Anti-thymocyte globulins for post-transplant graft-versus-host disease prophylaxis-A systematic review and meta-analysis.

BACKGROUND: Despite advances made in allogeneic hematopoietic stem cell transplantation (alloSCT), graft versus host disease (GvHD) remains a major problem. The main strategy to combat GvHD is prophylaxis and ATG plays a major role in this arena. Conflicting reports on the effectiveness of ATG on GvHD prevention prompted us to address this question by means of a systematic review and meta-analysis. METHODS: Six prospective randomized controlled trials (RCT) comparing the addition of ATG to standard immunosuppressive regimen as GvHD prophylaxis were analyzed. All ATG preparations were considered but homogeneity in type of preparation and dosage had to be observed within each trial. RESULTS: Our meta-analysis reveals that the incidence of grade II-IV GvHD was significantly lower in patients receiving ATG. Addition of ATG had no impact on overall survival, relapse or non-relapse mortality. CONCLUSIONS: Based on the current level of the data analyzed in this systematic review, we cannot conclude a general recommendation for the use of ATG for GvHD prophylaxis in alloSCT. In patients who are at high risk for severe GvHD it should be considered individually. However, due to the heterogeneity of the analyzable studies it seems likely that future studies might change the results of the pooled data of this meta-analysis. In order to improve the current level of data, further randomized studies in this topic are therefore urgently warranted.

Polyclonal anti-thymocyte globulins for the prophylaxis of graft-versus-host disease after allogeneic stem cell or bone marrow transplantation in adults.

BACKGROUND: Allogeneic haematopoietic stem cell transplantation (HSCT) is an established treatment for many malignant and non-malignant haematological disorders. Graft-versus-host disease (GVHD), a condition frequently occurring after HSCT, is the result of host tissues being attacked by donor immune cells. One strategy for the prevention of GVHD is the administration of anti-thymocyte globulins (ATG), a set of polyclonal antibodies directed against a variety of immune cell epitopes, leading to immunosuppression and immunomodulation. OBJECTIVES: To assess the effect of ATG used for the prevention of graft-versus-host disease (GVHD) in patients undergoing allogeneic HSCT with regard to overall survival, incidence and severity of acute and chronic GVHD, incidence of relapse, incidence of infectious complications, non-relapse mortality, early mortality within 100 days of transplantation, progression-free survival, quality of life and adverse events. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 3), MEDLINE (January 1950 to February 2012), trials registries and conference proceedings. The search was conducted in October 2010 and was updated in July 2011 and February 2012. We did not apply any language restrictions. SELECTION CRITERIA: We included randomised controlled trials (RCTs) investigating the impact of ATG on GVHD prophylaxis in adults suffering from haematological diseases and undergoing allogeneic HSCT. Treatment arms had to differ only in the addition of ATG to the standard GVHD prophylaxis regimen. DATA COLLECTION AND ANALYSIS: Two review authors screened abstracts, extracted data and analysed the data independently. We contacted study authors for additional information. MAIN RESULTS: We included in the meta-analysis six RCTs which met the pre-defined selection criteria, involving a total of 568 participants. Quality of data reporting was heterogeneous among these studies with a lack of detailed information in the early studies.The primary outcome of overall survival was not significantly changed by the addition of ATG for the prophylaxis of GVHD (harms ratio (HR) 0.88; 95% CI 0.67 to 1.15, P = 0.33).The incidence of treatment-requiring or severe acute GVHD (grade II to IV) was significantly lower in patients who received ATG (risk ratio (RR) 0.68; 95% CI 0.55 to 0.85, P = 0.009; number needed to treat (NNT) 8). Also, the incidence of severe acute GVHD (grade III to IV) was significantly reduced (HR 0.53; 95% CI 0.33 to 0.85, P = 0.0005; NNT 7) but comparable data were available for rabbit ATG only. However, pooled study results regarding the incidence of acute GVHD of all grades (I to IV) showed no significant benefit of ATG treatment (RR 0.89; 95% CI 0.74 to 1.06, P = 0.20).Meta-analysis of data regarding the incidence of overall chronic GVHD (both, limited and extensive) was not possible. Nevertheless, studies reporting on extensive chronic GVHD (only studies evaluating rabbit ATG) suggested a lower incidence of extensive chronic GVHD whereas others that only reported on overall chronic GVHD did not show an advantage for ATG.Pooled results regarding the incidence of relapse were not significantly different (RR 1.13; 95% CI 0.75 to 1.68, P = 0.56), as well as pooled results regarding non-relapse mortality (HR 0.82; 95% CI 0.55 to 1.24, P = 0.35).Due to the lack of comparable data, we could not perform meta-analysis of data regarding the incidence of chronic GVHD, relapse-related mortality, progression-free survival, quality of life, adverse events and engraftment. AUTHORS' CONCLUSIONS: Our systematic review suggests that the addition of ATG during allogeneic HSCT significantly reduces the incidence of severe grades (II to IV) of acute GvHD, whereas the incidence of overall acute GVHD (grades I to IV) was not significantly lowered. This indicates a reduction of the severity but not the incidence of acute GVHD. However, this effect did not lead to a significant improvement of overall survival, which may be due to the severe potential side effects of the consecutively increased immunosuppression.Furthermore, future research is needed to clarify the effect of ATG on the incidence and severity of chronic GVHD and consequently on all aspects of quality of life.From the currently available data, no recommendation on the general use of ATG in allogeneic HSCT can be supported. Therefore, a careful consideration of the use of ATG based on the patient's condition and the risk factors of the transplantation setting should be made.