Advertisement

Vorinostat plus tacrolimus/methotrexate to prevent GVHD following myeloablative conditioning unrelated donor HCT

Sung Won Choi, Thomas Braun, Israel Henig, Erin Gatza, John Magenau, Brian Parkin, Attaphol Pawarode, Mary Riwes, Greg Yanik, Charles A. Dinarello and Pavan Reddy

Key points

  • Grade 2-4 acute GVHD in URD HCT patients that received vorinostat and tacrolimus/methotrexate after myeloablative conditioning was 22%.

  • HDAC inhibition with vorinostat shows potential efficacy for GVHD prevention and should be investigated in a randomized phase 3 trial.

Abstract

The oral histone deacetylase (HDAC) inhibitor (vorinostat) is safe and results in low incidence of acute GVHD following reduced intensity conditioning, related donor HCT. However, its safety and efficacy in preventing acute GVHD in settings of heightened clinical risk that utilize myeloablative conditioning, unrelated donor (URD), and methotrexate are not known. We conducted a prospective, phase 2 study in this higher-risk setting (ClinicalTrials.gov NCT01790568). We enrolled 37 patients to provide 80% power to detect a significant difference in grade 2-4 acute GVHD of 50% compared with a reduction in target to 28%. Eligibility included adults with a hematological malignancy to receive myeloablative HCT from an available 8/8-HLA matched URD. Patients received GVHD prophylaxis with tacrolimus and methotrexate. Vorinostat (100 mg twice daily) was started on day -10 and continued through day +100 post-HCT. Median age was 56 (range 18-69) and 95% had AML or high-risk MDS. Vorinostat was safe and tolerable. The cumulative incidence of grade 2-4 acute GVHD at day 100 was 22% and grade 3-4 was 8%. The cumulative incidence of chronic GVHD was 29%; relapse, non-relapse mortality, GVHD-free relapse-free survival, and overall survival at 1-year were 19%, 16%, 47%, and 76%, respectively. Correlative analyses showed enhanced histone (H3) acetylation in PBMCs and reduced IL-6 (p=0.028) and GVHD biomarkers (Reg3, p=0.041; ST2, p=0.002) at day 30 post-HCT in vorinostat-treated subjects compared with similarly treated patients who did not receive vorinostat. Vorinostat for GVHD prevention is an effective strategy that should be confirmed in a randomized phase 3 study.

  • Submitted June 21, 2017.
  • Accepted July 17, 2017.