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3519 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)

Program: Oral and Poster Abstracts
Session: 722. Allogeneic Transplantation: Acute and Chronic GVHD and Immune Reconstitution: Poster II
Hematology Disease Topics & Pathways:
Research, Clinical trials, Combination therapy, Antibody Therapy, Clinical Research, Treatment Considerations, Biological therapies, Adverse Events, Transplantation (Allogeneic and Autologous)
Sunday, December 8, 2024, 6:00 PM-8:00 PM

Irwin Walker, MBBS1,2, Uday Deotare, MBBS, MD, MScHQ3,4,5*, Mohamed Elemary, MD, MSc, PhD6*, Mahmoud Elsawy, MD, MSc7,8*, Genevieve Gallagher, MD9*, David Kliman, MBBS, FRACP, FRCPA10*, Tony Panzarella, MSc11*, Nada Hamad, MBBS, MSc, BSc12,13,14, Kirk R. Schultz, MD15,16, Jan Storek, MD, PhD17 and Kristjan Paulson, MD18

1Department of Medicine, McMaster University, Hamilton, ON, Canada
2Juravinski Cancer Centre, Juravinski Hospital and Cancer Centre, Hamilton, ON, Canada
3Princess Margaret Cancer Centre, Toronto, ON, CAN
4Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, Canada
5Department of Medicine, Division of Hematology, University of Western Ontario, London, ON, Canada
6Provincial Hematology and Blood and Marrow Transplant Program, Saskatchewan Cancer Agency, University of Saskatchewan, Saskatoon, SK, Canada
7Dalhousie University, Halifax, NS, Canada
8QEII Health Sciences Center, Halifax, NS, Canada
9Centre intégré de cancérologie, CHU de Québec - Université Laval, Québec, QC, Canada
10GenesisCare North Shore, St Leonards, NSW, Australia
11University of Toronto, Toronto, ON, CAN
12St Vincent's Hospital, Sydney, NSW, Australia
13Haematology Department, The Kinghorn Cancer Centre, St Vincent's Hospital, Darlinghurst, NSW, Australia
14The University of New South Wales, Kensington, NSW, Australia
15University of British Columbia, Vancouver, BC, Canada
16B.C. Children's Hospital, Vancouver, BC, Canada
17The University of Calgary Department of Medicine, Calgary, Canada
18Cancercare Manitoba, Winnipeg, MB, Canada

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.

Disclosures: Walker: Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding. Elsawy: BMS: Honoraria; ABBVIE: Honoraria; SANOFI: Honoraria; KITE: Honoraria. Schultz: Novartis: Membership on an entity's Board of Directors or advisory committees.

*signifies non-member of ASH