Despite advances in high resolution HLA typing, GvHD remains a major complication after allo-HCT and results in significant mortality and morbidity. Transplant related mortality (TRM) in patients with severe acute GvHD has been estimated to be in the range of 28 to 92%. The 3-year risk for TRM in patients with chronic GVHD ranges from 28 to 48% depending on the extent of GVHD (limited versus extensive). Effective GvHD prophylaxis is key to prevention of GvHD. ATG is one of several immunosuppressive agents widely used for GvHD prophylaxis following allo-HCT. The effect of ATG for the prevention of GVHD has been evaluated in several randomized controlled trials (RCTs). However, data on the efficacy of ATG for the prevention of GvHD has been conflicting across RCTs. Informed clinical decision-making requires synthesis of all research evidence. Therefore, we have performed a systematic review to assess effect of ATG for GvHD prophylaxis in patients undergoing allo-HCT for various hematologic diseases.
All completed phase III RCTs comparing use of ATG versus control for the prevention of GVHD in patients undergoing allo-HCT were eligible for inclusion. Medline (PubMed), and Cochrane database of RCTs published through April 2010 were searched to identify potentially relevant studies. Abstracts from the annual proceedings of the American Society of Hematology (2008-2009), American Society for Clinical Oncology (2008-2009) were also searched. Data were extracted on benefits and harms associated with compared treatments (ATG versus “no ATG”). Outcomes analyzed included: (i) GvHD incidence (ii) overall survival and (iii) TRM. Data on the methodological quality of included RCTs were also extracted to assess the robustness of the findings. Any discrepancies in data extraction were resolved by consensus. Data were pooled under a random effects model. A formal statistical test for heterogeneity using the chi square and I2 test was performed. The meta-analysis was performed using Review Manager Software.
Initial search of Pubmed, Cochrane database of RCTs and ASH and ASCO meeting abstracts yielded 141 citations of which 7 RCTs met the pre-defined inclusion criteria. Altogether these RCTs enrolled a total of 733 patients. The pooled results showed a statistically non-significant benefit for overall survival (7 RCT, 733 patients) with use of ATG for the prevention of GVHD. The combined hazard ratio (HR) for the comparison of ATG versus no ATG was 0.91 (95%CI, 0.75 to 1.10; p=0.32). There was no heterogeneity among included studies. The results did not change when data was analyzed according to the source of ATG (horse versus rabbit). There was a statistically significant benefit associated with ATG use for the prevention of severe grade III-IV acute GVHD (5 RCTs, 609 patients). The risk ratio (RR) was 0.56 (95%CI, 0.38 to 0.82; p=0.003). There was a statistically significant heterogeneity among included trials. However, there was no benefit with use of ATG for the prevention of either grade II (3 RCTs, 238patients; RR=0.78; 95%CI, 0.47 to 1.29; p=0.33) or grade I acute GVHD (2 RCTs, 185 patients; RR=1.42; 95%CI, 0.75 to 2.69; p=0.28). Use of ATG was not associated with any significant effect on TRM. The risk ratio was 0.74 (95%CI, 0.53 to 1.03; p=0.08). The results were not affected by methodological quality of studies.
This comprehensive assessment of the effect of ATG in preventing GvHD in patients undergoing allo-HCT suggests that ATG has a beneficial effect on the prevention of severe grade III-IV acute GvHD. However, the available research evidence does not show a significant impact on overall survival. Additional prospective trials with adequate sample size are still needed to provide a more definitive answer.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.