Long-Term Follow-Up of Abatacept, Post-Transplantation Cyclophosphamide, and Sirolimus-Based Haploidentical Transplantation in Younger Patients with Nonmalignant Diseases.

Haploidentical (haplo) hematopoietic cell transplantation (HCT) for nonmalignant disease (NMD) carries inherent challenges of both alloreactivity and graft failure. Building on promising results from pilot studies in which abatacept was combined with post-transplantation cyclophosphamide (PTCy) and sirolimus (AbaCyS) in younger NMD patients undergoing haplo-HCT, we present the long-term outcomes of this protocol. On the back of uniform disease-specific conditioning regimens containing antithymocyte globulin 4.5 mg/kg from day -9 to day -7, GVHD prophylaxis with AbaCyS consisted of abatacept administered on days 0, +5, +20, +35, and monthly until 180 days with PTCy and sirolimus. The patients were followed up with longitudinal assessment of immune reconstitution, growth, and reproductive development and quality of life (QoL) analyses. Among 40 patients (aplastic anemia, n = 24; hemoglobinopathies, n = 14; and primary immunodeficiencies, n = 2) with a median age of 10 years (range, 2 to 25 years), 95% achieved sustained engraftment. Post-transplantation hemophagocytic syndrome was detected in 3 patients, leading to graft failure in 2 cases. The incidence of acute graft-versus-host disease (GVHD) was 2.6%, and that of chronic GVHD (cGVHD) was 14.3%. Cytomegalovirus, adenovirus, and Epstein-Barr virus infections were observed in 45%, 5%, and 0% respectively. Rates of nonrelapse mortality, overall survival, event-free survival, and GVHD-free, event-free survival were 5%, 95%, 90%, and 82%, respectively, at a median follow-up of 4.6 years. Absence of cGVHD correlated with younger patient age and early sustained recovery of regulatory T cells and mature natural killer cells, which in turn was associated with improved QoL and lack of late infections. The AbaCyS protocol was associated with excellent long-term survival, with attenuation of both early and late alloreactivity in >80% of younger patients undergoing haplo-HCT for NMD. This study sheds light on predispositions to cGVHD and its impact on QoL, warranting further optimization of this approach.