Clinical trials of chronic graft-versus-host disease (cGVHD) often use early endpoints, such as clinical response at 3 or 6 months, as the primary endpoint instead of measures of long-term treatment success, such as the ability to discontinue immunosuppressive treatment after development of immune tolerance and resolution of active disease. We evaluated the ability of defined overall and organ-specific response categories at 3 and 6 months to predict the subsequent success or failure of primary treatment. The analysis included 116 patients evaluated at 3 months after enrollment and 94 patients evaluated at 6 months after enrollment. Success was defined as withdrawal of systemic treatment after resolution of cGVHD without secondary therapy. Failure was defined as secondary systemic treatment, or death or development of bronchiolitis obliterans during primary treatment. With most definitions, response at 3 months and response at 6 months were not statistically significantly correlated with subsequent success of primary treatment. With some definitions, the absence of response at 6 months had a statistically significant correlation with subsequent failure of primary treatment. These findings suggest that early response to the agents currently used for primary treatment does not necessarily predict subsequent tolerance, an important endpoint in the management of cGVHD. Rigorously defined clinical response is an appropriate primary endpoint for studies of cGVHD, but future clinical trials should provide for extended follow-up to ascertain late outcomes that are not necessarily predictable by evaluation of response before 6 months.
Bibliographical noteFunding Information:
The authors thank Jeanne Maffit, MaryJoy Lopez, Sheri Shanabarger, Maggie Jackson, and Barbara Manion for study coordination; Jane Jocom for nursing support; Peggy Adams Myers for administrative assistance; Dr Katherine Guthrie for statistical support to the Data and Safety Monitoring Board (DSMB); Drs Donna Neuberg, Joachim Deeg, Andrew Gilman, John Zaia, and Steve Pavletic and Ms Susan Stewart for service as members of the DSMB; Caroline McKallor and Geoff Hirschi for assistance with data management; Sheree Miller and staff at the University of Washington and Daniel McMannis and the staff at Costco for pharmacy services. They thank the coordinating liaisons and study nurses at each of the participating centers for assistance with implementing the study at each participating site. They also thank Stuart Tenney for assistance in preparing the manuscript and Dr Yoshihiro Inamoto for reviewing the manuscript. They especially thank the patients who agreed to participate in the study. Participating centers included the Fred Hutchinson Cancer Research Center, University of Minnesota, Hackensack University Medical Center, University of Florida, Baylor University Medical Center at Dallas, Stanford University, University of Nebraska, Texas Transplant Institute, Vanderbilt University, University of Chicago, City of Hope Medical Center, Oregon Health and Science University, M.D. Anderson Cancer Center, Princess Margaret Hospital, and the University of Michigan. This research was supported by grant CA98906 from the National Cancer Institute, Department of Health and Human Services , by a grant from Roche Laboratories , represented by Dr. Kristine Golebski, and by a grant from the Office of Naval Research , administered through the National Marrow Donor Program. The double-blinded design of this study would not have been feasible without the study drug generously supplied by Roche Laboratories.
Financial disclosure: Paul J. Martin and Daniel Weisdorf received research funding from Roche Laboratories. None of the other authors declares any conflict of interest.
- Hematopoietic cell transplantation
- Mycophenolate mofetil
- Randomized controlled clinical trial