BFL-1 expression determines the efficacy of venetoclax in MYC+/BCL2+ double hit lymphoma

The appropriate balance between pro-survival and pro-death BCL-2 family members in healthy cells is often disrupted in malignant B cell malignancies, where an overexpression of anti-apoptotic BCL-2 proteins can promote oncogenesis and confer resistance to chemotherapeutic agents. BH3 mimetics are the first class of drugs to target the core of the apoptosis pathway by binding directly and specifically inhibiting the anti-apoptotic members of the BCL-2 family [1]. Among this drugs, the first-in-class BCL-2-specific BH3 mimetic venetoclax (ABT-199), recently approved the treatment of patients with relapsed/refractory (R/R) chronic lymphocytic leukemia with del(17p), has also demonstrated high response rates and good toxicity profiles in other subtypes of R/R B-cell non- Hodgkin lymphoma (NHL). However, a major hurdle to its successful application is the rise of primary and acquired resistance, which pushes for the search of new therapeutic approaches. In this sense, targeted inhibition of BCL-2 is likely to have a greater clinical impact when it is combined with other agents, and a number of studies are underway to assess the safety and efficacy of combining venetoclax with standard chemotherapy ({"type":"clinical-trial","attrs":{"text":"NCT03064867","term_id":"NCT03064867"}}NCT03064867, {"type":"clinical-trial","attrs":{"text":"NCT03054896","term_id":"NCT03054896"}}NCT03054896), monoclonal antibodies ({"type":"clinical-trial","attrs":{"text":"NCT03136497","term_id":"NCT03136497"}}NCT03136497, {"type":"clinical-trial","attrs":{"text":"NCT03135262","term_id":"NCT03135262"}}NCT03135262), B-cell receptor (BCR) signaling inhibitors ({"type":"clinical-trial","attrs":{"text":"NCT02756897","term_id":"NCT02756897"}}NCT02756897, {"type":"clinical-trial","attrs":{"text":"NCT02956382","term_id":"NCT02956382"}}NCT02956382, {"type":"clinical-trial","attrs":{"text":"NCT03112174","term_id":"NCT03112174"}}NCT03112174) or proteasome inhibitors ({"type":"clinical-trial","attrs":{"text":"NCT02755597","term_id":"NCT02755597"}}NCT02755597, {"type":"clinical-trial","attrs":{"text":"NCT02899052","term_id":"NCT02899052"}}NCT02899052), in NHL patients [2]