Nivolumab is effective in relapsed/refractory Hodgkin Lymphoma patients following allogeneic HCT

On March 4^th 2017 in Blood, Charles Herbaux from CHU Lille, Department of Hematology, Lille, France, and colleagues published their retrospective results exploring the efficacy and toxicity of single-agent nivolumab after allogeneic Hematopoietic Cell Transplantation (allo-HCT) in 20 patients with relapsed/refractory Hodgkin Lymphoma (HL).

Between March and September 2015, the French Medical Drug Agency (Agence Nationale de Sécurité du Médicament authorized a named patient Authorization for Temporary Use (ATU) program of nivolumab in patients with R/R HL after chemotherapy and brentuximab vedotin. For this analysis, the efficacy and toxicity of nivolumab was assessed using the medical records of 20 patients granted an ATU and who had previously undergone an allo-HCT.

Key Highlights

Patient characteristics

• Median age at time of transplant = 33 years (range, 20–51 years)
• Median number of prior systemic therapies = 7 (range, 4–13), including allo-HCT
• Grafts: unrelated donors = 6 pts (30%; 3 HLA-matched, 3 9/10-locus mismatched); matched-related siblings = 10 pts (50%); familial haploidentical donor = 1; cord blood = 3 pts (15%)
• Best response at allo-HCT: PR = 10 pts (50%); CR = 9 pts (45%); 1 patient received allo-HCT during PD
• Responses in 2 pts improved from PR to CR after allo-HCT
• Prior history of GvHD = 13 pts (10 aGvHD, no grade 3–4; 3 limited cGvHD)
• Mild to moderate cGvHD at nivolumab initiation = 4 pts

Nivolumab-induced GvHD

• Nivolumab-induced GvHD occurred in 6 pts (30%; 95% CI, 9.9–50.1%), causing discontinuation after 1 infusion
• All cases of aGvHD took place ≤1 week after first infusion
• All 6 pts had a previous history of GvHD
• No GvHD reported for pts without a history of GvHD
• Median time between allo-HCT and nivolumab treatment was shorter in nivolumab-induced GvHD pts (8.5 months [range, 2–19 months] vs. 28.5 months [range, 7–111 months]; P = 0.0082)
• Nivolumab-induced GvHD was successfully managed using standard GvHD treatment
• One of the 6 pts developed a febrile multiple organ dysfunction syndrome and died 3 weeks after nivolumab infusion
• Immunosuppressive therapy for nivolumab-induced GvHD did not reduce nivolumab efficacy on HL; 3/6 pts with nivolumab-induced GvHD are still responding after 1 nivolumab injection

Safety profile

• Two serious hematologic AEs in same patient = 1 grade 4 neutropenia and 1 grade 3 thrombocytopenia
• One non-hematologic AE reported = grade 2 cerebellar ataxia, which spontaneously resolved 4 days after nivolumab interruption
• Four deaths reported: 2 due to GvHD, 1 due to PD, and 1 due to complications of second allo-HCT performed after relapse
• Permanent nivolumab discontinuation occurred in 13 pts, due to: nivolumab-induced GvHD (n=6), disease progression (n=3), second allo-HCT (n=1), lack of response (n=1), hematologic toxicity (after 5 nivolumab infusions; n=1), and cerebellar ataxia (n=1)
• At last follow-up, 7 pts (35%) remain on nivolumab

Response

• Pts evaluable for response = 19/20
• Best ORR = 95% (95% CI, 74–100%; n=18); CR rate = 42% (95% CI, 21–67%; n=8); PR rate = 52% (95% CI, 29–76%; n=10)
• Relapses occurred in 5 pts after a median time of 132 days (range, 98–245 days)
• Median follow-up = 370 days (range, 24–486 days)
• Median PFS and OS not reached
• Probability of PFS at 12 months = 58.2% (95% CI, 33.1–76.7%)
• Probability of OS at 12 months = 78.7% (95% CI, 52.4–91.5%)

The authors concluded by stating that, in the largest known cohort of patients with HL treated with a PD-1 inhibitor after undergoing allo-HCT (including 10 patients with a history of aGvHD), the efficacy of nivolumab was confirmed in this indication. Moreover, the toxicity of nivolumab following allo-HCT was “manageable with careful monitoring and close clinical assessment.”

Abstract

Allogeneic hematopoietic cell transplantation (allo-HCT) is indicated for patients with relapsed and refractory Hodgkin lymphoma (HL). While long-term disease control can be achieved, relapse remains frequent. The programmed death 1 (PD-1) blocking antibody nivolumab has shown substantial therapeutic activity and an acceptable safety profile in relapsed and refractory HL who did not receive allo-HCT. However, PD-1-blocking strategy can increase the risk of Graft Versus Host Disease (GVHD) in murine models. We retrospectively assessed the efficacy and toxicity of nivolumab as a single agent in 20 HL patients relapsing after allo-HCT. GVHD occurred in six patients (30%) after nivolumab initiation. All six patients had prior history of acute GVHD. These nivolumab-induced GVHD were managed by standard treatment of acute GVHD. Two patients died of GVHD, one of progressive disease and one of the complications related to a second allo-HCT. Overall response rate was 95%. At a median follow-up of 370 days, one-year progression-free and overall survival rates were 58.2% [95%CI, 33.1 - 76.7] and 78.7% [95%CI, 52.4 - 91.5], respectively. Among 13 patients still in response, six received a single dose of nivolumab and seven remain on nivolumab. Compared to standard options in this indication, our results show that nivolumab is effective with an acceptable safety profile.