Treatment of Relapsed/Refractory Chronic Lymphocytic Leukemia After BTK Inhibitor and/or BCL-2 Inhibitor Failure


  • Sue Robinson, MD, FRCPC Department of Medicine, Dalhousie University Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia



The treatment landscape for first-line and relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) has tremendously advanced with the introduction of Bruton tyrosine kinase inhibitors (BTKi) and B-cell lymphoma 2 inhibitors (BCL-2i). However, in this new era of targeted therapy for CLL, there is, unfortunately, no evidence yet to guide the optimal sequencing of these drugs. It remains unknown whether treating first-line with a BTKi and relapse with BCL-2i or BCL-2i at first-line followed by BTKi at relapse results in any difference in overall survival (OS). Ibrutinib (BTKi) was first introduced in 2014, and venetoclax (BCL-2i) in 2016, and currently, there are limited prospective data and treatment options for patients who have relapsed after one or both targeted therapies. This article will provide an overview of the approach to treatment for patients with CLL/SLL when BTKi and/or BCL-2i therapy has failed.

Before launching into the treatment of R/R CLL, it is worth noting that guidelines for risk assessment of CLL recommend determining the immunoglobulin heavy chain gene (IGHV) mutational status once, usually before the first treatment, and fluorescence in situ hybridization FISH for del(17p) and next-generation sequencing (NGS) before each treatment.1 Other than TP53, NGS-detected mutations are not routinely considered when choosing a therapy, but they may help predict the duration of remission and may become standard of care in the future. 

Author Biography

Sue Robinson, MD, FRCPC, Department of Medicine, Dalhousie University Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia

Dr. Robinson is a Hematologist at the QEII Health Sciences Centre in Halifax, Nova Scotia. She is also a Professor at Dalhousie University and teaches at the undergraduate and post-graduate levels. She has been Program Director for the Hematology Residency Program and Hematology Unit Head for undergraduate medicine. She has a large clinical practice, including many CLL patients. She heads the provincial bleeding disorder clinic and is the local Principal Investigator for a number of CLL trials. She has set up a province wide CLL registry. 


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How to Cite

Robinson S. Treatment of Relapsed/Refractory Chronic Lymphocytic Leukemia After BTK Inhibitor and/or BCL-2 Inhibitor Failure. Can Hematol Today [Internet]. 2024 Jun. 27 [cited 2024 Jul. 23];3(2):49–53. Available from: