A Phase I/2 Study of Ixazomib for Chronic Graft-Versus-Host Disease (cGVHD) Prophylaxis after Allogeneic Transplantation (alloHCT).

Background Chronic GVHD (cGVHD) causes significant morbidity and mortality after alloHCT. Oral proteasome inhibitor, ixazomib (Ixa) regulates dendritic cell maturation, decreases proinflammatory cytokines and modulates GVHD in murine model. The efficacy of Ixa in preventing cGVHD is unknown. Methods We report here a phase 1/2 trial (NCT02250300) evaluating safety and efficacy of Ixa for cGVHD prophylaxis. Adult hematologic malignancy patients (pts) status post a peripheral blood (PB) alloHCT with tacrolimus/methotrexate-based GVHD prophylaxis and no grade 3-4 aGVHD or steroid-refractory aGVHD were eligible. Recipients of matched related donor (MRD) and matched unrelated donor (MUD) alloHCT were enrolled in 2 independent cohorts. In vivo and ex vivo T-cell depletion was not permitted. Oral Ixa was started days 60-90 post-HCT for 4 weekly doses. Primary outcome was cumulative incidence (CI) of cGVHD at 1-yr by NIH criteria. The cGVHD was graded by an Independent Review Panel (IRP). Results No dose-limiting toxicities were seen in phase I and recommended phase II dose was 4 mg. 25 MRD and 26 MUD alloHCT pts were enrolled. The IRP assessed CI of cGVHD at 1-yr was 31% and 37% in MRD and MUD cohorts, respectively. The respective figures for moderate-severe cGVHD were 22% and 28%. 1-yr non-relapse mortality and relapse in MRD and MUD cohorts were 0% and 4% and 20% and 35%, respectively. 1-yr PFS of 80% and 64% and 1-year OS of 92% and 88% were seen in MRD and MUD cohorts, respectively. Serum B-cell activating factor (BAFF) levels before and after Ixa exposure increased significantly in pts who did not develop cGVHD (median, 2459 vs. 6969 pg/mL, p=.001), and in those without moderate/severe cGVHD (median, 2989 vs. 6438 pg/mL, p=.002). Treg counts before and after Ixa (median, 34 vs. 34.5/µL) for the overall cohort were similar. Conclusion Ixa is feasible, safe and potentially effective for cGVHD prophylaxis after PB alloHCT. BAFF level after Ixa may serve as a biomarker for later development of cGVHD. [ABSTRACT FROM AUTHOR]