Less Chronic Graft-Versus-Host Disease, Immunosuppressive Therapy and Better Survival after Anti-Thymocyte Globulin in Unrelated Donor Stem Cell Transplant Recipients: Longer Follow-up of a Multicentre Cell Therapy Transplant Canada Randomized Trial

Background: We previously reported that pretreatment with rabbit anti-thymocyte globulin (ATG) decreases the use of immunosuppressive therapy (IST) and occurrence of chronic graft-versus-host disease (GVHD) 12 months after allogeneic stem cell transplantation from unrelated donors. We hypothesized these benefits would persist beyond 12 months with a positive clinical impact on patients. Methods: Phase 3, multicentre, open-label, randomized controlled trial at 10 centres in Canada and one in Australia. Patients aged 16-70 years with a hematological malignancy, a matched (HLA-A, B, C and DRB1) or 1-antigen/allele mismatched unrelated donor were eligible. Myeloablative, nonmyeloablative or reduced intensity conditioning regimens were permitted according to center clinical preference. Patients were randomized to receive or not to receive rabbit ATG (Thymoglobulin®, Sanofi Canada) as part of their conditioning. GVHD prophylaxis included either cyclosporine or tacrolimus plus methotrexate or mycophenolate mofetil. The ATG arm received 0.5, 2.0, 2.0 mg/kg of ATG on days -2, -1 and +1, respectively. Analyses were on a modified intention-to-treat basis for patients actually transplanted. Primary endpoint was freedom from all systemic IST without resumption up to 24 months after transplantation. Secondary endpoints included survival, relapse, non-relapse mortality, incidence and symptoms of chronic GVHD according to Lee scale and quality of life using different questionnaires including the Center for Epidemiologic Studies Depression (CES-D) scale. We also aimed to evaluate the recently described endpoints of graft-versus-host disease and relapse-free survival (GRFS) and chronic graft-versus-host disease and relapse-free survival (CRFS) in each cohort. This trial was registered at ISRCTN (#29899028) and clinicaltrials.gov (#NCT01217723). Results: Between 06/2010 and 07/2013, 203 patients were randomized and 196 available for end-points analysis, including 99 patients in the ATG group and 97 in the No ATG (control) group. Datalock was performed on April 1, 2019. The cumulative incidence of chronic GVHD at 24 months was significantly lower in ATG recipients (26.3% versus 41.2%, p=0.032). Similarly, more than twice patients in the ATG group were free from IST at 24 months (adjusted OR of 3.49 [95% CI : 1.60-7.60]; p = 0.002). Most patients retained the same IST status from 12 to 24 months (74.7% in the ATG and 81.4% in the control group). Symptoms of chronic GVHD were a