Resistance-Associated Mutations in Chronic Lymphocytic Leukemia Patients Treated With Novel Agents

Abstract

Inhibitors of B-cell receptor signaling, ibrutinib and idelalisib, and BCL-2 antagonist, venetoclax, have become the mainstay of treatment for chronic lymphocytic leukemia (CLL). Despite significant efficacy in most CLL patients, some patients develop resistance to these agents and progress on these drugs. We provide a state-of-the-art overview of the acquired resistance to novel agents. In 80% of patients with ibrutinib failure, acquired mutations in BTK and PLCG2 genes were detected. No distinct unifying resistance-associated mutations or deregulated signaling pathways have been reported in idelalisib failure. Acquired mutations in the BCL2 gene were detected in patients who had failed on venetoclax. In most cases, patients who have progressed on ibrutinib and venetoclax experience resistance-associated mutations, often present at low allelic frequencies. Resistance-associated mutations tend to occur between the second and fourth years of treatment and may already be detected several months before clinical relapse. We also discuss the development of next-generation agents for CLL patients who have acquired resistant mutations to current inhibitors.

Keywords: CLL; genetic aberrations; resistance-associated mutations; targeted therapy; treatment resistance.

Figure 1

B-cell receptor (BCR) signaling pathway and BCR inhibitors. Following antigen binding to the B-cell receptors, BCR signaling is chronically activated in CLL cells. As a consequence, the activated BCR pathway results in the production of second messengers and the activation of NF-kB and subsequent pro-proliferation and antiapoptotic pathways. Targets of the BCR inhibitors: ibrutinib, idelalisib, acalabrutinib, zanubrutinib, tirabrutinib, fenebrutinib, vecabrutinib, LOXO-305, ARQ-531, and entospletinib are depicted.

Figure 2

Position of known resistance-associated mutations in (A) BTK, (B) PLCG2, and (C) BCL2 genes. E, exon; PH, Pleckstrin homology domain; SH2/3, Src homology domain 2/3 (autoinhibitory domain); C2, Ca binding motive; X, catalytic domain; Y, catalytic domain; BH1-4, BCL-2 homology domain 1-4. Gene structure has been visualized according to a genome browser Ensembl (Ensembl release 99—January 2020, EMBL-EBI); protein domains and amino acid positions according UniProt Knowledgebase (2020_01 release—February 2020, UniProt Consortium).

Figure 3

Timeline and frequency of occurrence of resistance-associated mutations emergence in CLL patients who progressed on ibrutinib treatment. Resistance-associated mutations in BTK and PLCG2 genes usually develop between the second and fourth year of ibrutinib treatment. Mutated clones may occur at low allelic frequencies and may be detected several months before clinical relapse. Richter transformation is an early event that usually develops during the first 15 months of treatment with ibrutinib. Adapted from Ahn et al. (12).

Figure 4

Treatment strategies for patients with acquired resistance to ibrutinib. Approved treatment options are on the left (green), experimental ones on the right (yellow).

Figure 5

Resistance-associated BTK (C481) mutation and possibilities of its overcoming in ibrutinib-treated CLL patients. (A) After the occurrence of BTK (C481) mutation, ibrutinib does not bind to BTK causing the loss of its therapeutic effect leading to BCR and NF-kB pathway activation, both signaling pathways pivotal for maintenance and proliferation of CLL cells. Additionally, activating mutations in PLCG2 gene may result in continuous BCR signaling independently on BTK activation. To overcome the resistance by mutations in BTK/PLCG2 genes, other pathways may be targeted. (B) Idelalisib targets phosphatidylinositol 3-kinase (PI3K), resulting in the downregulation of PI3K/mTOR signaling pathway, irrespectively on the BTK mutation status. (C) Venetoclax targets BCL-2, thus leading to the apoptosis of CLL cells. As the previous treatment with BCR inhibitors results in an increased dependence on BCL-2 expression together with the fact that venetoclax complements ibrutinib-mediated apoptosis, a deep therapeutic effect on venetoclax is achieved.