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

Autor: Chhabra S; Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin; Blood and Marrow Transplant & Cellular Therapy Program, Froedtert & Medical College of Wisconsin, Milwaukee, Wisconsin; Center for International Blood and Marrow Transplant Research, Milwaukee Campus, Milwaukee, Wisconsin., Visotcky A; Department of Biostatistics, Medical College of Wisconsin, Milwaukee, Wisconsin., Pasquini MC; Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin; Blood and Marrow Transplant & Cellular Therapy Program, Froedtert & Medical College of Wisconsin, Milwaukee, Wisconsin; Center for International Blood and Marrow Transplant Research, Milwaukee Campus, Milwaukee, Wisconsin., Zhu F; Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin; Blood and Marrow Transplant & Cellular Therapy Program, Froedtert & Medical College of Wisconsin, Milwaukee, Wisconsin., Tang X; Center for International Blood and Marrow Transplant Research, Milwaukee Campus, Milwaukee, Wisconsin; Department of Biostatistics, Medical College of Wisconsin, Milwaukee, Wisconsin., Zhang MJ; Center for International Blood and Marrow Transplant Research, Milwaukee Campus, Milwaukee, Wisconsin; Department of Biostatistics, Medical College of Wisconsin, Milwaukee, Wisconsin., Thompson R; Center for International Blood and Marrow Transplant Research, Milwaukee Campus, Milwaukee, Wisconsin., Abedin S; Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin; Blood and Marrow Transplant & Cellular Therapy Program, Froedtert & Medical College of Wisconsin, Milwaukee, Wisconsin., D'Souza A; Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin; Blood and Marrow Transplant & Cellular Therapy Program, Froedtert & Medical College of Wisconsin, Milwaukee, Wisconsin; Center for International Blood and Marrow Transplant Research, Milwaukee Campus, Milwaukee, Wisconsin., Dhakal B; Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin; Blood and Marrow Transplant & Cellular Therapy Program, Froedtert & Medical College of Wisconsin, Milwaukee, Wisconsin., Drobyski WR; Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin; Blood and Marrow Transplant & Cellular Therapy Program, Froedtert & Medical College of Wisconsin, Milwaukee, Wisconsin., Fenske TS; Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin; Blood and Marrow Transplant & Cellular Therapy Program, Froedtert & Medical College of Wisconsin, Milwaukee, Wisconsin., Jerkins JH; Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin; Blood and Marrow Transplant & Cellular Therapy Program, Froedtert & Medical College of Wisconsin, Milwaukee, Wisconsin., Douglas Rizzo J; Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin; Blood and Marrow Transplant & Cellular Therapy Program, Froedtert & Medical College of Wisconsin, Milwaukee, Wisconsin; Center for International Blood and Marrow Transplant Research, Milwaukee Campus, Milwaukee, Wisconsin., Runaas L; Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin; Blood and Marrow Transplant & Cellular Therapy Program, Froedtert & Medical College of Wisconsin, Milwaukee, Wisconsin., Saber W; Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin; Blood and Marrow Transplant & Cellular Therapy Program, Froedtert & Medical College of Wisconsin, Milwaukee, Wisconsin; Center for International Blood and Marrow Transplant Research, Milwaukee Campus, Milwaukee, Wisconsin., Shah NN; Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin; Blood and Marrow Transplant & Cellular Therapy Program, Froedtert & Medical College of Wisconsin, Milwaukee, Wisconsin., Shaw BE; Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin; Blood and Marrow Transplant & Cellular Therapy Program, Froedtert & Medical College of Wisconsin, Milwaukee, Wisconsin; Center for International Blood and Marrow Transplant Research, Milwaukee Campus, Milwaukee, Wisconsin., Horowitz MM; Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin; Blood and Marrow Transplant & Cellular Therapy Program, Froedtert & Medical College of Wisconsin, Milwaukee, Wisconsin; Center for International Blood and Marrow Transplant Research, Milwaukee Campus, Milwaukee, Wisconsin., Hari PN; Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin; Blood and Marrow Transplant & Cellular Therapy Program, Froedtert & Medical College of Wisconsin, Milwaukee, Wisconsin; Center for International Blood and Marrow Transplant Research, Milwaukee Campus, Milwaukee, Wisconsin., Hamadani M; Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin; Blood and Marrow Transplant & Cellular Therapy Program, Froedtert & Medical College of Wisconsin, Milwaukee, Wisconsin; Center for International Blood and Marrow Transplant Research, Milwaukee Campus, Milwaukee, Wisconsin. Electronic address: mhamadani@mcw.edu.
Jazyk: angličtina
Zdroj: Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation [Biol Blood Marrow Transplant] 2020 Oct; Vol. 26 (10), pp. 1876-1885. Date of Electronic Publication: 2020 Jul 09.
DOI: 10.1016/j.bbmt.2020.07.005
Abstrakt: 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.
(Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: