A Significant Advance for Relapsed/Refractory Acute Leukemia

  • The FDA approval of revumenib (brand name Revuforj) as the first menin inhibitor ushers in a new treatment era for patients with relapsed/refractory (R/R) acute leukemia.
  • The approval was based on the pivotal findings from the AUGMENT-101 phase 1/2 trial. The trial included only patients harboring KMT2A translocations.
  • Revumenib demonstrated clinically meaningful results in a heavily pretreated KMT2Ar population, including high overall response rate and rates of measurable residual disease negativity.
  • This milestone provides hope for a previously underserved patient population and highlights the importance of targeted therapies in addressing the unique biology of aggressive leukemia subtypes.

The FDA’s recent approval of revumenib (brand name Revuforj), a menin inhibitor, marks a significant advancement in the treatment of adult and pediatric patients aged one year and older with relapsed or refractory (R/R) acute leukemia characterized by lysine methyltransferase 2A gene (KMT2A) translocations.

This approval represents a breakthrough for a population with limited therapeutic options and a historically poor prognosis.

“This patient population is extremely challenging to treat. They have poor responses to our traditional cytotoxic chemotherapy, and when they do respond, they often relapse very quickly,” Dr. Catherine E. Lai, Physician Leader at the Leukemia Clinical Research Unit. at University of Pennsylvania, tells SurvivorNet Connect.

“The goal for this patient population is to get them to transplant. This new study showed that the overall response rates were a little over 60% with a complete remission rate of a little over 20% with a median time to response of two months. And so, for these patients who are able to get into complete remission, they’re often able to then go onto allogeneic stem cell transplant, which is the only potential cure for this patient population,” Dr. Lai adds.

Mechanism of Action and Disease Context

KMT2A translocations, also referred to as mixed-lineage leukemia (MLL) rearrangements, are associated with aggressive leukemogenesis, driven by interactions between KMT2A fusion proteins and menin. These translocations occur in 5% to 10% of acute leukemias and are prevalent in both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).

“The class of drugs called the menin inhibitors targets two specific mutations in AML. One is KMT2A rearranged, and the other is NPM1 mutated patients. Revumenib, which was recently FDA approved, specifically was approved for the KMT2A rearrange patients,” adds Dr. Lai.

Prior to revumenib, no therapies specifically targeting the menin-KMT2A interaction had been approved, leaving a significant unmet need in the management of these patients.

AUGMENT-101 Study Overview

The approval was based on the pivotal findings from the AUGMENT-101 phase 1/2 trial (NCT04065399).

This open-label, multicenter study enrolled 104 patients (adult and pediatric) with R/R acute leukemia harboring KMT2A translocations. Patients received oral revumenib until disease progression, unacceptable toxicity, failure to achieve a morphological leukemia-free state by four cycles, or hematopoietic stem cell transplantation (HSCT).

The primary efficacy endpoint was the composite rate of complete remission (CR) and CR with partial hematologic recovery (CRh). Key secondary endpoints included the duration of response, transfusion independence, and overall safety.

Efficacy Outcomes

Revumenib demonstrated meaningful clinical activity:

-CR+CRh Rate: 21.2% (22/104 pts; 95% CI: 13.8%, 30.3%)
-Median Duration of CR+CRh: 6.4 months (95% CI: 2.7-not estimable)
-Median Time to CR or CRh: 1.9 months (range: 0.9-5.6)

Among 83 patients who were transfusion dependent at baseline, 14% achieved transfusion independence during any 56-day post-baseline period. Furthermore, 48% of patients who were transfusion independent at baseline maintained independence during this period.

A subgroup analysis highlighted differences in response rates across leukemia subtypes:

-AML: 21%
-ALL: 19%
-Mixed-phenotype acute leukemia (MPAL): 50%

Safety Profile

The safety analysis included 104 adults and 31 pediatric patients. The median duration of exposure was 2.3 months. The most common treatment-related adverse events (AEs) included:

-Nausea (51%)
-Musculoskeletal pain (42%)
-Differentiation syndrome (29%, grade 3/4 in 13%)
-Prolonged QT interval (29%, grade 3/4 in 12%)
-Infections (41%, grade 3/4 in 29%)

Serious AEs occurred in 73% of patients, and 3% experienced fatal events (differentiation syndrome, hemorrhage, sudden death).

Dose interruptions were required in 42% of patients, and 10% experienced dose reductions. Importantly, differentiation syndrome—a known complication of targeted therapies in leukemia—was manageable and did not necessitate therapy discontinuation in most cases.

Demographics and Disease Characteristics

The patient cohort in AUGMENT-101 was heavily pretreated:

-Median Number of Prior Regimens: 2 (range: 1-11)
-Prior HSCT: 44%
-Refractory or Relapsed Disease: 59%

Patients had diverse KMT2A fusion partners, including t(9;11), t(11;19), and other less common rearrangements. Notably, 25% of patients had an unknown KMT2A fusion partner, underscoring the heterogeneity of this population.

The recommended dosing regimen for revumenib is weight-based and adjusted for the concomitant use of CYP3A4 inhibitors. Due to delays in the commercial availability of the lowest dose strength, patients weighing less than 40 kg (about 88 lbs.) may access the therapy through an expanded access program (NCT05918913).

Clinical Implications

Revumenib represents a “major breakthrough” in the management of KMT2A-translocated R/R acute leukemia. The observed CR+CRh rates and durations of response compare favorably to historical outcomes, where remission rates were as low as 5% in patients receiving salvage therapy.

Revumenib also offers the potential for durable responses, as evidenced by the 6.4-month median duration of CR+CRh and the high rates of measurable residual disease (MRD) negativity observed in responders.