Resistance-associated mutations in chronic lymphocytic leukaemia patients treated with ibrutinib, idelalisib and venetoclax

Authors: L. Sedlaříková 1;  T. Papajík 2;  A. Petráčková 1;  P. Turcsányi 2;  E. Kriegová 1
Authors‘ workplace: Ústav imunologie, Lékařská fakulta Univerzity Palackého a Fakultní nemocnice, Olomouc 1;  Hemato-onkologická klinika, Lékařská fakulta Univerzity Palackého a Fakultní nemocnice, Olomouc 2
Published in: Transfuze Hematol. dnes,1, 2020, No. Online only, p. 1-17.


Targeted BCR signalling pathway inhibitors (ibrutinib, idelalisib) and BCL2 inhibitors (venetoclax) appear promising in patients with chronic lymphocytic leukaemia (CLL), as they have shown significant clinical efficacy in relapsed/refractory high-risk patients with deletion 17p and/or TP53 mutation, as well as in first-line treatment. Nevertheless, there is a growing body of evidence regarding the emergence of mutations leading to clinical resistance during treatment. So far, most information has been reported in patients treated with ibrutinib (an irreversible inhibitor of Bruton’s tyrosine kinase, BTK), where resistance-associated mutations have been found in the BTK and PLCG2 genes. For idelalisib (an inhibitor of the δ isoform of phosphatidylinositol 3-kinase, PI3K), no resistance-associated mutation and/or aberrant signalling pathway have been reported, but a number of various genetic aberrations associated with CLL have been found in relapsing patients. Recently, mutations in the BCL2 gene have been reported in resistant patients treated with venetoclax (BCL2 inhibitor). In most patients who progressed on novel agents, the mutations associated with resistance occurred at low allelic frequencies between the second and fourth years of therapy. Frequently, several subclones are present which can be detected several months prior to clinical relapse. In this review, we report state-of-the-art data about known gene variants associated with resistance to ibrutinib, idelalisib and venetoclax, and the latest findings of their clinical impact. Nevertheless, recent findings suggest that there are also alternative mechanisms of acquired resistance to treatment with these inhibitors, which will certainly become the subject of further studies. We also discuss recent findings in the development of next-generation pathway inhibitors for the treatment of CLL patients who have acquired resistant mutations to current inhibitors.


chronic lymphocytic leukaemia – targeted therapy – signalling pathway inhibitors – mutations associated with resistance – resistance to treatment

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