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Pharmacogenetic Risk Factors for Osteonecrosis of the Hip Among Children With Leukemia

From the Department of Pharmaceutical Sciences, Hematology-Oncology, Radiological Sciences, St Jude Children's Research Hospital; University of Tennessee, Colleges of Medicine and Pharmacy, Memphis, TN; Department of Human Genetics, University of Chicago, Chicago, IL; Department of Biostatistics, M.D. Anderson Cancer Center, Houston, TX.

Address reprint requests to Mary V. Relling, PharmD, Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, 332 N Lauderdale, Memphis, TN 38105-2794; e-mail: mary.relling{at}stjude.org

PURPOSE: One of the adverse effects of therapy for acute lymphoblastic leukemia (ALL) is osteonecrosis of the hip. Putative risk factors for osteonecrosis have included being female, white race, and older age. Our goal was to define possible genetic risk factors for osteonecrosis among children treated for newly diagnosed ALL.

METHODS: Using a candidate gene approach, we determined the genotypes for 16 common polymorphisms in genes likely to affect the pharmacokinetics or pharmacodynamics of antileukemic medications in 64 children with ALL. Therapy included glucocorticoids and antifolates. Magnetic resonance imaging of both hips was used to diagnose osteonecrosis, and was performed at similar times from the start of ALL therapy (P = .61) in the 25 patients with and the 39 patients without osteonecrosis (median, 447 days and 443 days, respectively).

RESULTS: In addition to age older than 10 years (odds ratio [OR], 24.2; P = .0001) and white race (OR, 11.1; P = .037), host factors for osteonecrosis included the vitamin D receptor FokI start site CC genotype (OR, 4.5; P = .045), and the thymidylate synthase low activity 2/2 enhancer repeat genotype (OR, 7.4; P = .049).

CONCLUSION: Because folate-related and vitamin D–receptor genetic variants have been associated with bone and vasculature morbidity, these pharmacogenetic associations likely reflect the interaction of antileukemic medications with germline sensitivity to drug actions, and might identify ALL patients at highest risk to develop osteonecrosis.

Supported by NCI CA51001, CA78224, CA21765, and the NIH/NIGMS Pharmacogenetics Research Network and Database (GM61393, GM61374 http://pharmgkb.org/</index.html) from the National Institutes of Health; by a Center of Excellence grant from the State of Tennessee; by an F.M. Kirby Clinical Research Professorship from the American Cancer Society; and by American Lebanese Syrian Associated Charities (ALSAC).

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

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