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Haematologica. 2019 May;104(5):986-992. doi: 10.3324/haematol.2018.204545. Epub 2018 Dec 13.

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.

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Department of Pediatrics, Children's Hospital of Wisconsin, Milwaukee, WI
U.S. Army Medical Research and Materiel Command, Fort Detrick, MD.
Department of Biostatistics, Colleges of Medicine and Public Health & Health Professions, University of Florida, Gainesville, FL.
Department of Pediatrics, Center for Cancer and Blood Disorders, Children's Hospital Colorado and The University of Colorado School of Medicine, Aurora, CO.
Department of Pediatrics, Maine Children's Cancer Program, Scarborough, ME.
Department of Pediatrics, Baylor College of Medicine, Houston, TX.
ImmunoGen, Inc, Waltham, MA.
Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD.
Department of Laboratory Medicine, University of Washington, Seattle, WA.
Department of Pathology, The Ohio State University School of Medicine, Columbus, OH.
Department of Genetics, University of Alabama at Birmingham, AL.
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX.
Department of Pediatrics, Perlmutter Cancer Center, New York University Langone Health, New York, NY.
Department of Pediatrics, Benioff Children's Hospital and the Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, CA.
Department of Pediatrics, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.


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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