randomized fashion, whether substitution with cyclophosphamide/etoposide (experimental arm 1) would improve the 4-year disease-free survival of children, adolescents, and young adults with very high-risk B-cell acute lymphoblastic leukemia compared to a modified Berlin-Frankfurt-Münster regimen (control arm). Patients 1-30 years of age with newly diagnosed very high-risk B-cell acute lymphoblastic leukemia were randomized after induction in a 1:2 fashion to the control arm or experimental arm 1 in which they were given cyclophosphamide (440 mg/m2 days 1-5)/etoposide (100 mg/m2 days 1-5) during part 2 of consolidation and delayed intensification. Prospective interim monitoring rules for efficacy and futility were included where futility would be determined for a one-sided P-value ≥0.7664. The study was stopped for futility as the interim monitoring boundary was crossed [hazard ratio 0.606 (95% confidence interval: 0.297 - 1.237)] and the very high-risk arm of AALL1131 was closed in February 2017. Using data current as of December 31, 2017, 4-year disease-free survival rates were 85.5±6.8% (control arm) versus 72.3±6.3% (experimental arm 1) (P-value = 0.76). There were no significant differences in grade 3/4 adverse events between the two arms. Substitution of this therapy for very high-risk B-cell acute lymphoblastic leukemia patients on the Children's Oncology Group AALL1131 trial (NCT02883049) randomized to cyclophosphamide/etoposide during part 2 of consolidation and delayed intensification did not improve disease-free survival.

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