Venclexta (venetoclax or ABT-199) is an oral small molecule developed and marketed by AbbVie and Genentech and approved by the U.S. Food and Drug Administration (FDA) to treat patients with different types of cancer,  including those with acute myeloid leukemia (AML) who are 75 or older and not eligible for standard chemotherapy. Venclexta is used in combination with Vidaza (azacitidine), Dacogen (decitabine), or low-dose cytarabine in AML.

How does Venclexta work?

Cancer cells in AML evade cell death mechanisms by up-regulating proteins that block apoptosis, or programmed cell death. One such oncogenic (cancer-promoting) protein is BCL-2.

Venclexta is a potent inhibitor of the BCL-2 protein. It binds to the so-called BH3-domain of the BCL-2 protein, which is required to prevent apoptosis by interacting with other pro-apoptotic proteins. Venclexta renders AML cells sensitive to apoptosis, either because of natural intracellular mechanisms or when treated with chemotherapy agents. Another advantage of Venclexta is that it does not induce significant thrombocytopenia (low platelet count, which is typically associated with AML), making it a clinically viable therapy for these patients.

Venclexta in clinical trials for AML

A Phase 1b, open-label, non-randomized, multicenter clinical trial (NCT02203773) is evaluating the safety, pharmacokinetics (movement in the body), and effectiveness of oral Venclexta in combination with Vidaza and Docogen in treatment-naïve AML patients who are at least age 60 and not eligible for standard induction therapy. This study includes dose-escalation and expansion phases.

During the dose-escalation phase, 400, 800, or 1,200 mg of Venclexta is given by mouth in combination with either 20 mg/mof Dacogen that is infused into the bloodstream on days 1 to 5, or 75 mg/m2 of Vidaza that is injected into the bloodstream or under the skin on days 1 to 7. The expansion phase doses are 400 or 800 mg of Venclexta with either chemotherapy agent.

Results from this study were reported in the journal Blood and showed that Venclexta, in combination with Dacogen or Vidaza, was effective and well-tolerated. The most common adverse side effects included low white blood counts, nausea, diarrhea, constipation, febrile neutropenia (fever in patients with low neutrophil counts), fatigue, hypokalemia (low blood potassium levels), and decreased appetite. In a median treatment time of 8.9 months, 67% of patients achieved complete remission (CR) and CR with incomplete blood count recovery (CRi), when all dose groups were evaluated. The CR + CRi rate was 73% for the 400 mg Venclexta group compared with 65% for the 800 mg Venclexta group. The median duration of CR + CRi was 11.3 months and the median overall survival was 17.5 months for all patients. The median overall survival had not been reached for the 400 mg Venclexta group compared with 11 months for the 800 mg Venclexta group, suggesting that 400 mg Venclexta was a better dose in combination with Vidaza or Dacogen.

A Phase 2, single-arm clinical trial (NCT01994837) evaluated the safety and effectiveness of Venclexta in high-risk relapsed/refractory AML patients who were unfit for intensive chemotherapy. Patients were given 800 mg of Venclexta daily. The response to treatment was evaluated according to the revised international working group (IWG) criteria.

The results of that study were reported in the journal Cancer Discovery. The overall response rate was 19%. An additional 19% of patients demonstrated partial bone marrow response and incomplete blood count recovery.  Venclexta was well-tolerated with the most common side effects being nausea, diarrhea, vomiting, febrile neutropenia, and hypokalemia.

A non-randomized, open-label Phase 1/2 clinical trial (NCT02287233) is investigating the safety and effectiveness of Venclexta in combination with low-dose cytarabine in 91 newly-diagnosed AML patients who are 60 or older and ineligible for intensive chemotherapy, including patients previously treated with a chemotherapy agent for myelodysplastic syndrome.

A total of 82 AML patients were already treated with 600 mg per day of oral Venclexta in 28-day cycles and under-the-skin injections of 20 mg/m2 of cytarabine on days 1 to 10. The key endpoints (goals) were safety, tolerability, response rates to treatment and their duration, and overall survival.

Results from the study were reported in the Journal of Clinical Oncology and showed that Venclexta and low-dose cytarabine were well-tolerated with a manageable safety profile, and led to high remission rates. The most common side effects were febrile neutropenia, thrombocytopenia, and low white blood cell counts. Fifty-four percent of all AML patients achieved CR or CRi. The median overall survival was 10.1 months, and the median duration of treatment response was 8.1 months. Among patients without prior exposure to chemotherapy agents, 62% achieved CR or CRi with a median duration of treatment response of 14.8 months, and a median overall survival of 13.5 months.

Two Phase 3 clinical trials (NCT02993523 and NCT03069352) are ongoing to further evaluate the overall survival rate of AML patients treated with Venclexta in combination with Vidaza or low-dose cytarabine, respectively.


Last updated: Feb. 14, 2020


Acute Myeloid Leukemia News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis or treatment. Always seek the advice of your physician or other qualified health providers with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.