Safety and Efficacy of GVHD Prophylaxis with Mini-Dose Methotrexate in Umbilical Cord Blood Transplantation – Njhsg-CBT18 Observational Study –

Tacrolimus (Tac) and methotrexate (MTX) is a standard graft-versus-host disease (GVHD) prophylaxis for umbilical cord blood transplantation (CBT); however optimal dose of MTX for CBT remains to be determined. We previously showed the safety and efficacy of reduced-dose MTX (mini-MTX, 5 mg/m 2 on days 1, 3 and 6) combined with tacrolimus (Tac) as a GVHD prophylaxis for CBT in a single-center retrospective study. Now, we conducted a multicenter observational study in the North Japan Hematology Study Group (NJHSG, NJHSG-CBT18). NJHSG-CBT18 study was conducted to evaluate the transplant outcomes according to GVHD prophylaxis in single unit CBT, in which patients with hematological malignancies scheduled for CBT were prospectively registered and followed over 2 years after CBT. A total of 112 patients were registered in NJHSG-CBT18, with a median age was 51 years. Eighty-nine patients received Tac + mini-MTX, 19 patients received Tac + mycophenolate mofetil (MMF), and 4 patients received Tac only as a GVHD prophylaxis. Multivariate analysis showed that GVHD prophylaxis other than Tac + mini-MTX was a significant risk factor for non-relapse mortality (NRM) (HR, 0.160; 95% CI, 0.065 – 0.391; P < 0.001), overall survival (OS) (HR, 2.971; 95% CI, 1.558 – 5.663; P < 0.001). We evaluated the clinical outcomes between the mini-MTX and MMF groups. The cumulative incidences of pre-engraftment immune reaction (5.7% vs. 42.1%, P < 0.001), HHV-6 encephalitis (2.3% vs. 15.8%, P = 0.011), grade II - IV acute GVHD (14.6% vs. 47.4%, P < 0.001), NRM (10.1% vs. 52.6%, P < 0.001, Figure A) were significantly lower, and that of immunosuppressant discontinuation (66.3% vs. 18.4%, P = 0.004) was significantly higher in the mini-MTX group than the MMF group, while relapse rate were comparable between the groups (Figure B). The probability of OS was also significantly higher in the mini-MTX group than the MMF group (70.6% vs. 31.6%, P < 0.001, Figure C). We evaluated risk factors for OS in the mini-MTX group. Multivariate analysis showed that high or very high risk of rDRI (HR, 3.896; 95% CI, 1.575 – 9.637; P = 0.003), high HCT-CI (HR, 3.338; 95% CI, 1.301 – 8.569; P = 0.012) were significant risk factors for OS. A combination of Tac + mini-MTX was a safe and effective GVHD prophylaxis in CBT.