Study Offers Proof of Concept for Ixazomib Switch-Maintenance for GVHD Prophylaxis

A recent study supports the use of the oral proteasome inhibitor ixazomib for switch-maintenance prophylaxis against graft-versus-host disease (GVHD) in patients who have had allogeneic hematopoietic cell transplantation (allo-HCT).

Patients who receive reduced-intensity or nonmyeloablative conditioning plus calcineurin inhibitor (CNI)–based prophylaxis against GVHD after allo-HCT often still develop GVHD when immunosuppressive therapy is tapered. Natasia Rodriguez, a clinical research nurse in the adult bone marrow transplant service at Memorial Sloan Kettering Cancer Center, and colleagues examined wither ixazomib could help support CNI taper without increasing the rate or severity of GVHD. Ixazomib has previously been shown to have immunomodulatory activity, anti-tumor activity, and the ability to inhibit pro-inflammatory cytokines.

The open-label, prospective, single-center pilot study involved 18 patients who underwent allo-HCT for a hematologic malignancy, with a reduced-intensity or nonmyeloablative conditioning regimen and CNI-based GVHD prophylaxis 100 to 150 days later. The patients received ixazomib once weekly for three weeks, followed by one week off, for a total of 28 days. Results were published in Transplantation and Cellular Therapy.

The researchers found that ixazomib was effective. Only five of the 18 patients developed GVHD during the study period. The cumulative incidence of grade II to IV acute or chronic GVHD one year after HCT was 33% (95% confidence interval [CI], 13–55).

The study also determined that ixazomib had an acceptable safety profile. No patients died during the study period, and only one experienced a relapse of their malignancy during the study. One other patient experienced a relapse after the study period. Five patients exited the study due to side effects or toxicities, but most adverse events were grade 1 or 2 cytopenia or elevation in transaminases.

The investigators concluded that the probability of progression-free survival and GVHD-free/relapse-free survival at one year were 89% (95% CI, 75–100) and 78% (95% CI, 61–100), respectively. Patients had rapid and sustained recovery of T-cell subpopulations and B cell reconstitution, and some patients had a vaccine response with protective antibody titers.

“This study demonstrated low incidence of recurrent and late acute and chronic GVHD within one year after HCT possible associated with switch-maintenance GVHD prophylaxis using ixazomib,” the authors wrote. “This approach allowed for CNI taper while preserving graft-versus-tumor effect, without aggravating GVHD.” They added that their results offer proof of concept for this prophylactic approach.