Relapsed/refractory chronic lymphocytic leukemia (R/R CLL) continues to be clinically challenging, and half of patients progressing on ibrutinib develop Richter’s syndrome/transformation (RS), an aggressive high-grade lymphoma transformation, for which standard chemotherapy has very limited efficacy. Ding and colleagues examined whether immune checkpoint blockade would re-establish antitumor immune response in progressive CLL/RS, and presented updated clinical data and correlative analysis of MC1485, a phase 2 study of the PD-1–blocking monoclonal antibody pembrolizumab in R/R CLL and RS.
Patients with R/R CLL, including those with RS, enrolled in the CLL arm of the MC1485 trial, with overall response rate (ORR) as the primary end point of the study. Pembrolizumab 200 mg was administered intravenously every 3 weeks. NCI CTCAE v4.0 and International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2008 criteria were used for nonhematologic adverse events (AEs) and for CLL grade hematologic AE. Tumor expression of PD-1 and PD-L1 were assessed with standard immunohistochemical (IHC) staining. A total of 25 patients including 16 CLL and 9 RS (biopsy-proven diffuse large B-cell lymphoma) were enrolled in the CLL arm; the patients had a median number of prior therapies of 4, with 96%, 72%, or 48% of patients having received an alkylator and anti-CD20 antibody, purine analog, or anthracycline. Fifteen (60%) patients had prior ibrutinib and 12 (48%) progressed clinically while receiving ibrutinib, including 6 who progressed to RS and 6 who developed progressive CLL. The median number of pembrolizumab doses was 3, administered over a median treatment duration of 11 weeks.
Drug-related AEs occurred in 21 (88%) patients, most commonly neutropenia in 9 (37%), cough in 7 (29%), and dyspnea in 6 (25%). Drug-related grade 3 or above AEs occurred in 9 (38%) patients, most commonly thrombocytopenia (21%), dyspnea (8%), and fatigue (8%). The most common immune-related AE was liver enzyme elevation (12%, 8% grade 3) and was reversible with therapy interruption or steroid therapy. Based on investigator assessment using the Revised Response Criteria for Lymphomas and iwCLL 2008 criteria, 1 RS patient had complete response (CR, 11%), and 2 RS patients had partial response (PR, 22%); 4 patients (44%) had stable disease (SD), and 1 had progressive disease (PD, 11%), resulting in an ORR in RS of 44%. No CLL patients achieved a CR/PR, 5 had SD, and 8 had PD. The ORR of all patients was 16%. After a median follow-up of 10.2 months, the median overall survival (OS) for all patients was 10.7 months (95% confidence interval, 5.4 to not reached). The 6-month OS rates for RS and CLL patients were 73% and 59%, respectively. Biomarker assessment using IHC analysis on 10 patients with available tumor/nodal tissues (6 RS and 4 CLL) showed an increased expression of PD-L1 (P=0.02), and a trend for increased expression of PD-1 (P=0.1) in the group of patients with CR/PR versus patients in the group with no clinical response. The authors concluded that pembrolizumab has an acceptable safety profile in R/R CLL and RS patients, with substantial therapeutic activity in RS. However, single-agent pembrolizumab does not appear to have significant therapeutic activity in R/R CLL.Ding W, et al. ASH 2016. Abstract 4392.