Nivolumab Is Effective and Reasonably Safe in Relapsed or Refractory Hodgkin's Lymphoma after Allogeneic Hematopoietic Cell Transplantation: A Study from the Lysa and SFGM-TC
Authors: Herbaux Charles , Gauthier Jordan , Brice Pauline , Fornecker Luc , Bouabdallah Krimo , Manson Guillaume , Ghesquières Hervé , Thiebaut-Bertrand Anne , Demarquette Hélène , Boyle Eileen , Ysebaert Loic , Houot Roch , Yakoub-Agha Ibrahim , Morschhauser Franck 
Published: October 2019

Abstract
BACKGROUND: It has been recently shown that nivolumab, a programmed death 1 (PD-1) blocking antibody, had substantial therapeutic activity and an acceptable safety profile in patients with relapsed or refractory Hodgkin's lymphoma (HL). To our knowledge, this drug has never been tested after allogeneic stem cell transplantation (allo-SCT) mainly because PD-1-blocking strategy may substantially increase the risk of Graft Versus Host Disease (GVHD). Nevertheless, some studies suggested that Reed-Sternberg cells exploit the PD-1 pathway to evade immune detection, possibly explaining why some patients resist to graft-versus-lymphoma effect.
PATIENTS AND METHODS: We retrospectively assessed the efficacy and toxicity of nivolumab as a single agent in 12 HL patients relapsing after allo-SCT. All patients had progressive disease at the nivolumab initiation. The dose was 3 mg/kg of body weight every 2 weeks. The median of previous systemic therapies was 9 (range 7-11), including allo-SCT. Patients were required to be off immune suppression for more than 4 weeks prior to nivolumab initiation, with no history of grades III-IV acute or extensive chronic GVHD. Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria for AEs (version 4.0). Efficacy was assessed by physical examination before each infusion and per IWG guidelines (Cheson 2007) after four injections of nivolumab.
RESULTS: Eight out of 12 patients were evaluable at the time of submission. Median age at time of transplant was 31 (range 28-42) and median time from allo-SCT to study treatment was 11 months (range 3 - 122). Eight patients had related donors and 4 patients had unrelated donors including one haploidentical transplantation. Best response before allo-SCT was RP in 8 patients and RC in 4 patients. Allo-SCT improved response in only 2 patients. Six patients had received therapy for HL progression/relapse post allo-SCT, including donor lymphocyte infusions (n=4). Median number of injection of nivolumab was 4 (range 1-10).
Acute GVHD occurred in 2 patients after 1 injection (grade III skin acute GVHD) and 2 injections (grade IV skin acute GVHD) of nivolumab. In one patient, GVHD responded quickly to corticosteroids therapy. The patient who received haplo-identical allo-SCT presented with corticosteroid-refractory grade IV skin GVHD reversed after several extracorporeal photopheresis sessions. Both patients had prior history of grade II acute GVHD in the three months before nivolumab administration and treatment was stopped. Nivolumab did not modify chimerism. The only serious hematological adverse events were grade 4 neutropenia (1 patient) and grade 3 thrombocytopenia (1 patient). No other non-hematological adverse event was observed except a grade 2 cerebellar ataxia. With a median follow-up of 60 days post nivolumab initiation, 1 patient discontinued due to progressive disease, 2 patients due to acute GVHD and 9 patients remain on nivolumab.
In our preliminary analysis of efficacy, 7 out of the 8 (87.5%) patients evaluable for response had clinical benefit, with 4 achieving partial response and 3 in complete response according to Cheson 2007 criteria. Of note, one of the patient developing acute GVHD post nivolumab achieved partial response. No data for the other patient presenting with acute GVHD after treatment was available at the time of analysis.
CONCLUSIONS: Our preliminary results suggest that nivolumab is effective with manageable toxicity in patients with relapsed or refractory Hodgkin's lymphoma after allo-SCT. These encouraging results emphasize the need to delineate indications and perform prospective protocols.

Disclosures
Morschhauser: Genentech Inc./Roche: Other: Advisory boards.