Wanda L Salzer1, Michael J Burke2, Meenakshi Devidas3, Si Chen3, Lia Gore4, Eric C Larsen5, Michael Borowitz6, Brent Wood7, Nyla A Heerema8, Andrew J Carroll9, Joanne M Hilden10,11, Mignon L Loh12, Elizabeth A Raetz13, Naomi J Winick14, William L Carroll15, Stephen P Hunger16. 1. US Army Medical Research and Materiel Command, Fort Detrick, Maryland. 2. Department of Pediatrics, Medical College of Wisconsin, Children's Hospital of Wisconsin, Milwaukee, Wisconsin. 3. Department of Biostatistics, Colleges of Medicine and Public Health & Health Professions, University of Florida, Gainesville, Florida. 4. Center for Cancer and Blood Disorders, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, Colorado. 5. Maine Children's Cancer Program, Scarborough, Maine. 6. Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland. 7. Department of Laboratory Medicine, University of Washington, Seattle, Washington. 8. Department of Pathology, Ohio State University School of Medicine, Columbus, Ohio. 9. Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama. 10. Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, Colorado. 11. Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado. 12. Department of Pediatrics, Benioff Children's Hospital, University of California at San Francisco, San Francisco, California. 13. Department of Pediatrics, University of Utah, Salt Lake City, Utah. 14. Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas. 15. Department of Pediatrics, Perlmutter Cancer Center, New York University Medical Center, New York, New York. 16. Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Abstract
BACKGROUND: Children, adolescents, and young adults with very high-risk (VHR) B acute lymphoblastic leukemia (B-ALL) have poor outcomes, and novel therapies are needed for this subgroup. The AALL1131 study evaluated postinduction therapy using cyclophosphamide (CPM), etoposide (ETOP), and clofarabine (CLOF) for patients with VHR B-ALL. METHODS:Patients who were 1 to 30 years old and had VHR B-ALL received modified Berlin-Frankfurt-Münster therapy after induction and were randomized to 1) CPM, cytarabine, mercaptopurine, vincristine (VCR), and pegaspargase (control arm), 2) CPM, ETOP, VCR, and pegaspargase (experimental arm 1), or 3) CPM, ETOP, CLOF (30 mg/m2 /d × 5), VCR, and pegaspargase (experimental arm 2) during the second half of consolidation and delayed intensification. RESULTS: The rates of grade 4/5 infections and grade 3/4 pancreatitis were significantly increased in experimental arm 2. The dose of CLOF was, therefore, reduced to 20 mg/m2 /d × 5, and myeloid growth factor was required after CLOF administration. Despite these changes, 4 of 39 patients (10.3%) developed grade 4 infections, with 1 of these patients developing a grade 5 acute kidney injury attributed to CLOF, whereas only 1 of 46 patients (2.2%) in experimental arm 1 developed grade 4 infections, and there were no grade 4/5 infections in the control arm (n = 20). Four patients in experimental arm 2 had prolonged cytopenias for >60 days, whereas none did in the control arm or experimental arm 1. Counts failed to recover for 2 of these patients, one having a grade 5 acute kidney injury and the other removed from protocol therapy; both events occurred 92 days after the start of consolidation part 2. CONCLUSIONS: In AALL1131, CLOF, administered with CPM and ETOP, was associated with unacceptable toxicity. Cancer 2018;124:1150-9.
RCT Entities:
BACKGROUND:Children, adolescents, and young adults with very high-risk (VHR) B acute lymphoblastic leukemia (B-ALL) have poor outcomes, and novel therapies are needed for this subgroup. The AALL1131 study evaluated postinduction therapy using cyclophosphamide (CPM), etoposide (ETOP), and clofarabine (CLOF) for patients with VHR B-ALL. METHODS:Patients who were 1 to 30 years old and had VHR B-ALL received modified Berlin-Frankfurt-Münster therapy after induction and were randomized to 1) CPM, cytarabine, mercaptopurine, vincristine (VCR), and pegaspargase (control arm), 2) CPM, ETOP, VCR, and pegaspargase (experimental arm 1), or 3) CPM, ETOP, CLOF (30 mg/m2 /d × 5), VCR, and pegaspargase (experimental arm 2) during the second half of consolidation and delayed intensification. RESULTS: The rates of grade 4/5 infections and grade 3/4 pancreatitis were significantly increased in experimental arm 2. The dose of CLOF was, therefore, reduced to 20 mg/m2 /d × 5, and myeloid growth factor was required after CLOF administration. Despite these changes, 4 of 39 patients (10.3%) developed grade 4 infections, with 1 of these patients developing a grade 5 acute kidney injury attributed to CLOF, whereas only 1 of 46 patients (2.2%) in experimental arm 1 developed grade 4 infections, and there were no grade 4/5 infections in the control arm (n = 20). Four patients in experimental arm 2 had prolonged cytopenias for >60 days, whereas none did in the control arm or experimental arm 1. Counts failed to recover for 2 of these patients, one having a grade 5 acute kidney injury and the other removed from protocol therapy; both events occurred 92 days after the start of consolidation part 2. CONCLUSIONS: In AALL1131, CLOF, administered with CPM and ETOP, was associated with unacceptable toxicity. Cancer 2018;124:1150-9.
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