Successful treatment of relapsed/refractory Hodgkins lymphoma with nivolumab in a heavily pretreated patient with progressive disease after both autologous and allogeneic stem cell transplantation

The programmed death-1 (PD-1) regulatory pathway is active in several tumors and a potent immunotherapeutic target with PD-1 inhibitors. Nivolumab is an anti-PD-1 monoclonal antibody that is approved for melanoma and squamous cell lung cancer. [1,2] It has also been shown that nivolumab has a profound therapeutic activity in patients with relapsed/refractory Hodgkin lymphoma, a disease with a genetic basis for PD-1 ligand overexpression and a marked but ineffective inflammatory and immune-cell infiltrate. [3] However, very little is known on its potential activity and safety after allogeneic stem cell transplantation (SCT), mainly because of the concerns that PD-1 blockage may increase the risk of graft versus host disease (GVHD). As allogeneic SCT remains potentially curative option for the treatment of younger patients with advanced classical Hodgkin lymphoma (cHL), these patients have limited treatment options if they fail allogeneic transplant. [4] We describe our experience with nivolumab in a patient with relapsed/refractory Hodgkin lymphoma who had progressive disease after both autologous and allogeneic SCT. 30-year-old male was diagnosed with cHL (nodular sclerosing type), stage IIIB, on November 2010. He received 6 cycles of adriamycin (doxorubicin), bleomycin, vinblastine and dacarbazine (ABVD) and achieved a clinical complete remission (CR), however, he relapsed on October 2011. Subsequently, he was given 2 cycles of ICE and achieved a clinical partial response (PR). He underwent high-dose chemotherapy followed by autologous SCT on February 2012 and achieved a clinical CR. Unfortunately, he had relapsed disease on September 2012. He received 3 cycles of Gemcitabine and Oxaliplatin (GemOx) but had progressive disease. He was given 4 cycles of Paclitaxel and achieved a clinical PR. Subsequently, he underwent an allogeneic SCT using reduced intensity conditioning (FþM) from his full-match mother by high resolution HLA typing on May 2013. However, he had clinical and radiographic evidence of disease progression by day 100 with full donor chimerism and no evidence of GVHD or GVL. Progression continued despite withdrawal of immunosuppression. On September 2013, he was started on brentuximab vedotin (BV), achieved a clinical PR and received a total of 16 cycles. BV was stopped after 16th cycle due to grade III motor and peripheral neuropathy. He was started on pregabalin and his neuropathy resolved completely within 3 months. He progressed on September 2014 and was given Bendamustin for 3 cycles with further progression. He was then given oral PECC (prednisone, etoposide, chlorambusil, CCNU) for 6 cycles with a brief clinical PR, however, progressed again on December 2015. The patient presented with weakness, nonproductive cough, and weight loss on December 2015. His physical examination revealed a large palpable mass at epigastric area. A PET-CT confirmed progressive disease (Figure 1(A)). Given the lack of any meaningful treatment option, we decided to treat the patient with off-label nivolumab. We obtained a written informed consent and nivolumab treatment was started at the dose of 3mg/kg every 2 weeks on January 2016. His treatment course was uneventful except that the patient experienced an intense abdominal pain radiating to his back within an hour of the first injection of nivolumab that eventually disappeared in hours. He was feeling very well with a significant decrease of his cough before the second injection and his examination revealed no evidence of palpable mass at his epigastric area. A PET-CT obtained after the 6th cycle of the nivolumab treatment showed complete resolution of his disease (Figure 1(B)). His biweekly maintenance nivolumab therapy is ongoing, after the 14th cycle of the treatment, he has a good allograft function and full donor chimerism with no evidence of drugrelated toxicity and GVHD so far. We have described successful treatment of a patient with highly refractory cHL with nivolumab after failing multiple lines of therapy including autologous and