Anti-Thymocyte Globulin for Patients Undergoing Hematopoietic Cell Transplantation from Unrelated Donors: A Randomized, Controlled, Open-Label, Phase 3, Multicentre Trial from Cell Therapy Transplant Canada

Abstract

Background: We previously reported that pretreatment with anti-thymocyte globulin (ATG) decreases the use of immunosuppressive therapy (IST) and the occurrence of chronic graft versus host disease (CGVHD) at 12 months after haematopoietic cell transplantation. We have now examined whether these benefits would persist at 24 months. Methods: This was a phase 3, multicentre, open-label, randomized controlled trial at 10 centres in Canada and one in Australia. Patients were eligible if they had a hematological malignancy and were to receive an unrelated donor graft. They could receive myeloablative or non-myeloablative/ reduced intensity conditioning, Patients were randomized to receive, or not receive, ATG 4·5 mg/kg as part of conditioning. The primary endpoint was freedom from all systemic immunosuppressive therapy (IST) without resumption up to 24 months after transplantation. Findings: Thirty-eight (38·3%) of 99 patients in the ATG group were free from IST at 24 months compared with 18 (18·6%) of 97 patients in the No ATG group (adjusted OR 3·49 [ 95 CI 1·60 - 7·60]; p = 0·002). Most patients retained the same IST status from 12 to 24 months, 74 (74·7%) and 79 (81·4%) in the ATG and No ATG and groups respectively. The cumulative incidence of relapse was 16 (16·2%) of 99 patients in the ATG group compared with 17 (17·5%) of 97 patients in the No ATG group (p=0·73). The cumulative incidence of CGVHD at 24 months was 26 (26·3%) of 99 patients in the ATG group compared with 40 (41·2%) in the No ATG group (p=0·032). Symptoms of CGVHD were more prevalent in the No ATG, the scores by Lee scale being 13·57 (SE 1·47) and 19.90 (SE 2·15) in the ATG and No ATG groups respectively; (p=0·017). The cumulative incidence of non-relapse mortality was 21 (21·2%) of 99 patients in the ATG group compared with 30 (30·9%) in the No ATG group (p=0·14). Overall survival at 12 months was 74·8% (SE 4·4) compared with 64·9% (SE 4·8) in the ATG and No ATG groups respectively (adjusted HR 0·56 [95% CI [0·35-0·90]; p=0·017)). At 24 months follow up of all patients, 70 (71%) patients out of 99 in the ATG group and 52 (53.6%) out of 97 in the No ATG group were alive (p=0·018). Both acute and chronic graft versus host disease- and relapse free-survivals (GRFS and CRFS) were significantly higher in the ATG group (p=0·0034 and p=0·01 respectively). Depressive symptoms were more prominent in the No ATG group, the mean CES-D scores being 10·39 (SE 1·29) in the ATG group compared with 14·63 (SE 1·48) in the No ATG group (p=0·034). Interpretation: Pretreatment with ATG provides long term benefits consisting of decreases in CGVHD and its symptoms, depressive symptoms, use of IST and improvement in survival. This trial is the first to demonstrate both a survival advantage and a decrease in depressive symptoms for patients receiving ATG. ATG should be included in the preparative regimens of all transplants that use unrelated donors. Clinical Trial Number: This trial was registered at ISRCTN, number 29899028 and at clinicaltrials.gov, number NCT01217723. Funding Statement: The Desroches Bone Marrow Transplant Fund, McMaster University (ON, Canada) provided funding for protocol development. Declaration of Interests: SJL reports personal fees from Pfizer, personal fees and non-financial support from Mallinckrodt, personal fees and non-financial support from Incyte, personal fees from Pfizer, personal fees from Kadmon, grants from Takeda, grants from Amgen, grants from Kadmon, grants from Syndax, grants from Pfizer, grants from AstraZeneca, outside the submitted work. GP and IW report consulting fees from Sanofi. TN and IW report financial grant support from Sanofi. GD, DS and TN report grants from Canadian Institutes of Health Research. All other authors declare no competing interests. Ethical Approval Statement: This study was approved by the Research Ethics Boards of all participating transplant centres.