Originally published as JCO Early Release 10.1200/JCO.2007.14.0418 on June 16 2008

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Patients With Acute Myeloid Leukemia and RAS Mutations Benefit Most From Postremission High-Dose Cytarabine: A Cancer and Leukemia Group B Study

Andreas Neubauer, Kati Maharry, Krzysztof Mrózek, Christian Thiede, Guido Marcucci, Peter Paschka, Robert J. Mayer, Richard A. Larson, Edison T. Liu, Clara D. Bloomfield

From the Department for Hematology, Oncology and Immunology, Philipps University, Marburg; Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus der Technischen Universität, Dresden, Germany; Division of Hematology and Oncology, Department of Internal Medicine, Comprehensive Cancer Center, Ohio State University, Columbus, OH; The Cancer and Leukemia Group B Statistical Center, Durham, NC; Dana-Farber Cancer Institute, Boston, MA; University of Chicago, Chicago, IL; and Genome Institute of Singapore, Singapore

Corresponding author: Clara D. Bloomfield, MD, Division of Hematology and Oncology, Comprehensive Cancer Center, Ohio State University, 519 James Cancer Hospital, 300 West Tenth Avenue, Columbus, OH 43210; e-mail: Clara.Bloomfield{at}osumc.edu

Purpose RAS mutations occur in 12% to 27% of patients with acute myeloid leukemia (AML) and enhance sensitivity to cytarabine in vitro. We examined whether RAS mutations impact response to cytarabine in vivo.

Patients and Methods One hundred eighty-five patients with AML achieving complete remission on Cancer and Leukemia Group B study 8525 and randomly assigned to one of three doses of cytarabine postremission were screened for RAS mutations. We assessed the impact of cytarabine dose on cumulative incidence of relapse (CIR) of patients with (mutRAS) and without (wild-type; wtRAS) RAS mutations.

Results Thirty-four patients (18%) had RAS mutations. With 12.9 years median follow-up, the 10-year CIR was similar for mutRAS and wtRAS patients (65% v 73%; P = .31). However, mutRAS patients receiving high-dose cytarabine consolidation (HDAC; 3 g/m² every 12 hours on days 1, 3, and 5 or 400 mg/m²/d x 5 days) had the lowest 10-year CIR, 45%, compared with 68% for wtRAS patients receiving HDAC and 80% and 100%, respectively, for wtRAS and mutRAS patients receiving low-dose cytarabine (LDAC; 100 mg/m²/d x 5 days; overall comparison, P < .001). Multivariable analysis revealed an interaction of cytarabine dose and RAS status (P = .06). After adjusting for this interaction and cytogenetics (core binding factor [CBF] AML v non-CBF AML), wtRAS patients receiving HDAC had lower relapse risk than wtRAS patients receiving LDAC (hazard ratio [HR] = 0.67; P = .04); however, mutRAS patients receiving HDAC had greater reduction in relapse risk (HR = 0.28; P = .002) compared with mutRAS patients treated with LDAC.

Conclusion AML patients carrying mutRAS benefit from higher cytarabine doses more than wtRAS patients. This seems to be the first example of an activating oncogene mutation favorably modifying response to higher drug doses in AML.

published online ahead of print at www.jco.org on June 16, 2008.

Supported in part by a Grant Transregio 17 (to A.N.) from the Deutsche Forschungsgemeinschaft; Grants No. CA77658, CA101140, CA114725, CA31946, and CA16058 from the National Cancer Institute, Bethesda, MD; and The Coleman Leukemia Research Foundation.

Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL (abstr 6514).

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

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