Impact of post-transplant cyclophosphamide and anti-thymocyte globulin on immune reconstitution in MUD allo-HCT

Insufficient immune reconstitution (IR) is a major determinant of morbidity and mortality after allogeneic hematopoietic cell transplantation (allo-HCT). Strategies for graft-versus-host disease (GVHD)-prophylaxis, such as anti-thymocyte globulin (ATG) and post-transplant cyclophosphamide (PTCy), modulate immune recovery, but their effects on IR in matched unrelated donor (MUD) allo-HCT remain incompletely defined. In this retrospective bi-centric study, we analyzed patients with myeloid malignancies undergoing MUD allo-HCT who received ATG or PTCy per center policy. Longitudinal IR and clinical outcomes were assessed. IR was defined as sustained recovery of CD3+CD4+ cells >200/μl and CD19+ cells >50/μl. The impact of GVHD-prophylaxis (ATG vs PTCy) on IR dynamics was explored. A total of 252 patients were included. By day +365, 16.7% achieved IR, which was independently associated with superior OS (HR 0.39, 95% CI 0.17-0.90; p=0.026) and lower TRM (HR 0.08, 95% CI 0.01-0.63; p=0.017). In multivariable competing-risk analyses, younger donor age (sHR 0.97, 95% CI 0.94-1.00; p=0.037) and PTCy (sHR 0.49, 95% CI 0.27-0.84; p=0.01) were associated with higher probability of IR by month +18. The association between PTCy and IR was attenuated after adjusting for therapy-requiring acute or chronic GVHD, which independently delayed IR (HR 0.31, 95% CI 0.20-0.48; p<0.001). ATG and PTCy showed distinct IR trajectories: ATG associated with earlier NK expansion, PTCy led to enhanced adaptive T- and B-cell recovery from day +100. IR strongly predicted survival, independently of GVHD-prophylaxis. Prospective studies are warranted to better define determinants of IR after MUD allo-HCT in the PTCy era.