Examining Vorinostat to Prevent Graft-Versus-Host Disease After Unrelated Donor HCT

While the histone deacetylase (HDAC) inhibitor vorinostat led to a low incidence of acute graft-versus-host disease (GVHD) following hematopoietic cell transplantation (HCT) with reduced-intensity conditioning and a related donor, its safety and efficacy have not been determined in HCT with an unrelated donor and more intense, myeloablative conditioning.

In a prospective, phase II trial published in Blood, Sung Won Choi, MD, from Michigan Medicine in Ann Arbor, and co-authors evaluated whether treatment with vorinostat plus standard GVHD prophylaxis was similarly effective in patients undergoing HCT from a human leukocyte antigen (HLA)-matched unrelated donor (URD).

“Given that most patients lack a suitable, related donor and that the risks of GVHD and its related mortality are increased following unrelated donor HCT, we sought to expand the use of vorinostat in GVHD prevention to this higher-risk population,” the authors wrote. They determined that “vorinostat for GVHD prevention is an effective strategy that should be confirmed in a randomized, phase III study.”

The trial included 37 patients (median age = 56 years; range = 18-69 years) with hematologic malignancies who were eligible for myeloablative HCT with a URD; 95 percent of patients had acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS). Patients undergoing a total-body irradiation–based conditioning regimen or those who received an HDAC inhibitor within 30 days of enrollment were excluded.

Patients received a myeloablative conditioning regimen consisting of intravenous fludarabine 160 mg/m2 and intravenous busulfan 12.8 mg/kg, followed by an infusion of stem cells on the day of HCT. GVHD prophylaxis consisted of tacrolimus (0.03 mg/kg/day intravenously or 0.045 mg/kg/day orally, starting 3 days before HCT) and methotrexate (5 mg/m2 intravenously, once-daily, 1, 3, 6, and 11 days after HCT). All patients received vorinostat 100 mg twice-daily, starting 10 days before transplant and continuing through day 100 after HCT.

Most patients (n=32; 86%) received an HCT from an HLA-matched URD (8/8 HLA-A, B, C, and DRB1; n=32; 86%), and five patients received HCT from a DQ-mismatched donor. All patients achieved sustained engraftment while taking vorinostat with tacrolimus and methotrexate, and no cases of graft failure were reported.

All but one patient (97%) received at least 60 percent of the planned vorinostat daily dose, and the median duration of vorinostat treatment in the entire study population was 106 days (range = 39-111 days).

Twenty-six patients (70%) required dose modifications, and 24 patients (65%) had vorinostat withheld for one to 59 days. Most adjustments were related to low platelet counts, gastrointestinal (GI) symptoms, or elevated creatinine or bilirubin levels. Overall, the researchers reported that there were no deaths attributable to vorinostat, and “no drug-related toxic effects arose that warranted discontinuation of vorinostat.”

Eight patients (22%) developed acute grade 2-4 GVHD at 100 days post-HCT (primary endpoint), including five patients with grade 2 and three with grade 4 GVHD, with a median time to onset of 32 days (range = 19-48 days). The three patients who developed grade 4 acute GVHD died during study follow-up.

“The low incidence of acute GVHD persisted through day 180, over two months after cessation of vorinostat,” the authors reported. At one year, the incidence of acute GVHD was 32 percent because of three cases of GI GVHD after day 180. This incidence “compared favorably” with previous studies, including “seminal studies of GVHD prophylaxis with tacrolimus and methotrexate, which reported 42 to 49 percent incidence of grade 2-4 acute GVHD at day 100 following URD HCT.”

After a median follow-up of 368 days (range = 51-1,275 days), the one-year overall survival rate was 76 percent. Ten patients died because of relapse (n=4), GVHD-related complications (n=3), failure to thrive (n=1), respiratory failure secondary to infection (n=1), or interstitial pulmonary fibrosis (n=1).

Nineteen percent of patients relapsed at one year after HCT, a median of 94 days post-HCT (range = 61-916 days). The one-year cumulative incidence of chronic GVHD that required systemic corticosteroid therapy was 29 percent, for a GVHD-free, relapse-free survival rate of 47 percent. This suggests “that sufficient graft-versus-leukemia responses were preserved,” the authors wrote.

To characterize the on-target effects of vorinostat, the researchers also conducted correlative lab tests on blood samples from study patients and a control group of HCT recipients who did not receive vorinostat. Acetylated-H3 levels appeared to be higher in vorinostat-treated patients, compared with controls (p=0.026). Levels of interleukin-6 (p=0.028) and biomarkers of GVHD (Reg3α, p=0.041; soluble ST2, p=0.002) taken at day 30 post-HCT also appeared to be reduced, “consistent with attenuated systemic inflammation,” the authors noted.

The study is limited by the small population and the single-arm, single-center design.

The authors report no conflicts.


Reference

Choi SW, Braun T, Henig I, et al. Vorinostat plus tacrolimus/methotrexate to prevent GVHD following myeloablative conditioning unrelated donor HCT. Blood. 2017 August 7. [Epub ahead of print]

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