Abstract
B-cell receptor (BCR) signaling pathway and Bcl-2 family prosurvival proteins, specifically Bcl-2 and Mcl-1, are functional in the pathobiology of chronic lymphocytic leukemia (CLL). A pivotal and apical molecule in the BCR pathway is Bruton’s tyrosine kinase (BTK). Together, BTK, Bcl-2, and Mcl-1 participate in the maintenance, migration, proliferation, and survival of CLL cells. Several ongoing and published clinical trials in CLL reported high rates of remission, namely, undetectable measurable residual disease (u-MRD) status with combined BTK inhibitor ibrutinib and Bcl-2 antagonist, venetoclax. While the majority of patients achieve complete remission with undetectable-measurable residual disease, at least one third of patients do not achieve this milestone. We hypothesized that cells persistent during ibrutinib and venetoclax therapy may be sensitive to combined venetoclax and Mcl-1 inhibitor, AMG-176. To test this hypothesis, we took peripheral blood samples at baseline, after Cycle 1 and Cycle 3 of ibrutinib monotherapy, after one week and 1 cycle of ibrutinib plus venetoclax therapy. These serial samples were tested for pharmacodynamic changes and treated in vitro with AMG-176 or in combination with venetoclax. Compared to C1D1 cells, residual cells during ibrutinib and venetoclax treatment were inherently resistant to endogenous cell death. Single agent exposure induced some apoptosis but combination of 100 nM venetoclax and 100 or 300 nM of AMG-176 resulted in 40–100% cell death in baseline samples. Cells obtained after four cycles of ibrutinib and one cycle of venetoclax, when treated with such concentration of venetoclax and AMG-176, showed 10–80% cell death. BCR signaling pathway, measured as autophosphorylation of BTK was inhibited throughout therapy in all post-therapy samples. Among four anti-apoptotic proteins, Mcl-1 and Bfl-1 decreased during therapy in most samples. Proapoptotic proteins decreased during therapy. Collectively, these data provide a rationale to test Mcl-1 antagonists alone or in combination in CLL during treatment with ibrutinib and venetoclax.
Highlights
Survival, proliferation, migration, and maintenance of normal B cells and chronic lymphocytic leukemia (CLL) B cells are dependent on B-cell receptor (BCR) signaling pathway [1, 2]
We evaluated if peripheral blood cells at baseline (C1D1), during ibrutinib alone (C2D1, C4D1), or ibrutinib and venetoclax (C4D8 and C5D1) were sensitive to additional ex vivo incubations with 100 nM and 300 nM AMG-176, 100 nM venetoclax, or venetoclax in combination with 100 nM or 300 nM AMG-176 (Supplementary Figure 1 and Table 2)
Our current investigations suggest that peripheral blood cells that persist after a few cycles of ibrutinib and one cycle of venetoclax therapy are inherently less primed for apoptosis
Summary
Proliferation, migration, and maintenance of normal B cells and chronic lymphocytic leukemia (CLL) B cells are dependent on B-cell receptor (BCR) signaling pathway [1, 2]. A pivotal molecule in the BCR signaling pathway is Bruton’s tyrosine kinase (BTK) which is at the apex of this nexus. Ibrutinib irreversibly inhibits BTK by covalently binding to the C481 residue of the kinase domain [3]. The importance of BTK inhibition was clearly demonstrated by achievement of long-term progression-free and overall survival with ibrutinib monotherapy in patients with CLL versus standard chemotherapy or chemoimmunotherapy [4, 5]. The drug was FDA approved as monotherapy for all CLL subgroups, namely, elderly patients [6] and patients with 17pdel [7]. The complete remission rate was less than 5% in previously untreated patients with CLL [5]
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