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.
Bibliographical noteFunding Information:
The authors would like to thank the National Heart, Lung, and Blood Institute and the National Cancer Institute for supporting this study (grant #U10HL069294). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We thank the laboratory of Jerome Ritz for performing all of the immunophenotyping and measuring serum BAFF levels. We thank Saurabh Chhabra, Gregory Yanik, Richard Maziarz, Suhag Parikh, Mark Litzow, Hillard Lazarus, Marcelo Pasquini, Andrew Artz, Krishna Gundabolu, Mark Juckett, Peter Westervelt, Pablo Parker, George Selby, George Chen, John Wingard, Scott Rowley, Scott Solomon, David Porter, Carlos Bachier, Paul Shaughnessy, James Essell, Marcie Riches, Thomas Shea, Michael Pulsipher, Edward Ball, John McCarty, Samantha Jaglowski, Guenther Koehne, and John Lister for enrolling patients on this trial. We thank the members of the Blood and Marrow Transplant Clinical Trials Network, the research nurses, and the patients who participated in this trial.
© 2018 Ferrata Storti Foundation.