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Homocysteine, Pharmacogenetics, and Neurotoxicity in Children With Leukemia

Shinji Kishi, James Griener, Cheng Cheng, Soma Das, Edwin H. Cook, Deqing Pei, Melissa Hudson, Jeffrey Rubnitz, John T. Sandlund, Ching-Hon Pui, Mary V. Relling

From the Department of Pharmaceutical Sciences, Biostatistics, Hematology-Oncology, St. Jude Children’s Research Hospital, and University of Tennessee, Memphis, TN; Texas Tech School of Pharmacy, Amarillo, TX; and Department of Human Genetics, University of Chicago, Chicago, IL.

Address reprint requests to Mary V. Relling, PharmD, Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, 332 North Lauderdale, Memphis, TN 38105; email: mary.relling{at}stjude.org.

Purpose: Despite its clinical success, methotrexate (MTX) therapy is associated with toxicities such as seizures, the pathogenesis of which remains unclear. It has been suggested that hyperhomocysteinemia is caused by MTX and is responsible for its neurotoxic effects. The purposes of this study were to explore whether hyperhomocysteinemia was related to MTX administration and toxicity and whether homocysteine or MTX toxicity differed by methylenetetrahydrofolate reductase (MTHFR) or reduced folate carrier (RFC) genetic polymorphisms.

Patients and Methods: We studied 53 children with newly diagnosed acute lymphoblastic leukemia who were consecutively treated on a single clinical protocol that included two courses of high-dose MTX (high-dose methotrexate [HDMTX]; 2.5 or 5.0 g/m² per day) as consolidation therapy.

Results: The study participants’ median plasma homocysteine concentrations at 23 and 44 hours after HDMTX (9.00 µmol/L and 10.12 µmol/L, respectively) were greater than the concentrations immediately before HDMTX (5.77 µmol/L, P < .0001 for both comparisons). Seven days after HDMTX treatment, their plasma concentration returned to baseline. Nine patients experienced seizures, and five patients experienced thrombosis during the first 15 months of therapy, with a tendency for there to be higher plasma homocysteine in patients with seizures across all time points (P = .063) but not in patients with thrombosis (P = .59). We observed no significant differences in plasma or cerebrospinal fluid homocysteine levels or in toxicity based on the MTHFR 677C/T or RFC 80G/A genotypes.

Conclusion: We conclude that homocysteine was transiently elevated after HDMTX and may be related to seizure risk in children with leukemia.

Supported by grant nos. CA 51001, CA 78224, and CA21765 from the National Cancer Institute and the National Institutes of Health/National Institute of General Medical Sciences Pharmacogenetics Research Network and Database grant nos. U01GM61393 and U01GM61374 from the National Institutes of Health, Bethesda, MD; by a Center of Excellence grant from the State of Tennessee; and by American Lebanese Syrian Associated Charities. C-H.P. is an American Cancer Society F.M. Kirby Clinical Research Professor.

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