title: Polyclonal anti-thymocyte globulins for the prophylaxis of graft-versus-host disease after allogeneic stem cell or bone marrow transplantation in adults.
abstract: 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.
  
  
  OBJECTIVE
  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.
  
  
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  Two review authors screened abstracts, extracted data and analysed the data independently. We contacted study authors for additional information.
  
  
  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.
  
  
  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.
authors.affiliation: Department I of Internal Medicine, Stem Cell Transplantation Program, University Hospital of Cologne, Cologne, Germany. sebastian.theurich@uk-koeln.de.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Theurich
authors.forename: Hans
authors.initials: H
authors.lastname: Fischmann
authors.forename: Alexander
authors.initials: A
authors.lastname: Shimabukuro-Vornhagen
authors.forename: Jens M
authors.initials: JM
authors.lastname: Chemnitz
authors.forename: Udo
authors.initials: U
authors.lastname: Holtick
authors.forename: Christof
authors.initials: C
authors.lastname: Scheid
authors.forename: Nicole
authors.initials: N
authors.lastname: Skoetz
authors.forename: Michael
authors.initials: M
authors.lastname: von Bergwelt-Baildon
mesh_terms: D000208:Acute Disease; D000328:Adult; D000961:Antilymphocyte Serum / Q000627:therapeutic use*; D016026:Bone Marrow Transplantation / Q000009:adverse effects* / Q000276:immunology; D002908:Chronic Disease; D006086:Graft vs Host Disease / Q000209:etiology / Q000401:mortality / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D015994:Incidence; D016032:Randomized Controlled Trials as Topic; D012008:Recurrence; D014184:Transplantation, Homologous
chemical_list: D000961:Antilymphocyte Serum