MCL-1 dependence may predict response to alvocidib in relapsed, refractory acute myeloid leukemia

SAN DIEGO — Researchers investigating potential biomarkers of response to alvocidib found the investigational CDK9 inhibitor had clinical activity against relapsed or refractory acute myeloid leukemia in patients who were MCL-1 dependent.

This is the first prospective study to evaluate MCL-1 dependence as a predictor of response to alvocidib, according to Joshua F. Zeidner, MD, assistant professor of medicine at the University of North Carolina (UNC) at Chapel Hill and researcher at UNC’s Lineberger Comprehensive Cancer Center.

During a presentation at the ASH Annual Meeting and Exposition, Zeidner stressed the need for more effective treatments for patients with relapsed/refractory AML.

“I don’t think this audience needs any convincing that relapsed or refractory AML patients have a dismal prognosis with a lack of standard care,” he said. “Although we have been fortunate in the AML community to have eight new drugs approved for this disease in the past 2 years and three drugs approved in the past week, unfortunately, the majority of patients with relapsed or refractory AML have limited effective therapeutic options.”

According to Zeidner, alvocidib, formerly known as flavopiridol, administered in a time-sequential treatment regimen with cytarabine and mitoxantrone (ACM) has been extensively researched in patients with newly diagnosed, relapsed or refractory AML, “with encouraging findings to date.”

“We were interested in assessing for potential biomarkers of response to alvocidib and ACM in AML patients,” he said. “Based on the mechanism of action of alvocidib, we are particularly interested in assessing for MCL-1 dependence as a predictor of response.”

MCL-1, he added, is a gene that prevents apoptosis and is associated with cell survival. It is upregulated in patients with AML, representing a “dominant pro-survival mechanism.”

Zeidner and colleagues previously assessed whether MCL-1 dependence can predict a response to alvocidib in patients newly diagnosed with AML who were enrolled in a randomized phase 2 study of ACM vs. continuous infusion of cytarabine for 7 days with an anthracycline for 3 days, also known as 7 + 3 chemotherapy.

“We saw a 100% complete response (CR) rate with ACM patients who were determined to be MCL-1 dependent compared with a 30% CR rate in patients who were treated with ACM and determined not to be MCL-1 dependent,” he said. “But we did not see the same significant correlation in response with MCL-1 dependence in those treated with 7 + 3.”

The researchers sought to further investigate the potential of MCL-1 dependence as a biomarker of ACM response in the phase 2 Zella 201 study. They screened 170 adult patients with relapsed or refractory AML to identify those who were MCL-1 dependent. To do this, they assessed patients’ cell survival after exposure to NOXA, which is an antagonist to MCL-1.

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“In brief, leukemia cells are isolated from bone marrow and exposed to a NOXA. If cells are dependent on MCL-1 for survival, exposure to NOXA would lead to apoptosis,” he explained. “We can then stain intact mitochondria by a protein known as DiOC6, which will stain cells that survive after exposure to NOXA. Then we can detect the relative percentage of apoptosis vs. cell survival after exposure to NOXA and come up with an overall signal of MCL-1 dependence.”

Of the 170 patients screened, 28% were MCL-1 dependent. Among them, 23 were enrolled in the current analysis.

On days 1, 2 and 3, the patients received 30 mg/m² of IV alvocidib over 30 minutes, followed by 60 mg/m² over 4 hours. On days 6, 7 and 8, the patients received 667 mg/m² of a continuous IV infusion of cytarabine. On day 9, they received 40 mg/m² of IV mitoxantrone.

The combined rate of CR and CR with incomplete hematologic recovery (CRi) was 57% in the overall population and 68% in an evaluable for response population, which excluded patients who died before response assessment. The median duration of response was 8.5 months (95% CI, 2.1-15.9), and the median OS was 11.2 months (95% CI, 3.0-16.8). Ten patients proceeded to undergo an allogeneic stem cell transplant.

The toxicity of ACM was similar to previously published data, according to Zeidner. The most common grade 3 adverse events included diarrhea (24%) and tumor lysis syndrome (20%).

“Tumor lysis syndrome is something that can occur very rapidly after the first dose of alvocidib administration,” Zeidner noted. “We see tumor lysis syndrome as early as 4 to 8 hours after the first dose of alvocidib. It is typically biochemical without a clinical consequence.”

The 60-day mortality rate was 20%. There were four early deaths, three of which were caused by sepsis and one by mitral valve rupture.

“In conclusion, ACM has demonstrated clinical activity in MCL-1 dependent relapsed/refractory AML patients, with encouraging CR rate and an OS rate trend that compares favorably well with historical controls,” Zeidner said. “We can get a biomarker score back within 48 hours, so this biomarker does not prohibit us from evaluating patients and waiting for the results. Stage 2 of this trial is underway comparing ACM to CM [without alvocidib] in a randomized fashion with a primary endpoint of CR rate. We plan to enroll 106 patients in this stage of the study.” – by Stephanie Viguers

Reference:

Zeidner JF, et al. Abstract 30. Presented at: ASH Annual Meeting and Exposition; Dec. 1-4, 2018; San Diego.

Disclosure: Zeidner reports receiving honoraria from Boston Biomedical, Celgene, Pfizer and Tolero; research funding from Merck, Takeda and Tolero; travel fees from Takeda; and consulting fees from Asystbio Laboratories.