Allogeneic hematopoietic stem cell transplantation and checkpoint inhibitors therapy are immune-based therapies that have activity in selected refractory hematologic malignancies. Interest has developed in combining these treatments for high-risk hematologic diseases. However, there is concern that checkpoint blockade could augment graft-versus-host disease (GvHD) and several preliminary reports suggest that toxicity, including veno-occlusive disease (VOD) of the liver occur when immune checkpoint inhibitors are used before or after allogeneic transplantation. Very few studies have evaluated the safety of checkpoint inhibitors in the pre-allogeneic setting.
We report the outcomes of 5 patients with relapsed/refractory classical Hodgkin's-lymphoma that were treated with the anti-PD-1 antibody “nivolumab” as bridge to allogeneic-SCT.
Between June 2016 and January 2019, 5 cases of relapsed/refractory classical Hodgkin's lymphoma after a media of 4 lines of chemotherapies (range, 4-5; ABVD; radioterapy; IGEV/BEGEV plus autologus-SCT; brentuximab alone; brentuximab plus bendamustine) received nivolumab 3 mg/Kg every 2 weeks as their last salvage therapy immediately before allo-SCT. Immune-related adverse events were graded using Common Terminology Criteria for Adverse Events (version 4.0). GvHD was assessed using the Center for International Blood and Marrow Transplant Research GvHD index.
Three female and 2 male with median age of 34 years (range, 21-44). All patients received a median of 6 cycles of single-agent nivolumab (range, 4-12). Two patients achieved a complete response, 2 patients received a partial response and 1 patients a stable disease. The median interval from last nivolumab treatment to transplant was 45 days (range, 41-59). Two mismatched unreleted, 2 matched unrelated and 1 matched related donors were used. Two patients are waiting for transplantation, while 3 patients received reduced-intensity conditioning. Two out 3 were conditioned with fludarabine, thiotepa and endoxan and received bone marrow allograft (MNC × 108/Kg 0,52; CNT × 108/Kg 2,08; CD34+ × 106/Kg 1,54 and MNC × 108/Kg 0,48; CNT × 108/Kg 3,5; CD34+ × 106/Kg 1,85 respectively) while 1 with fludarabina and endoxan and received peripheral blood grafts (CD34+ × 106/Kg 6.08). GvHD prophylaxis with mycophenolate and cyclosporine was administered. All three patients had full hematologic recovery after allo-SCT. The median day to an absolute neutrophil count of 0.5 × 109/L was 11 days (range 11-16), and the median day to platelet transfusion independence was 17 days (range 12-23). By 32 days post-transplant, all patients achieved full donor T-cell engraftment. No graft failures was experienced. At a median follow-up of 16 months (range, 14-25), all patients continue to exhibit full donor chimerism. No patient experienced VOD of the liver or grade 3-4 aGvHD. Two patient experienced grade 2 cutaneous aGvHD and responded to steroids. There were no other immune-related adverse events, or grade 3 fevers and no chronic GvHD. Whit a median follow-up of 16 months (range, 14-25) all patients remain in continuous complete remission.
Based on our experienced, allo-SCT after checkpoint inhibitors “nivolumab” seems to be feasible, not associated with higher mortality, severe GvHD or disease progression. However, careful consideration should be given for prevention, early detection and effective treatment of GvHD in these cases. Additional prospective data with larger number of patients are needed to assess the exact role and toxicity of nivolumab as a bridge to allo-SCT.