Revumenib Receives FDA Approval for Relapsed or Refractory Acute Leukemia with a KMT2A Translocation

On 15 November 2024, the FDA approved the menin inhibitor revumenib (Revuforj, Syndax Pharmaceuticals, Inc.) for adults and pediatric patients aged 1 year and older with relapsed or refractory acute leukemia (R/R AL) with a lysine methyltransferase 2A (KMT2A) gene translocation.

Why Does Revumenib Matter? The Frequency of KMT2A Translocations

KMT2A translocations characterize a high-risk subgroup of acute leukemia, and these patients generally have a poor prognosis.

1. Overall Frequency in Acute Leukemia:

   • KMT2A translocations occur in 5-10% of acute leukemias. The proportion varies by subtype:
     • Acute Lymphoblastic Leukemia (ALL): 5-10% of childhood ALL.
     • Acute Myeloid Leukemia (AML): 15-20% of pediatric AML.
     • Mixed-Lineage Leukemias (MPAL): KMT2A translocations are much more common in mixed lymphoid-myeloid leukemias.

2. Defining Features of KMT2A:

   • KMT2A is located at chromosome 11q23.3, and 112 different fusion partners have been identified to date. These translocations can produce different disease phenotypes (ALL, AML, MPAL).
   • The most common breakpoints cluster in the gene's BCR1 (breakpoint cluster region 1) and, less frequently, BCR2 regions.

3. Clinical Features:

   • Leukemias with a KMT2A translocation generally follow an aggressive course.
   • Resistance to standard treatments is more common, making targeted treatments such as menin inhibitors particularly valuable.

How Revumenib Works

Revumenib targets menin, a protein inhibited by this medicine. In particular, it blocks the growth and proliferation of acute leukemia cells driven by the menin-MLL (KMT2A) fusion protein. This is the specific pathway involved in the development of these leukemia cells. A KMT2A translocation causes genetic rearrangement in leukemia cells, leading to continuous activation of leukemic genes through menin. By blocking this process, revumenib stops leukemic cell growth.

What Is Menin?

Menin is a protein in the cell nucleus that regulates the expression of many genes.

• Normal role: Menin is part of a complex that controls genetic information and regulates the production of certain proteins, known as the menin-MLL complex.
• Role in leukemia: Translocations in KMT2A (formerly MLL) produce an abnormal fusion protein. It binds menin, causing genes that are normally switched off in leukemia cells to remain continuously active. This leads to uncontrolled cell growth and proliferation.

Why Is Targeting Menin Important?

• Specificity: Menin inhibitors target only leukemia cells carrying certain genetic mutations. This may reduce the risk of harming healthy cells.
• Effect of the KMT2A translocation: This translocation occurs in approximately 10% of pediatric and adult acute leukemias and may confer resistance to standard treatments. Menin inhibitors offer an effective treatment option for these patients.

By targeting menin, revumenib offers a genetically based treatment approach, considered an important advance in leukemia treatment.

FDA Approval Based on AUGMENT-101

Revumenib's efficacy was assessed in a single-arm cohort of the open-label, multicenter AUGMENT-101 trial (NCT04065399). It enrolled 104 adult and pediatric patients with relapsed or refractory acute leukemia and a KMT2A translocation. The main outcome measures were:

• Complete remission (CR) and complete remission with partial hematological recovery (CRh):

  • Rate: 21.2% (95% CI: 13.8-30.3)
  • Median CR+CRh duration: 6.4 months (95% CI: 2.7, not estimable)
  • Time to CR or CRh: 1.9 months (range: 0.9-5.6 months)

• Transfusion independence:

  • Of the 83 patients dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 12 (14%) became transfusion-independent during treatment.
  • Of the 21 patients independent of RBC and platelet transfusions, 10 (48%) maintained independence.

Most Common Side Effects

The most common side effects reported during treatment were (≥20%):

• Bleeding, nausea, musculoskeletal pain, and infection
• Laboratory abnormalities: Increased phosphate, elevated AST/ALT, and low potassium
• Clinical complications: Differentiation syndrome, febrile neutropenia, and QT prolongation

Dosage and Administration

Revumenib dosing varies with body weight and concomitant use of strong CYP3A4 inhibitors. An expanded access program is available for patients weighing <40 kg because a lower-dose formulation is not commercially available. For details, consult the relevant NCT05918913 study information.

An Innovative Approach to FDA Review

The approval was expedited through the FDA's Real-Time Oncology Review (RTOR) pilot program and the voluntarily submitted Assessment Aid to facilitate review of the application. As a result, approval was granted 6 weeks before the application's completion deadline.

Conclusion

Revumenib offers an innovative option for patients with relapsed or refractory acute leukemia with a KMT2A translocation, bringing hope to this challenging group. Clinical data show meaningful improvements in efficacy and safety. However, side effects must be carefully managed during treatment.