Background: Graft-versus-host disease (GVHD) remains a significant complication following allogeneic HCT. At lower doses, histone deacetylase (HDAC) inhibition (vorinostat) has been shown to reduce GVHD through immunomodulation and may potentially offer neuroprotective effects. We conducted a phase I/II prospective, multi-site, open-label clinical trial combining vorinostat with standard immunosuppression for GVHD prevention in children and AYA patients undergoing allogeneic HCT (NCT03842696).

Methods: Eligible patients were 3–39 years old, diagnosed with a hematologic malignancy, had Lansky/Karnofsky scores >70% without organ dysfunction, and were undergoing allogenic transplant from either a fully HLA-matched (8/8 allelic match at the HLA-A, -B, -C, and -DRB1 loci) or haploidentical donor. In matched-donor transplants, patients received standard GVHD prophylaxis (tacrolimus and methotrexate) plus vorinostat (60 mg/m2 twice daily) from day -10 through day +30 post-HCT. In haploidentical-donor transplants, patients received post-transplant cyclophosphamide, mycophenolate mofetil, and tacrolimus, with vorinostat (60 mg/m2 twice daily) initiated on day +5 and continued through day +30 post-HCT. The primary endpoint was the incidence of grade 2–4 acute GVHD by day 100 post-HCT. Forty-three patients were needed to achieve 80% power to detect a reduction in grade 2–4 acute GVHD incidence of 50% to 28%, with a Type I error rate of 5%. Secondary endpoints included the incidence of relapse, non-relapse mortality (NRM), and overall survival (OS). Data were analyzed using intention-to-treat analysis. All patients were considered for toxicity through day 180, for acute GVHD through day 100, and secondary endpoints through day 365. Exploratory endpoints included neurocognitive assessments, pharmacokinetic analyses, and laboratory correlatives. Neurocognition was assessed using the NIH toolbox cognitive battery, Wide Range Achievement Test (WRAT), and Wechsler Abbreviated Scale of Intelligence (WASI). Scores were standardized based on normative data by age, with outcomes reported as standard scores (mean=100, SD=15).

Results: Between 2020–2025, 43 patients were enrolled (median age 19 years [range 3-39]; 27 males and 16 females); with diagnoses of MDS/AML (n=29) or ALL (n=14). Transplants included 25 HLA-matched unrelated donors, 7 HLA-matched related donors, and 11 haploidentical donors. Neutrophil engraftment occurred at a median of 14.5 days with no primary graft failures. No dose-limiting toxicities definitely attributable to the study drug were observed in the phase I or II portions of the study. The cumulative incidence of grade 2–4 acute GVHD was 16.2% [95% confidence interval (CI), 0.07-0.29] and 6.9% [95% CI, 0.02-0.17] for grade 3–4. The cumulative incidence of chronic GVHD requiring systemic immunosuppression was 20.9% [95% CI, 0.10-0.34]. At 1-year post-HCT, 6 patients (14.3% [95% CI, 0.0572-0.266]) experienced relapse and 4 patients (9.3%) died with a 4.6% [95% CI, 0.008- 0.14] 1-year NRM. One-year OS was 90.5% [95% CI, 0.82-0.99]. Baseline neurocognitive assessments showed significant impairments compared to the normative population.Specifically, the overall NIH Toolbox composite score was significantly lower (P<0.001), as were performances on individual subtests of processing speed (P<0.05), attention (P<0.001), and executive functioning (P<0.001). Scores of the WRAT Math subtest were also significantly lower than the normative population (P<0.001). By one-year post-HCT, there were universal upward trends across all cognitive domains. There was no longer significant impairment in overall cognitive functioning among transplant patients compared to normal controls. However, individual impairments persisted on tests of attention (P<0.001) and executive functioning (P<0.01).

Conclusions: Vorinostat for GVHD prophylaxis was well-tolerated with a low incidence of acute and chronic GVHD and encouraging 1-year OS in children and AYA patients. No dose-limiting toxicities or SAEs/AEs definitely attributable to vorinostat were observed. If validated in a larger cohort, vorinostat may serve as a promising option for acute GVHD prevention in both HLA-matched and haploidentical donor transplants, without increasing relapse rates . Additionally, our findings highlight significant neurocognitive effects that children and AYA patients bring into allogeneic HCT. Pharmacokinetic and laboratory correlative analyses are ongoing.

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2025
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