ABC: Highly active and entirely calcineurin and m-TOR inhibitor-free gvhd prevention regimen Free

Background: We previously reported results of posttransplant cyclophosphamide (PTCy) and bortezomib (CyBor) combination in graft-versus-host disease (GvHD) prophylaxis following allogeneic blood and marrow transplantation (BMT). Building upon this entirely calcineurin (CN) and m-TOR inhibitor-free platform, we hypothesized that adding abatacept, a selective co-stimulation blocker, could further enhance the efficacy of CyBor combination. Herein, we report interim results of the ABC phase I-IIb trial.

Methods: Patients (pts) with hematologic malignancies undergoing peripheral blood BMT were enrolled in two cohorts: matched related (MRD) and matched unrelated (MUD) cohort and 7 out of 8 mismatched unrelated donor (MMUD) cohort. Conditioning regimens consisted of fludarabine (Flu) and busulfan (Bu) (2 days) or Flu, Bu (3 days) and thiotepa. rATG (Thymoglobulin ®), 5 mg/Kg total dose, split over days -4 to -2 was added for all recipients of grafts from unrelated donors. GvHD prophylaxis included PTCy (50 mg/Kg on days +3 and +4, bortezomib (1.3 mg/m² on days 0 and +3) and abatacept 10mg/Kg. During phase I, the dose of abatacept was escalated according to a standard 3&3 design from 1 dose on day +5 (3 pts), to 2 doses on days +5 and +14 (3pts) and finally to 3 doses on days +5, +14 and +28. No dose limiting toxicity was encountered and the 3-dose regimen was adopted for the phase IIb segment. After the first 25 pts were enrolled, the study was amended, decreasing the dose of PTCy to 37.5 mg/Kg per dose. Survival outcomes were estimated using Kaplan–Meier analysis. Cumulative incidences were estimated using Gray's competing risk model.

Results: 54 pts have been thus far enrolled (MRD 10, MUD 31 and MMUD 13 pts) with a median follow-up of 8.7 months (1–40.3 months). 9 out of 10 pts who received MRD grafts received full dose PTCy. 55.5% of pts were male. Median age was 59.5 years (24–76). The most common diagnoses were AML (55.6%), MDS (16.7%) and NHL (13%). At transplant, 66.7% of pts were in CR1, 14.8% in CR2+ and 18.5% had active disease. HCT-CI was ≥3 in 38.8% of pts. Disease risk index (DRI) was high or very high in 38.8%. Thiotepa-containing conditioning regimen was administered to 24 pts. The median CD34+ cell dose was 6.0 10⁶/Kg. Engraftment was achieved in all pts with median time to neutrophil engraftment of 17 and 15 in the high and reduced dose of PTCy groups, respectively (p=0.021). Three pts did not achieve platelet engraftment. For the remaining pts, median time to platelet engraftment were 25.5 and 21 in the 2 PTCy dose groups (p=0.044). Four pts, all received full dose of PTCy, experienced poor graft function with 3 requiring CD34⁺ cell boost. There was no primary or secondary graft failure. Estimated cumulative incidences of grades II-IV acute and moderate to severe chronic GvHD were 9.3% (95% CI 2.8-20.1) and 14.3% (95% CI 4.9–28.5%), respectively. No grade III-IV acute GvHD events occurred. Of note, 3 out of the total 5 cases of chronic GvHD occurred in patients who received MRD grafts and high dose PTCy (without rATG). The estimated cumulative incidence of treatment-related mortality (TRM) at 1 year was 2.54%. Estimated cumulative incidence of relapse at 1 year was 23% (95% CI 10.9–27.8%). Estimated 1-year overall survival, relapse-free survival and GvHD- and relapse-free survival (GFRS) were 92.1% (95% CI 76.9-95%), 72.6% (95% CI 45.9-84.5%) and 64.3% (95% CI 46-77.1%), respectively. The incidence of CMV and EBV reactivation requiring pre-emptive therapy weas 29.6% and 14.8%, respectively. Two pts required treatment for adenovirus reactivation. One patient developed EBV-positive posttransplant lymphoproliferative disorder and responded to rituximab. There was no significant difference in immune reconstitution between PTCy dose groups on day +30, +100 and +180.

Conclusion: These results confirm the feasibility and high efficacy of the ABC regimen as entirely CN and m-TOR inhibitor-free GvHD prophylaxis in allogeneic peripheral blood BMT. Viral reactivation was manageable. TRM was extremely low. PTCy dose reduction resulted in earlier engraftment. Longer follow-up is necessary to determine whether rATG allows for PTCy dose reduction without increasing the incidence of chronic GvHD in peripheral blood allogeneic BMT. Clinicaltrials.gov: NCT06681922.