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).
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.
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.
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.
Fresenius Biotech GmbH.