The Optimal Dosage of Methotrexate for Graft-Versus-Host Disease Prophylaxis in Umbilical Cord Blood Transplantation

Abstract

Introduction The combination of methotrexate (MTX) and a calcineurin inhibitor is widely used for GVHD prophylaxis in umbilical cord blood transplantation (UCBT). However, the optimal MTX dosage for GVHD prophylaxis in UCBT remains unclear. Methods We investigated the impact of the MTX dosage on clinical outcomes of UCBT. We retrospectively analyzed a cohort of 70 patients who received first UCBT between October 2002 and December 2017 in our hospital. Of the 70 recipients, 37 received MTX at doses of 10 mg/m2 on day 1, and 7 mg/m2 on days 3 and 6 (low-dose MTX: LD-MTX), and 33 received MTX at doses of 15 mg/m2 on day 1, and 10 mg/m2 on days 3 and 6 (standard-dose MTX: SD-MTX), in combination with tacrolimus (TAC).The following conditions within day 180 were considered to be transplant-related complications with endothelial cell damage: sinusoidal occlusive syndrome, systemic transplant-associated microangiopathy (TAM), intestinal TAM, capillary leak syndrome, idiopathic pneumonia syndrome, and diffuse alveolar hemorrhage. We defined grade 3-4 acute GVHD and/or transplant-related complications with endothelial cell damage as severe transplant-related complications in this study. Results The characteristics of patients and transplantation procedures were comparable between the two groups. T-cell depletion was not used as GVHD prophylaxis in our study. The median follow-up period for surviving patients was 1504 days (range, 302-3864). The cumulative incidence of neutrophil engraftment by day 42 was 97.3% (95% CI, 71.5%-99.8%) for the LD-MTX group and 93.9% (95% CI, 73.1%-99.8%) for the SD-MTX group (P = 0.36). The cumulative incidence of platelet engraftment by day 60 was 78.4% (95% CI, 60.6%-88.8%) for the LD-MTX group and 87.9% (95% CI, 69.0%-95.6%) for the SD-MTX group (P = 0.40). Univariate analysis findings revealed that the risk of grade 3-4 acute GVHD was significantly lower in the SD-MTX group than in the LD-MTX group (P = 0.013). Multivariate analysis findings revealed that SD-MTX was significantly associated with a lower incidence of severe transplant-related complications (HR = 0.25; 95% CI, 0.07-0.87; P = 0.029). Non-relapse death was not observed in patients with standard-risk disease in the SD-MTX group (n = 22). There was no significant difference between the two groups in the 2-year incidence of relapse: 27.0% (95% CI, 13.9%-42.0%) for the LD-MTX group and 15.3% (95% CI, 5.4%-29.7%) for the SD-MTX group (P = 0.55). Conclusion Our study demonstrated that the GVHD prophylaxis consisting of SD-MTX and TAC led to a significantly lower incidence of severe acute GVHD and/or TRC-EC than the combination of LD-MTX and TAC without increasing the risk of graft failure and relapse. Thus, while our findings need to be further verified by multicenter studies with larger cohorts of patients, for now SD-MTX is optimal in combination with TAC for GVHD prophylaxis in UCBT.