December 05, 2020
Targeted therapy venetoclax improving acute myeloid leukemia treatment options
BY Clayton Boldt, Ph.D.
Targeted therapies are designed to work against specific vulnerabilities in a cancer cell.
The targeted therapy drug venetoclax is designed to block the function of the B-cell lymphoma-2 (Bcl-2) protein, which normally works to prevent cell death.
Venetoclax was first approved in 2016 for treating certain patients with chronic lymphocytic leukemia, which has high levels of Bcl-2. More recently, venetoclax has begun to show promise for treating acute myeloid leukemia (AML), which also has elevated Bcl-2. The results of several promising clinical trials were presented this week at the virtual 2020 Annual Meeting of the American Society of Hematology (ASH).
“Many cancers, particularly leukemias, have usurped the normal function of Bcl-2 as a survival mechanism to keep cancer cells from dying,” says Tapan Kadia, M.D. “We’ve been working to develop treatments that overcome this survival approach. If we can give chemotherapy and shut down Bcl-2, we could potentially make the cancer cells more susceptible to chemo because they would have less resistance against it.”
Early studies of venetoclax focus on older acute myeloid leukemia patients
For acute myeloid leukemia patients under age 60, high-intensity chemotherapy options are effective. But these treatments come with many side effects that patients over 60 years don’t tolerate as well. Therefore, standard treatments for older patients typically include low-intensity chemotherapy, such as hypomethylating agents (HMAs).
Treatment with a single HMA, like 5-azacitidine, achieves a response in fewer than 20% of patients. In an MD Anderson-led clinical trial, treatment with venetoclax alone was well tolerated in these patients, but also resulted in modest results.
However, when venetoclax was combined with 5-azacitidine, MD Anderson researchers saw responses in 40% to 60% of patients. After multiple clinical trials, including several led by MD Anderson, the Food and Drug Administration approved the combination of 5-azacitidine plus venetoclax as the standard of care for older patients with acute myeloid leukemia.
“Clearly, we’re seeing the synergistic benefits of the two drugs, intensifying the potency and reducing the cancer’s protective mechanism,” says Kadia. “This really flips the script, because now we have a lower intensity therapy that is tolerable but also highly effective.”
Expanding acute myeloid leukemia treatment options for older patients
Knowing that venetoclax was effective when combined with 5-azacitidine in older patients, researchers next looked at combining it with a different low-intensity chemotherapy, cladribine and low-dose cytarabine.
In previous research, this chemotherapy combination had achieved response rates of about 65%. In an ongoing Phase II clinical trial presented by Kadia at ASH (Abstract 25), the addition of venetoclax resulted in responses in 93% of the 54 participants, and 78% had a complete remission.
Importantly, 93% of patients who achieved complete remission had no evidence of minimal residual disease at the time of remission, which suggests a low risk of recurrence.
“It’s early on in our study, but this type of response rate is unheard of in these patients,” says Kadia.
Venetoclax combinations for younger AML patients
Given the positive results from combining venetoclax with chemotherapy in older patients, Kadia and colleagues evaluated combining venetoclax with higher intensity chemotherapy in younger patients.
Early results from a Phase II clinical trial suggest that the approach also is effective in younger patients with newly diagnosed AML. Patrick Reville, M.D., presented findings at ASH (Abstract 2854) of treatment with venetoclax plus the chemotherapy agents cladribine, high-dose cytarabine and idarubicin.
In 31 patients, the combination resulted in a 90% response rate, including complete remission in 74% of patients. Of note, this therapy is more intensive and, as expected, resulted in more side effects, including increased immune suppression and infection rates.
Similarly, a different Phase Ib/II clinical trial evaluated venetoclax plus high-intensity chemotherapy (fludarabine, cytarabine, granulocyte-colony stimulating factor, and idarubicin) in patients with newly diagnosed and relapsed AML. Results were presented at ASH by Curtis Lachowiez, M.D. (Abstract 332).
Of the 62 participants, the response rate was 84%, with complete remission in 76% of patients. The 27 newly diagnosed patients had a 96% response rate, and 89% of patients achieved complete remission.
New approaches for advanced disease
New therapeutic options are necessary for patients with relapsed AML or refractory disease that no longer responds to available treatments, explains Kadia.
Taking a similar strategy, Kadia and colleagues evaluated the combination of venetoclax with CPX-351, a different formulation of the chemotherapy cytarabine plus daunorubicin. CPX-351 currently is approved for secondary AML, but in patients with relapsed/refractory AML, response rates are around 23%.
In a Phase II study presented by Kadia at ASH (Abstract 28), 44% of 16 patients had a response with the combination therapy. Additionally, of the eight patients who achieved a remission, seven (88%) were able to go on to receive a bone marrow transplant, which is an important goal for these patients, says Kadia.
“With the encouraging results from all of these studies, we’re in a great time right now,” says Kadia. “We’re learning more about the biology, understanding how to target the cancer with specific drugs. The future of treatment for patients with AML is moving away from one-size-fits-all to a very individualized approach.”
Refer a patient to MD Anderson online or by calling 1-877-632-6789.
TopicsAcute Myeloid Leukemia
The future of treatment for patients with AML is going to moving away from one-size-fits-all to a very individualized approach.
Tapan Kadia, M.D.
Physician & Researcher