Donor methylenetetrahydrofolate reductase genotype is associated with graft-versus-host disease in hematopoietic stem cell transplant patients treated with methotrexate

Steroid refractory acute GVHD (SR aGVHD) is associated with high morbidity and mortality. This study attempted to generate a risk model for SR aGVHD using 259 single nucleotide polymorphisms (SNPs) in 53 genes of recipients and donors. A total of 268 patients with aGVHD who were treated with systemic steroids were included. Patients were randomly divided into training (n = 180) and validation sets (n = 88). Clinical risk factors were also evaluated. In the training set, 85 (47.2%) developed SR aGVHD. Gastrointestinal involvement (P o0.0001) and donor genotypes of IL6 (rs1800797; P = 6.2 × 10 −4 ) and IFNG (rs2069727; P = 4.4 × 10 −4 ) were significant risk factors. Scores were assigned to the above risk factors. Patients were divided into low (score 0, n = 74) vs high risk (scores 1-3; n = 106) in risk model. Higher incidence of SR aGVHD was noted in the high risk (61.3%) vs the low-risk group (27%; P o 0.0001, odds ratio (OR) 4.28). Predictive effect of risk model was replicated in the validation set (P = 0.0045, OR 3.74). This risk model was associated with response to therapy, overall and GVHD-specific survival and non-relapse mortality. Our study suggested that this risk model could identify patients at high risk of SR aGVHD with donor genotype of IL6 (rs1800797) and IFNG (rs2069727) along with gastrointestinal involvement of aGVHD.

Section: Introductionmentioning

confidence: 99%

Risk model incorporating donor IL6 and IFNG genotype and gastrointestinal GVHD can discriminate patients at high risk of steroid refractory acute GVHD

Alam

Atenafu

et al. 2015

“…26 In addition, another study demonstrated that MTHFR 677CT and TT genotypes in HLA-matched related donors are associated with a decreased risk of GVHD. 27 Recently, an analysis of the impact of donor and recipient MTHFR polymorphisms demonstrated not only differential effects of MTHFR polymorphisms on outcomes but also varying effects in response to FA administration. FA administration, however, was based on the treating physician's discretion, making it difficult to reach definitive conclusions.…”

Section: Discussionmentioning

confidence: 99%

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

Hudspeth

Heath

Chiuzan

et al. 2012

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

“…Two SNPs in the MTHFR gene, 677T/C and T1298 A/C, have been shown to alter its enzymatic activity. A study by Murphy et al 45 identified an association between donor MTHFR SNP 677T* and a decreased incidence of both aGVHD and cGVHD. Later studies also reported an association between recipient MTHFR SNP 677T* and a decreased risk of aGVHD.…”

Section: Candidate Gene Studiesmentioning

confidence: 99%

Genomic studies of GVHD—lessons learned thus far

Ting

Alterovitz

Merlob

et al. 2012

GVHD remains the most significant complication of hematopoietic SCT, despite advances in HLA matching and the identification of risk various factors. To account for the variation in the incidence and severity of this disease, many genetic association studies have been performed in order to explore the role of immunoregulatory gene polymorphisms. These genes include those that encode cytokines, chemokines, and costimulatory molecules. Polymorphisms in other classes of genes such as those involved in drug metabolism, protein folding, and DNA replication have also been studied. In this review, we address the current knowledge of the role of genetic polymorphisms in GVHD. We also discuss the potential pitfalls inherent in genetic association testing and alternative strategies to address these problems.