Methotrexate Toxicity in Bone Marrow Transplant Patients

John D. Potter, Ph.D.
University of Washington
P30ES07033

Background: Methotrexate is a chemotherapeutic drug used to prevent graft-versus-host disease (GVHD) in patients undergoing bone marrow transplantation. Methotrexate has its effects by blocking enzymes involved in folate production and metabolism which is necessary for nucleotide synthesis. The enzyme 5,10-methylene tetrahydrofolate reductase (MTHFR) is part of this pathway. A common polymorphism of MTHFR known as the TT genotype results in about a 70% reduction of enzyme activity and occurs in 10-12% of white and Asian populations. Heterozygotes, those carrying the CT genotype, have about a 40% reduction in activity and make up about 40% of these populations. These researchers hypothesized that methotrexate toxicity could be increased in patients with either the TT or CT genotypes.

Advance: Patients with chronic myelogenous leukemia underwent bone marrow transplants and were given methotrexate to prevent GVHD. DNA analysis was conducted on all patients to determine which genotype they carried. Patients were observed for methotrexate toxicity using standard tests including the oral mucositis index and platelet and granulocyte cell counts. Methotrexate was found to cause higher oral mucositis indices among patients with the TT and CT genotypes as compared to those with the wild-type genotype. Recovery of platelet counts was slower among those patients with variant genotypes.

Implication: As hypothesized, patients with the TT and CT genotypes experienced increased methotrexate toxicity as evidenced by higher oral mucosity indices and delayed recovery of platelet counts. The high prevalence of these genotypes and the ability to perform genotyping on prospective rapidly and inexpensively suggest that these tests should be done prior to methotrexate administration. Although drug alternatives to methotrexate for GVHD are limited, dose adjustment or new less toxic drugs may be appropriate.

Publication: Ulrich CM, Yasui Y, Storb R, Schubert MM, Wagner JL, Bigler J, Ariail KS, Keener CL, Li S, Liu H, Farin FM, Potter JD. Pharmacogenetics of methotrexate: toxicity among marrow transplantation patients varies with the methylenetetrahydrofolate reductase C677T polymorphism. Blood. 2001 Jul 1;98(1):231-4.