Anti-thymocyte globulins for the prevention of graft-versus-host disease in patients receiving allogeneic stem cell transplantation

Allogeneic haematopoietic (blood) stem cell transplantation (HSCT) is a potentially curative therapeutic option for a variety of malignant and some non-malignant haematological (blood-related) diseases. For this therapy, blood stem cells are transferred from a healthy person who has compatible tissue markers, so-called human leukocyte antigen (HLA) markers, to a matched recipient. Even though the donor and the recipient are matched concerning these markers, immune cells that are part of the transferred cells ('the graft') are prone to recognise tissues of the recipient ('the host') as being to some extent incompatible or foreign, which then can induce inflammation ('graft-versus-host-disease' or 'GVHD'). GVHD typically involves the skin, the gastrointestinal tract and the liver. GVHD is divided into acute and chronic forms based on the clinical features and the time of occurrence after transplantation. In order to prevent this potentially life-threatening condition, reactive immune cells can be depleted in the recipient by administering antibodies which are directed against them. These antibodies are called anti-thymocyte globulins (ATG) and are derived from animals which were immunised with human thymocytes or T-cells. Different types of ATG have been used for decades to decrease the occurrence and severity of GVHD but they bear the risk of severe side effects such as increased infection rates or the risk of disease relapse. Also, severe side effects such as allergic reactions or serum sickness with shortness of breath and fever, blood coagulation disturbances or liver failure can harm the patient during the infusion of ATG. So far, no systematic analysis of the advantages and disadvantages of the use of ATG has been done.

In this systematic review, we included six randomised controlled trials comprising 568 adult patients. In summary, we found evidence that the addition of ATG reduced the occurrence of only the severe forms (grade II to IV) of acute GVHD with a number needed to treat (NNT) of 8 concerning grade II to IV acute GVHD and a NNT of 7 concerning acute GVHD grade III to IV. This means that eight or seven patients have to be treated with ATG, respectively, in order to prevent one case of severe acute GVHD. However, neither overall survival nor the overall occurrence rate of acute GVHD was improved by the use of ATG. Moreover, we did not find a difference between ATG treated patients and those who did not receive ATG regarding relapse of the underlying disease or non-relapse mortality. The effect of ATG on quality of life after stem cell transplantation, which would be an important issue, has not been evaluated in randomised studies so far.

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.

Read the full abstract...

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.


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 strategy: 

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.