Brief Articles Steroids Versus Steroids Plus Additional Agent in Frontline Treatment of Acute Graft-versus-Host Disease: A Systematic Review and Meta-Analysis of Randomized Trials Armin Rashidi 1 , * , John F. DiPersio 1 , Brenda M. Sandmaier 2 , Graham A. Colditz 3 , Daniel J. Weisdorf 4 1 Section of Bone Marrow Transplantation and Leukemia, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri 2 Clinical Research Division, Fred Hutchinson Cancer Research Center and University of Washington School of Medicine, Seattle, Washington 3 Division of Public Health Sciences, Washington University School of Medicine, St. Louis, Missouri 4 The Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, Minnesota Article history: Received 15 January 2016 Accepted 19 February 2016 Key Words: Graft-versus-host disease Meta-analysis Randomized clinical trial Steroids abstract Despite extensive research in the last few decades, progress in treatment of acute graft-versus-host disease (aGVHD), a common complication of allogeneic hematopoietic cell transplantation (HCT), has been limited and steroids continue to be the standard frontline treatment. Randomized clinical trials (RCTs) have failed to find a beneficial effect of escalating immunosuppression using additional agents. Considering the small number of RCTs, limited sample sizes, and frequent early termination because of anticipated futility, we conducted a systematic review and an aggregate data meta-analysis to explore whether a true efficacy signal has been missed because of the limitations of individual RCTs. Seven reports met our inclusion criteria. The control arm in all studies was 2 mg/kg/day prednisone (or equivalent). The additional agent(s) used in the experimental arm(s) were higher-dose steroids, antithymocyte globulin, infliximab, anti-interleukin-2 re- ceptor antibody (daclizumab and BT563), CD5-specific immunotoxin, and mycophenolate mofetil. Random effects meta-analysis revealed no efficacy signal in pooled response rates at various times points. Overall survival at 100 days was significantly worse in the experimental arm (relative risk [RR], .83; 95% confidence interval [CI], .74 to .94; P ¼ .004, data from 3 studies) and showed a similar trend (albeit not statistically significantly) at 1 year as well (RR, .86; 95% CI, .68 to 1.09; P ¼ .21, data from 5 studies). In conclusion, these results argue against the value of augmented generic immunosuppression beyond steroids for frontline treatment of aGVHD and emphasize the importance of developing alternative strategies. Novel forms of immunomodulation and targeted therapies against noneimmune-related pathways may enhance the efficacy of steroids in this setting, and early predictive and prognostic biomarkers can help identify the subgroup of patients who would likely need treatments other than (or in addition to) generic immunosuppression. Ó 2016 The American Society for Blood and Marrow Transplantation. INTRODUCTION Acute graft-versus-host disease (aGVHD) continues to be a major complication of allogeneic hematopoietic cell trans- plantation (HCT) and is associated with significant morbidity and mortality [1]. Despite more than 5 decades of research, there is no Food and Drug Administrationeapproved agent for frontline treatment of aGVHD and prednisone 2 mg/kg/ day (or equivalent) is nearly universally used for grades II to IV aGVHD [2]. Considering the limited response of aGVHD to standard frontline treatment (durable complete response [CR] < 40%) [3] and the excessive mortality (>70%) of steroid- refractory aGVHD [4], more effective strategies are desirable. Unfortunately, however, randomized frontline trials are scarce and a number of trials were halted early because of unacceptable toxicity or futility on interim analysis. This raises the question of whether a true efficacy signal exists but has not been demonstrated by individual studies. We addressed this question using an aggregate data meta- analysis of randomized clinical trials (RCTs) comparing out- comes of frontline aGVHD treatment with steroids versus steroids plus additional agent(s). Financial disclosure: See Acknowledgments on page 1136. * Correspondence and reprint requests: Armin Rashidi, MD, PhD, Departments of Hematology and Oncology Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8056, St. Louis, MO 63110. E-mail address: arashidi@dom.wustl.edu (A. Rashidi). http://dx.doi.org/10.1016/j.bbmt.2016.02.021 1083-8791/Ó 2016 The American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant 22 (2016) 1133e1144 Biology of Blood and Marrow Transplantation journal homepage: www.bbmt.org