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Related Collections Transplantation Brief Reports Related Letter in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 July 2001, Vol. 98, No. 1, pp. 231-234 BRIEF REPORT Pharmacogenetics of methotrexate: toxicity among marrow transplantation patients varies with the methylenetetrahydrofolate reductase C677T polymorphism Cornelia M. Ulrich, Yutaka Yasui, Rainer Storb, Mark M. Schubert, John L. Wagner, Jeannette Bigler, Kiley S. Ariail, Cassie L. Keener, Sue Li, Hao Liu, Federico M. Farin, and John D. Potter From the Public Health Sciences Division and Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, and School of Medicine, School of Dentistry, and School of Public Health, University of Washington, Seattle.     Abstract Top Abstract Introduction Study design Results and discussion References This study investigated whether a polymorphism in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene (C677T) modifies responses to methotrexate (MTX) in patients undergoing bone marrow transplantation. About 10% to 12% of the population carry the MTHFR TT genotype (enzyme activity, 30% of wild type [CC]). Patients (n = 220) with chronic myelogenous leukemia underwent marrow allografts and were given a short course of MTX. MTX toxicity measures included the oral mucositis index (OMI), speed of engraftment (platelet and granulocyte counts), and bilirubin. Patients with lower MTHFR activity (TT genotype) had 36% higher mean OMI during days 1 to 18 (+5.7, P = .046) and 20% higher OMI between days 6 and 12 (+3.8, P = .27). Platelet counts recovered more slowly among patients with the TT genotype compared to wild type (24% slower recovery to 10 000 platelets/µL, P = .23; 34% slower to 20 000/µL, P = .08). Patients with decreased MTHFR activity appear at risk of higher MTX toxicity. Because of the high prevalence of the TT genotype, these results may have implications for MTX dosage. (Blood. 2001;98:231-234) © 2001 by The American Society of Hematology.     Introduction Top Abstract Introduction Study design Results and discussion References Methotrexate (MTX) is an antifolate chemotherapeutic drug,1 and is used in patients undergoing marrow transplantation to prevent graft-versus-host disease (GVHD).2 Toxicities include mucositis and myelosuppression.1 We hypothesized that MTX sensitivity would vary with genetic variability in folate-metabolizing enzymes. Folate is essential for nucleotide synthesis. The effectiveness of MTX is largely attributable to its role as an inhibitor of dihydrofolate reductase. Its metabolites also inhibit other folate enzymes, including 5,10-methylenetetrahydrofolate reductase (MTHFR),1,3,4 which converts 5,10-methylenetetrahydrofolate to 5,10-methyltetrahydrofolate. A common MTHFR polymorphism (C677T) results in reduced activity.5 The variant TT genotype, associated with about 30% of wild-type (CC) activity, is present in about 10% to 12% of white and Asian populations. Heterozygotes (CT) (about 60% activity) constitute approximately 40% of the population. Variations are seen in risk of acute lymphocytic leukemia,6 colorectal neoplasia,7-10 neural tube defects,11,12 and possibly cardiovascular disease,13 largely in the presence of low folate levels. Because MTX induces a low folate state, we hypothesized that toxicity would be aggravated among patients with the TT and, possibly, the CT genotype.     Study design Top Abstract Introduction Study design Results and discussion References Study design and patient population We undertook a study of patients undergoing marrow transplantation at the Fred Hutchinson Cancer Research Center (FHCRC) from 1992 to 1999. The following criteria applied: (1) first chronic phase of chronic myelogenous leukemia14; (2) first transplantation; (3) conditioning regimen: either busulfan/cyclophosphamide15 or cyclophosphamide/total body irradiation, as described15,16; (4) age at transplantation, at least 18 years; and (5) available DNA. All patients received 4 doses of MTX (intravenously, day 1, at 15 mg/m,2 and days 3, 6, and 11, at 10 mg/m2) and cyclosporine (as previously described15) for prevention of GVHD.2 All patients gave informed consent. The study was approved by the FHCRC Institutional Review Board. Data collection Data were abstracted by a single abstractor (blinded to genotypes) on previous interferon treatment, smoking, MTX administration, and, if applicable, MTX serum levels and leucovorin administration. Data from the patient database included: (1) conditioning regimen; (2) donor/matching status; (3) demographics; (4) weight, height, and calculated body mass index and surface area; (5) platelet and granulocyte counts; (6) bilirubin and creatinine; and (7) survival status or day of last contact. Mucositis is a major toxicity associated with folate antagonists. The oral mucositis index (OMI) was developed17 to measure severity of oral mucosal changes; patients were examined every 2 to 3 days. Oral mucositis usually peaks between days 7 and 11 and resolves by days 18 to 21 after transplantation. We assessed mean scores on days 6 to 12 (peak period) and days 1 to 18 (overall mucositis course). MTHFR genotyping Genotyping for the MTHFR C677T polymorphism was performed,9 blinded to outcome measures; 10% blinded duplicate samples yielded 100% concordance. Genotypes were in Hardy-Weinberg equilibrium. Statistical data analysis The primary outcome was oral mucositis, as measured by the OMI (mean, days 6-12, at least 2 assessments; and days 1-18, at least 4 assessments). Secondary outcomes included granulocyte engraftment, assessed as time to the first of 3 consecutive days of counts exceeding 100/µL and 500/µL; platelet engraftment, assessed as time to the first of 7 consecutive days of counts exceeding 10 000/µL and 20 000/µL without transfusion; and bilirubin, days 1 to 18. We were limited in our ability to investigate other measures of MTX toxicity: MTX serum levels, leucovorin administration as a rescue drug, and intestinal mucositis. The original cohort consisted of 238 patients with chronic myelogenous leukemia (CML). Charts for 227 patients were abstracted. For 7 patients, we could not verify that 4 doses of MTX had been given; 136 and 124 patients, respectively, met inclusion criteria for OMI measurement during days 6-12 and 1-18. All analyses were performed to investigate differences in outcomes by MTHFR genotype: individuals with the CT and TT genotypes were each compared to those with the CC genotype. Linear regression was used for continuous variables. Adjusted OMI means were calculated for all genotypes with covariates set at mean levels. Comparisons across genotypes were made using t tests. Measures of engraftment were analyzed using proportional hazards. Patients were censored on day 29 because surveillance was incomplete after this time. Patients who died before day 29 were censored on day of death (n = 2). All analyses were adjusted for age, sex, conditioning regimen (corresponding to donor type), total delivered MTX dose, weight, and height. Engraftment analyses were also adjusted for creatinine. Other covariates that did not affect the relationship between genotype and outcome were race, smoking status, birthplace, and previous interferon treatment.     Results and discussion Top Abstract Introduction Study design Results and discussion References Characteristics of the patients are shown in Table 1. Patients with lower MTHFR activity had a higher OMI during days 1 to 18 (Figure 1). The mean (95% confidence interval) for patients with the CC (wild type) genotype was 15.9 (13.2-18.6); for the CT genotype, 17.5 (14.8-20.3); and for the TT genotype, 21.6 (16.8-26.4) (P < .05 compared to CC). The increase across CT (+1.6) and TT genotypes (+5.7) corresponds to the approximate residual MTHFR enzyme activity among those who carry the variant allele (CT, 60% activity; TT, 30% activity). Similar trends were observed for days 6 to 12: OMI differences [compared to the mean for CC genotype = 18.4 (15.2-21.7)]: CT genotype: +2.7, P = .25; TT genotype: +3.8, P = .27). Higher levels of mucositis among patients with a TT genotype correspond to a 36% increase in the mean OMI during days 1 to 18.                                 View this table: [in this window] [in a new window]   Table 1. Characteristics of the study population View larger version (27K): [in this window] [in a new window]   Figure 1. Differences in oral mucositis index (OMI) days 6 to 12 and 1 to 18 after transplantation (mean ± SE). Patients with the homozygous variant MTHFR TT genotype have higher OMI scores. Adjusted mean OMI scores in patients with the wild type CC genotype (reference group) are 18.4 for days 6 to 12 and 15.9 for days 1 to 18 after transplantation, corresponding to an increase of 20% and 36% in the OMI score, respectively, among patients with the TT genotype. All analyses are adjusted for patients' age, sex, conditioning regimen, total methotrexate dose, height, and body weight. Recovery of platelet counts was slower among patients with variant genotypes than among those with the CC genotype (Table 2). Recovery to 10 000/µL was 24% slower for the TT genotype (P = .23), and recovery to 20 000/µL, 34% slower (P = .08). Recovery of granulocytes was slightly slower among individuals with variant genotypes, although neither was statistically significant nor showed a trend.                                View this table: [in this window] [in a new window]   Table 2. Indicators of engraftment by 5,10-methylenetetrahydrofolate reductase genotype Mean bilirubin levels and increases in bilirubin levels between days 1 and 18 were not related to genotype (data not shown). To our knowledge, this is the first study illustrating a relationship between a folate-related variant and MTX toxicity. As hypothesized, patients with the MTHFR TT genotype experienced higher toxicity, evidenced by increased oral mucositis and a trend toward delayed platelet recovery. Imbalances in folate pools in those with the TT genotype are predictable18 and have been demonstrated.19 Low folate (dietary or MTX induced) may further decrease availability of folate for nucleotide synthesis.9 A model of oral mucositis has recently been described.20 In patients undergoing marrow transplantation, mucosal toxicity induced by the conditioning regimens predominates. We showed that patients with the MTHFR TT genotype experience higher OMI levels during days 1 to 18, with an effect size similar to that of cyclophosphamide/total body irradiation conditioning over busulfan/cyclophosphamide conditioning (> 30%). Among these patients, reduced DNA repair capacity, attributable to a decreased synthesis of nucleotides, probably results in delayed healing. Engraftment of platelets was similarly affected. One might predict that the donor genotype would be more relevant for this outcome. However, the observed delay in recovery may indicate that the presence of the much larger number of recipient somatic cells affects folate pools. The product of MTHFR is 5'-methyl-tetrahydrofolate reductase, the transport form of folate. Thus, patients with a TT genotype may show a decreased availability of folate.19,21-23 For consent reasons we were not able to genotype the donors. Future studies should obtain both patient and donor genotypes to enhance understanding of this possible interaction and its impact. The high prevalence of the MTHFR variant allele and the ability to perform genotyping for this single nucleotide polymorphism, rapidly and inexpensively, may render it a candidate for expanding tailored therapy24; genotyping may reduce MTX toxicity among a subgroup of patients. Although alternatives to MTX for GVHD prevention are limited, dose adjustment or newly evaluated drugs25 may be appropriate.     Acknowledgments We are indebted to the staff members who were involved in the conduct of this study: Lori Hubbard who performed the chart abstraction, Gary Schoch who provided support with the master patient database, and Sheryl Marks, Eileen van Hollebecke, and members of the FHCRC Collaborative Data Services who performed the data entry of the chart abstraction data. We thank Anajane Smith, Eric Mickelson, and Dr Effie Petersdorf for support in DNA retrieval, Michele Lloid for performing the OMI exams, Juanita Leija for technical assistance with the genotyping, and Mari Nakayoshi for graphical and word processing assistance.     Footnotes Submitted August 24, 2000; accepted February 27, 2001. Supported by the National Cancer Institute Cancer Center Support Grant Interdisciplinary Pilot Program, by the National Institutes of Health grants CA18029, CA18221, CA 15704 (Core), and HL 36444, and by the National Institutes of Environmental Health Sciences Center ES-07033. The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734. Reprints: Cornelia Ulrich, Fred Hutchinson Cancer Research Center, Cancer Prevention Research Program, 1100 Fairview Ave N, MP-900, Seattle, WA 98109-1024; e-mail: nulrich{at}fhcrc.org.     References Top Abstract Introduction Study design Results and discussion References 1. Chu E, Allegra C. Antifolates. In: Chabner B,Longo D, eds. Cancer Chemotherapy and Biotherapy. 2nd ed. Philadelphia, PA: Lippincott-Raven; 1996:109-148. 2. Storb R, Deeg HJ, Whitehead J, et al. Methotrexate and cyclosporine compared with cyclosporine alone for prophylaxis of acute graft versus host disease after marrow transplantation for leukemia. N Engl J Med. 1986;314:729-735[Abstract]. 3. Baggott JE, Vaughn WH, Hudson BB. Inhibition of 5-aminoimidazole-4-carboxamide ribotide transformylase, adenosine deaminase and 5'-adenylate deaminase by polyglutamates of methotrexate and oxidized folates and by 5-aminoimidazole-4-carboxamide riboside and ribotide. Biochem J. 1986;236:193-200[Medline] [Order article via Infotrieve]. 4. Chu E, Drake JC, Boarman D, Baram J, Allegra CJ. Mechanism of thymidylate synthase inhibition by methotrexate in human neoplastic cell lines and normal human myeloid progenitor cells. J Biol Chem. 1990;265:8470-8478[Abstract/Free Full Text]. 5. Frosst P, Blom HJ, Milos R, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase [letter]. Nat Gen. 1995;10:111-113[CrossRef][Medline] [Order article via Infotrieve]. 6. Skibola CF, Smith MT, Kane E, et al. Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults. Proc Natl Acad Sci U S A. 1999;96:12810-12815[Abstract/Free Full Text]. 7. Ma J, Stampfer MJ, Giovannucci E, et al. Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancer. Cancer Res. 1997;57:1098-1102[Abstract/Free Full Text]. 8. Chen J, Giovannucci E, Kelsey K, et al. A methylenetetrahydrofolate reductase polymorphism and the risk of colorectal cancer. Cancer Res. 1996;56:4862-4864[Abstract/Free Full Text]. 9. Ulrich C, Kampman E, Bigler J, et al. Colorectal adenomas and the C677T MTHFR polymorphism: evidence for gene-environment interaction? Cancer Epidemiol Biomarkers Prev. 1999;8:659-668[Abstract/Free Full Text]. 10. Slattery ML, Potter JD, Samowitz W, Schaffer D, Leppert M. Methylenetetrahydrofolate reductase, diet, and risk of colon cancer. Cancer Epidemiol Biomarkers Prev. 1999;8:513-518[Abstract/Free Full Text]. 11. Shaw GM, Rozen R, Finnell RH, Wasserman CR, Lammer EJ. Maternal vitamin use, genetic variation of infant methylenetetrahydrofolate reductase, and risk for spina bifida. Am J Epidemiol. 1998;148:30-37[Abstract/Free Full Text]. 12. Ou CY, Stevenson RE, Brown VK, et al. 5,10-Methylenetetrahydrofolate reductase genetic polymorphism as a risk factor for neural tube defects. Am J Med Genet. 1996;63:610-614[CrossRef][Medline] [Order article via Infotrieve]. 13. Kluijtmans LA, Kastelein JJ, Lindemans J, et al. Thermolabile methylenetetrahydrofolate reductase in coronary artery disease. Circulation. 1997;96:2573-2577[Abstract/Free Full Text]. 14. Thomas ED, Clift RA, Fefer A, et al. Marrow transplantation for the treatment of chronic myelogenous leukemia. Ann Intern Med. 1986;104:155-163. 15. Clift RA, Buckner CD, Thomas ED, et al. Marrow transplantation for chronic myeloid leukemia: a randomized study comparing cyclophosphamide and total body irradiation with busulfan and cyclophosphamide. Blood. 1994;84:2036-2043[Abstract/Free Full Text]. 16. Hansen JA, Gooley TA, Martin PJ, et al. Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia. N Engl J Med. 1998;338:962-968[Abstract/Free Full Text]. 17. Schubert MM, Williams BE, Lloid ME, Donaldson G, Chapko MK. Clinical assessment scale for the rating of oral mucosal changes associated with bone marrow transplantation: development of an oral mucositis index. Cancer. 1992;69:2469-2477[CrossRef][Medline] [Order article via Infotrieve]. 18. Selhub J, Miller JW. The pathogenesis of homocysteinemia: interruption of the coordinate regulation by S-adenosylmethionine of the remethylation and transsulfuration of homocysteine. Am J Clin Nutr. 1992;55:131-138[Abstract/Free Full Text]. 19. Bagley PJ, Selhub J. A common mutation in the methylenetetrahydrofolate reductase gene is associated with an accumulation of formylated tetrahydrofolates in red blood cells. Proc Natl Acad Sci U S A. 1998;95:13217-13220[Abstract/Free Full Text]. 20. Sonis ST. Mucositis as a biological process: a new hypothesis for the development of chemotherapy-induced stomatotoxicity. Oral Oncol. 1998;34:39-43[CrossRef][Medline] [Order article via Infotrieve]. 21. Harmon DL, Woodside JV, Yarnell JW, et al. The common "thermolabile" variant of methylene tetrahydrofolate reductase is a major determinant of mild hyperhomocysteinaemia. QJM. 1996;89:571-577[Abstract]. 22. Ma J, Stampfer MJ, Christensen B, et al. A polymorphism of the methionine synthase gene: association with plasma folate, vitamin B12, homocyst(e)ine, and colorectal cancer risk. Cancer Epidemiol Biomarkers Prev. 1999;8:825-829[Abstract/Free Full Text]. 23. Molloy AM, Daly S, Mills JL, et al. Thermolabile variant of 5,10-methylenetetrahydrofolate reductase associated with low red-cell folates: implications for folate intake recommendations. Lancet. 1997;349:1591-1593[CrossRef][Medline] [Order article via Infotrieve]. 24. Roses AD. Pharmacogenetics and the practice of medicine. Nature. 2000;405:857-865[CrossRef][Medline] [Order article via Infotrieve]. 25. Yu C, Seidel K, Nash RA, et al. Synergism between mycophenolate mofetil and cyclosporine in preventing graft-versus-host disease among lethally irradiated dogs given DLA-nonidentical unrelated marrow grafts. Blood. 1998;91:2581-2587[Abstract/Free Full Text]. © 2001 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? 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