Chronic Lymphocytic Leukemia (CLL) patients treated with ibrutinib, Bruton Tyrosine Kinase (BTK) inhibitor, and progress early often develop Richter’s Transformation (RT), a transformation into aggressive lymphoma. Additionally, CLL patients who develop RT have a poor survival outcome, hence a clinically unmet need.1
In June 2017, Wei Ding and colleagues from the Mayo Clinic, Rochester, published an article in Blood, reporting results of their single-center phase II study (NCT02332980) which investigated the efficacy and safety of pembrolizumab, a humanized PD-1- blocking antibody, in patients with relapsed or RT CLL.2
In total, 25 patients (median age = 69 years) with relapsed CLL (n = 16) and RT (all proven DLBCL, n = 9) were enrolled in this study.
- Pembrolizumab 200 mg was administered intravenously every 3 weeks
- Fifteen (60%) patients received prior ibrutinib
- Twelve patients progressed with RT (n = 6) and progressive CLL (n = 6) while receiving ibrutinib
- Overall Response Rate (ORR)
- CLL patients = 0% (95% CI, –)
- RT patients = 44% (95% CI, 14–79)
- Median Overall Survival (OS)
- Median follow-up of 10.4 months (range, 2.7–16.1)
- CLL patients = 11.2 months (95% CI, 2.8–NR)
- RT patients = 10.7 months (95% CI, 4.4–NR)
- CLL patients with prior ibrutinib therapy = 4.3 months (95% CI, 0.6–NR)
- RT patients with prior ibrutinib therapy = NR (95% CI, 4.4–NR)
- AEs were reported in all patients (n = 25)
- Most frequent treatment-related grade 3–4 AEs include thrombocytopenia (20%), anemia (20%), neutropenia (20%), dyspnea (8%), and hypoxia (8%)
- Biomarker assessment
- Patients with confirmed clinical response had a significant increase in the expression of PD-L1 compared to non-responders; P = 0.03
- Patients with confirmed clinical response had an increase in the expression of PD-1 compared to non-responders; P = 0.10
Overall, the authors concluded that the results from their study “demonstrate single-agent pembrolizumab selective activity in CLL patients with RT” but not in relapsed CLL patients. Moreover, they suggested that “PD-L1 and PD-1 expression in the tumor microenvironment” could be promising biomarkers to select RT patients for PD-1 blockade”.
They further highlighted that their study is the first to demonstrate a benefit for PD-1 blockade in CLL patients with RT. However, the authors noted that their study was limited by the small sample size and proposed that a large trial with a longer follow-up is required to confirm their findings in this subgroup of CLL patients with RT. As a result, an international phase II study (NCT02576990) of single-agent pembrolizumab in CLL patients with RT was initiated and it is currently underway.
Chronic lymphocytic leukemia (CLL) patients progressed early on ibrutinib often develop Richter transformation (RT) with a short survival of about 4 months. Preclinical studies suggest that programmed death 1 (PD-1) pathway is critical to inhibit immune surveillance in CLL. This phase 2 study was designed to test the efficacy and safety of pembrolizumab, a humanized PD-1–blocking antibody, at a dose of 200 mg every 3 weeks in relapsed and transformed CLL. Twenty-five patients including 16 relapsed CLL and 9 RT (all proven diffuse large cell lymphoma) patients were enrolled, and 60% received prior ibrutinib. Objective responses were observed in 4 out of 9 RT patients (44%) and in 0 out of 16 CLL patients (0%). All responses were observed in RT patients who had progression after prior therapy with ibrutinib. After a median follow-up time of 11 months, the median overall survival in the RT cohort was 10.7 months, but was not reached in RT patients who progressed after prior ibrutinib. Treatment-related grade 3 or above adverse events were reported in 15 (60%) patients and were manageable. Analyses of pretreatment tumor specimens from available patients revealed increased expression of PD-ligand 1 (PD-L1) and a trend of increased expression in PD-1 in the tumor microenvironment in patients who had confirmed responses. Overall, pembrolizumab exhibited selective efficacy in CLL patients with RT. The results of this study are the first to demonstrate the benefit of PD-1 blockade in CLL patients with RT, and could change the landscape of therapy for RT patients if further validated. This trial was registered at www.clinicaltrials.gov as #NCT02332980.
- Maddocks K. J. et al. Etiology of Ibrutinib Discontinuation and Outcomes in Chronic Lymphocytic Leukemia Patients. JAMA Oncol. 2015 Apr 1; 1 (1): 80–87. DOI: 1001/jamaoncol.2014.218.
- Ding W. et al. Pembrolizumab in patients with CLL and Richter transformation or with relapsed CLL. Blood. 2017 Jun 29; 129 (26): 3419–3427. DOI: 1182/blood-2017-02-765685. Epub 2017 Apr 18.