A phase II/III randomized, multicenter trial of prednisone/sirolimus versus prednisone/sirolimus/calcineurin inhibitor for the treatment of chronic graft-versus-host disease: BMT CTN 0801

• Type of Material: Article
• Authors: Paul A. Carpenter, Fred Hutchinson Cancer Research Center; Brent R. Logan, Medical College of Wisconsin; Stephanie J. Lee, Fred Hutchinson Cancer Research Center; Daniel J. Weisdorf, University of Minnesota; Laura Johnston, Stanford Hospital & Clinics; Luciano J. Costa, University of Alabama Birmingham; Carrie L. Kitko, Vanderbilt University; Javier Bolanos-Meade, Johns Hopkins; Stefanie Sarantopoulos, Duke University; Amin M. Alousi, University of Texas MD Anderson Cancer Center; Sunil Abhyankar, University of Kansas; Edmund Waller, Emory University; Adam Mendizabal, Emmes Corporation; Jiaxi Zhu, Emmes Corporation; Kelly A. O'Brien, Emmes Corporation; Aleksandr Lazaryan, University of Minnesota; Juan Wu, Emmes Corporation; Eneida R. Nemecek, Oregon Health and Science University; Steven Z. Pavletic, National Cancer Institute; Corey S. Cutler, Dana Farber Cancer Institute; Mary M. Horowitz, Medical College of Wisconsin; Mukta Arora, University of Minnesota
• Language: English
• Date: 2018-10-31
• Publisher: Ferrata Storti Foundation
• Publication Version: Final Published Version
• Copyright Statement: © 2018 Ferrata Storti Foundation.
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3324/haematol.2018.195123
• Title of Journal or Parent Work: Haematologica
• ISSN: 0390-6078
• Volume: 103
• Issue: 11
• Start Page: 1915
• End Page: 1924
• Grant/Funding Information: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.; The authors would like to thank the National Heart, Lung, and Blood Institute and the National Cancer Institute for supporting this study (grant #U10HL069294).
• Keywords: Hematology; Science & Technology; CRITERIA; Life Sciences & Biomedicine; FAILURE-FREE SURVIVAL; REGULATORY T-CELLS; MEASURING THERAPEUTIC RESPONSE; RAPAMYCIN; DIAGNOSIS; CYCLOSPORINE; CLINICAL-TRIALS; CONSENSUS DEVELOPMENT PROJECT; EXTRACORPOREAL PHOTOCHEMOTHERAPY
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Oncology; Health Sciences, Pharmacology

Abstract

Initial therapy of chronic graft-versus-host disease is prednisone ± a calcineurin-inhibitor, but most patients respond inadequately. In a randomized, adaptive, phase II/III, multicenter trial we studied whether prednisone/sirolimus or prednisone/sirolimus/photopheresis was more effective than prednisone/sirolimus/calcineurin-inhibitor for treating chronic graft-versus-host disease in treatment-naïve or early inadequate responders. Primary endpoints of this study were proportions of subjects alive without relapse or secondary therapy with 6-month complete or partial response in phase II, or with 2-year complete response in phase III. The prednisone/sirolimus/photopheresis arm closed prematurely because of slow accrual and the remaining two-drug versus three-drug study ended in phase II due to statistical futility with 138 evaluable subjects. The two-drug and three-drug arms did not differ in rates of 6-month complete or partial response (48.6% versus 50.0%, P=0.87), or 2-year complete response (14.7% versus 15.5%, P=0.90). Serum creatinine values >1.5 times baseline were less frequent in the calcineurin-inhibitor-free arm at 2 months (1.5% versus 11.7%, P=0.025) and 6 months (7.8% versus 24.0%, P=0.016). Higher adjusted Short Form-36 Physical Component Summary and Physical Functioning scores were seen in the two-drug arm at both 2 months (P=0.02 and P=0.04, respectively) and 6 months (P=0.007 and P=0.001, respectively). Failure-free survival and overall survival rates at 2 years were similar for patients in the the two-drug and three-drug arms (48.6% versus 46.2%, P=0.78; 81.5% versus 74%, P=0.28). Based on similar long-term outcomes, prednisone/sirolimus is a therapeutic alternative to prednisone/sirolimus/calcineurin-inhibitor for chronic graft-versus-host disease, being easier to administer and better tolerated. Clinicaltrials.gov identifier: NCT01106833.