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Vorinostat may prevent graft-versus-host disease after unrelated donor bone marrow transplant
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Vorinostat appeared safe and effective combined with standard graft-versus-host disease prophylaxis for patients undergoing matched unrelated donor hematopoietic stem cell transplantation with myeloablative conditioning, according to a single-center, prospective phase 2 study published in Blood.
Despite standard immunosuppressive prophylaxis, GVHD develops in more than half of patients who receive allogeneic HSCT from unrelated donors, accounting for 13% to 16% of the mortality following this type of transplant, Pavan Reddy, MD, co-director of the leukemia, lymphoma and bone marrow transplant program at University of Michigan Comprehensive Cancer Center, and colleagues wrote.
Vorinostat (Zolinza, Merck) — an oral histone deacetylase inhibitor — is FDA approved to treat patients with cutaneous T-cell lymphoma. However, preclinical models and a phase 1/phase 2 study have demonstrated vorinostat effectively reduced rates of severe GVHD.
“Given that most patients lack a suitable, related, donor and that the risks [for] GVHD and its related mortality are increased following unrelated donor [HSCT], we sought to expand the use of vorinostat in GVHD prevention to this higher-risk population and to determine whether a similar reduction in the incidence of acute GVHD can be achieved in the setting of unrelated donor [HSCT],” Reddy and colleagues wrote.
The researchers evaluated the efficacy and safety of oral vorinostat in combination with tacrolimus and methotrexate — the standard GVHD prophylaxis — in 37 patients (median age, 56 years; 49% men) with a hematologic malignancy receiving myeloablative HSCT from an 8/8 HLA-matched unrelated donor. Patients received 100 mg oral vorinostat twice daily starting 10 days prior to transplantation through day 100 after HSCT (median duration, 106 days).
In total, 73% of patients had acute myeloid leukemia and 22% had myelodysplastic syndrome; nearly 20% had high-risk disease.
The incidence of grade 2 to grade 4 acute GVHD by day 100 following transplant served as the primary endpoint.
Dose modification occurred in 70% of patients, and treatment was withheld in 65% of patients.
The safety profile of vorinostat appeared consistent with previous studies.
At day 100, grade 2 to grade 4 acute GVHD occurred in eight patients (22%; 95% CI, 11-39), with a median time to onset of 32 days. The three patients with grade 4 GVHD died.
At 1 year, incidence of acute GVHD increased to 32% (95% CI, 19-51) due to the development of three cases of gastrointestinal acute GVHD after day 180.
Nineteen percent (95% CI, 9-36) of patients experienced relapse by 1 year after a median of 94 days following transplantation.
Nonrelapse mortality at 1 year occurred in 16% (95% CI, 7-34); median time to death of any cause was 146 days.
After a median follow-up of 368 days, 76% (95% CI, 63-92) of patients achieved 1-year OS following transplantation.
Twenty-nine percent (95% CI, 15-50) of patients with chronic GVHD required systemic treatment with corticosteroids at 1 year, which resulted in a GVHD-free, relapse-free survival rate of 47% (95% CI, 32-69).
Correlative analyses demonstrated patients treated with vorinostat showed enhanced histone acetylation in peripheral blood marrow cells (P = .026) and reduced IL-6 (P = .028) compared with similar patients who did not receive vorinostat.
In addition, GVHD biomarkers (Reg3, P = .041; ST2, P = .002) at day 30 after HSCT also appeared lower in vorinostat-treated patients.
“It is possible that vorinostat could decrease the risk for relapse in the posttransplant setting,” Reddy and colleagues wrote. “Nonetheless, randomized trials are warranted to confirm the impact of histone deacetylase inhibition across HSCT settings.” – by Kristie L. Kahl
Disclosures: The researchers report they have no relevant financial disclosures.
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