Dual Inhibition of Bruton’s Tyrosine Kinase and BCL2: A Promising Therapeutic Strategy for Myeloid and Lymphoid Leukemias

Genomics sequencing efforts have found a broad spectrum of mutations in many hematologic malignancies. Given the complex and heterogeneous nature of genetic subclones and the tumor microenvironment, it is likely that multiagent combinations with complementary mechanisms of action will be required to treat these diseases effectively over the disease continuum.

In this study, an ex vivo screening assay was used to identify small-molecule targeted inhibitors and inhibitor combinations demonstrating selective efficacy across broad categories of leukemia. Specimens isolated from 588 patients with leukemia were evaluated in the presence of a graded-concentration panel of more than 120 single-agent inhibitors or combinations spanning several different drug classes. Leukemia subgroups included acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia, and myeloproliferative neoplasms/myelodysplastic syndrome. The combinations selected for the analysis were designed as drug pairs that target different biological pathways and, therefore, have the potential to represent complementary mechanisms of action.

Statistical analyses revealed that the combination of venetoclax, a B-cell lymphoma 2 (BCL2) inhibitor, and ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, showed greater clinical benefit compared with either single agent in both myeloid and lymphoid malignancies, including AML, ALL, and CLL. When evaluating subgroups by mutational status in AML, researchers found that venetoclax + ibrutinib was particularly effective in patient samples with FLT3-ITD or NPM1 mutations.

These important preclinical findings demonstrated that both lymphoid- and acute myeloid–derived primary leukemia cells show sensitivity to combined inhibition of BCL2 and BTK with the combination of venetoclax and ibrutinib, suggesting this combination may have broad therapeutic indications.

Eide CA, et al. ASH 2018. Abstract 214.

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