Vorinostat for graft-versus-host disease prevention in pediatric and young adult patients with hematologic malignancies

BACKGROUND. This prospective, single-arm, multicenter phase 1/2 trial evaluated vorinostat added to standard graft-versus-host disease (GVHD) prophylaxis in pediatric, adolescent, and young adult (AYA) patients undergoing allogeneic hematopoietic cell transplantation (HCT) from HLA-matched related, HLA-matched unrelated, and haploidentical donors. METHODS. Patients aged 3–39 years received twice-daily vorinostat with tacrolimus/methotrexate after HLA-matched HCT from day −10 to +30, or with post-transplant cyclophosphamide/tacrolimus/mycophenolate mofetil after haploidentical HCT from day +5 to +30. The primary endpoint was cumulative incidence of grade II–IV acute GVHD by day +100. All outcomes were based on intention-to-treat analysis. RESULTS. Forty-three patients were enrolled; median age was 19 years, with 74% receiving HLA-matched and 26% haploidentical HCT. The recommended phase 2 dose was 60 mg/m² twice daily. No dose-limiting toxicities, unexpected vorinostat-related serious adverse events, or primary graft failures occurred. Median neutrophil and platelet recovery occurred at 14 and 18 days, respectively. Day +100 grade II–IV and III–IV acute GVHD were 14% (95% CI, 5.6, 26) and 4.7% (95% CI, 0.83, 14), respectively. One-year overall survival was 88.4% (95% CI, 79.3, 98.5), relapse 14% (95% CI: 5.6, 26), nonrelapse mortality 4.7% (95% CI: 0.8, 14), and GVHD-free/relapse-free survival 55.8% (95% CI: 42.8, 72.8). Correlative studies demonstrated on-target HDAC activity, with increased histone acetylation and lower proinflammatory cytokines. CONCLUSION. These findings support randomized evaluation of vorinostat-based GVHD prophylaxis in pediatric and AYA HCT. TRIAL REGISTRY. ClinicalTrials.gov, NCT03842696.