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Tuesday, June 9, 2020

Voruciclib Plus Venetoclax: A Promising Combination for Treatment of CLL

By Sarah LaCorte

Although a lasting cure for B-chronic lymphocytic leukemia (CLL) has not yet been found, treating the disease with small molecule inhibitors has shown promise. A study presented at 2020 ASCO Annual Meeting showed that voruciclib + venetoclax is a very promising combination to improve treatment of CLL patients (Abstract e20009).

To more effectively treat patients with adverse prognostic factors, and relapsed/refractory patients, further treatments directed at key molecular targets in the CLL B cell need to be developed.

Study authors Connie Lesnick, MSc, Jamie Wood, PhD, Sameer Ashok Parikh, MBBS, and Neil E. Kay, MD, from the Mayo Clinic evaluated the impact of two novel drugs with non-overlapping mechanisms of action on CLL B cells: voruciclib, a cyclin-dependent kinase (CDK) inhibitor targeting CDKs 9, 6, 4, and 1, and venetoclax, a BCL-2 inhibitor.

In order to mimic the protective effect of the CLL microenvironment, voruciclib and venetoclax were tested for killing activity alone and in combination against CLL cells co-cultured with healthy human bone marrow mesenchymal stromal cells (BMSC). CLL B cells were from untreated patients stratified on risk of disease progression. Low-risk patients had mutated and high-risk patients had unmutated IVGH genetic status.

The researchers cultured CLL cells on BMSCs with a series of escalating doses of individual drugs and drug combinations at fixed molar ratios. They then Annexin/PI stained for viability testing by flow cytometry. The study authors then analyzed killing curves generated for each drug/combination by the combination index (C.I.) approach of Chou and Talalay with Calcusyn, characterizing interactions as synergistic, additive or inhibitory, with C.I. value hierarchy classes synergy as moderate (0.7-0.9), synergistic (0.3-0.7), strong (0.1-0.3), and very strong (below 0.1).

Through this approach, the researchers found CLL cells with unmutated IGVH status were more sensitive to voruciclib than mutated IGVH both with and without BMSCs. The combination voruciclib +venetoclax showed synergism for all patients regardless of risk; half strongly to very strongly. Similar synergistic effects were seen with relapsed/refractory patients.

The authors concluded that they were encouraged by these results. They speculated that CDK9 inhibition, which regulates transcription of MCL-1, with BCL-2 inhibition results in potent apoptosis induction in CLL B cells.

Sarah LaCorte is associate editor.