Venetoclax is an oral selective BCL2 inhibitor, which can restore apoptotic activation particularly in tumor cells that are dependent on this dysregulated pathway. This drug is approved for various lymphoid neoplasms, and is now undergoing evaluation in myeloid neoplasia.
Preclinical data ranging from cytotoxicity studies to BH3 profiling in cell lines and primary blood and marrow samples demonstrated anti-leukemic activity with venetoclax in myeloid diseases including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML).
In AML and MDS, venetoclax has limited activity as monotherapy so has been combined with less intensive chemotherapy such as low-dose cytarabine (LDAC) and hypomethylating agents (HMA) azacitidine and decitabine. Initial reports have shown high response rates with encouraging durability, especially when the combination is used as initial therapy rather than in HMA-refractory patients, leading to accelerated approval in older patients with newly diagnosed AML who are not candidates for intensive induction chemotherapy.
Common adverse events include myelosuppression, fever and infectious complications in the setting of neutropenia. With intra-patient dose ramp up and prophylaxis, tumor lysis syndrome has been mitigated. In MDS, continuous dosing of venetoclax is associated with septic death and so prophylactic antimicrobials are essential, with interrupted dosing (e.g. days 1-14 of 28-day cycle) being tested in the ongoing studies.
Recently, at the European Hematology Association Annual Meeting (June 2020), the phase 3 VIALE-A study demonstrated statistically significant improvement in overall survival with combination azacitidine plus venetoclax compared to azacitidine with placebo (14.7 months versus 9.6 months, respectively; P <0.001), which marks a major breakthrough for frontline leukemia therapy. The parallel phase 3 VIALE-C study similarly had encouraging findings with combination venetoclax plus LDAC compared to LDAC alone, but it was not until there was longer follow-up that a statistically significant improvement in overall survival was observed (8.4 months versus 4.1 months, respectively; P=0.04).
In the future, we should be able to predict which patients will respond to venetoclax by performing BH3 profiling on primary patient samples. For those who are not sensitive to venetoclax, inhibitors of other survival signals such as MCL1 are in development. In addition, the drug is being added to other agents for frontline AML "triplet" therapies and for the treatment of acute lymphoid leukemia and myeloproliferative neoplasms.