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
Paul A. Carpenter,
Brent R. Logan,
Stephanie J. Lee,
Daniel J. Weisdorf,
Laura Johnston,
Luciano J. Costa,
Carrie L. Kitko,
Javier Bolaños-Meade,
Stefanie Sarantopoulos,
Amin M. Alousi,
Sunil Abhyankar,
Edmund K. Waller,
Adam Mendizabal,
Jiaxi Zhu,
Kelly A. O’Brien,
Aleksandr Lazaryan,
Juan Wu,
Eneida R. Nemecek,
Steven Z. Pavletic,
Corey S. Cutler,
Mary M. Horowitz,
Mukta Arora
Affiliations
Paul A. Carpenter
Fred Hutchinson Cancer Research Center, Seattle, WA
Brent R. Logan
Medical College of Wisconsin, Milwaukee, WI
Stephanie J. Lee
Fred Hutchinson Cancer Research Center, Seattle, WA
Daniel J. Weisdorf
University of Minnesota, Minneapolis, MN
Laura Johnston
Stanford Hospital and Clinics, Stanford, CA
Luciano J. Costa
University of Alabama at Birmingham, AL
Carrie L. Kitko
Vanderbilt University School of Medicine, Nashville, TN
Javier Bolaños-Meade
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD
Stefanie Sarantopoulos
Duke University Medical Center, Durham, NC
Amin M. Alousi
University of Texas MD Anderson Cancer Center, Houston, TX
Sunil Abhyankar
The University of Kansas Medical Center, Kansas City, KS
Edmund K. Waller
Emory University School of Medicine, Atlanta, GA
Adam Mendizabal
The Emmes Corporation, Rockville, MD
Jiaxi Zhu
The Emmes Corporation, Rockville, MD
Kelly A. O’Brien
The Emmes Corporation, Rockville, MD
Aleksandr Lazaryan
University of Minnesota, Minneapolis, MN
Juan Wu
The Emmes Corporation, Rockville, MD
Eneida R. Nemecek
Oregon Health and Sciences University, Portland, OR
Steven Z. Pavletic
Experimental Transplantation and Immunology Branch, National Cancer Institute, Bethesda, MD
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.
