A new experimental drug, revumenib (SNDX-5613), has demonstrated significant progress in the treatment of acute leukaemia by inhibiting a critical interaction between the protein menin and the lysine methyltransferase 2A (KMT2A) gene. The first-in-human phase 1 clinical trial, conducted across nine sites in the United States, showed that the potent and selective oral inhibitor led to a 30% rate of complete remission or partial hematologic recovery in patients with relapsed or refractory acute leukaemia.
The study specifically targeted acute leukaemia patients with KMT2A rearrangements or mutated nucleophosmin 1 gene (NPM1), two common genetic alterations in acute myeloid leukaemia (AML). The findings were published in the journal Nature.
AML patients with KMT2A rearrangements have a poor prognosis, with a 5-year overall survival rate of less than 25%. NPM1 mutations are the most prevalent genetic alteration in adult AML, affecting up to 30% of patients. Despite their frequency, no targeted therapies have been specifically approved for acute leukaemia with KMT2A rearrangements or mutated NPM1.
Menin inhibition is a therapeutic strategy for susceptible acute leukaemia subtypes. The trial provides clinical evidence of the effectiveness of menin inhibition with oral targeted therapy, the first epigenetic therapy that evicts protein complexes from chromatin, leading to remissions in patients with acute leukaemia. The menin inhibitor revumenib has the potential to address unmet needs in the treatment of patients with relapsed or refractory acute leukaemia, with deep molecular remissions and minimal toxicities observed in both children and adults.
The phase 1 dose-escalation study, which included 68 patients with relapsed or refractory acute leukaemia, established menin inhibition as a therapeutic strategy for susceptible acute leukaemia subtypes. The results showed a low frequency of grade 3 or higher treatment-related adverse events and identified asymptomatic prolongation of the QT interval on electrocardiography as the only dose-limiting toxicity.
While the drug has completely eliminated cancer in a third of the participants, scientists remain hopeful as the results indicate that the pill might pave the way to a cure for leukaemia in the future. The drug works by reprogramming leukaemia cells back into normal cells, and the preliminary results showed that 53% of patients responded to revumenib, and 30% had a complete remission with no cancer detectable in their blood.
The experimental pill targets the most common mutation in acute myeloid leukaemia, a gene called NPM1, and a less common fusion called KMT2A. Combined, these mutations are estimated to occur in about 30%–40% of people with acute myeloid leukaemia.
The phase 1 trial enrolled 68 patients at nine US hospitals. All of them had seen their leukaemia return after other treatments or had never responded well to traditional chemotherapy drugs in the first place.
According to co-author Dr Ghayas Issa, a leukaemia physician at the MD Anderson Cancer Center at the University of Texas, although this drug is fairly safe when compared to standard treatments for leukaemia, two main side effects have been identified. The first affects the heart’s electrical system and can be detected with an electrocardiogram (ECG).
But reducing the dosage or halting the treatment resolved the issue in all cases. The second side effect is referred to as differentiation syndrome, a group of potentially life-threatening reactions to blood cancer treatments, but it can be managed effectively if it’s recognized early and appropriate measures are taken to shut it down. According to Issa, all cases of differentiation syndrome in this study were successfully managed without any complications for the patients.
The study is still in its early stages, and the results remain preliminary. Phase 1 studies like this one aim to test whether a drug is safe and to find the highest dose that can be given to them without causing severe side effects. A phase 2 study specifically looking at the effectiveness of revumenib is now underway.
Twelve patients in the trial who responded to the drug went on to receive a stem cell or bone marrow transplant. Such transplants require that patients have no cancer or only very low levels of cancer in their blood – and revumenib helped them get there.
While the experimental pill is not a definitive cure, the researchers who worked on the trial are optimistic. The drug’s potential to target specific mutations and induce complete remission in a significant percentage of patients is a major breakthrough in leukaemia treatment. The breakthrough has led to the US Food and Drug Administration granting revumenib “breakthrough therapy designation” in December 2022 to help fast-track its development and regulatory review.
The emergence of resistance mutations highlights the critical role of the menin-KMT2A interaction in the pathogenesis of KMT2A rearrangements and NPM1-mutant acute leukaemia. Further research is needed to build on these findings and develop targeted therapies that can overcome resistance mutations and improve patient outcomes.
The results of phase 1 clinical trial for revumenib are promising and have the potential to change the treatment landscape for acute leukaemia patients with KMT2A rearrangements or mutated NPM1. The drug’s ability to target specific mutations and induce complete remission in a significant percentage of patients is a major breakthrough in leukaemia treatment.
Further research is needed to build on these findings and develop targeted therapies that can overcome resistance mutations and improve patient outcomes. The success of this study gives hope to patients with relapsed or refractory acute leukaemia, especially those with KMT2A rearrangements or mutated NPM1, who have had limited treatment options.
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