Clinical Challenges: Targeting Menin in Acute Myeloid Leukemia

Over the last several years, menin has emerged as an important targetable pathway in acute myeloid leukemia (AML), with multiple drugs under development and in early trials.

“Menin is a protein that is important for many transcription factors that cause acute leukemia,” Ghayas Issa, MD, of the University of Texas MD Anderson Cancer Center in Houston, told MedPage Today, noting that the most important ones under investigation include mixed-lineage leukemia (MLL, or KMT2A)-rearranged leukemias and NPM1-mutant leukemia.

At the most recent meeting of the Society of Hematologic Oncology, Eytan Stein, MD, of Memorial Sloan Kettering Cancer Center in New York City, explained that a series of studies performed between 2004 and 2006 showed that “the leukemia proto-oncoprotein MLL binds to menin, and whether that MLL complex is rearranged as an abnormal fusion protein, or not, that can lead to the pathogenesis of acute leukemia via the upregulation of HOX gene.”

Furthermore, Stein noted, later preclinical studies showed that “it is not just the MLL-rearranged complex that fuses with menin, but the wild-type MLL complex can also fuse with menin in the context of NPM1-mutant AML.”

Therefore, when you have menin that binds to the MLL complex, “that leads to the upregulation of HOX genes and MEIS1 genes that promote leukemogenesis,” Stein said.

“That was the preclinical basis of all these trials,” Issa said. “So recently, small molecule inhibitors — we’re calling them menin inhibitors — have been identified and multiple studies have begun. These are essentially disrupting the binding of menin to KMT2A.”

According to Issa, KMT2A rearrangements can occur in infants, adults, and children, and are associated with an adverse prognosis. It is seen in about 5% of adult patients with de novo AML, and more frequently in pediatric patients, while NPM1 mutations are the most common genetic alteration in AML.

Data from two clinical trials evaluating menin inhibitors were presented at the latest annual meeting of the American Society of of Hematology (ASH), and the data suggest “menin inhibition works,” said Issa, who participated in both trials.

In the first, Issa reported on results from a phase I study that evaluated revumenib (SNDX-5613) in patients with relapsed or refractory acute leukemia.

The AUGMENT-101 trial included 68 patients (median age 43, range 10 months to 79 years), 82% of whom had AML.

The overall response rate (ORR) in the trial’s efficacy population (n=60) was 53%, which included a complete response (CR) rate of 20%, CR with incomplete hematologic (CRh) recovery rate of 10%, and CR with incomplete platelet (CRp) recovery rate of 8%. The measurable residual disease-negative rate among patients with CR/CRh/CRp was 78%. Patients with KMT2A rearrangement or mutant NPM1 had an ORR of 59%.

Median time to response was 1.9 months, and the median duration of CR/CRh response was 9.1 months.

“Median overall survival was 7 months, which is an improvement over what we would expect in a heavily refractory population, which is about 3 months,” Issa said.

Differentiation syndrome, all grade 2, was reported in 11 patients (16%) and resolved with steroids and/or hydroxyurea. Grade ≥3 treatment-related adverse events (TRAEs) included diarrhea, fatigue, and anemia (3% each); as well as tumor lysis syndrome, neutropenia, thrombocytopenia, hypercalcemia, and hypokalemia (2% each). No TRAEs led to treatment discontinuation or death.

In the second study at ASH, Harry Erba, MD, PhD, of the Duke Cancer Institute in Durham, North Carolina, reported that monotherapy with ziftomenib (KO-539) demonstrated an “encouraging safety profile and tolerability” when given at a 600-mg dose.

Patients in this phase I/II study were heavily pretreated and had received a median of three prior lines of therapy, with the majority having received prior venetoclax (Venclexta) and a quarter having progressed after at least one prior stem-cell transplant.

“There were no patterns of toxicity by dose, and overall, events were consistent with the effects of the underlying disease,” Erba noted.

As for efficacy, said Issa, it was “mostly seen in the MPN1-mutant acute leukemia, and that led to a roughly similar ORR response to that seen in SNDX — but less efficacy in the MLL-rearranged population.”

Specifically, Erba reported, of the 20 patients with NPM1-mutant disease treated at the 600-mg dose, eight responded (40%), including six complete remissions. In the 18 KMT2A-rearranged patients treated at the 600-mg dose, the ORR was 16.7%, with just one achieving a CR/CRh response.

Other trials investigating menin inhibitors include:

• DSP-5336 in relapsed or refractory acute leukemia with or without MLL rearrangements or NPM1 mutations
• DS-1594b with or without azacitidine, venetoclax, or mini-HCVD (hyperfractionated cyclophosphamide, vincristine, and dexamethasone) in relapsed or refractory acute leukemias
• JNJ-75276617 in participants with acute leukemia
• BMF-219, a covalent menin inhibitor, in adults with acute leukemias with KMT2A, NPM1, and other mutations

“There could be multiple combinations that could be studied with menin inhibitors, as well,” Issa pointed out. “The best way to get a cure is to use combinations, and there are many studies that have started already with combinations — the immediate ones are hypomethylating agents and venetoclax plus menin inhibitors.”

“In addition, they may be added to standard of care — 7+3 in combination with a menin inhibitor — that is for younger, fit patients,” he said. “Other various combinations are possible, such as in combination with FLT3 inhibitors, which has an excellent preclinical rationale.”