Journal de la leucémie
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Treatment Refractoriness to Pathway Inhibitors in Chronic Lymphocytic Leukemia

Nawar Maher*, Samir Mouhssine, Gianluca Gaidano

Therapeutic options for Chronic Lymphocytic Leukemia (CLL) rely on pathway inhibitors targeting Bruton Tyrosine Kinase (BTK) or B Cell Lymphoma 2 (BCL2), while the use of Chemo Immunotherapy (CIT) is limited to contexts where pathway inhibitors are not available or accessible. Biomarkers of treatment refractoriness to CIT include the unmutated status of immunoglobulin heavy chain variable genes and genetic alterations of TP53, NOTCH1, and BIRC3. Acquired mutations of BTK and PLCG2 genes represent the most common resistance mechanisms in patients receiving covalent BTK inhibitors (BTKi)-based therapy. The most frequent BTK mutations are C481S and C481R and impair binding of the drug to its target. Mutations of PLCG2 promote B cell receptor signaling despite BTK inhibition. Recently, several BTK point mutations causing acquired resistance to non-covalent BTKi have been reported, including T474I, L528W, A428D, M437R, and V416L. Concerning BCL2 inhibitors (BCL2i), multiple mutations affecting the BCL2 gene reduce or hinder the binding affinity between the BCL2i venetoclax and the anti-apoptotic BCL2 protein. The G101V substitution is the most common BCL2 mutation and reduces the clinical response to venetoclax. Several additional BCL2 mutations have been detected among CLL patients resistant to venetoclax. Interestingly, acquired 8p loss and 1q gain occur in a fraction of venetoclax-resistant patients and deregulate the expression of the anti-apoptotic MCL1 gene. Leukemic cells characterized by 8p loss and 1q gain display increased resistance to venetoclax and exhibit an augmented sensitivity to MCL1 inhibition. Knowledge of the molecular mechanisms of resistance to pathway inhibitors may help to better understand the sequencing and cross-resistance of available drugs and may contribute to the design of a precision medicine algorithm to be applied to the individual CLL patient.