Ixazomib for Chronic Graft-versus-Host Disease Prophylaxis following Allogeneic Hematopoietic Cell Transplantation

Abstract

Chronic graft-versus-host disease (cGVHD) is major cause of morbidity and mortality following allogeneic hematopoietic cell transplantation (HCT). Ixazomib is an oral, second-generation, proteasome inhibitor that has been shown in preclinical models to prevent GVHD. We conducted a phase I/II trial in 57 patients to evaluate the safety and efficacy of ixazomib administration for cGVHD prophylaxis in patients undergoing allogeneic HCT. Oral ixazomib was administered on a weekly basis for a total of 4 doses, beginning days +60 through +90, to recipients of matched related donor (MRD, n = 25) or matched unrelated donor (MUD, n = 26) allogeneic HCT in phase II portion of the study, once the recommended phase II dose of 4 mg was identified in phase I (n = 6). All patients received peripheral blood graft and standard GVHD prophylaxis of tacrolimus and methotrexate. Ixazomib administration was safe and well tolerated, with thrombocytopenia, leukopenia, gastrointestinal complaints, and fatigue the most common adverse events (>10%). In phase II (n = 51), the cumulative incidence of cGVHD at 1 year was 36% (95% confidence interval [CI], 19% to 54%) in the MRD cohort and 39% (95% CI, 21% to 56%) in the MUD cohort. One-year cumulative incidence of nonrelapse mortality (NRM) and relapse was 0% and 20% (95% CI, 8% to 36%) in the MRD cohort, respectively. In the MUD cohort, the respective NRM and relapse rates were 4% (0% to 16%) and 34% (17% to 52%). The outcomes on the study were compared post hoc with contemporaneous matched Center for International Blood and Marrow Transplant Research (CIBMTR) controls. This post hoc analysis showed no significant improvement in cGVHD rates in both the MRD (hazard ratio [HR] = 0.85, P = .64) or MUD cohorts (HR = 0.68, P = .26) on the study compared with CIBMTR controls. B cell activating factor plasma levels were significantly higher after ixazomib dosing in those who remained cGVHD free compared with those developed cGVHD. This study shows that the novel strategy of short-course oral ixazomib following allogeneic HCT is safe but did not demonstrate significant improvement in cGVHD incidence in recipients of MRD and MUD transplantation compared with matched CIBMTR controls. This study is registered at www.clinicaltrials.gov as NCT02250300.

Keywords: Allogeneic hematopoietic cell transplantation; Graft-versus-host disease; Ixazomib.

Figure 1.

A. Cumulative incidence of chronic GVHD and moderate/severe chronic GVHD at 1 year in the matched related donor cohort of the phase II study B. Cumulative incidence of chronic GVHD and moderate/severe chronic GVHD at 1 year in the matched unrelated donor cohort of the phase II study

Figure 2.

A. Baseline (pre-ixazomib) BAFF levels in phase II patients with no chronic GVHD vs. with chronic GVHD B. Pre- and post-ixazomib BAFF levels in phase II patients with no chronic GVHD C. Pre- and post-ixazomib BAFF levels in phase II patients with chronic D. Post-ixazomib BAFF levels in phase II patients with no chronic GVHD vs. with chronic GVHD E. Pre- and post-ixazomib BAFF: B cell ratio levels in phase II patients with chronic GVHD F. Pre- and post-ixazomib BAFF: B cell ratio levels in phase II patients with no chronic GVHD G. Pre- and post-ixazomib Tregs in phase II patients with no chronic GVHD H. Pre- and post-ixazomib Tregs in phase II patients developing chronic GVHD