RESISTANCE TO VENETOCLAX IN CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL)

Venetoclax, the BCL2 inhibitor, is highly effective for the treatment of chronic lymphocytic leukaemia (CLL), a disease marked by BCL2 overexpression. The highly encouraging results from clinical trials has led to its approval in many jurisdictions, including recent listing in Australia on the Pharmaceutical Benefits Scheme (PBS). In spite of its efficacy, many treated patients will eventually experience disease progression after several years.

At the current time, we do not fully understand why resistance emerges. Our research group is well placed to address this question as we have access to one of the largest cohorts of venetoclax-treated patients, and access to serially collected samples such as prior to venetoclax therapy and at progression.

Our preliminary data indicates that amongst patients who have progressive CLL while on venetoclax, multiple mechanisms drive resistance even within a patient. While the recently discovered BCL2 G101V mutation accounted significantly for the resistance, we found evidence for co-existing adverse genetic changes (e.g. BCLxL upregulation). Moreover, we observed that CLL cells from the lymph nodes at disease progression are less sensitive to venetoclax compared to ones present in peripheral blood. Strikingly, we could recapitulate this phenotype by maintaining CLL cells in culture under conditions that mimic the lymphoid tissue microenvironment. Interestingly, such culture conditions promote the growth of more activated CLL cells which express an altered repertoire of BCL2 family proteins that probably accounts for the reduced sensitivity to venetoclax.

Taken together, our studies will help us understand why resistance emerges and have significant implications for how venetoclax is best used, for preventing the development of therapy resistance or to develop strategies to tackle resistance once it emerges.