Academic Background

Acute leukemia is a malignant hematologic disease caused by genetic mutations in hematopoietic cells, characterized by a block in differentiation during hematopoiesis and uncontrolled cellular proliferation. Among these, KMT2A gene rearrangements (KMT2A-rearranged, KMT2Ar) occur in up to 10% of acute leukemias in children and adults, particularly in certain types of infant and childhood acute leukemias. KMT2Ar leukemia is often associated with drug resistance and poor prognosis, especially in patients who have undergone multiple lines of therapy. Currently, there are no approved targeted therapies for KMT2Ar leukemia, and patients primarily rely on conventional chemotherapy or Venetoclax-based combinations, with limited efficacy.

Menin protein is a crucial mediator in the pathogenesis of KMT2Ar leukemia. It binds to the KMT2A protein complex, promoting the expression of HOX genes, which drives leukemogenesis. Preclinical studies have shown that disrupting the Menin-KMT2A interaction can reverse this aberrant gene expression, promote hematopoietic differentiation, and exert antileukemic effects. Based on this mechanism, Revumenib, an oral small-molecule inhibitor of the Menin-KMT2A interaction, has demonstrated promising safety and preliminary efficacy in early clinical trials.

Source of the Paper

This paper was co-authored by Ghayas C. Issa, Ibrahim Aldoss, and other researchers from multiple institutions, including The University of Texas MD Anderson Cancer Center, City of Hope National Medical Center, and Memorial Sloan Kettering Cancer Center. The study was published on August 9, 2024, in the Journal of Clinical Oncology, titled “Menin Inhibition with Revumenib for KMT2A-Rearranged Relapsed or Refractory Acute Leukemia (AUGMENT-101).”

Study Process

Study Design

AUGMENT-101 is a phase I/II, open-label, dose-escalation and expansion study designed to evaluate the efficacy and safety of Revumenib in patients with relapsed/refractory (R/R) leukemia harboring KMT2Ar or NPM1 mutations. This paper reports the results of the phase II, registration-enabling portion of the study. The study was conducted across 22 clinical sites in five countries. Patients aged ≥30 days with KMT2Ar acute leukemia or AML with NPM1 mutation were enrolled. Revumenib was administered orally every 12 hours at a dose of 163 mg (95 mg/m² for patients weighing <40 kg) in combination with a strong cytochrome P450 inhibitor, in 28-day cycles.

Patient Enrollment

The study enrolled 94 patients with a median age of 37 years (range: 1.3-75 years), including 78 patients with AML, 14 with ALL, and 2 with mixed phenotype acute leukemia (MPAL). All patients had undergone multiple lines of therapy, with 43.6% having received ≥3 prior lines of treatment.

Primary Endpoints

The primary endpoints were the rate of complete remission (CR) or CR with partial hematologic recovery (CRh), as well as the safety and tolerability of Revumenib. Secondary endpoints included overall response rate (ORR), duration of response, and overall survival (OS).

Data Analysis

The study employed Simon’s two-stage design, with a planned evaluation of the CR + CRh rate in 64 adult patients. A prespecified futility analysis was conducted after the first 38 patients. Enrollment would continue if ≥5 responses were observed in these initial 38 patients.

Key Results

Safety

Among the 94 patients, 93 (98.9%) experienced treatment-related adverse events (AEs). The most common AEs included febrile neutropenia (37.2%), differentiation syndrome (16.0%), and QT prolongation (13.8%). Fourteen patients (14.9%) died due to AEs.

Efficacy

In the 57 efficacy-evaluable patients, the CR + CRh rate was 22.8% (95% CI, 12.7-35.8), exceeding the prespecified null hypothesis of 10% (p = 0.0036). The overall response rate was 63.2% (95% CI, 49.3-75.6), with 15 patients (68.2%) achieving minimal residual disease (MRD)-negative status.

Duration of Response

The median duration of CR + CRh was 6.4 months (95% CI, 3.4-not reached), and the median overall survival was 8.0 months (95% CI, 4.1-10.9).

Conclusion

Revumenib demonstrated high remission rates and a predictable safety profile in patients with KMT2Ar relapsed/refractory acute leukemia. The results suggest that Revumenib monotherapy provides clinical benefit beyond current therapies. Additionally, Revumenib was well-tolerated, with manageable AEs such as differentiation syndrome and QT prolongation.

Highlights of the Study

1. Key Findings: Revumenib showed significant remission rates in KMT2Ar leukemia patients, particularly in heavily pretreated patients, with a CR + CRh rate of 22.8%.
2. Innovation: This is the largest study to date evaluating a targeted therapy for KMT2Ar leukemia patients, providing the first evidence of the clinical value of Menin inhibitors in this patient population.
3. Future Applications: The efficacy and safety of Revumenib lay the groundwork for its use in combination therapies, particularly with BCL2 or FLT3 inhibitors.

Significance of the Study

This study offers a new treatment option for patients with KMT2Ar relapsed/refractory acute leukemia. The high remission rates and predictable safety profile of Revumenib make it an important therapeutic option for this patient population. Furthermore, the results provide a basis for future investigations into the efficacy of Revumenib in newly diagnosed AML patients.