Roxanne Nelson

December 20, 2012

ATLANTA, Georgia — Adding vorinostat (Zolinza) to standard therapy given before, during, and after hematopoietic stem cell transplantation (HSCT) appears to reduce the incidence and severity of graft-vs-host disease (GVHD).

Patients who received vorinostat in addition to standard GVHD prophylaxis had a significantly lower cumulative incidence of grade 2 to 4 GVHD than historic control subjects (22% vs 42%). These patients also had lower rates of severe (grade 3 to 4) GVHD than control subjects (4% vs 19%) and of transplant-related mortality at 1 year (13% vs 19%).

There were no differences in the rates of infectious complication or the incidence of relapse, indicating that vorinostat could help lower the risk for GVHD without compromising patient immune systems.

The study results were presented here at the American Society of Hematology 54th Annual Meeting.

Dr. Pavan Reddy

"We spent the last decade studying this particular medication and its implications, and we found that over the years, this drug can actually reduce inflammation and increase regulatory T cells.... In animal models, it reduced graft-vs-host disease," said senior author Pavan Reddy, MD, who presented the results at a press briefing.

"Our data demonstrate the translation of our experimental observations into a human trial. Obviously, it needs to be studied further in...randomized controlled trials," said Dr. Reddy, who is codirector of the bone marrow transplant and hematologic malignancies program at the University of Michigan in Ann Arbor.

Testing the Hypothesis

Allogeneic HSCT is a potentially curative therapy for a wide range of hematologic malignancies, the researchers note, but its use is limited by GVHD, which can affect anywhere from 35% to 55% of transplant recipients.

Vorinostat, a histone deacetylase inhibitor, received approval from the US Food and Drug Administration for the treatment of cutaneous manifestations of cutaneous T cell lymphoma in patients with progressive, persistent, or recurrent disease on or after 2 systemic therapies.

Some data have shown that histone deacetylase inhibitors can reduce proinflammatory cytokines, increase T regulatory cell numbers, and attenuate GVHD in experimental models, Dr. Reddy explained.

To test this hypothesis, the researchers translated their experimental observations into the first human clinical trial. The primary objective was to determine whether histone deacetylase inhibition is safe and can reduce the severity of GVHD in patients undergoing matched related-donor reduced-intensity conditioning allogeneic HSCT. The primary end point was the cumulative incidence of grade 2 to 4 acute GVHD, with a target risk of 25%.

Dr. Reddy and colleagues conducted a phase 1/2 trial at the University of Michigan and at Washington University in St. Louis, Missouri, from 2009 to 2012. For their analysis, 47 patients were evaluable.

All patients received standard prophylaxis therapy with fludarabine 40 mg/m² for 4 days, busulfan 3.2 mg/kg for 2 days, and mycophenolate mofetil for 29 days. Tacrolimus levels were maintained at 8 to 12 ng/mL until day 56, and were tapered off by day 180 (in the absence of GVHD). Vorinostat was administered orally from day 10 to day 100.

The control subjects received standard GVHD prophylaxis with tacrolimus and mycophenolate mofetil.

Reduced Incidence of GVHD

To date, there have been no cases of graft failure, excessive toxicity, or death attributable to vorinostat, explained Dr. Reddy. The median time to neutrophil and platelet engraftment was similar in the vorinostat and control groups (12 vs 11 days). In an analysis of bone marrow chimerism, the percent of myeloid (CD33+) engraftment was 94% on day 30, 100% on day 100, and 100% on day 365, and of whole T cell (CD3+) engraftment was 74.5%, 75%, and 100%, respectively.

The incidence of acute GVHD was reduced in all target organs, and only 1 patient in the cohort failed to respond rapidly to standard steroid therapy. The incidence of relapse was similar in the vorinostat and control groups (17% vs 20%), as was the incidence of infectious complication.

Previous studies have shown that this class of agents have anticancer activity and can decrease the incidence of acute GVHD, said Vanderson Rocha, MD, PhD, professor of hematology at the University of Oxford in the United Kingdom.

"But this is an important study because it is showing that immunosuppressants are not the only drugs that can be used to prevent graft-vs-host disease," said Dr. Rocha, who moderated the press briefing.

The study was partly funded by the National Institutes of Health. The authors have disclosed no relevant financial relationships.

American Society of Hematology (ASH) 54th Annual Meeting: Abstract 740. Presented December 10, 2012.