Venetoclax’s regulatory approvals, its success as monotherapy for chronic lymphocytic leukemia (CLL) and other lymphoid neoplasms, and its activity in combination against acute myeloid leukemia (AML) have helped pave the way for BCL2 and MCL1 inhibitors that target prosurvival, antiapoptosis proteins.
A first-in-class specific inhibitor of BCL2, A review by Andrew W. Roberts, MD, of the Walter and Eliza Hall Institute of Medical Research, Melbourne, and associates details their key features, including their activity and tolerability and resistance issues. The review was published in Blood .
BH3 mimetics
BH3 mimetics, a new class of small-molecule anticancer drugs, enable specific targeting of BCL2 and MCL1, commonly expressed antiapoptotic proteins in hematologic cancers. The BH3 mimetics inhibit prosurvival BCL2 proteins, enabling activation of the apoptosis effectors BAX and BK that make the outer mitochondrial membranes permeable. This result triggers apoptosis in many cells, while sensitizing others to cell death when the BH3 mimetics are combined with other antineoplastic drugs. The BAX/BAK–driven effect on mitochondrial membranes is to undermine normal energy production, allowing leakage of cell contents, including cytochrome c, a trigger of proteolytic enzymes and cellular demolition.
Navitoclax was the first potent BCL2 inhibitor to enter clinical trials. While it demonstrated moderate single-agent activity in relapsed CLL and indolent B-cell lymphomas, its dose-limiting toxicity of thrombocytopenia precluded further exploration of BCL2 inhibition. Navitoclax is being developed for hematologic disease (for example, myelofibrosis and acute lymphoblastic leukemia). Clinical development of other BH3 mimetics is only in the earliest stages, the authors wrote.
Venetoclax, to avoid this on-target thrombocytopenia, was designed to specifically inhibit BCL2 with great selectivity, a feature not found in naturally occurring BH3-only proteins. The fact that it could inhibit a single prosurvival protein and have important clinical activity proved enormously stimulating to development of this drug class. Potent BH3 mimetics now can also selectively target MCL1, which plays a central role in plasma cells (mature B lymphocytes are highly reliant on BCL2).
In CLL, dependence on BCL2 is high. Venetoclax, since it was first approved by the Food and Drug Administration in April 2016 as monotherapy for relapsed/refractory del(17p) CLL, has been approved widely in combination with rituximab in relapsed/refractory CLL and for unfit patients with newly diagnosed CLL in combination with obinutuzumab. With venetoclax monotherapy, quickly achieved high objective response rates (79%) and complete remissions (20%) revealed the drug’s dose-limiting toxicity of tumor lysis syndrome (TLS). This necessitated gradual ramp-up dosing in those with high disease burden or reduced renal function. Also, despite the adoption of a venetoclax/rituximab combination as standard for relapsed/refractory CLL, the authors underscored that evidence for an additive rituximab benefit is modest and limited.
Resistance
While resistance to venetoclax leading to treatment failure is uncommon in the first year, secondary resistance occurs through several independently occurring mechanisms, including mutations in BCL2 (for example, Gly101Val), overexpression of MCL1, and overexpression of BCLxL. Usual venetoclax therapy is now time limited. Early data on re-exposure shows high rates (about 70%) of secondary responses.
AML
In AML, a more heterogeneous disease than CLL, BCL2 expression varies widely and can be heterogeneous even within a single patient’s leukemic cell population. While responses to venetoclax monotherapy were not durable, combination therapy with azacitidine has revealed enhanced activity. The venetoclax/azacitidine combination has been widely adopted as first-line therapy for older and unfit AML patients. Myelosuppression is the major toxicity.
“As venetoclax is the first in a new class of anticancer drug,” Andrew W. Roberts, MD, said in an interview, “we are still in the process of working out how it can be best utilized. Regimens free of DNA-damaging chemotherapy using this BCL2 inhibitor in combination with obinutuzumab or rituximab in CLL are established. Across B-cell neoplasia (e.g. CLL, mantle cell lymphoma, follicular lymphoma), the challenge is to work out whether venetoclax can enhance other ‘chemotherapy-free’ regimens.” He continued: “In contrast, for AML, learning how venetoclax can be safely combined with intensive chemotherapy is a priority, as we seek to improve outcomes for patients with poor prognosis disease. For MCL1 inhibitors, there is excitement about their potential, but their clinical development remains in its infancy.”
The authors reported multiple financial disclosures.