A new targeted therapy called revumenib has demonstrated remarkable efficacy in treating advanced acute myeloid leukemia (AML), achieving complete remission in approximately one-third of heavily pretreated patients who had exhausted other treatment options. The results from the phase 1 AUGMENT-101 trial, published in Nature, represent a significant breakthrough for one of the most challenging leukemias to treat.
Novel Mechanism Targets Root Cause of Leukemia
Revumenib belongs to a new class of drugs called menin inhibitors, which work through a fundamentally different mechanism than existing AML therapies. Rather than blocking dysfunctional proteins, the drug prevents the expression of genes affected by common AML-driving mutations in the first place.
"The menin-MLL1 complex is the key that starts the engine of leukemia cell production," explained Dr. Ghayas Issa of the University of Texas MD Anderson Cancer Center, who helped lead the trial. "Revumenib creates a wedge between the key and the engine by binding to menin, which prevents it from binding to MLL1."
The drug specifically targets leukemias with KMT2A rearrangements and NPM1 mutations, genetic alterations that cause blood cells to regress and behave like stem cells, ultimately forming leukemia cells instead of functional blood cells. These mutations are found in approximately 30-40% of AML cases, with menin inhibition potentially having a role in 40-50% of all acute myeloid leukemias.
Promising Results in Heavily Pretreated Patients
The AUGMENT-101 trial enrolled 68 patients across nine US hospitals, including 60 adults and 8 children with leukemia. All participants had received extensive prior treatment, with a median of four previous therapies, and nearly half had already undergone stem cell transplants.
Of the 60 patients with KMT2A rearrangements or NPM1 mutations, 18 achieved complete remission with full or partial recovery of healthy blood cell counts, lasting for a median of 9 months. Overall, 53% of patients responded to the treatment.
"If patients' cancers have progressed on that many lines of therapy, the chances of responding to anything else we currently have is less than 10%," noted Dr. Issa, highlighting the significance of these results in a heavily pretreated population.
Twelve patients who achieved remission went on to receive stem cell transplants, with nine continuing in remission at the time of the last analysis. One participant remained in remission more than 16 months after starting treatment.
Manageable Safety Profile
The trial identified QT interval prolongation, affecting the heart's electrical activity, as the dose-limiting side effect. Other serious side effects included drops in white and red blood cell counts. Notably, no participants had to permanently discontinue revumenib due to side effects, and no deaths were attributed to the drug.
Eleven patients developed differentiation syndrome, a potentially dangerous immune reaction that occurs when leukemia cells transform back into normal cells. However, all cases were mild and resolved with anti-inflammatory treatments.
Understanding and Overcoming Resistance
A companion study published simultaneously in Nature revealed how some leukemia cells develop resistance to revumenib. Researchers found that resistant tumors acquired new mutations in the MEN1 gene, which encodes menin, preventing the drug from disrupting the menin-MLL1 complex.
"The fact that leukemia cells have to mutate in order to escape this drug really means that we're getting at the Achilles' heel of these leukemia subtypes," said Dr. Sheng Cai of Memorial Sloan Kettering Cancer Center, who led the resistance study.
Future Development and Combination Strategies
Revumenib is now being tested in a phase 2 study aimed at obtaining FDA approval for treating advanced AML with specific genetic alterations. The drug received breakthrough therapy designation from the FDA in December 2022 to expedite its development.
Researchers are also exploring combination approaches, including pairing revumenib with venetoclax, another targeted AML therapy, and with standard chemotherapy in the ongoing AUGMENT-102 trial.
"To harvest the true benefit of menin inhibitors, we may really need to move them up earlier in treatment, when we have the best chance at a cure," said Dr. Eunice Wang of Roswell Park Comprehensive Cancer Center.
The success of revumenib has generated excitement about the potential for an entirely new class of AML treatments, offering hope for patients with limited therapeutic options in a disease where approximately 50-60% of cases lack targetable mutations addressed by current therapies.
