Novel drug combination is safe and benefits people with acute myeloid leukemia who have a specific genetic profile

(Press-News.org) A combination therapy that adds a recently approved drug to the current standard of care for newly diagnosed acute myeloid leukemia (AML) showed high rates of complete remission in an early-phase clinical trial conducted at UNC Lineberger Comprehensive Cancer Center and 11 other sites nationwide.

The trial findings will be published in the Journal of Clinical Oncology (JCO) and presented at the European Hematology Association Congress in Milan, Italy, both on June 12. Joshua F. Zeidner, MD, associate professor of medicine and chief of leukemia research at UNC Lineberger and the UNC School of Medicine, is the paper’s corresponding author and will deliver the presentation.

AML is a very heterogeneous disease with more than a dozen different subtypes. This warrants a personalized treatment approach given the distinct biology of each genetic subtype.

The National Cancer Institute estimates that more than 20,000 Americans will be diagnosed with AML this year, and approximately 11,000 will die from the disease. The overall five-year survival rate is about 33%, but this drops to roughly 17% for individuals over the age of 60 — the age group represented in this trial.

In this study, the investigators were looking at AML with two specific gene alterations: nucleophosphmin-1 (NPM1m) or lysine methyltransferase 2A (KMT2Ar) rearrangements. NPM1m is the common mutation in AML seen in about 30% of AML patients whereas KMT2Ar is relatively rare, seen in about 5% of AML patients. Notably, both alterations share a gene expression profile that contributes to the development and progression of AML. A new class of targeted agents known as menin inhibitors has been shown to be clinically active in patients with these alterations. Revumenib is an oral menin inhibitor that is approved for patients with relapsed AML with a KMT2Ar alteration.

The study was part of the Leukemia and Lymphoma Society’s Beat AML Master Clinical Trial protocol that uses advanced genomic technology to identify gene alterations associated with each patient’s leukemia. With this technology, the patient’s unique genomic profile can be ascertained within 3 to 5 days of a blood draw and genomic testing. This information is then used to create an individualized treatment approach for each patient with AML.

This phase 1 clinical trial is the first to investigate whether adding a menin inhibitor to the standard therapy is safe and effective for newly diagnosed older adults with AML The study enrolled 43 patients at 12 centers nationwide. The patients were given a combination of the current standard of care, azacitidine and venetoclax, two established chemotherapy drugs, with revumenib.

The overall response rate, defined as no evidence of leukemia, was 88.4%. The complete remission rate, meaning no evidence of leukemia along with normal blood counts, was 67.4%. These response rates are higher than expected compared to the current standard of care.

All patients responded to the treatment after one to two 28-day cycles; 84% of responders achieved remission within the first cycle. After one year on the trial, 62.9% of patients were still alive.

“The promising findings from our phase 1 safety trial have directly led to the design and implementation of a randomized phase 3 study to determine whether the addition of revumenib to standard azacitidine and venetoclax improves overall survival in people with NPM1m or KMT2Ar AML,” Zeidner said. “This regimen has the potential to be practice-changing for patients whose AML harbors the specific gene alterations we focused on.”

Zeidner will be the lead U.S. investigator for the phase 3 trial and UNC Lineberger will serve as the lead site.

“As there are only 12 centers currently part of the Beat AML consortium, we are adding an additional 10 to 12 U.S. centers in order to successfully launch this study. The phase 3 trial will be led by the HOVON group, a European Cooperative Oncology Group, to make the phase 3 trial as robust as possible and hopefully provide definitive evidence of the efficacy of this drug combination,” Zeidner said.

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