A Randomized Pilot Trial Comparing Anti-Thymocyte Globulin (ATG) with ATG Plus Post Transplant Cyclophosphamide (PTCy) for Prophylaxis Against Acute and Chronic Graft Versus Host Disease (GVHD) in Matched Donor Hematopoietic Cell Transplants (HCT)

Background: Anti-thymocyte globulin (ATG, or ATLG) and post-transplant cyclophosphamide (PTCy) are used for the prevention of graft-versus-host disease (GVHD). Two ongoing randomized trials (ISRCTN50290131; NCT05153226) are comparing these agents for efficacy and safety, but the safety and efficacy of the combination is unknown and has not been well studied. We conducted a randomized pilot trial of a combination of these agents to assess safety, with the aim of an expansion phase III trial. Methods: Following CONSORT guidelines, we conducted a randomized pilot trial to compare ATG (standard Arm A, 4.5 mg/kg) with ATG plus PTCy (experimental Arm BE, ATG 4.5 mg/kg, PTCy 50 mg/kg x 2) with short term feasibility endpoints at 100 days but otherwise following a phase III design. Patients consented to two years follow-up in anticipation of an expansion to phase III, as described in the CONSORT extension for pilot trials (Abbade LPF et al (2018) DOI 10.1186/s40409-018-0142-2). Overall survival was calculated using the Kaplan-Meier estimate; the log-rank test was used to compare treatment differences. We randomized a pre-planned convenience sample of 79 eligible and transplanted patients. Median (range) age was 59 (19 to 74), 47 (59.5 %) were male. Patients had either AML (n=55) or MDS (n=24) and were transplanted using either myeloablative (n=49) or reduced intensity (n=30) conditioning. Donors, either sibling (n=28) or unrelated (n=51), were 8/8 HLA-matched. The primary feasibility endpoints included: (1) recruitment of the intended sample size, (2) 100-day survival of the experimental arm B to be at least 90% compared with the standard arm A, (3) complete data on 95% of recipients at 12 months and (4) completion of the trial within budget. A variety of secondary endpoints, both efficacy and safety, were included. Objectives 1, 3, and 4 were fulfilled and this abstract describes the safety and efficacy outcomes related to objective (2). Results at day 100: Forty-one patients were randomized to Arm A and thirty-eight patients to Arm BE. At the time of data lock (May 14, 2024), all patients had been followed for at least 100 days. Thirty-nine (95.1%) patients in Arm A and 36 (94.7%) in Arm B survived to 100 days (primary endpoint). Acute graft versus host disease (AGVHD) was reported in 15 and 6 patients in Arms A and BE respectively, of which 6 and 3 had grades II-IV and 3 and 0 had grades III-IV. At 100 days, 3 patients in Arm A and 3 patients in Arm BE were receiving systemic corticosteroids. Serious Adverse Effects (SAEs) were experienced by 31 patients in Arm A and 25 in Arm BE. Graft failure at 28 days occurred in 2 patients in each arm, with all patients achieving engraftment eventually. Median (range) days to engraftment was 19 (13-45) for Arm A and 22.5 (15-56) for Arm BE. Cytomegalovirus reactivations occurred in 10 and 7 patients in Arm A and Arm BE respectively and Epstein-Barr virus reactivations occurred in 7 and 4 patients in Arm A and Arm BE respectively. Results Follow Up: Median follow up of living patients was 23.6 months (range 3.19- 25.92) for Arm A patients and 22.9 months (range 1.64-25.07). Overall survival between the arms was similar at 12-months; 68.9% (standard error (SE) 7.5%) in the standard arm A and 75.4% (SE 7.6%) in the experimental arm BE (p = 0.52). Relapse or disease progression were seen in 7 patients in Arm A and 7 patients in Arm BE. AGVHD was reported in 18 patients in Arm A and 9 in Arm BE (grades II-IV 11 and 5, grades III-IV 5 and 1), with late (>100 days) AGVHD occurring in 3 and 2 cases in Arms A and BE respectively. CGVHD has been reported to date in 7 patients in Arm A and 4 patients in Arm BE, moderate or severe grade in 2 patients and 2 patients respectively. Conclusion: The addition of PTCy to ATG did not result in excessive adverse events in this pilot trial (to day 100), and long-term results remained consistent. The combination of ATG and PTCy can be used safely in future trials to further prevent graft-versus-host disease. Based on the demonstrated safety and feasibility of this combination, and encouraging signals of efficacy, planning for an expansion to a full phase III trial with a primary endpoint of GVHD, relapse free survival is underway.