Standard graft-versus-host disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trial

Summary

Background

Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality after allogeneic haematopoietic cell transplantation from unrelated donors. Anti-T-cell globulins (ATGs) might lower the incidence of GVHD. We did a prospective, randomised, multicentre, open-label, phase 3 trial to compare standard GVHD prophylaxis with ciclosporin and methotrexate with or without anti-Jurkat ATG-Fresenius (ATG-F).

Methods

Between May 26, 2003, and Feb 8, 2007, 202 patients with haematological malignancies were centrally randomly assigned using computer-generated centre-stratified block randomisation between treatment groups receiving ciclosporin and methotrexate with or without additional ATG-F. One patient in the ATG-F group did not undergo transplantation, thus 201 patients who underwent transplantation with peripheral blood (n=164; 82%) or bone marrow (n=37; 18%) grafts from unrelated donors after myeloablative conditioning were included in the full analysis set, and were analysed according to their randomly assigned treatment (ATG-F n=103, control n=98). The primary endpoint was severe acute GVHD (aGVHD) grade III–IV or death within 100 days of transplantation. The trial is registered with the numbers DRKS00000002 and NCT00655343.

Findings

The number of patients in the ATG-F group who had severe aGVHD grade III–IV or who died within 100 days of transplantation was 12 and 10 (21·4%, 95% CI 13·4–29·3), respectively, compared with 24 and nine (33·7%, 24·3–43·0) patients, respectively, in the control group (adjusted odds ratio 0·59, 95% CI 0·30–1·17; p=0·13). The cumulative incidence of aGVHD grade III–IV was 11·7% (95% CI 6·8–19·8) in the ATG-F group versus 24·5% (17·3–34·7) in the control group (adjusted hazard ratio [HR] 0·50, 95% CI 0·25–1·01; p=0·054), and cumulative incidence of aGVHD grade II–IV was 33·0% (n=34; 95% CI 25·1–43·5) in the ATG-F group versus 51·0% (n=50; 95% CI 42·0–61·9) in the control group (adjusted HR 0·56, 0·36–0·87; p=0·011). The 2-year cumulative incidence of extensive chronic GVHD was 12·2% (n=11; 95% CI 7·0–21·3) versus 42·6% (n=34; 95% CI 33·0–55·0; adjusted HR 0·22, 0·11–0·43; p<0·0001). There were no differences between treatment groups with regard to relapse, non-relapse mortality, overall survival, and mortality from infectious causes.

Interpretation

The addition of ATG-F to GVHD prophylaxis with ciclosporin and methotrexate resulted in decreased incidence of acute and chronic GVHD without an increase in relapse or non-relapse mortality, and without compromising overall survival. The use of ATG-F is safe for patients who are going to receive a haematopoietic cell transplantation from matched unrelated donors.

Funding

Fresenius Biotech GmbH.

Introduction

Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality after allogeneic haematopoietic cell transplantation. Haematopoietic cell transplantation from unrelated donors results in an increased risk of severe GVHD compared with matched sibling donor transplants using the same regimen for GVHD prophylaxis, which usually contains ciclosporin and short-course methotrexate.1, 2, 3 Strategies using intensified GVHD prophylaxis including T-cell depletion did not result in better outcome due to increased risks of infection and relapse.4, 5 Different types of anti-T-cell globulin (ATG) preparations have been tested as part of conditioning regimens to achieve in-vivo T-cell depletion to prevent GVHD. ATG preparations can differ substantially in potency and dose due to different production methods, namely the cells used for immunisation of the source animal. In a sequential randomised trial testing two doses of ATG (Thymoglobulin; Genzyme, Boston, MA, USA) in 109 patients, the lower dose of ATG did not lead to a difference in incidence and severity of acute GVHD compared with standard prophylaxis, whereas the higher dose reduced severe GVHD but was accompanied by a higher risk of lethal infections.⁶

The use of rabbit anti-Jurkat cell-line T-lymphoblasts, or ATG-Fresenius (ATG-F; Fresenius Biotech, Graefelfing, Germany) in addition to ciclosporin and methotrexate has shown promising results in several phase 2 trials for transplantation from matched or mismatched unrelated donors.7, 8 A dose of 60 mg/kg was found to be effective for reducing severe GVHD in a dose-escalation study in patients transplanted with marrow from unrelated donors.⁹

Here we report the results of, to our knowledge, the first large prospective, randomised, multi-centre, open-label, phase 3 trial comparing standard GVHD prophylaxis with ciclosporin and short-course methotrexate, with or without ATG-F at a cumulative dose of 60 mg/kg.