Oral proteasome inhibitor ixazomib for switch-maintenance prophylaxis of recurrent or late acute and chronic graft-versus-host disease after day 100 in allogeneic stem cell transplantation Journal Article
| Authors: | Rodriguez, N.; Lee, J.; Flynn, L.; Murray, F.; Devlin, S. M.; Soto, C.; Cho, C.; Dahi, P.; Giralt, S.; Perales, M. A.; Sauter, C.; Ponce, D. M. |
| Article Title: | Oral proteasome inhibitor ixazomib for switch-maintenance prophylaxis of recurrent or late acute and chronic graft-versus-host disease after day 100 in allogeneic stem cell transplantation |
| Abstract: | 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, singlecenter pilot study in patients with hematologic malignancies who received an RI or NMA conditioning and CNI-based GVHD prophylaxis thatwere within day 100 to 150 after HCT (n = 18). Patientswere treatedwith 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 acutemanifestations 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 progressionfree 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. (C) 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved. |
| Keywords: | bortezomib; dendritic cell; unrelated donor transplantation; tacrolimus; phase-ii; t-cell; free survival; cyclosporine-a; chronic gvhd; initial therapy; multiple-myeloma patients; recurrent gvhd; late acute gvhd; switch-maintenance |
| Journal Title: | Transplantation and Cellular Therapy |
| Volume: | 27 |
| Issue: | 11 |
| ISSN: | 2666-6375 |
| Publisher: | Elsevier Inc. |
| Date Published: | 2021-11-01 |
| Start Page: | 920.e1 |
| End Page: | 920.e9 |
| Language: | English |
| ACCESSION: | WOS:000711385800013 |
| DOI: | 10.1016/j.jtct.2021.05.008 |
| PROVIDER: | wos |
| PUBMED: | 34029766 |
| PMCID: | PMC9126556 |
| Notes: | Article -- Source: Wos |
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