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Mantle cell lymphoma (MCL) is a rare B-cell non-Hodgkin lymphoma, and remains a clinically challenging disease entity, particularly in the relapsed setting where outcomes are poor. However, recent innovations in targeted therapeutics have expanded treatment options and demonstrate significant efficacy even in relapsed disease. MCL frequently harbours aberrations of apoptosis pathways including over-expression of the anti-apoptotic protein BCL2. Such aberrancy promotes and sustains lymphomagenesis, thus rendering MCL an attractive target for venetoclax, the highly specific, orally bioavailable inhibitor of BCL2. Pre-clinical and early clinical data of venetoclax monotherapy demonstrated high response rates in relapsed/refractory MCL, though the durability of response in high-risk patients appears modest. More recently, clinical trials deploying combination strategies that pair venetoclax with other novel agents have been undertaken, with some promising early data reported. In this article, we review the biological rationale for deploying venetoclax in MCL, as well as the emerging data from clinical trials of venetoclax monotherapy and novel combinations.