Abstract
7 min readOVERVIEW Graft-versus-host disease (GVHD) is a potentially life-threatening complication that frequently occurs following allogeneic hematopoietic cell transplantation (HSCT). Matching of donor and recipient for major histocompatibility antigens reduces the risk of development of GVHD; however, 35–40% of fully matched recipients will still develop acute GVHD (aGVHD) due to unmatched minor histocompatibility antigens. To further reduce the risk of GVHD, various GVHD prophylactic and treatment strategies have been developed. The agents used in these strategies generally focus on reducing immune responses in the recipient post-transplant, specifically by targeted destruction, reduced production, or inhibition of T cells. Reducing graft immune response post-transplantation reduces the risk of GVHD; however, it also reduces the graft’s ability to destroy residual host tumour cells and to re-establish a host immune system, potentially leading to higher risks of relapse, infection, and mortality. The ideal strategy to prevent or treat GVHD would reduce the incidence or health impact of GVHD, with no increase in relapse or mortality. Balancing benefits with harms remains a challenge. Objectives Addressed in this Review • To compare the benefits (i.e., prevention of GVHD) and harms (e.g., risk of relapse, infection, and mortality) of competing regimens for prophylaxis of GVHD in patients undergoing HSCT, and to establish a hierarchy of intervention strategies according to their efficacy and safety. • To compare the benefits (i.e., resolution of GVHD) and harms (e.g., risk of relapse, infection, and mortality) of competing regimens for treatment of GVHD in patients undergoing HSCT, and to establish a hierarchy of intervention strategies according to their efficacy and safety. OVERVIEW OF RESEARCH METHODS Using data from randomized controlled trials, networks of evidence of GVHD prophylaxis regimens and GVHD treatment regimens were developed. For regimens that have never been directly compared in head-to-head trials, their effects can be compared using network meta-analysis to derive comparisons between therapies and to rank all regimens according to their relative effects on the outcomes of interest (e.g., the incidence of GVHD, relapse, and mortality). This approach allows us to understand the strength of the evidence supporting various interventions for the prevention and treatment of GVHD. This is helpful to generate recommendations for the optimal management of patients with GVHD, and to consider design of future RCTs that leverage the existing foundation of evidence to select the most appropriate control arm. SYSTEMATIC REVIEW METHODS The databases Medline, PubMed, Embase, and the Cochrane Register of Controlled Trials were searched for randomized trials of patients undergoing HSCT. Studies were included if patients underwent allogeneic HSCT in the treatment of hematologic neoplasias or benign disease and were randomly allocated to receive a pharmacological intervention for the prophylaxis or treatment of acute or chronic GVHD. Outcomes of interest included overall mortality, relapse of underlying disease, incidence of acute and chronic GVHD (prophylaxis review), resolution of acute and chronic GVHD (treatment review), weaning from GVHD interventions (treatment review), and specific harms. We conducted separate analyses for the prophylaxis and treatment of GVHD, using Bayesian network meta-analysis to compare interventions for outcomes of interest, where feasible. All outcomes were analysed as binary endpoints, with summary comparisons between regimens reported as odds ratios with 95% credible intervals. For outcomes for which network meta-analysis were not possible, detailed narrative summaries were prepared. RESULTS Thirty-two trials assessed 19 unique GVHD prophylactic regimens in 3,875 total patients. Overall 7 trials assessed 10 unique treatment strategies for aGVHD (4 studies) and chronic GVHD (cGVHD) (3 studies) in 830 total patients; represented regimens are listed in Table 1. Overall, there was substantial variability in patient populations with respect to age, underlying hematologic disease, disease risk of relapse/mortality, and transplant donor status (i.e., related vs. unrelated, matched vs. unmatched). Trial publication dates ranged from 1979–2015. __________________________________________________________________ Interventions compared in networks of GVHD prophylaxis and treatment a) GVHD prophylaxis • MTX+TAC • MTX • CSA • CSA+MTX • CSA+Steroids • MTX+Steroids • CSA+MTX+Steroids • MTX+TAC+Steroids • MTX+TAC+SIR • MTX+ATG+Steroids • CSA+MTX+ATG+Steroids • CSA+MTX+UDCA+Steroids • CSA+MTX+MSCs • CsA+HCQ • SIR+TAC • MMF+TAC+RTX • MMF+TAC • THAL+standard prophylaxis • Placebo+standard prophylaxis b) GVHD treatment • Steroids • CsA • CsA+Steroids • ATG+Steroids • AZA+Steroids • MMF+Steroids • ETN+Steroids • THAL+CsA+Steroid • MMF+(CsA or TAC or SIR)+Steroids • PLB+(CsA or TAC or SIR)+Steroids Abbreviations. ATG = anti-thymocyte globulin; CsA = cyclosporin A; ETN = etanercept; HCQ = hydroxychloroquine; MMF = mycophenolate mofetil; MTX = methotrexate; RITX = rituximab; SIR = sirolimus; TAC = tacrolimus; THAL = Thalidomide; UDCA = ursodeoxycholic acid. Objective 1: Comparing regimens for GVHD prophylaxis Most comparisons between treatment regimens were informed only by indirect evidence (i.e. head-to-head trials were not available), and many of the direct comparisons were informed by single studies with small numbers of patients. Thus, a sparse evidence base and considerable between-study heterogeneity in patient populations complicates targeting of findings from meta-analyses. The ideal outcome to assess cGVHD (i.e., incidence of extensive cGVHD in patients alive 100 days post-transplant) was unavailable for many trials. In its place, data for overall cGVHD in randomized patients was used. Regarding disease relapse, only studies following patients for a median duration of between 2–3 years were included for analysis. Clinical interpretation of findings from network meta-analyses were as follows: - Prevention of aGVHD and cGVHD: Compared to the reference treatment MTX+TAC, data suggested that MTX+SIR+TAC and SIR+TAC were superior for prevention of aGVHD, while CsA+MTX+ATG+Steroids was superior for prevention of cGVHD. Five regimens were statistically significantly poorer than MTX+TAC at preventing aGVHD; these were CsA+MTX, CsA+Steroids, CsA, MTX, and MTX+Steroids. Inspection of results used to inform relative rankings of all regimens for the prevention of aGVHD showed that although MTX+SIR+TAC was ranked highest, there was little difference in efficacy in the top 4 ranked interventions (MTX+SIR+TAC, SIR+TAC, CsA+MTX+MSCs, and MTX+TAC+Steroids), given their relatively similar SUCRA values (range: 0.81–0.92). For the prevention of cGVHD, CsA+MTX+ATG+Steroids was ranked highest, demonstrating significantly improved efficacy compared to all other interventions except the second-ranked intervention, HCQ+CsA. - Disease relapse and overall mortality: The best regimens at preventing acute and chronic GVHD (MTX+SIR+TAC, SIR+TAC, CsA+MTX+ATG+Steroids) and the standard of care (MTX+TAC) were the 4 regimens ranked lowest for prevention of relapse of underlying disease within 2–3 years of transplant compared to 7 other regimens that had available data for use in network meta-analysis. For these same regimens in the analysis of mortality within 1 year of transplant, SIR+TAC and MTX+SIR+TAC were ranked 12th and 13th out of 15 regimens with available data for network meta-analysis, while CsA+MTX+ATG+Steroids and MTX+TAC were ranked 4th and 9th. While the addition of ursodeoxycholic acid to CsA+MTX+Steroids significantly reduced the risk of death within 1 year of transplant, the addition of mesenchymal stem cells (MSCs) to CsA+MTX significantly increased the risk of death compared to all but one other regimen. 100-day mortality was not significantly influenced by any of the regimens evaluated. - Additional harms-related findings: Other adverse events including specific organ toxicity and infections were described in a small number of studies, precluding performance of meta-analyses. Based on available data, the addition of steroids or ATG appeared to increase the risk of CMV reactivation, while the use of SIR appeared to increase the risk of VOD. Key clinical messages regarding interventions for GVHD prophylaxis were as follows: • Regimens of single agents were less efficacious to prevent GVHD than regimens involving multiple agents; however, single-agent regimens generally were more efficacious at preventing relapse of underlying disease within 2–3 years of transplant. • Regimens containing a calcineurin inhibitor (i.e., TAC or CsA) had greater efficacy to prevent aGVHD than regimens without; however, there was no significant difference between TAC- or CsA-containing regimens. Objective 2: Comparing regimens for GVHD treatment Network meta-analyses could not be performed to compare GVHD treatment regimens. This was a consequence of two limitations of the evidence base: (1) few studies for treatment were located (n = 7), and these were split between treatment of cGVHD and aGVHD and did not produce robust networks of evidence for analysis; and (2) studies were found to be associated with several important sources of between-study heterogeneity including endpoint definitions and duration of follow-up. As formal meta-analysis was judged inappropriate, within-study comparisons were assessed and described narratively. Primary findings from included studies were as follows: - Response to treatment: MMF+Steroids was superior to Etanercept+Steroids in the treatment of aGVHD after 28 and 56 days of follow-up, and Steroids alone were superior to Alemtuzumab+Steroids in the treatment of cGVHD after 9 months. No other comparisons were associated with statistically significant differences between regimens. No treatment for aGVHD or cGV
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