A new generation of Menin inhibitors revolutionizes the treatment of acute leukemia, giving Hong Kong patients new hope

Several studies presented at the 2024 American Society of Hematology (ASH) annual meeting showed that, in addition to the already approved revumenib, several novel menin inhibitors demonstrate unique advantages in the treatment of acute myeloid leukemia (AML). These drugs, used in combination with chemotherapy in newly diagnosed and relapsed/refractory AML patients, offer new hope for two difficult-to-treat subtypes of AML—those with KMT2A rearrangements and NPM1 mutations—which account for approximately 40% of AML cases.

Newly diagnosed AML: Ziftomenib combined with intensive chemotherapy regimen

The Phase I KOMET-007 trial, reported by Professor Amer Zeidan of the Yale Cancer Center, showed that:

• Treatment plan：Oral ziftomenib (once daily) in combination with "7+3" chemotherapy (cytarabine + daunorubicin)
• Key advantages：Does not interact with azole drugs and carries no risk of QT interval prolongation.
• Efficacy data：
  • NPM1 mutation group: 100% complete remission rate (CR), 75% MRD negativity rate
  • KMT2A rearrangement group: 83% complete remission rate
• security：Only one case of grade 3 differentiation syndrome was observed (in the highest dose group), and there were no dose-limiting toxicities.

Professor Zeidan emphasized, "This is a true complete remission observed in a high-risk patient group, and we have planned to launch a Phase III registration clinical trial."

For the latest advancements in the treatment of acute leukemia, please refer to the hematology treatment information provided bythe Hong Kong Hospital Authority..

Newly diagnosed AML: Bleximenib combination therapy

A Phase Ib dose-finding study reported by Professor Christian Recher of the Toulouse Cancer Institute in France:

• Treatment plan：Bleximenib (30-100 mg twice daily) combined with "7+3" chemotherapy.
• Efficacy data (21 evaluable patients):
  • Overall remission rate: 95%
  • Complete remission rate (CR/CRh/CRi): 86%
  • MRD negativity rate: 8/9 cases (89%)
• security：No differentiation syndrome or QT prolongation was observed, and myelosuppression was comparable to that of chemotherapy alone.

Relapsed/Refractory AML: Advances in Novel Therapies

Bleximenib monotherapy (cAMeLot-1 trial)

• Recommended Phase II dosage: 100 mg twice daily
• The complete remission rate was 44% in the KMT2A rearrangement group and 33% in the NPM1 mutation group.
• 14% of patients developed differentiation syndrome (including 2 deaths).

Enzomenib

• The unique chemical structure reduces off-target toxicity.
• The overall remission rate for KMT2A-rearranged cases was 73%, with a complete remission/complete remission with incomplete hematologic recovery rate of 40%.
• 11% developed differentiation syndrome (all were self-limiting).

Expert view

Professor Rory Shallis of Yale University pointed out: "Although these menin inhibitors have shown similar efficacy in single-arm trials, the existing data still have limitations:

• Differences in inclusion criteria and baseline characteristics across studies
• Lack of randomized controlled data
• MRD detection methods are not yet standardized

Differentiation syndrome, as a class effect of these drugs, requires close monitoring and timely treatment with corticosteroids."

Clinical application prospects

At present, a number of Phase III trials of frontline treatments are under preparation, including：

• Menin inhibitor combined with "7+3" intensive chemotherapy
• Menin inhibitor combined with azacitidine + venetoclax regimen

Professor Shallis specifically emphasized: "Ziftomenib is more convenient for clinical use due to the absence of QT prolongation and drug interaction risks. Early data on bleximenib in newly diagnosed patients is also encouraging."

Disclosure of interests

Each research author declared cooperative relations with pharmaceutical companies such as Syndax and Kura Oncology.

Source of information：ASCO Post report on Clinical Trials of Menin Inhibitors

Find out more about treatment information：

For more information about acute leukemia and the treatment of Menin inhibitors, please visit the relevant pages of the United Cancer Center of Hong Kong below.