Checkpoint Inhibition Prior to Allogeneic Stem-Cell Transplantation in Relapsed/Refractory Hematologic Malignancies: Balancing Efficacy and Risk

Background: Relapsed/refractory (R/R) hematologic malignancies remain a major therapeutic challenge, with allogeneic stem-cell transplantation (alloSCT) representing the only curative option for many patients. Checkpoint inhibitors (CPI), including PD-۱ inhibitors (nivolumab, pembrolizumab), PD-L۱ inhibitors (atezolizumab, durvalumab), and CTLA-۴ inhibitors (ipilimumab), have shown significant efficacy in achieving disease control and enabling patients to proceed to alloSCT. Methods: We reviewed current clinical and translational data on the use of CPI as a bridging strategy before alloSCT in R/R hematologic malignancies, focusing on efficacy, safety, and strategies to mitigate transplant-related complications. Results: CPI exposure before alloSCT is associated with high response rates in Hodgkin lymphoma and encouraging disease clearance in other malignancies such as acute myeloid leukemia and myelodysplastic syndromes. However, pre-transplant CPI increases the risk of severe immune-related complications, particularly acute and chronic graft-versus-host disease (GVHD) and non-relapse mortality. Prolonged antibody half-life and residual immune activation are key contributors. Mitigation strategies, including extended washout intervals, use of post-transplant cyclophosphamide (PTCY)-based prophylaxis, and stringent patient selection, have demonstrated potential in reducing toxicity. Conclusion: Checkpoint inhibition prior to alloSCT represents a promising but double-edged therapeutic approach. While CPI can provide a crucial bridge to transplantation by inducing deep remission in R/R patients, the increased risk of post-transplant GvHD necessitates careful timing, optimized prophylaxis, and individualized patient selection. Future prospective trials are essential to define the safest integration of PD-۱, PD-L۱, and CTLA-۴ blockade into the alloSCT pathway.