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Ixazomib for Chronic Graft-versus-Host Disease Prophylaxis following Allogeneic Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant 2020 Oct;26(10):1876-1885

Date

07/13/2020

Pubmed ID

32653622

Pubmed Central ID

PMC7571859

DOI

10.1016/j.bbmt.2020.07.005

Scopus ID

2-s2.0-85089134303   1 Citation

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.

Author List

Chhabra S, Visotcky A, Pasquini MC, Zhu F, Tang X, Zhang MJ, Thompson R, Abedin S, D'Souza A, Dhakal B, Drobyski WR, Fenske TS, Jerkins JH, Douglas Rizzo J, Runaas L, Saber W, Shah NN, Shaw BE, Horowitz MM, Hari PN, Hamadani M

Authors

Sameem Abedin MD Assistant Professor in the Medicine department at Medical College of Wisconsin
Anita D'Souza MD Associate Professor in the Medicine department at Medical College of Wisconsin
Binod Dhakal MD Associate Professor in the Medicine department at Medical College of Wisconsin
William R. Drobyski MD Professor in the Medicine department at Medical College of Wisconsin
Timothy Fenske MD Professor in the Medicine department at Medical College of Wisconsin
Mehdi H. Hamadani MD Professor in the Medicine department at Medical College of Wisconsin
Mary M. Horowitz MD, MS Professor in the Medicine department at Medical College of Wisconsin
James H. Jerkins MD Assistant Professor in the Medicine department at Medical College of Wisconsin
Marcelo C. Pasquini MD, MS Professor in the Medicine department at Medical College of Wisconsin
J. Douglas Rizzo MD, MS Director, Center Associate Director, Professor in the Medicine department at Medical College of Wisconsin
Lyndsey Runaas MD Assistant Professor in the Medicine department at Medical College of Wisconsin
Wael Saber MD, MS Professor in the Medicine department at Medical College of Wisconsin
Nirav N. Shah MD Associate Professor in the Medicine department at Medical College of Wisconsin
Bronwen E. Shaw MBChB, PhD Center Director, Professor in the Medicine department at Medical College of Wisconsin
Alexis M. Visotcky Biostatistician III in the Institute for Health and Equity department at Medical College of Wisconsin
Mei-Jie Zhang PhD Professor in the Institute for Health and Equity department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Boron Compounds
Chronic Disease
Glycine
Graft vs Host Disease
Hematopoietic Stem Cell Transplantation
Humans
Tacrolimus
Transplantation Conditioning