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Adverse Prognostic Significance of KIT Mutations in Adult Acute Myeloid Leukemia With inv(16) and t(8;21): A Cancer and Leukemia Group B Study

Peter Paschka, Guido Marcucci, Amy S. Ruppert, Krzysztof Mrózek, Hankui Chen, Rick A. Kittles, Tamara Vukosavljevic, Danilo Perrotti, James W. Vardiman, Andrew J. Carroll, Jonathan E. Kolitz, Richard A. Larson, Clara D. Bloomfield

From the Division of Hematology and Oncology, Department of Internal Medicine, and Division of Human Cancer Genetics, Department of Microbiology, Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH; The CALGB Statistical Center, Duke University Medical Center, Durham, NC; Department of Pathology, Department of Medicine and Cancer Research Center, University of Chicago, Chicago, IL; Department of Genetics, University of Alabama at Birmingham, Birmingham, AL; and the Department of Medicine, North Shore University Hospital, Manhasset, NY

Address reprint requests to Guido Marcucci, MD, The Ohio State University, The Comprehensive Cancer Center, A433B Starling-Loving-Hall, 320 W 10th Ave, Columbus, OH 43210; e-mail: guido.marcucci{at}osumc.edu

PURPOSE: To analyze the prognostic impact of mutated KIT (mutKIT) in core-binding factor acute myeloid leukemia (AML) with inv(16)(p13q22) and t(8;21)(q22;q22).

PATIENTS AND METHODS: Sixty-one adults with inv(16) and 49 adults with t(8;21), assigned to postremission therapy with repetitive cycles of higher dose cytarabine were analyzed for mutKIT in exon 17 (mutKIT17) and 8 (mutKIT8) by denaturing high-performance liquid chromatography and direct sequencing at diagnosis. The median follow-up was 5.3 years.

RESULTS: Among patients with inv(16), 29.5% had mutKIT (16% with mutKIT17 and 13% with sole mutKIT8). Among patients with t(8;21), 22% had mutKIT (18% with mutKIT17 and 4% with sole mutKIT8). Complete remission rates of patients with mutKIT and wild-type KIT (wtKIT) were similar in both cytogenetic groups. In inv(16), the cumulative incidence of relapse (CIR) was higher for patients with mutKIT (P = .05; 5-year CIR, 56% v 29%) and those with mutKIT17 (P = .002; 5-year CIR, 80% v 29%) compared with wtKIT patients. Once data were adjusted for sex, mutKIT predicted worse overall survival (OS). In t(8;21), mutKIT predicted higher CIR (P = .017; 5-year CIR, 70% v 36%), but did not influence OS.

CONCLUSION: We report for the first time that mutKIT, and particularly mutKIT17, confer higher relapse risk, and both mutKIT17 and mutKIT8 appear to adversely affect OS in AML with inv(16). We also confirm the adverse impact of mutKIT on relapse risk in t(8;21) AML. We suggest that patients with core-binding factor AML should be screened for mutKIT at diagnosis for both prognostic and therapeutic purposes, given that activated KIT potentially can be targeted with novel tyrosine kinase inhibitors.

Supported in part by National Cancer Institute (Bethesda, MD) Grants No. CA77658, CA101140, CA31946, CA16058, CA102031, CA41287, CA095512, and K08-CA90469, and The Coleman Leukemia Research Foundation.

Presented at the Plenary Session of the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, June 2-6, 2006.

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

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