Reduced dose post-transplant cytoxan (Intermediate -Dose) in combination with abatacept after matched unrelated donor transplant for high -risk hematological malignancy may reduce treatment related mortality and risk of relapse.

Abstract Post-transplant cyclophosphamide (PTCy) at the standard dose of 50 mg/kg on D+3 and +4 has evolved as the backbone for graft-versus-host disease (GVHD) prophylaxis after allogeneic stem cell transplantation. However, the toxicity at this dose has limited its use in older patients and those with comorbidities. Recent studies have explored the use of reduced dose PTCy in combination with other agents. Here we aim to evaluate the safety and efficacy of reduced-dose PTCy in combination with abatacept (ABA) and tacrolimus (TAC) for GVHD prophylaxis in MUD PBSCT patients. Methods: Patients that received a 8/8 MUD PSBCT with reduced dose PTCy, ABA and TAC between February 2023 and April 2025 were retrospectively reviewed. Cy was dosed at 25 mg/kg on D+3 and +4; ABA was dosed at 10 mg/kg on D-1, +5, +14 and +28. In August 2024, our institutional protocol was amended to include an extra dose of ABA on D+56 after 3 patients developed severe GI GVHD after D+180. All patients received TAC starting on D+5 targeting 5-12 ng/dL. Results: A total of 36 patients were included with a median duration of follow-up of 348 days as of July 15, 2025 (range 75-852). The median age was 58.1 years (range 24-77) and 61% were male. The primary disorders included 20 patients with AML, 8 with MDS, 3 with T-cell ALL, 2 with B-cell ALL, and one each with bi-phenotypic acute leukemia that evolved from CML, MF, and Blastic plasmacytoid dendritic cell neoplasm (BPDCN) . TP53 was detected in 7/28 AML-MDS patients (25%). One patient with bi-phenotypic acute leukemia that evolved from CML had inversion 16 and a 9;22 translocation. Two patients had a CDKN2A mutation, and one patient had 7;14 translocation with a notch1mutation. At the time of transplant, 19 patients were in CR1, and 2 patients were in CR2. Six patients had either primary induction failure or relapsed disease, 8 patients had stable disease, and 1 patient had hematological improvement. The HCT-CI score 5 in18 patients (50%), 3-4 in 11 patients (30%), and 0-2 in 7 patients (20%). There were 7 pairs of CMV seronegative donor/recipients, with all other pairs including a CMV seropositive donor or recipient. Patients' conditioning regimens included reduced intensity (RIC) Flu/Bu2 in 8 patients, full intensity (FIC) Flu/Bu3 in 2 patients, RIC Flu/Mel in 20 patients, RIC Flu/Cy/TBI in 5 patients, and FIC Flu/TBI in 1 patient. Eleven patients received an additional dose of abatacept on D+56 after a protocol adjustment was amended. One patient did not receive D+28 abatacept because of an early relapse on D+29. The CIBMTR One Year Survival Outcomes Calculator 2024 average for the cohort was 56.8%. All patients engrafted with median absolute neutrophil and platelet recovery of 12.6 days (range 11-16) and 20.6 days (range 14-83), respectively. All patients achieved full chimerism by D+30 with no graft failures. The OS by log rank test at D+100 and 1 year was 97% and 76.4% respectively. The cumulative incidence of relapse was 8.3% and 21.3% at D+100 and 1 year respectively. The cumulative incidence of NRM was 0% at D+100 and 12.3% at 1 year. The cumulative incidence of aGVHD was 38.9%, with all events being grade 1/2. Although the cumulative incidence of cGVHD was high at 70.8%, only 9 patients (36%) had residual cGVHD at the time of the last evaluation. cGVHD was mild limited in 3 patients, mild extensive in 1 patient, moderate extensive in 10 patients and severe extensive in 4 patients. CMV reactivation occurred in 16 patients, with no CMV disease. HHV-6, EBV, and adenovirus reactivation occurred in 1, 10 and 1 patients respectively and resolved spontaneously. There was one case of mucor after treatment with high-dose corticosteroids for post-transplant HLH. Immune reconstitution data were available for 25 patients on D+30 and D+100. The average immune reconstitution of CD3, CD4, CD8, CD16/56 and CD19 were 219, 98, 91, 263, and 2.72 on D+30 and 297, 120, 167, 163, and 32 on D+100 respectively. Conclusion: (450 characters) We observed low treatment-related mortality and relapse rates in this cohort of patients with high-risk disease and significant comorbidities. Reduced dose PTCy in combination with ABA and TAC was safe and tolerable. Immune reconstitution studies revealed diminished immune recovery in all lymphocyte subsets except NK cells. The robust recovery of NK cells may suggest improved GVL. Larger prospective studies are needed to validate these findings.