Description

Chronic Lymphocytic Leukemia (CLL) is a malignant B-cell disorder characterized by the accumulation of CD19+CD5+ lymphocytes in the bone marrow, lymph nodes, spleen, and peripheral blood. It has an incidence of approximately 4.2 cases per 100,000 people annually, with a median diagnosis age of 72 years. CLL exhibits marked biological and clinical heterogeneity, influenced by prognostic factors such as Immunoglobulin Heavy Chain Variable Region (IGHV) mutation status, TP53 alterations, and complex karyotypes. The disease is typically indolent, and treatment initiation follows criteria established by the International Workshop on CLL (IWCLL). Symptoms, when present, include lymphadenopathy, cytopenias, and infections. About one-third of patients require treatment at diagnosis, another third within ten years, and the remaining third may never need therapy. Although incurable, CLL generally has favorable progression-free and overall survival rates.Historically, chemotherapy was the main treatment, but the advent of targeted oral therapies-particularly Bruton tyrosine kinase inhibitors (BTKi) and BCL-2 inhibitors (BCL-2i)-has significantly improved patient outcomes. BTKi block the BTK enzyme critical for B-cell receptor signaling, thereby inhibiting malignant B-cell proliferation and survival. BCL-2 inhibitors induce apoptosis by binding to the anti-apoptotic BCL-2 protein, which CLL cells often overexpress. Combined use of these agents with monoclonal antibodies has become standard care. Despite these advances, approximately 20% of patients develop resistance to chemotherapy or targeted therapies. A rare but clinically significant subgroup, termed double refractory, fails to respond to both BTKi and BCL-2i and has a poor prognosis. Defining resistance includes clinical progression on therapy and biological markers such as mutations associated with drug resistance. Resistance to BTKi arises from compensatory signaling pathways or mutations within BTK, whereas resistance to BCL-2 inhibitors is typically identified when patients relapse during or soon after treatment.. To overcome resistance to BTKi, novel BTK degraders (BTKd) are under development. Unlike BTKi, these heterobifunctional molecules induce proteasomal degradation of the BTK protein via ubiquitination, showing promising preclinical efficacy. However, limited clinical data exist on BTKd, and researchers still need to carry out a full evaluation of their effectiveness against other resistance mechanisms and in combination with current immunotherapies. To gain a better understanding of resistance and response to BTKd, establishing a dedicated cohort and biobank of samples from double-refractory CLL patients is essential. Collaborating with research teams specialized in hematologic malignancies, such as the CRCI²NA group, and leveraging existing frameworks like the FILO/LYSA ( French Innovative Leukemia Organization/Network for clinical lymphomas and CLL/WM research) networks, will enable comprehensive translational studies. This initiative aims to address the urgent need for novel therapeutic strategies in this challenging patient population.