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Venetoclax Pro-Apoptotic Therapy Benefits Older Patients With AML

Goodwin, Peter M.

doi: 10.1097/01.COT.0000530888.20223.fd
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acute myeloid leukemia

acute myeloid leukemia

ATLANTA—Adding anti-BCL-2 therapy with the small-molecule drug venetoclax to standard low-dose cytarabine (LDAC) chemotherapy tripled response rates over historical comparators and extended survival in older patients with acute myeloid leukemia (AML) who were ineligible for intensification of their chemotherapy in a phase I/II study reported at the 2017 American Society of Hematology Annual Meeting (Abstract 890).

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High Response Rate

“With this new combination, we seem to achieve very high complete response rates. We achieve response quickly—which means that patients have better quality of life, potentially less risk of fatal infections, and also less need for blood transfusions and supportive care,” said lead study author Andrew Wei, MBBS, PhD, FRACP, FRCPA, Clinical Hematologist and Head of Leukemia Research at the Alfred Hospital in Melbourne, Australia.

“Elderly patients with acute myeloid leukemia have not benefited from intensive chemotherapy escalation through many decades of clinical research. And clinical outcomes are extremely poor in this population,” Wei noted.

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Restore Apoptosis

To fill this unmet need, his group opted to test a pro-apoptotic molecular approach using venetoclax—a small-molecule inhibitor of the cancer cell survival protein BCL-2.

“BCL-2 is a pro-survival protein that manages to keep cancer cells alive and also causes chemo-resistance,” said Wei. “And venetoclax is a small molecule which selectively binds the BCL-2 protein and causes release of pro-apoptotic molecules—which were bound to BCL-2—which are now free to induce cell death in cancer cells.”

The study aim was to kill cancer cells while minimizing the risk of adding toxicities or even fatalities in this group of frail patients.

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Study Details

Wei's open-label study (NCT02287233) evaluated the safety and preliminary efficacy of daily oral venetoclax combined with LDAC in patients who were at least 65 years old, had no previous treatment for their AML (other than hydroxyurea), and were ineligible for intensive chemotherapy. Sixty-one patients were given venetoclax 600 mg for a median duration of 6 months. Thirty-eight of them (62%) achieved complete remissions (CR) with a median duration of 14.9 months. Median overall survival (OS) was 11.4 months and the observed 12-month OS rate was 46 percent. Only one patient subsequently had bone marrow transplantation.

“The safety was quite good,” said Wei. “The combination was well-tolerated. The main side effects—which were predominantly of low grade—were gastrointestinal in nature, and also fatigue and febrile neutropenia—which is common in acute myeloid leukemia.”

Thirty-day mortality rate was 3 percent. Patients with CR lived for a median of 18.4 months and the 12-month OS rate for those who achieved CR was 70.4 percent. Among 19 patients who received the combination for at least 12 months, 17 were still alive at the time of reporting.

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Improvement Over Historical Data

“If we consider the results with low-dose LDAC alone—which venetoclax was combined with—historical complete remission rates range between 11 percent and 19 percent compared to 62 percent with this combination,” Wei stated. “Furthermore, survival expectations with low-dose LDAC alone were approximately 5.5 months and now we have a scenario where the combination produces a survival rate of in excess of 12 months.

“Various subgroups have traditionally done very poorly with chemotherapy—conditions like secondary AML, complex karyotype AML, and AML with p53 mutations. In these very poor risk patients, we noticed the complete response rates to be approximately 50 percent. However, despite this, the long-term survivals were still low for this population,” he said.

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Genetic Variants

All patients with NPM1 mutation (including three with a co-mutation in FLT3-ITD) achieved CR. Patients with DNMT3A, FLT3-ITD, and SRSF2 mutations had CR rates of at least 75 percent, whereas those with TP53 mutations had the lowest CR rates of 44 percent.

“In patients with poor-risk karyotype p53 mutation, we still need to identify better combinations or better ways of using venetoclax to make the survival durations longer,” Wei explained.

He concluded that the combination of venetoclax with LDAC had low early mortality in elderly patients with AML and achieved a high overall response rate (even though nearly half of the patients had secondary AML). Also, some molecular subtypes appeared to have been especially responsive to the combination. He said the results underpinned the need for the phase III investigation already in progress.

Peter M. Goodwin is a contributing writer.

Wolters Kluwer Health, Inc. All rights reserved.
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