Association of methylenetetrahydrofolate reductase (MTHFR) C677T, MTHFR A1298C, and CYP3A4 A290G gene polymorphisms with clinical outcomes of HLA-matched sibling allogeneic hematopoietic cell transplantation in an Egyptian patient/donor cohort

Abstract

The impact of non-HLA drug-metabolizing gene polymorphisms on post-transplant outcomes is well recognized. We aimed to evaluate the impact of 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T and A1982C and CYP3A4 A290G polymorphisms on the outcomes of patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) from fully matched siblings. Using PCR-RFLP and according to DNA availability, MTHFR and CYP3A4-V polymorphisms were evaluated. In total 60 patient/donor pairs were investigated. The MTHFR genotypes exhibited similar frequencies in both patients and donors; the MTHFR wild-type in patients correlated with a trend towards reduced incidence of GVHD and improved overall survival rates. Most patients (84.9 %) and donors (76.8 %) had CYP3A4 A wild type. Acute GVHD occurred only in patients with the wild type (10/45 AA vs 0/8 AG or GG) and 9/43 vs 1/13 in recipients from donors with AA vs. AG + GG. GVHD prophylaxis regimens that do not include methotrexate demonstrated a 5.5-fold increased risk of acute GVHD (p = 0.03). Alternative conditioning regimens to Busulphan/Cyclophosphamide exhibited a 19.1-fold increase in the risk of transplant-related mortality (TRM), with statistical significance (p = 0.007). Severe oral mucositis was correlated with male gender (p = 0.03) and a diagnosis of leukaemia (p = 0.007). Renal toxicity is correlated with an age of ≥ 18 years (p = 0.04) and male gender (p = 0.04). In conclusion, methotrexate in GVHD prophylaxis correlates with a reduced risk of GVHD, while the Busulphan/Cyclophosphamide conditioning regimen is linked to a lower incidence of TRM. Although statistical significance was not achieved due to the predominance of the CYP3A4 wild type, its nearly exclusive association with GVHD may hold clinical significance. Therefore, genotyping patients and adjusting the CsA dose for individuals with the CYP3A4 wild type is recommended.