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Pembrolizumab in patients with chronic lymphocytic leukemia with Richter's transformation and relapsed CLL

Wei Ding, Betsy R. LaPlant, Timothy G. Call, Sameer A. Parikh, Jose F. Leis, Rong He, Tait D. Shanafelt, Sutapa Sinha, Jennifer Le-Rademacher, Andrew L. Feldman, Thomas M. Habermann, Thomas E. Witzig, Gregory A. Wiseman, Yi Lin, Erik Asmus, Grzegorz S. Nowakowski, Michael J. Conte, Deborah A. Bowen, Casey N. Aitken, Daniel L. Van Dyke, Patricia T. Greipp, Xin Liu, Xiaosheng Wu, Henan Zhang, Charla R. Secreto, Shulan Tian, Esteban Braggio, Linda E. Wellik, Ivana Micallef, David S. Viswanatha, Huihuang Yan, Asher A. Chanan-Khan, Neil E. Kay, Haidong Dong and Stephen M. Ansell

Key points

  • Pembrolizumab was first shown to be clinically active in CLL patients with Richter's transformation.

  • PD-1 and PD-L1 expression in tumor microenvironment are promising biomarkers to select RT patients for PD-1 blockade.

Abstract

CLL patients progressed early on ibrutinib often develop Richter's transformation (RT) with short survival 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 MC1485 (NCT02332980) 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 the 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-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.

  • Submitted February 3, 2017.
  • Accepted April 10, 2017.