The Impact of Methylenetetrahydrofolate Reductase C677T Gene Polymorphism on Engraftment after Allogeneic Hematopoetic Cell Transplantation.

Methotrexate (MTX) is an antifolate agent used to prevent graft versus host disease (GVHD) in allogeneic hemapoietic cell transplantation (AHCT). The effectiveness of MTX is largely attributable to its role of MTHR and its gene polymorphism is a common (10–12% homozygote and 40% heterozygote) variation in the population. It was shown by Ulrich et al that C677T polymorphism leads to variations in toxicities. Depending on to this finding, we investigated whether methylenetetrahyrofolate reductase (MTHFR) C677T gene polymorphism has any affect on engraftment kinetics of patients undergoing AHCT. We retrospectively analyzed our cohort of 82 allogeneic stem cell recipients whose MTHFR gene polymorphism of C677T region was analyzed by RQ-PCR for the pretransplant evaluation of hereditary thrombophilia. The patient’s median age was 31 (range, 14–50) years, with a M/F: 50/32 and diagnosis; 35 AML, 26 CML, 12 ALL and 9 other. Nearly all the patients received ablative conditioning regimen (BU-CY) or CY-TBI. All the patients received CSA and short term MTX for GVHD prophylaxis. Stem cell source was bone marrow (BM) in 23 and peripheral blood (PB) in 59. MTHFR gene polymorphism was detected in 32 (39%) of all patients, whose 90% were heterozygote (MTHFR HeZ). When we compared the engraftment kinetics, granulocyte engraftment was found to be late in MTHFR HeZ group (neutrophil 1000 median 19 vs 17 d; p=0.01) but no difference in platelet engraftment. In order to eliminate the effect of stem cell source on engraftment kinetics we have done the same analysis for BM and PB group separately. We have observed that MTHFR gene polymorphism had a prominent effect on BM recipients, as both neutrophil 500 and 1000 and also platelet engraftments were affected (granulocyte 500 median 21 vs 15 p=0.005; granulocyte 1000 median 22.5 vs 17 p=0.0001 and plt 20 median 27 vs 21 p=0.03) significantly. On the contrary, there was no difference in the PB group. There was no difference in acute GVHD incidence. Our knowledge on epigenetic data will help us on tailoring the chemotherapy regimen for conditioning and GvHD prophylaxis in transplant recipients. Our data on a limited patient size suggests that the presence of MTHFR HeZ may have an impact on allo HCT recipients’ engraftment kinetics while using MTX for GVHD prophylaxis and BM as stem cell source.