Lymphoma and Chronic Lymphocytic Leukemias

Despite significant advances in chemoimmunotherapy, chronic lymphocytic leukemia (CLL) is still incurable. This has prompted the development of new drugs and therapeutic strategies that include reactivating the impaired apoptosis (programed cell death). Several approaches to target apoptosis-regulating proteins have attracted attention. Among them, the approach to inhibit the activity of prosurvival members of the BCL-2 family with small-molecule BH3 mimetics (navitoclax, ABT-199) has proved to be most promising in clinical trials with CLL patients. Recently, the first BH3 mimetics targeting selectively the particular prosurvival protein MCL-1 (whose overexpression is involved in therapeutic resistance) have been identified. Furthermore, small molecules capable of directly activating proapoptotic proteins of the BCL-2 family have been characterized, indicating that novel BH3-mimetic drugs displaying this property may be designed. These discoveries are opening a new era in the development of BH3 mimetics for improving CLL therapy.