Treatment outcomes for patients with chronic lymphocytic leukemia (CLL) have improved with the use of targeted agents, such as ibrutinib, yet complete remissions (CRs) are rare, and the outcomes of patients with relapsed CLL still remain suboptimal.1 T cells from patients with CLL express higher levels of checkpoint inhibitory molecules, such as PD-1, compared with normal T cells.2 Moreover, CLL cells express ligands for these molecules, including PD-L1 and PD-L2. Ibrutinib is known to modulate immune responses, and has been shown to be synergistic with checkpoint blockade in preclinical models.3 Jain and colleagues report on the results of a clinical trial of combining the immune checkpoint inhibitor nivolumab with ibrutinib for patients with relapsed or refractory (R/R) CLL or Richter transformation (RT).
This was an investigator-initiated phase 2 clinical trial combining nivolumab (anti–PD-1 monoclonal antibody) with ibrutinib in patients with R/R CLL or RT, and included 2 cohorts: cohort 1 (R/R CLL or RT) and cohort 2 (patients with CLL who achieved partial remission (PR) after at least 9 months on ibrutinib). In cohort 1, patients received a lead-in window of nivolumab monotherapy 3 mg/kg IV every 2 weeks for course 1; ibrutinib 420 mg once daily was added starting with course 2. In cohort 2, patients were already receiving ibrutinib when they entered the study, and continued ibrutinib; nivolumab was added from course 1. The primary objective of the trial was CR/CRi rate in cohort 1, and the rate of conversion from PR to CR/CRi in cohort 2. Peripheral blood and bone marrow samples were collected at baseline and serially on treatment to assess for T-cell subsets and immune marker expression. The authors now report data on the first 13 patients. Five patients with R/R CLL were treated on cohort 1, with a median number of prior therapies of 1 (range, 1-3). Of these, 1 patient achieved a CR that has lasted >10 months; 3 patients achieved PR; 1 patient had no response and came off study after course 5.
Three patients were enrolled in cohort 2 [(del 17p (n = 2), del13q (n = 1); unmutated IGHV (n = 2); no polymerase chain reaction amplification (n = 1)]. Patients had been on ibrutinib from 13 to 32 months prior to study enrollment. All 3 patients demonstrated stable disease and noted a decrease in the lymphocytic infiltrate in the marrow, but no patients achieved CR/CRi. All 3 patients are continuing on study with a follow-up from 5 to 9 months. One patient in cohort 2 developed grade 2 thyroiditis and 1 patient in cohort 1 developed grade 2 pneumonitis. No other immune-related adverse events were noted. Correlative studies, including flow cytometry and immunohistochemistry, for PD-1 and PD-L1 in serial blood and marrow samples demonstrated an increased PD-1 expression on tumor cells in patients with RT. The authors conclude that the combination of nivolumab and ibrutinib is well-tolerated and has encouraging activity in patients with RT, but only modest activity in relapsed/refractory CLL.
Jain N, et al. ASH 2016. Abstract 59.
- Jain N, et al. Blood Rev. 2016;30:233-244.
- Ramsay AG, et al. Blood. 2012;120:1412-1421.
- Sagiv-Barfi I, et al. Proc Natl Acad Sci U S A. 2015;112:E966-E972.