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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.

SUBMITTER: Chhabra S

PROVIDER: S-EPMC7571859 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Graft-versus-host disease (GVHD) is a frequent complication in the first year after allogeneic stem cell transplantation (allo-HCT). Recipients of reduced-intensity (RI) or nonmyeloablative (NMA) conditioning combined with calcineurin inhibitor (CNI)-based GVHD prophylaxis frequently develop GVHD in the context of immunosuppression taper. Ixazomib is an oral proteasome inhibitor with a wide safety profile that has demonstrated immunomodulatory properties, inhibition of pro-inflammatory cytokines, and anti-tumor activity. We hypothesized that switch-maintenance GVHD prophylaxis using ixazomib would facilitate CNI taper without increased GVHD frequency and severity while maintaining graft-versus-tumor (GVT) effect and an acceptable safety profile. We conducted an open-label, prospective, single-center pilot study in patients with hematologic malignancies who received an RI or NMA conditioning and CNI-based GVHD prophylaxis that were within day 100 to 150 after HCT (n = 18). Patients were treated with ixazomib once weekly on a 28-day cycle (3 weeks on, 1 week off). Treatment was safe; most adverse events were grade 1 or 2, with cytopenia and elevation in transaminases the most common. Five patients were removed from the study because of toxicity or side effects. Only 5 of 18 patients developed GVHD during the study, and its severity was driven by acute manifestations while chronic involvement was mild. The cumulative incidence of grade II-IV acute and chronic GVHD at 1-year after HCT was 33% (95% confidence interval [CI], 13-55). No patients died during the study, and only 1 had malignant relapse. An additional patient relapsed after completion of the study but within 1 year after HCT. The probability of progression-free survival and GVHD-free/relapse-free survival (composite endpoint) at 1 year were 89% (95% CI, 75-100) and 78% (95% CI, 61-100), respectively. Immune reconstitution analysis showed a rapid and sustained recovery in T-cell subpopulations and B cell reconstitution, and vaccine response in a subset of patients demonstrated continuing or de novo positive protective antibody titers. This study demonstrated low incidence of recurrent and late acute and chronic GVHD within 1 year after HCT possible associated with switch-maintenance GVHD prophylaxis using ixazomib. This approach allowed for CNI taper while preserving GVT effect, without aggravating GVHD. Our findings support further development of this approach and provide a proof-of-concept for switch-maintenance GVHD prophylaxis.

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

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