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J Clin Oncol. 2018 Aug 1;36(22):2306-2314. doi: 10.1200/JCO.2017.76.7228. Epub 2018 May 29.

Dasatinib Plus Intensive Chemotherapy in Children, Adolescents, and Young Adults With Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Results of Children's Oncology Group Trial AALL0622.

Author information

1
William B. Slayton, John A. Kairalla, Meenakshi Devidas, Xinlei Mi, and Sherri L. Mizrahy, University of Florida, Gainesville, FL; Kirk R. Schultz, BC Children's Research Institute, University of British Columbia, Vancouver, British Columbia, Canada; Michael A. Pulsipher, Children's Hospital of Los Angeles, Los Angeles; Lance Sieger, University of California Los Angles-Harbor, Torrance; Mignon L. Loh, University of California San Francisco, San Francisco, CA; Bill H. Chang, Oregon Health and Science University, Portland, OR; Charles Mullighan, Ilaria Iacobucci, and Thomas Merchant, St Jude's Research Hospital, Memphis, TN; Lewis B. Silverman, Dana-Farber Cancer Institute, Boston, MA; Michael J. Borowitz, Johns Hopkins University, Baltimore, MD; Andrew J. Carroll, University of Alabama at Birmingham, Birmingham, AL; Nyla A. Heerema, Ohio State University; Julie M. Gastier-Foster, Nationwide Children's Hospital, Columbus, OH; Brent L. Wood, University of Washington Seattle, Seattle, WA; Valerie I. Brown, Penn State Health Children's Hospital, Hershey; Stephen P. Hunger, Children's Hospital of Philadelphia, Philadelphia, PA; Marilyn J. Siegel, Washington University School of Medicine, St Louis, MO; Elizabeth A. Raetz, University of Utah, Salt Lake City, UT; Naomi J. Winick, University of Texas Southwestern Medical Center, Dallas, TX; and William L. Carroll, New York University Langone Health Center, New York, NY.

Abstract

Purpose Addition of imatinib to intensive chemotherapy improved survival for children and young adults with Philadelphia chromosome-positive acute lymphoblastic leukemia. Compared with imatinib, dasatinib has increased potency, CNS penetration, and activity against imatinib-resistant clones. Patients and Methods Children's Oncology Group (COG) trial AALL0622 (Bristol Myers Squibb trial CA180-204) tested safety and feasibility of adding dasatinib to intensive chemotherapy starting at induction day 15 in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia age 1 to 30 years. Allogeneic hematopoietic stem-cell transplantation (HSCT) was recommended for patients at high risk based on slow response and for those with a matched family donor regardless of response after at least 11 weeks of therapy. Patients at standard risk based on rapid response received chemotherapy plus dasatinib for an additional 120 weeks. Patients with overt CNS leukemia received cranial irradiation. Results Sixty eligible patients were enrolled. Five-year overall (OS) and event-free survival rates (± standard deviations [SD]) were 86% ± 5% and 60% ± 7% overall, 87% ± 5% and 61% ± 7% for standard-risk patients (n = 48; 19% underwent HSCT), and 89% ± 13% and 67% ± 19% for high-risk patients (n = 9; 89% underwent HSCT), respectively. Five-year cumulative incidence (± SD) of CNS relapse was 15% ± 6%. Outcomes (± SDs) were similar to those in COG AALL0031, which used the same chemotherapy with continuous imatinib: 5-year OS of 81% ± 6% versus 86% ± 5% ( P = .63) and 5-year disease-free survival of 68% ± 7% versus 60% ± 7% ( P = 0.31) for AALL0031 versus AALL0622, respectively. IKZF1 deletions, present in 56% of tested patients, were associated with significantly inferior OS and event-free survival overall and in standard-risk patients. Conclusion Dasatinib was well tolerated with chemotherapy and provided outcomes similar to those with imatinib in COG AALL0031, where all patients received cranial irradiation. Our results support limiting HSCT to slow responders and suggest a potential role for transplantation in rapid responders with IKZF1 deletions.

PMID:
29812996
PMCID:
PMC6067800
[Available on 2019-08-01]
DOI:
10.1200/JCO.2017.76.7228

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