Characteristics and Outcomes of Patients with Double Refractory and Double Exposed Chronic Lymphocytic Leukemia

• The median overall survival of patients with double refractory CLL whose disease progressed during BTK and BCL2 inhibition was 2.2 years.

• Double exposed CLL represented a less aggressive disease state with preserved sensitivity to targeted and cellular therapies.

We analyzed the characteristics and outcomes of 95 patients with chronic lymphocytic leukemia (CLL) post-Bruton tyrosine kinase inhibitor (BTKi) and B-cell lymphoma 2 inhibitor (BCL2i) failure. To clearly distinguish sensitivity and resistance to the targeted treatment classes, we defined double refractory (DR) CLL when progressive disease occurred during active treatment with a BTKi and a BCL2i given sequentially or in combination and double exposed (DE) disease when treatment with either or both of these agents was discontinued due to reasons other than progression. Thirty (31.6%) patients had DR CLL and 65 (63.2%) had DE CLL. The DR group more frequently had unmutated IGHV (97%), TP53 aberration (73%), and BTK mutations (59%) than the DE group (75%, 46%, and 27%, respectively). The median number of total lines of therapy was 6 for DR and 3 for DE. Nearly all (97%) DR patients required subsequent therapy after developing DR CLL. The most commonly used treatment was non-covalent BTKis (34%), followed by concurrent covalent BTKi and BCL2i (28%) and CD19 chimeric antigen receptor-modified T cells (24%). Treatment for DE CLL was less frequently observed (26%). Median overall survival (OS) was 2.2 years once DR developed despite frequent initial responses to non-covalent BTKis or cellular therapy in the cohort. Patients with DE CLL demonstrated favorable survival (median OS not reached) and durable response to subsequent therapy.