title: Steroids Versus Steroids Plus Additional Agent in Frontline Treatment of Acute Graft-versus-Host Disease: A Systematic Review and Meta-Analysis of Randomized Trials.
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 receptor 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 = .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 = .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 non-immune-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.
authors.affiliation: Section of Bone Marrow Transplantation and Leukemia, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri. Electronic address: arashidi@dom.wustl.edu.
authors.forename: Armin
authors.initials: A
authors.lastname: Rashidi
authors.affiliation: Section of Bone Marrow Transplantation and Leukemia, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: John F
authors.initials: JF
authors.lastname: DiPersio
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center and University of Washington School of Medicine, Seattle, Washington.
authors.forename: Brenda M
authors.initials: BM
authors.lastname: Sandmaier
authors.affiliation: Division of Public Health Sciences, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Graham A
authors.initials: GA
authors.lastname: Colditz
authors.affiliation: The Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Weisdorf
mesh_terms: D000208:Acute Disease; D004359:Drug Therapy, Combination / Q000592:standards*; D006086:Graft vs Host Disease / Q000188:drug therapy*; D006801:Humans; D007165:Immunosuppression Therapy / Q000379:methods*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D013256:Steroids / Q000627:therapeutic use*
chemical_list: D007166:Immunosuppressive Agents; D013256:Steroids
keywords: Graft-versus-host disease; Meta-analysis; Randomized clinical trial; Steroids