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Menin Inhibition
Menin Inhibition in the Treatment of MLL-Rearranged Acute Leukemias: A Promising New Strategy

Released: October 26, 2022

Expiration: October 25, 2023

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Key Takeaways
  • Inhibition of menin promotes cell differentiation and downregulation of key transcription factors involved in leukemia development.
  • Menin inhibitor monotherapy has shown promising antileukemic activity.
  • Differentiation syndrome is a key toxicity associated with menin inhibitors.

In this commentary, I will review the role of menin inhibition in the treatment of mixed lineage leukemia (MLL)-rearranged and NPM1-mutant acute leukemias and discuss key menin inhibitors in ongoing clinical trials.

Menin is a nuclear protein that regulates gene expression and interacts with multiple transcription factors and chromatin regulators. The menin gene initially was identified as a germline mutation in patients with multiple endocrine neoplasm type 1 syndrome. Menin inhibition has now been developed as a promising approach for targeting the underlying biology of acute leukemias based on the importance of the menin protein interaction with basic mechanisms driving leukemogenesis.

Menin inhibition is a new therapeutic approach for the treatment of 2 biological subsets of acute leukemia: acute leukemia characterized by NPM1 mutation and the KMT2A gene, formerly known as MLL1-rearranged acute leukemias. KMT2A-rearranged or MLL-rearranged acute leukemias constitute 5% to 10% of all aggressive leukemias. By contrast, NPM1 mutations are identified in up to one third of patients with newly diagnosed acute myeloid leukemia (AML).

Emerging Menin Inhibitors
Menin inhibitors are a novel class of protein–protein inhibitors that target the interaction between menin and a KMT2A complex, which drives leukemia development. Small-molecule inhibitors of the menin KMT2A protein–protein interaction in preclinical AML models have shown to induce cell differentiation and downregulate critical gene expressions driven by HOXA9 and MEIS1 transcription factors, which are known to be key mediators of leukemia development. These transcription factors drive proliferation and and self‑renewal of leukemic stem cells. Treatment with targeted menin inhibitors has shown in preclinical studies to cause differentiation of acute leukemia blasts and leukemia cell death and prolong survival of leukemia mouse models.

Multiple first-in-human phase I/II clinical trials evaluating the safety, tolerability, and efficacy of menin inhibitors are ongoing and have shown evidence of promising clinical activity in patients with relapsed or refractory (R/R) AML and acute lymphoblastic leukemia (ALL) with an NPM1 mutation and/or KMT2A gene rearrangement.

The agent with the most data at this time is revumenib, formerly known as SNDX-5613. Revumenib is an oral small-molecule inhibitor of the menin–KMT2A protein–protein interaction and has exhibited potent antileukemic activity in preclinical models. The AUGMENT-101 trial (NCT04065399) is a first-in-human phase I/II dose-expansion and dose-escalation trial evaluating revumenib in adult and pediatric patients with NPM1-mutant or KMT2A-rearranged acute leukemia. Results of the AUGMENT-101 trial showed a complete remission (CR) and CR with incomplete hematologic recovery (CRh) rate of 24%, with clinical benefit occurring in >50% of patients. Toxicity was well managed, with only 14% of patients experiencing differentiation syndrome. The most common toxicity was QTc prolongation, which occurred in 49% of patients. Revumenib has now entered into phase II trials and is being planned for combinatorial approaches with intensive and less-intensive chemotherapy to further enhance the efficacy of this agent in patients with both newly diagnosed and R/R acute leukemia.

Ziftomenib (formerly known as KO-539) is a second small-molecule inhibitor in development. Preclinical data also supported the potency of ziftomenib, and early results from the first-in-human phase I KOMET-001 study (NCT04067336) presented at the American Society of Hematology (ASH) 2020 annual meeting demonstrated efficacy. Of note, 1 CR was reported in a patient lacking an NPM1 mutation or KMT2A gene rearrangement. Ziftomenib is now in phase II expansion, and further results of this trial are anticipated to be presented at the 2022 ASH annual meeting.

A key feature of menin inhibition that has arisen across clinical trials is the occurrence of differentiation syndrome. Although this was not seen in a large number of patients who received revumenib in the AUGMENT‑101 trial, there have been reports of higher incidence and severity of differentiation syndrome with other agents. Differentiation syndrome is not a new phenomenon and is a toxicity that occurs with other antileukemic agents, including retinoic acid for acute promyelocytic leukemia, IDH1/2 inhibitors, and FLT3 tyrosine kinase inhibitors. Given the biological efficacy and mechanism of action of menin inhibition specifically inducing differentiation in responding cells, this toxicity must be carefully monitored and addressed for these agents to move forward. For this reason, there is interest in potentially combining menin inhibitors with cytotoxic chemotherapy not only to improve efficacy, but also to cytoreduce the tumor burden, thereby mitigating the differentiation syndrome events seen with monotherapy.

Compounds that target menin—including JNJ-75276617, DS-1594b, DSP-5336, and BMF-219—are being evaluated, and patients are being actively recruited for clinical trials. Many of these agents are being explored in early‑phase testing, with plans to expand to patients with AML and ALL with NPM1 mutations or KMT2A rearrangements.

Future Directions With Menin Inhibitors
Preclinical studies also have demonstrated that the combination of menin inhibition with other targeted therapies, including BCL2 inhibition with venetoclax and FLT3 inhibition, may improve the efficacy and response rates reported with menin inhibitor monotherapy. Investigator-initiated trials evaluating some of these novel targeted strategies, as well as use of these agents in earlier lines of therapy, are highly anticipated over the next few months to next year.

Menin inhibitors represent a novel class of targeted therapeutics for leukemia, but which patient subsets would benefit most remains a question. We do know that NPM1- and KMT2A-rearranged leukemias will respond, but there are other biological subtypes of acute leukemia that similarly have HOXA9 and MEIS1 upregulation and/or have gene expression profiles that also may be amenable to menin inhibition. It is intriguing to investigate the possibility that menin inhibition could be used in additional types of acute leukemia, and this is being researched in ongoing clinical trials. Given the importance of clinical development of these agents, the initial trials have largely focused on patients with the specific subgroups known to most likely see benefit. However, as the drugs are developed further, there is interest in looking at menin inhibition in more mutation-agnostic clinical settings.

To learn more about menin inhibitors in acute leukemias, please click here to read a short text module with slides developed by Eytan Stein, MD.

Upcoming Symposium on AML at ASH 2022!
For more insights into optimizing the care of patients with AML by applying current guidelines, as well as the latest on emerging therapeutic approaches, join us for an upcoming CME-certified satellite symposium titled, “Acute Myeloid Leukemia: Reviewing Current Best Practice and Exploring Novel Paradigms Ahead” at ASH 2022 in New Orleans, Louisiana, on Friday, December 9, at 7:30 AM CT. For details and to register for this symposium, click here. If you are unable to attend in person, register for the live simulcast of the presentation here!

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