Pathway inhibitors targeting Bruton tyrosine kinase (BTK) and B-cell lymphoma-2 (BCL-2) have dramatically changed the treatment landscape for both treatment-naïve and relapsed/refractory chronic lymphocytic leukemia (CLL). However, with increased utilization, a growing number of patients will experience progressive disease on both agents. This subgroup of "double refractory" patients has limited treatment options and poor prognosis. Chimeric antigen receptor (CAR)-T cells have transformed the treatment of relapsed/refractory B-cell malignancies. Although the earliest success of CAR-T cell therapy was in CLL, the clinical application of this modality has lagged until the recent approval of the first CAR-T cell product for CLL. In this review, we describe the current treatment options for upfront and subsequent therapies and the unmet need for novel agents highlighted by the burgeoning role and challenges of CAR-T cell therapy.
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