Vorinostat for graft-versus-host disease prevention in pediatric and young adult patients with hematologic malignancies.
In a 43-patient, multicenter, single-arm phase 1/2 trial, adding vorinostat to standard GVHD prophylaxis after matched or haploidentical allogeneic HCT produced low reported day +100 acute GVHD incidence, acceptable early safety and engraftment findings, and evidence of HDAC target engagement in pediatric and AYA patients with hematologic malignancies.
Open original publication →What the AI sees
In a 43-patient, multicenter, single-arm phase 1/2 trial, adding vorinostat to standard GVHD prophylaxis after matched or haploidentical allogeneic HCT produced low reported day +100 acute GVHD incidence, acceptable early safety and engraftment findings, and evidence of HDAC target engagement in pediatric and AYA patients with hematologic malignancies.
Research significance
The trial provides preliminary evidence that short-course vorinostat can be feasibly combined with established GVHD prophylaxis and is associated with histone acetylation, lower proinflammatory cytokines, and favorable GVHD estimates; it remains an inference—requiring randomized comparison—that HDAC inhibition causally reduces GVHD without increasing relapse, graft failure, or other clinically important toxicity.
Source abstract
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. CLINICALTRIALS: gov, NCT03842696.