Pharmacogenetics of methotrexate: toxicity among marrow transplantation patients varies with the methylenetetrahydrofolate reductase C677T polymorphism

Ulrich, Cornelia M.; Yasui, Yutaka; Storb, Rainer; Schubert, Mark M.; Wagner, John L.; Bigler, Jeannette; Ariail, K.; Keener, Cassie L.; Li, Sue; Líu, Hao; Farin, Federico M.; Potter, John D.

doi:10.1182/blood.v98.1.231

Cited by 257 publications

(138 citation statements)

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“…For example, MTHFR TT677 patients with CML who received MTX for the prevention of a graft-versus-host disease, experienced higher toxicity, as documented by increased oral mucositis and delayed platelet recovery. 15 Increased MTX toxicity was also noted in ovarian cancer patients with the TT677 genotype, 28 and in patients with rheumatoid arthritis who were carriers of the T677A1298 haplotype. 16 MTX-associated effects observed in these studies were suggested to arise due to low 5-methyl-THF levels associated with the T677 variant.…”

Section: Discussionmentioning

confidence: 98%

“…11,12 Recently, the potential role of these polymorphisms in response to MTX treatment has been addressed in several studies. [13][14][15][16] Higher in vitro MTX sensitivity of a patient's lymphoblasts with the TT677 genotype has been shown. 13 Likewise, among adult acute lymphoblastic leukemia (ALL) and chronic myelogenic leukemia (CML) patients receiving MTX, higher drug toxicity was observed in TT677 homozygotes as compared to individuals with other MTHFR genotypes.…”

Section: Introductionmentioning

confidence: 97%

“…13 Likewise, among adult acute lymphoblastic leukemia (ALL) and chronic myelogenic leukemia (CML) patients receiving MTX, higher drug toxicity was observed in TT677 homozygotes as compared to individuals with other MTHFR genotypes. 14,15 The G to A substitution at position 1958 of the MTHFD1 gene, causing an alanine to glycine substitution at codon 653 located within the 10-formyl-THF synthetase enzyme domain, has recently been reported. 17 The role of an MTHFD1 A1958 variant in NTD susceptibility suggested the possibility of its functional impact.…”

Section: Introductionmentioning

confidence: 99%

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Role of polymorphisms in MTHFR and MTHFD1 genes in the outcome of childhood acute lymphoblastic leukemia

Krajinović

Lemieux-Blanchard²,

Chiasson³

et al. 2003

Pharmacogenomics J

150

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The central role of 5,10-methylenetetrahydrofolate reductase (MTHFR) and methylenetetrahydrofolate dehydrogenase (MTHFD1) in folate metabolism renders polymorphisms in genes encoding these enzymes potential modulators of therapeutic response to antifolate chemotherapeutics. The analysis of 201 children treated with methotrexate for childhood acute lymphoblastic leukemia (ALL) showed that patients with either the MTHFR T677A1298 haplotype or MTHFD1 A1958 variant had a lower probability of event-free survival (EFS) in univariate analysis (hazard ratio (HR) ¼ 2.2, 95% confidence interval (CI), 1.0-4.7 and 2.8, 95% CI, 1.1-7.3, respectively). Multivariate analysis supported only the role of the MTHFR variant (HR ¼ 2.2, 95% CI, 0.9-5.6). However, the association of both genes with ALL outcome appears to be more obvious in the presence of another event-predisposing variant belonging to the same path of drug action. The combined effect of a thymidylate synthase (TS) triple repeat associated with increased TS levels, with either the MTHFR T677A1298 haplotype or MTHFD1 A1958 allele, resulted in a highly significant reduction of EFS (multivariate HR ¼ 9.0, 95% CI, 1.9-42.8 and 8.9, 95% CI, 1.8-44.6, respectively). These results reveal the role of gene-gene interactions within a folate pathway, and how they can correlate with relapse probabilities in ALL patients.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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Role of polymorphisms in MTHFR and MTHFD1 genes in the outcome of childhood acute lymphoblastic leukemia

Krajinović

Lemieux-Blanchard²,

Chiasson³

et al. 2003

Pharmacogenomics J

150

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“…This SNP has been associated with increased oral mucositis and delayed platelet recovery in patients undergoing allogeneic HSCT for chronic myelogenous leukemia who received cyclophosphamide/TBI or busulfan/cyclophosphamide conditioning and MTX prophylaxis for GVHD. 50 Controlling for other risk factors, patients with lower MTHFR activity and the TT genotype had significantly higher mean mucositis scores. These results were confirmed by Robien et al 51 after excluding patients who required leucovorin rescue and adjusting for pretransplant vitamin use.…”

Section: Renal Failurementioning

confidence: 99%

Genomic screening and complications of hematopoietic stem cell transplantation: has the time come?

Kallianpur

2004

Bone Marrow Transplant

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Summary:The occurrence of toxic complications following hematopoietic stem cell transplantation (HSCT) is highly variable and dependent on a multitude of host, donor, and treatment factors. The increasingly broad indications for HSCT and the need to provide this treatment option to older and/or more debilitated patients emphasizes the importance of refining our methods of predicting and ameliorating these toxicities. Late complications (occurring after day 100) also pose a threat to quality of life after HSCT. Genetic polymorphisms in key molecular pathways in the host are likely to contribute significantly to the observed variability in the development HSCT-associated complications. Hepatic veno-occlusive disease and acute lung injury, two of the most serious organ toxicities that occur, represent useful paradigms for the identification of genetic polymorphisms in enzyme systems that modulate local and systemic responses to oxidant stress during transplant conditioning therapy. Ongoing studies in this area are providing clues to the prevention of adverse clinical outcomes based on the genetic milieu. This review of studies in HSCT that explore genetic risk factors for transplant complications indicates that significant progress is being made in this rapidly evolving area. However, further large-scale clinical and translational studies are needed before genomic screening can be widely used to individualize treatment. Bone Marrow Transplantation (2005) Clinicians are continually challenged by the need to predict the responses of individual patients to potentially toxic treatments. The increasing promise of cure for patients who undergo hematopoietic stem cell transplantation (HSCT) for life-threatening disorders is overshadowed by the very real threat of short-term, often fatal, complications resulting from the transplant regimen and graft-versushost disease (GVHD). However, significant variation is observed between similarly treated individuals in the development of complications. It is an appealing concept, therefore, and one to which many clinicians now subscribe, that a significant portion of this variability has a genetic basis. Identifying important genetic variables will allow for better prediction of HSCT-related outcomes, and in the process of identifying these susceptibilities, it may also be possible to gain sufficient knowledge of the underlying pathophysiology of these toxicities to develop targeted interventions.This review will focus on genomic screening of the host for the prediction of specific complications, touching briefly on selected donor factors. Other rapidly evolving areas that are not covered include molecular genetic testing to predict graft failure and disease relapse after HSCT. The role of clinical and biochemical risk factors in the pre-transplant evaluation of HSCT candidates has also been reviewed recently in this journal. 1 Importance of context-dependent genetic effectsThe study of uncommon disease-associated mutations has been invaluable to our understanding of basic pathophy...

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“…For patients with the homozygous TT variant (lower enzyme activity), there was a significant increase in mucositis and time to platelet engraftment. 25 This same cohort was slightly expanded and underwent further analyses of an additional MTHFR polymorphism (A1298C) as well as two polymorphisms in the thymidylate synthase gene. In an analysis of combined genotypes, the MTHFR A1298C polymorphism with a wild-type MTHFR 677CC genotype showed no changes in the risk of mucositis while the MTHFR C677T genotype persisted as a risk factor for mucositis.…”

Section: Discussionmentioning

confidence: 99%

Folinic acid administration after MTX GVHD prophylaxis in pediatric allo-SCT

Hudspeth

Heath

Chiuzan

et al. 2012

Bone Marrow Transplant

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Cyclosporine (CsA) and MTX are commonly used for GVHD prophylaxis in pediatric allo-SCT. Mucositis and hepatic toxicity frequently restrict the delivery of the fourth dose of MTX. Folinic acid (FA) may ameliorate MTX toxicity. We conducted a retrospective chart review of all pediatric patients who received CsA and MTX for GVHD prophylaxis from January 2000 to July 2010. Patients treated before July 2007 (N ¼ 29) did not receive FA and those treated from July 2007 onward did receive FA (N ¼ 18). Patients who received FA were significantly more likely to receive day þ11 MTX (odds ratio (OR) 10.42, 95% confidence interval (CI): 1.21-262.27) but there was no significant difference in Grade III-IV GVHD between the two groups (OR 1.15, 95% CI: 0.08-18.14). FA did not impact relapse-free survival (RFS) (P ¼ 0.82). Increased likelihood of receiving day þ11 MTX suggests that FA ameliorates MTX toxicity, such as severe mucositis. FA administration for MTX GVHD prophylaxis should be studied in a prospective, randomized fashion. Keywords: MTX; folinic acid; GVHD INTRODUCTIONAs the annual number of transplants continues to increase worldwide, GVHD remains a leading cause of non-relapse mortality after allo-SCT. 1 Earliest efforts at utilizing immunosuppressive agents to reduce GVHD used single-agent therapy, with no notable decreases in acute GVHD when Cyclosporine (CsA) was compared with MTX. 2-4 After the successful combination of CsA and MTX in canine BM transplantation models, seminal trials in humans demonstrated the superiority of the combined regimen over CsA alone in reducing acute GVHD. [5][6][7][8] From this first report, however, it was noted that there was a significantly increased incidence of severe oral mucositis and hyperbilirubinemia in patients receiving CsA and MTX. In addition, only 58% (25/43) of the patients received full-dose MTX due to renal impairment. 7 Administration of folinic acid (FA) after MTX decreased toxicity without increasing GVHD in canine transplantation models, and later the administration of FA with MTX appeared to reduce toxicities compared with CsA alone in humans as well. 8,9 Consequently, several adult BMT studies have supported the reduction of regimen-related toxicity by the administration of FA rescue with CsA and MTX combination therapy. 10,11 Despite this, FA administration after MTX has not been widely adopted in practice. An European Group for Blood and Marrow Transplantation (EBMT) survey regarding GVHD prophylaxis and treatment in 1995 revealed that 46% (37/81) gave FA after MTX. There was considerable variation, however, in the administration schedule. 12 Similarly, a survey of allo-SCT centers in Australia and New Zealand reported that 44% (8/18) of responding centers routinely administered FA after MTX. 13 Although there are no published studies examining the effects of FA rescue with CsA and MTX combination therapy in pediatric patients, the EBMT

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Pharmacogenetics of methotrexate: toxicity among marrow transplantation patients varies with the methylenetetrahydrofolate reductase C677T polymorphism

Cited by 257 publications

References 20 publications

Role of polymorphisms in MTHFR and MTHFD1 genes in the outcome of childhood acute lymphoblastic leukemia

Role of polymorphisms in MTHFR and MTHFD1 genes in the outcome of childhood acute lymphoblastic leukemia

Genomic screening and complications of hematopoietic stem cell transplantation: has the time come?

Folinic acid administration after MTX GVHD prophylaxis in pediatric allo-SCT

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