by Dr. C.H. Weaver M.D. updated 9/2020
Venclexta has previously been granted accelerated approval by the US Food and Drug Administration (FDA) in combination with azacitidine, or decitabine, or low-dose cytarabine for the treatment of people with newly-diagnosed AML who are aged 75 years or older, or for those ineligible for intensive induction chemotherapy due to coexisting medical conditions.
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About Venclexta (venetoclax)
Venclexta/Venclyxto is a precision cancer medicine designed to selectively bind and inhibit the B-cell lymphoma-2 (BCL-2) protein. In some blood cancers BCL-2 builds up and prevents cancer cells from dying or self-destructing, a process called apoptosis. Venclexta blocks the BCL-2 protein and works to restore the process of apoptosis.
About Acute myeloid leukemia (AML)
Acute myeloid leukemia is diagnosed in approximately 20,000 individuals each year in the United States. It is an aggressive leukemia, with the lowest survival rates of any acute leukemias. AML prevents certain immune cells from developing properly, leaving them in immature stages. These cancerous cells, referred to as “blasts”, are not able to fight infection as intended, and rapidly accumulate in the body. This crowds out other blood cells so that they are not able to carry out their essential functions.
With currently available treatments approximately 27 percent of patients diagnosed with AML will survive five years or more. Disease recurrence occurs in most patients within three years of diagnosis. Older individuals diagnosed with AML fare worse and only about one-third of those older than age 60 are able to tolerate the intensive chemotherapy required to achieve optimal results. (1-5)
The VIALE-A Clinical Trial in Newly Diagnosed AML Patients
VIALE-A compared Venclexta plus azacitidine, a hypomethylating agent to azacytidine alone in 431 people with previously untreated acute myeloid leukaemia who are ineligible for intensive chemotherapy. Data from the VIALE-A clinical trial suggests that Venclexta® (venetoclax) in combination with azacitidine, a hypomethylating agent, showed a statistically significant improvement in overall survival in people with previously untreated acute myeloid leukaemia (AML) who were ineligible for intensive induction chemotherapy, compared to azacitidine alone.
In a second trial a team of researchers conducted a dose-escalation study phase 1b clinical trial to evaluate the safety and effectiveness of escalated doses of Ventclexta, combined with a 5 + 2 chemotherapy regimen in fit elderly patients with AML. Patients aged 65 years or older, or 60 years or older with monosomal karyotype, were eligible.
Overall, 51 patients were included in the CAVEAT clinical trial which treated AML patients with a median age of 72 years with 5 different dosing schedules. Treatment was generally well tolerated and overall 72% of patients responded to treatment; including 43% of those with secondary AML. The median overall survival of treated patients was 11.2 months but significantly less for those with TP53 mutations. (11)
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Venclexta® & Low-doses of Cytarabine Effective in Elderly with Myeloid Leukemia
The treatment combination consisting of Venclexta® (venetoclax) plus low-doses of the chemotherapy agent cytarabine appears to be an effective and tolerable treatment regimen for elderly patients with acute myeloid leukemia (AML) who are not eligible for intensive therapy. These results were presented at the 2016 annual meeting of the American Society of Hematology (ASH) and updated in 2020.
Importantly, the majority of patients diagnosed with AML are elderly, and are not able to tolerate the more aggressive therapies often used in younger patients. Researchers conducted a clinical trial to evaluate the effectiveness of Venclexta and low-doses of the chemotherapy agent cytarabine among elderly patients with AML. The trial included 20 patients with a median age of 74 years, who were considered not eligible for receiving intensive chemotherapy.
- Anti-cancer responses were achieved in approximately 75% of patients.
- Although the median survival time had not been reached at the time of the presentation of this data, the estimated overall survival of patients at one year following therapy was nearly 75%.
- Among patients who achieved anti-cancer responses to therapy, nearly 87% were estimated to still be alive at one year following therapy.
- The most common serious side effects besides low levels of blood cells were the following: fever accompanied by low immune cells; high blood pressure and low levels of phosphate in the blood.
Combining Venclexta with low-dose cytarabine was further evaluated in a larger study and confirmed a clinically meaningful improvement in overall survival in older patients with previously untreated AML according to data from the VIALE-C trial which was updated at the ASCO20 Virtual Scientific Program
In the VIALE-C trial III 211 patients aged 75 years or older or those unable to undergo intensive chemotherapy were treated with Venclexta plus low-dose cytarabine and directly compared. Venclexta based therapy doubled average survival from 4 to 8.4 months and tripled the complete remission rate from 13% to 48%. Venclexta + low-dose cytarabine represents an effective front-line treatment option for older patients with AML. Venclexta plus low-dose cytarabine is an effective and well-tolerated treatment regimen for elderly patients with AML. (7,9,10)
Venetoclax Plus High-Dose Chemo Active for Relapsed AML in Children
Venetoclax plus chemotherapy in high-risk pediatric patients with acute myeloid leukemia had a 70% complete response rate, according to the results of a phase 1 dose-escalation clinical trial. A total of 36 patients less that 22 years of age were enrolled in the phase 1, dose-escalation study and treated with venetoclax plus high-dose chemotherapy between July 1, 2017, and July 2, 2019 in order to determine optinal dosing. Of 35 patients evaluable after cycle 1, a total of 24 (69%) had overall responses. Complete response were achieved in 14 (70%) of 20 patients treated at the recommended dose, and 2 patients had partial responses.(8)
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- Döhner H, et al. Acute myeloid leukemia. N Engl J Med. 2015;373(12):1136-1152.
- National Cancer Institute (2018). Adult Acute Myeloid Leukemia Treatment (PDQ®)–Patient Version. Accessed July 2018.
- National Cancer Institute (2018). Acute Myeloid Leukemia – SEER Stat Fact Sheets. Accessed July 2018.
- Preisler HD, et al. The frequency of long-term remission in patients with acute myelogenous leukaemia treated with conventional maintenance chemotherapy: a study of 760 patients with a minimal follow-up time of 6 years. Br J Haematol. 1989; 71:189-194.
- Schiffer CA, et al. Long-term follow-up of Cancer and Leukemia Group B studies in acute myeloid leukemia. Cancer. 1997; 80:2210-2214.
- American Cancer Society (2018). Typical Treatment of Most Types of Acute Myeloid Leukemia (Except Acute Promyelocytic M3). Accessed July 2018.
- Wei A, Strickland S, Roboz G, et al. Safety and efficacy of venetoclax plus low-dose cytarabine in treatment-naive patients aged ≥65 years with acute myeloid leukemia. Proceedings from the 2016 annual meeting of the American Society of Hematology (ASH). Abstract #102.
- Lancet Oncol. 2020 Mar 11. Epub ahead of print.
- Blood. 2020;135:2137-2145
- Chua CC, Roberts AW, Reynolds J, et al. Chemotherapy and venetoclax in elderly acute myeloid leukemia trial (CAVEAT): a phase Ib dose-escalation study of venetoclax combined with modified intensive chemotherapy. J Clin Oncol. Published online July 22, 2020. doi:10.1200/JCO.20.00572