Safety and Efficacy of Allogeneic Stem Cell Transplantation after PD-1 Blockade for Patients with Relapsed/Refractory Classical Hodgkin Lymphoma

Introduction: The programmed-death 1 blockade with nivolumab demonstrated high efficiency in patients with relapsed and refractory Hodgkin lymphoma (rrHL) with acceptable toxicity profile. However, most of the patients treated with immune checkpoint inhibitor (CPIs) will eventually progress on this therapy. Allogeneic hematopoietic stem cells transplantation (allo-HSCT) is a potentially curative option for patients with rrHL. Therefore, allo-HSCT is a consideration for selected patients with HL after treatment with CPIs. There are concerns that CPIs before allo- HSCT may increase the incidence of graft-versus-host disease, immune-related adverse events, and nonrelapse mortality (NRM). At present, there is no consensus regarding the optimal transplant strategy for patients previously treated with immune checkpoint blockade. The aim of this study was to evaluate outcomes in patients with rrHL who received CPIs as a bridge to allo-HSCT.

Patients and methods: We retrospectively evaluated the results of allo-HSCT in 22 patients who had been transplanted after prior PD-1 blockade between 2017 and 2019 at the R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantology at the First St. Petersburg State Pavlov Medical University (CIC 725). All patients received reduced-intensity conditioning regimen (fludarabine 30 mg/m2, bendamustine 130 mg /m2 per day for 3 days (FluBe)) and post-transplant cyclophosphamide-based GvHD prophylaxis (PTCy). Patients received immune checkpoint inhibitors before allo-HSCT as a single-agent nivolumab or in combination with brentuximab vedotin or chemotherapy. The best response to PD-1 therapy was a complete response (CR) in 9 patients, partial response in 5 patients, 5 patients received transplant during the disease progression and 3 patients were transplanted in indetermined response according to the LYRIC. Patients received a median of 20 (range, 6-32) cycles of a PD-1 inhibitor. The median time from the last dose of anti-PD-1 therapy to HSCT was 83 days (range, 50-350).

Results: At the time of analysis, median follow-up was 14 months (range, 1-26 months). Ninety one percent of patients engrafted. One patient had primary graft failure and one died on the day of the haploidentical graft transfusion due to cytokine release syndrome. The 1-year OS and EFS were 91% and 78% respectively, whereas the 1-year cumulative incidences of relapse and NRM were 9% and 9% respectively.Two patients with relapse after allo-HSCT were treated with donor lymphocyte infusion (DLI) in combination with chemotherapy. Both patients remain alive. 4/20 of the engrafted patients developed grade 2 GvHD and all responded to steroids. 4/20 patients developed severe grade 3-4 GvHD and only 1 patient responded to steroids. The cumulative incidence of chronic GVHD (cGVHD) was 35%, including 3 patients with severe, steroid-refractory cGVHD. There were no other immune-related adverse events. No cases sinusoidal obstruction syndrome was observed

Conclusions: Our study demonstrates that HSCT after PD-1 blockade is feasible and not associated with higher mortality. We suggest that prior PD-1 blockade should not be considered a contraindication to HSCT in patients with relapsed and refractory Hodgkin lymphoma. severe The rate of severe acute and chronic GvHD was relatively higher than previously reported for PTCy-based prophylaxis, but was manageable in the majority of cases. The time between anti-PD-1 therapy and allo-HSCT and PTCy is likely to be important in the successful outcome of the transplant.