Cytokine release syndrome after allogeneic hematopoietic stem cell transplantation using posttransplant cyclophosphamide: current understanding and management

Post-transplant cyclophosphamide (PTCy) is increasingly used for graft-versus-host disease (GVHD) prophylaxis in allogeneic hematopoietic stem cell transplantation (alloHCT), across both haploidentical and HLA-matched donor settings. However, PTCy-based alloHCT is associated with post-transplant cytokine release syndrome (CRS), an early inflammatory toxicity driven by donor T-cell alloreactivity. Mechanistically distinct from chimeric antigen receptor (CAR) T-cell therapy-associated CRS, post-transplant CRS is driven by conditioning-induced tissue injury and donor T-cell alloreactivity. The incidence of CRS varies by donor type, occurring in approximately 10% of matched sibling, 20 to 75% of matched unrelated, and 80 to 90% of haploidentical donor transplants. Risk factors include peripheral blood grafts, HLA class II mismatch, and high-intensity conditioning. Severe CRS has been linked to delayed engraftment, increased acute GVHD, decreased chronic GVHD, and may contribute to non-relapse mortality through mechanisms such as third-spacing, infectious complications, and neurologic toxicity. Tocilizumab is effective for CRS treatment, though its impact on subsequent GVHD risk requires further study. Early initiation of calcineurin inhibitors and use of pre-transplant anti-thymocyte globulin have shown promise in reducing CRS incidence. CRS-associated neurotoxicity, resembling immune effector cell-associated neurotoxicity syndrome (ICANS), is increasingly recognized, particularly among patients with severe CRS, and can result in delayed, fatal encephalopathy. In summary, post-transplant CRS is a clinically significant complication of PTCy-based alloHCT. Optimizing prophylaxis and management strategies is essential to mitigate its impact on transplant outcomes.