https://canadianhematologytoday.com/ Catalytic Health en-US Canadian Hematology Today 2816-5152 https://canadianhematologytoday.com/article/view/4-s06-Puckrin <p class="p1">Managing patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who have been treated with both a covalent Bruton’s tyrosine kinase (BTK) and BCL2 inhibitor represents an increasingly common and complex clinical challenge. While some patients may be candidates for retreatment with a covalent BTK and/or BCL2 inhibitor, those who are refractory to both classes have limited therapeutic options beyond phosphoinositide 3-kinase (PI3K) inhibitors or allogeneic hematopoietic stem cell transplantation, which is typically feasible only for highly selected individuals. In this context, enrollment in clinical trials or compassionate access programs provides the best opportunity to access promising novel therapies, including next-generation BTK inhibitors and T-cell–directed immunotherapy approaches. This review provides a practical approach for assessing and managing double-exposed CLL/SLL in the current Canadian context.</p> Robert Puckrin Copyright (c) 2025 Canadian Hematology Today https://creativecommons.org/licenses/by-nc-nd/4.0 2025-10-29 2025-10-29 2–8 2–8 10.58931/cht.2025.4s0676