When Youling Sun was diagnosed in Shanghai, China, with acute myeloid leukemia (AML) in 2018, he called his son, Conghao, in Boston, for advice. His son’s message was unequivocal: Come to Boston for your treatment.
Today, Sun, a retired office worker from Shanghai, has multiple reasons to be thankful he took that advice — both for his initial treatment, which put the disease into remission, and, when it relapsed, for a clinical trial at Dana-Farber of a new agent that has kept his cancer at undetectable levels for more than two years.
The agent, dubbed revumenib, targets a protein called menin that drives the development of leukemias with an abnormality in the gene KMT2A. Its success in Sun’s case is especially gratifying at Dana-Farber, where research in the laboratory of Scott Armstrong, MD, PhD, into the basic workings of certain leukemias was crucial to the drug’s development.
Sun was 76 when a blood test at a routine check-up led to a diagnosis of AML. He was treated at Beth Israel Deaconess Medical Center and was in remission for three years. When the disease re-emerged in 2021, he was referred to Dana-Farber and to Jacqueline Garcia, MD, a specialist in acute leukemias in adults.
“For someone who’s 79 years old, there are no standard therapies once AML relapses,” says Garcia. She told Sun about the trial of revumenib, a pill taken continuously on a 28-day cycle.
“She explained that I’d be taking the drug as part of a clinical trial and talked about how it works inside the body,” Sun says. Asked to describe how well revumenib was working, his thumbs-up and smile were all that was necessary.
“Usually I feel good,” he said. “There’s some fatigue, but that could be because I’m aging.” His return to health has enabled him and his wife to travel back to China several times in the past few years to visit relatives and enjoy regional cuisine.
Garcia is as impressed as Sun himself at how well he’s responded to revumenib. “I learned about the power of this drug with Mr. Sun, as he was an early trial participant,” she remarks. “With this single-agent therapy, he’s achieved a complete remission for the last two years, and now has no measurable disease. He and this novel therapy are remarkable. This is a good example of a drug that in a phase I trial has shown encouraging safety and efficacy. And the underlying science came from Dana-Farber researchers.”
A misfiled gene
Menin inhibitors like revumenib are the product of more than 20 years of research into the basic biology of AMLs with a particular kind of genetic mix-up. Formerly known as a mixed-lineage leukemia (MLL) rearrangement, the problem occurs when the KMT2A gene gets spliced into the wrong section of the genome. KMT2A and its neighboring gene give rise to a cobbled-together “fusion” protein that bodes trouble for the cell.
“My lab has long been working to understand how gene rearrangements like those involving KMT2A lead to leukemia,” says Armstrong. Over time, it became clear that the menin protein is critical for the function of the protein created by the KMT2A rearrangement.”
The finding put a bull’s eye on menin as a target for new drugs. Armstrong’s lab worked with Syndax Pharmaceuticals to identify small molecules that are active against menin. A study in 2019 showed that one such molecule, dubbed VTP50469, could eradicate KMT2A-rearranged leukemias in animal models. Syndax tweaked the molecule to create revumenib as Armstrong’s lab tested its effectiveness in laboratory work.
A recent study by Armstrong and colleagues at Memorial Sloan Kettering Cancer Center showed why, in zeroing in on menin as a drug target, researchers had hit upon an Achilles’ heel of cancer.
“We’ve been studying how leukemias might become resistant to Revumenib. While a high percentage of KMT2A-rearranged AMLs are sensitive to Menin inhibition, some develop mutant forms of Menin as an escape mechanism,” Armstrong explains. “The mutants have alterations that prevent drug molecules like Revumenib from binding to them.”
While this may complicate the task of developing therapies that cancer has difficulty evading, it also shows researchers are on the right track. “When a cancer goes to the trouble of developing a mutation to prevent a drug molecule from binding, it means that molecule is incredibly important to the cancer’s survival,” Armstrong comments.
As that work continues, Sun and his family are making the most of the time revumenib have provided. “My care team at Dana-Farber, and the health care system in the U.S. in general, have been great,” he says.