Originally published as JCO Early Release 10.1200/JCO.2008.21.2514 on October 5 2009

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Improved Early Event-Free Survival With Imatinib in Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia: A Children's Oncology Group Study

From the Children's Oncology Group; Department of Pediatrics, Division of Hematology, Oncology, and Blood and Marrow Transplant, British Columbia's Children's Hospital, University of British Columbia, Vancouver, BC; Cook Children's Medical Center, Hematology and Oncology, Fort Worth; Pediatric Hematology and Oncology, University of Texas Southwestern Medical Center, Dallas, TX; Phyllis and David Komansky Center for Children's Health, Weill Cornell Medical Center, New York; Department of Pediatrics, New York University Medical Center, New York, NY; Department of Pediatrics and University of Florida Shands Cancer Center, University of Florida College of Medicine; Children's Oncology Group Statistics and Data Center, and the Department of Epidemiology and Health Policy Research, University of Florida, Gainesville, FL; Department of Preventive Medicine, University of Southern California; Hematology and Oncology Children's Hospital Los Angeles, Los Angeles; Children's Oncology Group Coordinating Center, Arcadia, CA; Pediatric Hematology and Oncology, The Children's Hospital and University of Colorado Cancer Center, Aurora, CO; Stem Cell Transplantation, Children's Hospital Medical Center Cincinnati, Cincinnati; Department of Pathology, The Ohio State University, Columbus, OH; Thomas Jefferson University, Philadelphia, PA; Department of Radiation Oncology, Nova Scotia Cancer Centre and Dalhousie University, Halifax, NS; Midwest Children's Cancer Center, Department of Pediatrics, Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, WI; University of Alabama at Birmingham, Birmingham AL; and Department of Pathology, Johns Hopkins Hospital, Baltimore, MD.

Corresponding author: Kirk R. Schultz, MD, Department of Pediatrics, Division of Hematology/Oncology/Bone Marrow Transplantation, University of British Columbia, B.C.'s Children's Hospital, 4480 Oak St, Vancouver, BC, V6H 3V4, Canada; e-mail: kschultz{at}interchange.ubc.ca.

Purpose Imatinib mesylate is a targeted agent that may be used against Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL), one of the highest risk pediatric ALL groups.

Patients and Methods We evaluated whether imatinib (340 mg/m²/d) with an intensive chemotherapy regimen improved outcome in children ages 1 to 21 years with Ph+ ALL (N = 92) and compared toxicities to Ph– ALL patients (N = 65) given the same chemotherapy without imatinib. Exposure to imatinib was increased progressively in five patient cohorts that received imatinib from 42 (cohort 1; n = 7) to 280 continuous days (cohort 5; n = 50) before maintenance therapy. Patients with human leukocyte antigen (HLA) –identical sibling donors underwent blood and marrow transplantation (BMT) with imatinib given for 6 months following BMT.

Results Continuous imatinib exposure improved outcome in cohort 5 patients with a 3-year event-free survival (EFS) of 80% ± 11% (95% CI, 64% to 90%), more than twice historical controls (35% ± 4%; P < .0001). Three-year EFS was similar for patients in cohort 5 treated with chemotherapy plus imatinib (88% ± 11%; 95% CI, 66% to 96%) or sibling donor BMT (57% ± 22%; 95% CI, 30.4% to 76.1%). There were no significant toxicities associated with adding imatinib to intensive chemotherapy. The higher imatinib dosing in cohort 5 appears to improve survival by having an impact on the outcome of children with a higher burden of minimal residual disease after induction.

Conclusion Imatinib plus intensive chemotherapy improved 3-year EFS in children and adolescents with Ph+ ALL, with no appreciable increase in toxicity. BMT plus imatinib offered no advantage over BMT alone. Additional follow-up is required to determine the impact of this treatment on long-term EFS and determine whether chemotherapy plus imatinib can replace BMT.

See accompanying editorial on page 5121 and articles on pages 5168 and 5189

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Clinical trial information can be found for the following: NCT00022737 [ClinicalTrials.gov] .

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