Vorinostat Lowers Acute GVHD in Patients Receiving Unrelated Donor HSCT

Wayne Kuznar
Published Online: Sunday, Feb 26, 2017

Vorinostat (Zolinza) combined with tacrolimus and methotrexate represents a potentially effective combination to mitigate graft-versus-host disease (GVHD) in the setting of matched unrelated donor myeloablative conditioning hematopoietic stem cell transplant (HSCT).1

In a phase II single-arm study, the cumulative incidence of grade 2-4 acute GVHD at day 100 with the vorinostat combination was 22%, which met the primary endpoint of the study (target incidence of less than 28%). The historical incidence of acute GVHD despite standard immunosuppressive prophylaxis in patients receiving HSCT is 50%, said Israel Henig, MD, who presented the data at the 2017 BMT Tandem Meetings. In the study, the relapse rate at 1 year post-transplant was also low, at 19%.

“The reduction in acute GVHD is much more than we expected,” said Henig, a research fellow at the University of Michigan Comprehensive Cancer Center, Ann Arbor. “We’re excited. We’re looking at data for relapse because vorinostat is used in many clinical trials now as an anti-cancer drug. The relapse rate in our short-term follow-up was encouraging. The acute leukemia population is not an easy population. Most of our patients had acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS), and these are patients for which you would expect higher rates of relapse. We need longer follow-up to know.”

Acute GVHD remains a significant barrier to a more widespread application of allogeneic HSCT for patients with hematologic malignancies. Vorinostat is a histone deacetylase inhibitor (HDAC). Inhibiting HDAC has been shown to regulate GVHD in experimental models of HSCT. In these models, vorinostat suppressed pro-inflammatory cytokines, regulated antigen-presenting cells through induction of indoleamine 2,3-dioxygenase, and enhanced T-regulatory functions while preserving graft-versus-leukemia responses.

An earlier, first-in-human study by Henig’s group demonstrated that vorinostat was safe to administer and resulted in a low incidence of acute GVHD following related donor-reduced intensity conditioning HSCT.2

In the phase II trial, 37 patients ≥18 years with a hematologic malignancy for which myeloablative HSCT was appropriate were paired with 8/8 HLA-A, -B, -C unrelated donors. GVHD prophylaxis consisted of intravenous (IV) tacrolimus at 0.03 mg/kg/day starting 3 days before transplant through 180 days after along with IV methotrexate at 5 mg/m2 once daily on days 1, 3, 6 and 11 posttransplant. Vorinostat at 100 mg orally twice daily was initiated 10 days before transplant and continued through day 100 posttransplant.

Mean age of the patients was 56 years; 27 had AML, 8 had MDS, 1 had chronic myelogenous leukemia, and one had acute undifferentiated leukemia. Twenty one of the 37 patients (56.8%) had low disease status at baseline.

All patients engrafted. Vorinostat was safe and tolerable with no excessive toxicity or death attributable to vorinostat. At median follow-up of 1 year, 10 patients died: 4 from relapse and 3 from acute GVHD-related infection.

The cumulative incidence of grade 2-4 acute GVHD was 22% at day 100 and 22% at day 180. The cumulative incidence of grade 3-4 acute GVHD was 8% and 11% at day 100 and day 180, respectively.

The cumulative incidence of chronic GVHD at 1 year was 29%. The cumulative incidence of relapse and nonrelapse mortality at 1 year posttransplant was 19% and 18%, respectively. Estimated overall survival at 1 year was 76%.

Blood samples from study subjects were obtained at day 30 to perform correlative pharmacodynamics studies and biomarker analyses. Acetylated histone (H3) levels were significantly higher at day 30 in peripheral blood mononuclear cells from vorinostat-treated patients  compared with similarly treated patients who did not receive vorinostat (P = .026). Day 30 plasma levels of inflammatory cytokines interleukin (IL)-6 and IL-10 were significantly lower (P = .02759 and P = .03111, respectively) in vorinostat patients compared with historical samples, as were 2 biomarkers used to predict acute GVHD: Reg3-alpha (P = .0411) and ST2 (P = .001714). “This is biological confirmation that the drug is working,” said Israel.

HDAC inhibition as a strategy for GVHD prevention should be further investigated in a multicenter phase III randomized study.
References
  1. Henig I, Choi SW, Braun T, et al. A phase 2 trial of vorinostat plus tacrolimus and methotrexate in patients receiving unrelated donor HCT following myeloablative conditioning. Presented at: BMT Tandem Meetings; February 23-26, 2017; Orlando, Florida. Abstract LBA5.
  2. Reddy P, Maeda Y, Hotary K, et al. Histone deacetylase inhibitor suberoylanilide hydroxamic acid reduces acute graft-versus-host disease and preserves graft-versus-leukemia effect. Proc Natl Acad Sci USA. 2004;101:3921-3926.


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