Study Reveals Potential Cause of Levmenib Resistance in Patients with Acute Leukemia

From ASCO Post Staff

Posted: 2023/03/20 9:22:00 AM

Last update: Mar 20, 2023 8:46:34 AM

Levmenib, a new menin inhibitor, not only caused remission in acute myeloid leukemia (AML) patients, but also revealed a mechanism by which cancer cells became resistant to therapy. Issa and others and Perner et al.,Each, Nature.

Results from the first study showed that approximately 40% of patients with the acute leukemia subtype responded completely to levmenib. Findings from a second study revealed a molecular counter-motility that could cause acute leukemia cells to evade the drug and reassert their proliferation.

Both new studies highlight the potential for targeted approaches to acute leukemia treatment, typified by levmenib, and the potential to expand its efficacy with agents that inhibit resistance mechanisms.

Background

“The two genetic subtypes of acute leukemia involved in this study account for approximately 40% of all cases of acute myeloid leukemia (AML). [pediatric] and adult [patients]explained the co-principal authors of the second study. Scott Armstrong, MD, PhD, David G. Nathan, Professor of Pediatrics, Harvard Medical School; Associate Chief, Department of Hematology/Oncology, Boston Children’s Hospital; Director, Department of Pediatric Oncology, Dana-Farber Cancer Institute; President Institute/Boston Children’s Hospital Cancer and Hematology Center. “They are, MLL1 gene or mutation of NPM1 gene. Both types rely on a protein called menin to sustain growth,” he added.

Menin is an important part of the cellular epigenetic mechanisms that switch gene activity on and off. As a scaffolding protein, it binds to chromatin and calls and binds large protein complexes. The complex tightens or loosens the DNA coil, altering the level of gene activity at that site. One of the key proteins within these complexes is MLL1. MLL1 gene.

Methods and Results of the Levmenib Study

In the first study, including results from the Phase I/II clinical AUGMENT-101 trial, investigators tested the efficacy of menin-targeting levumenib in 68 patients with acute leukemia who had not responded to previous therapy Did. Of the 60 evaluable patients, 53% (n = 32) responded to the drug and 30% (n = 18) had a complete response.

“For patients with acute leukemia who had received some prior therapy, this is a very encouraging result. However, after two cycles of therapy, some patients developed resistance to levmenib,” Dr. Armstrong said. emphasized.

In a second study, a follow-up to the first, Dr. Armstrong and his colleagues looked for the source of that resistance.

“Levmenib contains a small molecule that inhibits the interaction of menin and MLL1. The AUGMENT trial shows that levmenib produces remission in a high percentage of patients,” emphasized Dr. Armstrong. .

When researchers analyzed bone marrow samples from some of the patients who had become resistant to levmenib, they found that many of them developed the disease male 1 A mutation results in a menin protein. This mutation may result in a modified version of menin that does not bind levumenib well but is able to bind MLL1. When menin and MLL1 resume their interaction, leukemia cells begin to proliferate again.

Conclusion

Dr. Armstrong stressed that the new findings “formally prove to patients that menin itself is a valid target for therapy in both genetic subtypes of AML.”

He explained: male 1 To survive, it strongly indicates that the cells are reaching the targets they truly depend on. The ability of levmenib to stress leukemic cells to generate mutations that keep them alive may prove the efficacy of this drug. This is the first time it has been shown to exert that degree of pressure on cancer. ”

By tracking the development of male 1 By examining mutations and other genes in patients with acute leukemia, researchers may be able to identify patients at high risk of recurrence.the discovery of male 1 Mutation as a resistance mechanism suggests that new drugs that specifically target menin or other chromatin-associated proteins may prevent or delay levmenib resistance.

“To see Dr. Armstrong’s work elegantly translated into a clinic that includes patients, some of whom have had dramatic reactions in dire circumstances, has been very personal and professional. satisfied,” said the study authors. Richard Stone, M.D.“We are now poised to extend the impact of these results by conducting clinical trials combining levmenib with standard chemotherapy and novel agents, also led in large part by Dr. Armstrong. It is also based on well-researched preclinical studies,” he concluded.

Disclosure: For full disclosure of the study authors, please see: Nature.com and Nature.com.

The content of this post has not been reviewed by the American Society of Clinical Oncology (ASCO®) and does not necessarily reflect the views or opinions of ASCO®.

---