Haematologica (Nov 2018)

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

DOI
https://doi.org/10.3324/haematol.2018.195123
Journal volume & issue
Vol. 103, no. 11

Abstract

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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.