A Randomized Trial of Rabbit Anti-Thymocyte Globulin, Given on Day+7 after Alternative Donor Transplants.

Abstract

Background. We have shown that the risk of transplant mortality (TRM) can be predicted by using laboratory values, on day+7 after an allogeneic hemopoietic stem cell transplant (HSCT) (Sormani et al, Bone Marrow Transpl.2003). TRM in patients with low, intermediate and high risk on day+7, is 15%, 40% and 69%: increased mortality is mainly, but not exclusively, due to increased acute graft versus host disease (GvHD). In a pilot study we have shown that a small dose of rabbit anti-thymocyte globulin (rATG) (Thymoglobulin, Genzyme), was feasible and reduced GvHD and TRM.Aim of the study. We have therefore opened a randomized trial testing this hypothesis in patient undergoing an unrelated donor HSCT, with rATG (7.5 mg/kg) in the conditioning regimen.Patients. 170 were eligible: all patients received rATG 3.75 mg/kg x2 pre-transplant, and on day+7 they were scored and randomized to receive an additional dose of rATG (1,25 mg/kg day +7 and day+9) (n=84) or to receive no further treatment (n=86) (control arm). The two groups were balanced for age, disease phase and day+7 score.Results. The predictive value of day+7 score on TRM was confirmed in the control arm (18% vs 42% for intermediate and high risk patients, p=0.03), whereas in the day+7 ATG arm, there was no difference (29% vs 29%, p=1.0). TRM was overall reduced from 35% in the control arm to 29% in the ATG day+7 arm (p=0.37) : the difference was more pronounced in patients with early disease and high risk on day 7 (35% vs 15% p=0.08). Acute GvHD grade III–IV was reduced overall from 16% to 6% (p=0.04), and chronic GvHD was reduced 32% to 14% (p=0.02). In multivariate COX analysis TRM and overall survival was predicted by risk score day7 and disease phase.Conclusions. We confirm that patients with different risk of TRM can be identified on day+7 after HSCT. Administration of rATG on day+7 can influence the risk of TRM, by reducing acute and chronic GvHD. Additional intensified supportive care (including anti-infectious therapy) may further reduce TRM in patients with a high risk score on day+7.