According to results from a prospective, open-label, exploratory phase 1/2a study, the combination of ibrutinib and nivolumab was administered to 4 cohorts of patients with relapsed or refractory high-risk chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (del17p or del11p), follicular lymphoma, diffuse large B-cell lymphoma (DLBCL), or Richter transformation. Of these groups, only the latter patient cohort was found to have a promising overall response rate (ORR) compared with historical controls of single-agent ibrutinib in this subgroup. This study was published in Lancet Haematology

There is preclinical evidence for synergistic antitumor activity of ibrutinib and anti-PD-1 agents, even in models that were unresponsive to ibrutinib alone. Hence, it has been suggested that ibrutinib may enhance the activity of immune checkpoint inhibitors. 

A total of 141 patients received study treatment. In the phase 1 portion of the study, 2 doses of oral ibrutinib (420 mg and 560 mg daily) in combination with nivolumab (3 mg/kg delivered intravenously every 2 weeks) were administered to 14 patients (ie, 7 patients in each dosing arm) in order to determine the phase 2 doses of ibrutinib in each patient cohort. Based on evaluations of safety, it was determined that the optimal phase 2 doses of ibrutnib were 420 mg for patients with CLL or small lymphocytic leukemia and 560 mg for the other 3 cohorts. In addition, ibrutinib and nivolumab pharmacokinetic parameters were not affected by concurrent administration. 

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In the dose-expansion portion of the study, 35 and 92 patients received the lower and higher doses of ibrutinib, respectively, in combination with nivolumab. The ORRs for the individual patient cohorts were: 61% (CLL or small lymphocytic lymphoma), 33% (follicular lymphoma), 36% (DLBCL), and 65% (Richter transformation). Compared with historical controls from studies of single-agent ibrutinib in these patient groups, only the Richter transformation cohort demonstrated an ORR that was higher than observed in studies of single-agent ibrutinib. 

In this study, diarrhea, neutropenia, and fatigue were the adverse events reported most frequently. The most common grade 3/4 adverse event were neutropenia and anemia. Grade 3/4 rates of neutropenia ranged from 18% in patients with DLBCL to 53% in patients with CLL or small lymphocytic lymphoma, whereas grade 3/4 rates of anemia ranged from 13% in patients with follicular lymphoma to 35% in patients with Richter transformation. Rash and increased alanine aminotransferase were the grade 3/4 immune-related adverse events reported most frequently. The rate of grade 3-5 adverse events was higher in this study compared with studies of single-agent ibrutinib evaluated in similar patient populations, although the rates of immune-related reactions were similar to those observed in studies of patients receiving nivolumab alone. 

Some of the limitations of this study included the relatively small numbers of patients in each patient cohort, as well as relatively short follow-up. 

Given these preliminary efficacy results, along with the findings of increased toxicity for the combination of ibrutinib plus nivolumab compared with results from other studies evaluating ibrutinib alone, the authors wrote in conclusion that “the overall response with the ibrutinib and nivolumab combination regimen in patients with Richter transformation was promising and warrants confirmation in patients with Richter transformation” who do not respond to ibrutinib single-agent therapy. Nevertheless, they wrote that the patients with Richter transformation included in their study had not been previously treated with ibrutinib. 


  1. Younes A, Brody J, Carpio C, et al. Safety and activity of ibrutinib in combination with nivolumab in patients with relapsed non-Hodgkin lymphoma or chronic lymphocytic leukaemia: a phase 1/2a study. Lancet Haematol. 2019 Feb;6(2):e67-e78. doi: 10.1016/S2352-3026(18)30217-5