Eytan M. Stein, MD, is the Chief of the Leukemia Service, Associate Attending Physician, Clinical Investigator, and Director of the Program for Drug Development

ytan M. Stein, MD, is the Chief of the Leukemia Service, Associate Attending Physician, Clinical Investigator, and Director of the Program for Drug Development 

"One rationale for combining menin inhibitors, specifically with chemotherapeutic agents, is that one of the issues with menin inhibitors is that they can cause fairly severe differentiation syndrome. [Therefore], if you can actually debulk the leukemia a little bit [with chemotherapeutic agents] before you introduce your menin inhibitor, that may lower the rates of differentiation syndrome overall and [reduce the incidence of] grade 3 or higher differentiation syndrome."

Eytan M. Stein, MD, chief of Leukemia Service Director, Program for Drug Development in Leukemia, Division of Hematologic Malignancies at Memorial Sloan Kettering Cancer Center, discussed how menin inhibitors could fit into combination treatment strategies for for the frontline treatment of certain subsets of patients with acute myeloid leukemia (AML).

According to Stein, the rationale for these combinations is based on the complementary mechanisms of action between menin inhibitors and existing chemotherapeutic backbones and other systemic agents. Agents such as cytarabine and venetoclax (Venclexta) exert broad cytotoxic effects; menin inhibitors such as revumenib (Revuforj) specifically inhibit menin and disrupt the its interaction with other proteins. This dual approach is designed to simultaneously promote leukemic cell death and differentiation, and the goal of moving targeted agents like menin inhibitors to frontline combinations could help boost remission rates in that setting.

The frontline combinations aim to build on the efficacy and safety of menin inhibitors in the relapsed/refractory setting. In November 2024, 

 for the treatment of adult and pediatric patients aged 1 year and older with relapsed or refractory acute leukemia and a 

 to a supplemental new drug application seeking the approval of revumenib for the treatment of patients with relapsed/refractory, 

 for the treatment of adult patients with relapsed/refractory AML harboring an 

Stein noted that one of the challenges of menin inhibition is the risk of differentiation syndrome; however, incorporating the agents into treatment with chemotherapy up-front may help reduce leukemic burden, which could lower the risk of differentiation syndrome, Stein said.

Findings from the phase 1b portion of the BEAT AML trial (NCT03013998) showed that older patients with newly diagnosed AML harboring NPM1 mutations or KMT2A rearrangements treated with revumenib plus azacitidine and venetoclax (n = 43) experienced a complete remission (CR) rate of 67%, a composite CR rate of 81%, and an overall response rate of 88%.

Ultimately, Stein explained that menin inhibitor–based combinations could expand therapeutic options in AML, particularly for biomarker-selected patients. As more data become available, he expects further refinement in patient selection and management strategies that incorporate both molecularly targeted agents and cytotoxic therapies to improve clinical outcomes in AML subgroups.

Videos

Eytan M. Stein, MD, discusses the emerging role of menin inhibitors such as revumenib in combination treatment strategies for AML.

Dr Stein on the Emerging Role of Menin Inhibitors in Frontline Combinations for AML

Eytan M. Stein, MD, director, Program for Drug Development in Leukemia, Division of Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, discusses the phase 1/2 KOMET-001 trial (NCT04067336) in relapsed/refractory acute myeloid leukemia (AML).

The phase 1/2 KOMET-001 trial is a first-in-human, dose-escalation study that is evaluating the tolerability of the menin inhibitor, KO-539 (ziftomenib) in patients with relapsed/refractory AML.

Although there is limited data currently available from the trial, findings shared at a previous meeting demonstrated KO-539 elicited responses, even in patients who did not have 

These initial findings prompted investigators to hypothesize whether menin inhibitors can be effective in patients with AML beyond the specific subgroup of patients with 

Eytan M. Stein, MD, discusses the phase 1/2 KOMET-001 trial in relapsed/refractory acute myeloid leukemia.


Dr. Stein on the KOMET-001 Trial in Relapsed/Refractory AML

Eytan M. Stein, MD, director, Program for Drug Development in Leukemia, Division of Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, discusses the key highlights of the phase 1/2 AUGMENT-101 trial (NCT04065399) in leukemias.

The phase 1 dose-escalation study is examining the maximum tolerated dose of SNDX-5613 in patients with leukemias harboring acute 

Preclinical data suggest that menin, an adapter protein, plays a role in the pathogenesis of 

-mutant leukemia, Stein says. Leukemia is driven by the upregulation of leukemogenic genes, and that occurs when menin binds to the KMT2A complex, Stein explains.

It is hypothesized that blocking the interaction between the menin and the MLL complex, those cells will not be primed to develop leukemia. Additionally, the leukemic cells transform into normal cells, Stein concludes.

Eytan M. Stein, MD, discusses the key highlights of the phase 1/2 AUGMENT-101 trial in leukemias.


Dr. Stein on Key Highlights of the AUGMENT-101 Trial in Leukemias

Eytan M. Stein, MD, hematologic oncologist, Memorial Sloan Kettering Cancer Center, discusses the importance of testing for measurable residual disease (MRD) in acute myeloid leukemia (AML). 

At the time of complete remission, the presence of MRD has been shown to be an adverse prognostic factor. Patients with MRD at the time of allogeneic bone marrow transplant have a higher risk of relapse following transplant than if they were MRD negative, says Stein. Notably, the presence of MRD also appears to predict risk of relapse for favorable-risk patients who are not undergoing transplant.

As such, clinical trials are needed to test agents that could induce MRD negativity, says Stein. Of equal concern will be the potential survival benefit and toxicities of the drug, concludes Stein. 

Eytan M. Stein, MD, discusses the importance of measuring for measurable residual disease in acute myeloid leukemia.

Dr. Stein on the Importance of MRD in AML

Eytan M. Stein, MD, internist, hematologic oncologist, Memorial Sloan Kettering Cancer Center, discusses recent advances that have been made in the treatment of patients with acute myeloid leukemia (AML).

Over the past couple years, several new therapies have been approved for patients with AML. For patients with newly diagnosed disease, the combination of midostaurin (Rydapt) and chemotherapy serves as an option for those with 

-mutated disease. For patients who are unfit for induction chemotherapy, hypomethylating agents or low-dose cytarabine (LD-AraC) can be given in combination with venetoclax (Venclexta). Moreover, the hedgehog inhibitor glasdegib (Daurismo) can be used in combination with LD-AraC. CPX-351 is a liposomal formulation of daunorubicin and cytarabine and can be offered to patients with therapy-related AML and AML with myelodysplastic-related changes.

In the relapsed/refractory setting, physicians have access to 3 newly approved agents, including the IDH1 inhibitor ivosidenib (Tibsovo), the IDH2 inhibitor enasidenib (Idhifa), and the FLT3 inhibitor gilteritinib (Xospata). Physicians are also anticipating the FDA approval of quizartinib within the coming months for the treatment of patients with 

Dr. Stein on Recent Treatment Advances in AML

Eytan M. Stein, MD, internist, hematologic oncologist, Memorial Sloan Kettering Cancer Center, discusses some of the potential combinations that could be explored with novel agents in the treatment of patients with acute myeloid leukemia (AML).

With several new agents in the pipeline for AML, Stein sees endless possibilities for combination regimens. One novel agent is midostaurin, which has demonstrated a 7% overall survival benefit at approximately 5 years when combined with induction chemotherapy for patients with 

Some clinical studies have examined combinations involving the BCL-2 inhibitor venetoclax (Venclexta), or the novel antibody-drug conjugate SGN-CD33A, paired with hypomethylating agents.

Overall, Stein sees this as a very exciting time in AML. There have not been any new drug approvals for this disease in the past several years, so many experts would agree that the field is now long overdue for one in the coming years.

Eytan M. Stein, MD, internist, hematologic oncologist, Memorial Sloan Kettering Cancer Center, discusses some of the potential combinations that could be explored with novel agents in the treatment of patients with acute myeloid leukemia.

Eytan M. Stein, MD

Articles

Dr Stein on the Emerging Role of Menin Inhibitors in Frontline Combinations for AML

Dr. Stein on the KOMET-001 Trial in Relapsed/Refractory AML

Dr. Stein on Key Highlights of the AUGMENT-101 Trial in Leukemias

Dr. Stein on the Importance of MRD in AML

Dr. Stein on Recent Treatment Advances in AML

Dr. Eytan Stein on Novel Combinations in AML