Safety and efficacy of allogeneic stem cell transplantation after Nivolumab therapy for patients with relapsed/refractory classical Hodgkin lymphoma

Summary

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 patients treated with immune checkpoint inhibitor (CPIs) will eventually progress on these therapies. 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 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 20 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 I. Pavlov Medical University (CIC 725). All the patients received a reduced-intensity conditioning regimen (FluBe, fludarabine 30 mg/m², bendamustine 130 mg/m² per day for 3 days), and post-transplant cyclophosphamide-based GvHD prophylaxis (PTCy). Before allo-HSCT, the patients received immune checkpoint inhibitors (CPI) as a single-agent nivolumab, or in combination with brentuximab vedotin, or chemotherapy. The best registered response to PD-1 therapy was a complete response (CR) in 9 patients, partial response in 4 patients. Five patients received transplant during the disease progression, and 2 patients were transplanted in indetermined response, according to the LYRIC criteria. The 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). All the patients showed full hematological recovery after allo-HSCT. The one-year overall survival and event-free survival were 95% and 85%, respectively, whereas the one-year cumulative incidences of relapse and non-relapse mortality were 10% and 5%, respectively. Two patients with relapse after allo-HSCT were treated with donor lymphocyte infusion (DLI) in combination with chemotherapy. At the median follow-up of 30 days, all the patients remain alive. 4/20 patients developed grade 2 GvHD, and all responded to steroids. 4/20 patients developed severe, grade 3-4 GvHD, and only one 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 of sinusoidal obstruction syndrome were 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. 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.

Keywords

Hodgkin’s lymphoma, hematopoietic stem cells transplantation, allogeneic, immune checkpoint inhibitor, nivolumab, overall survival, event-free survival, graft-versus-host disease, post-transplant cyclophosphamide.