Current Treatment Options in Relapsed and Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: a Review

Opinion StatementTreatment of relapsed and refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) has changed dramatically over the past decade due to the development of oral targeted agents in several therapeutic classes, including BTK inhibitors (such as ibrutinib, acalabrutinib, zanubrutinib, and the non-covalent BTK inhibitor pirtobrutinib), the first in class BCL2 inhibitor venetoclax, PI3K inhibitors (idelalisib and duvelisib), and monoclonal antibodies in monotherapy and in combination. My approach to treatment of the R/R patient draws heavily on prior therapies, such that a patient with no exposure to prior novel therapies would be offered either a BTK or BCL2-based regimen, whereas patients with prior BTK inhibitor exposure would likely receive a BCL2 inhibitor and vice versa. For patients who are intolerant to a BTK inhibitor but are otherwise responding, an alternate BTK inhibitor may be considered. For those patients who have received a fixed-duration BCL2 inhibitor-based regimen and have maintained a response for greater than 12-24 months, re-treatment with a BCL2 inhibitor-based regimen at progression may be considered based on limited data, recognizing that robust prospective clinical trials are lacking in this space. For those patients who are "double refractory" and have progressed on both a BTK inhibitor and a BCL2 inhibitor-based regimen, clinical trials are strongly preferred. In absence of a clinical trial, these patients can be challenged with PI3K inhibitors, though responses are usually not durable, and toxicity is high. Combination cytotoxic chemotherapy with novel agents, allogeneic hematopoietic stem cell transplant, and cellular therapy may be considered for very high-risk populations, such as patients with Richter's transformation, though novel approaches are urgently needed and clinical trial enrollment is highly encouraged.