A drug combination regimen has shown high response and remission rates in patients 60 years and older who are newly diagnosed with acute myeloid leukemia (AML). The treatment introduces a recently approved cancer drug, revumenib, to the standard of care for patients carrying one of two genetic abnormalities linked with the development and progression of this form of cancer.
“This regimen has the potential to be practice-changing for patients whose AML harbors the specific gene alterations we focused on,” said Joshua F. Zeidner, MD, associate professor of medicine and chief of leukemia research at the University of North Carolina (UNC) Lineberger and the UNC School of Medicine.
The study, published in the Journal of Clinical Oncology, is part of the Beat AML Master Clinical Trial, a collaborative precision medicine trial using genomic analysis to match AML patients to the most promising targeted treatment for their individual genetic makeup. The current substudy focused on AML patients carrying either nucleophosmin-1 mutations (NPM1m) or lysine methyltransferase 2A rearrangements (KMT2Ar), two types of genetic abnormalities that share similar gene expression profiles and are present in 30% and 5% of all AML patients, respectively.
Older patients who are newly diagnosed with AML are often eligible for intensive chemotherapy due to their age or comorbidities. The standard frontline treatment for this patient population is a combination of azacitidine and venetoclax, but while these drugs have significantly improved outcomes for older AML patients, 33% of patients are refractory to treatment and long-term survival remains low.
The trial enrolled a total of 43 AML patients with NPM1m or KMT2Ar, who received revumenib, an oral menin inhibitor, in addition to azacitidine and venetoclax. In November 2024, revumenib received FDA approval to treat relapsed or refractory acute leukemia in adult and pediatric patients with a KMT2Ar genetic profile.
Patients treated with the combination regimen achieved an overall response rate of 88.4%, and a complete remission rate of 67.4%. In comparison, treatment with azacitidine and venetoclax alone has previously been reported to achieve 37% complete remission. The addition of revumenib to the standard of care was found to be safe, with no effects on hematologic toxicity or early mortality.
Among patients who responded to the treatment, 84% achieved a response within one 28-day cycle of treatment, and the rest achieved it within the second cycle. Importantly, all patients who showed remission achieved minimal residual disease (MRD), which is considered a critical milestone in AML associated with longer remissions and improved survival.
“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,” said Zeidner, who will be the lead investigator for the projected phase 3 trial.
“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,” he added. “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.”
