Ibrahim Aldoss, MD

In heavily pretreated patients with a challenging type of acute leukemia, the menin inhibitor revumenib demonstrated clinically meaningful activity, including high rates of response and measurable residual disease (MRD) negativity, according to the efficacy and safety results of the phase II AUGMENT-101 trial, reported at the 2023 American Society of Hematology (ASH) Annual Meeting & Exposition.¹

“Revumenib is effective and safe in pediatric and adult patients with relapsed or refractory KMT2A-rearranged acute leukemia…. The study was stopped early after meeting the primary efficacy endpoint at the predefined interim analysis, and a new drug application for KMT2A-rearranged leukemia has been initiated,” said Ibrahim Aldoss, MD, of City of Hope National Medical Center, Duarte, California. KMT2A-rearranged leukemia is defined as leukemia with rearrangement of the histone-lysine N-methyltransferase 2A gene.

“The study was stopped early after meeting the primary efficacy endpoint at the predefined interim analysis, and a new drug application [for revumenib] for KMT2A-rearranged leukemia has been initiated.”

— IBRAHIM ALDOSS, MD

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In brief, treatment with revumenib led to a high rate of MRD negativity, durable remissions, and the ability of many responders to undergo allogeneic stem cell transplantation. Treatment discontinuations and dose reductions because of adverse events were uncommon, Dr. Aldoss reported in this late-breaking abstract.

Background

KMT2A-rearranged acute leukemia represents about 10% of all acute leukemias. It can present either as lymphoid or myeloid leukemia and can be seen in infants (as the most common leukemia) as well as in older children and adults. After chemotherapy and transplantation, the risk of relapse is high. About 5% of relapsed patients achieve complete remission with second-line or later salvage therapy, and the median overall survival is less than 3 months.

In KMT2A-rearranged leukemia, the interaction between menin and the KMT2A fusion proteins is a key driver of leukemogenesis. Although there is currently no approved treatment targeting the menin-KMT2A interaction, this may soon change, considering the outcomes being observed with the small-molecule inhibitor of menin-KMT2A interactions revumenib, one of several such compounds in development.

“These drugs essentially block this interaction…,” explained Dr. Aldoss. “They allow the immature cells to become mature, healthy, functioning cells. NPM1-mutated leukemias and some other genetic subtypes of leukemia are also driven by this interaction, and they can be susceptible to revumenib therapy,” he noted in a press briefing. Regarding the potential role of revumenib in NPM1-mutated leukemia (the cohort is still enrolling), Dr. Aldoss shared these thoughts: “In relapse, this type of leukemia can behave as badly as the KMT2A-rearranged leukemias, so we are excited about the potential for the drug in this area as well. We hope to have these results soon.”

About AUGMENT-101

AUGMENT-101 included 94 patients (aged ≥ 30 days) with relapsed or refractory KMT2A-rearranged acute leukemia. Patients in this analysis were enrolled in cohort A (acute lymphoblastic leukemia [ALL]/mixed phenotype acute leukemia [MPAL]) or cohort B (acute myeloid leukemia [AML]). Cohort C continues to enroll patients with NPM1 mutations and is not included in this analysis.

Patients’ median age was 34 years for the 57 patients in the efficacy population (centrally confirmed KMT2A-rearranged disease, and with ≥ 6 months of follow-up or treatment discontinuation) and 37 years for the 94 patients in the safety population (KMT2A-rearranged disease regardless of centrally confirmed disease and received at least one dose), with almost one-quarter of patients being younger than age 18. In the efficacy population, 86% had AML, 12% had ALL, and 2% had MPAL or other types of leukemia. A few patients had co-mutations in FLT3, RAS, and TP53. Almost half the patients in the efficacy population had received at least three prior lines of therapy, and almost half had undergone transplantation.

“We have not seen this level of activity with any other available treatment in this advanced disease setting.”

— IBRAHIM ALDOSS, MD

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“These patients were heavily pretreated. For about one-quarter of the patients, disease was treatment-refractory, and no remission was achieved, and more than half were refractory to the last salvage therapy regardless of whether they achieved remission or not,” Dr. Aldoss noted.

Patients were treated with oral revumenib every 12 hours plus a strong oral cytochrome CYP450 3A4 inhibitor in 28-day cycles. Treatment was continued until unacceptable toxicity or lack of at least a morphologic leukemia-free state after four cycles of treatment. The primary endpoint was the rate of complete response plus complete response with partial hematologic recovery.

Primary Endpoint Met

With a median follow-up of 6.1 months in the efficacy population, the overall response rate was 63%, with 23% of patients having complete remission or complete remission with partial hematologic recovery, the study’s primary objectives, and 44% of patients having composite complete remission, the secondary endpoint. Composite ccomplete remission is the sum of complete response plus complete response with partial hematologic recovery plus complete remission with incomplete platelet recovery, and complete remission with incomplete hematologic recovery.The percentage of patients achieving MRD negativity was 70% among patients reaching complete response plus complete response with partial hematologic recovery and 68% among patients with composite complete response. Responses were noted across all preidentified subgroups and across KMT2A rearrangements. Median time to complete response or complete response with partial hematologic recovery was 1.9 months, and median duration of response was 6.4 months.

Dr. Aldoss continued: “We have not seen this level of activity with any other available treatment in this advanced disease setting…. After achieving a response, 39% of responders were able to go on to allogeneic stem cell transplant, which is generally our ultimate goal for patients with relapsed or refractory leukemia. And about half these patients resume revumenib as maintenance…, to try to maintain disease control and reduce the risk of relapse, until the transplant has time to work.”

Safety Profile

“The overall safety profile was encouraging, and the rate of drug discontinuation because of treatment-related adverse events was only 6%,” Dr. Aldoss said. The most common any-grade treatment-emergent toxicities of any grade were gastrointestinal events, including nausea (45%), febrile neutropenia (38%), diarrhea (35%), vomiting (31%), differentiation syndrome (28%), hypokalemia (28%), epistaxis (27%), and QTc prolongation (25%).

Describing the rates of grade ≥ 3 toxicities, Dr. Aldoss noted that the most common was neutropenic fever. “Revumenib is a differentiating agent, so there was concern about differentiation syndrome,” he said, but it was limited to 16% of patients. QTc prolongation grade ≥ 3 was observed in about 14% of treated patients and was usually reversible. No patients discontinued treatment because of differentiation syndrome, QTc prolongation, or cytopenias, according to Dr. Aldoss. 

DISCLOSURE: Dr. Aldoss has served as a consultant to Takeda, Amgen, Pfizer, Jazz Pharmaceuticals, Sobi, and Kite Pharma and has received honoraria from Amgen.

REFERENCE

1. Aldoss I, Issa GC, Thirman M, et al: Revumenib monotherapy in patients with relapsed/refractory KMT2Ar acute leukemia: Topline efficacy and safety results from the pivotal AUGMENT-101 phase 2 study. 2023 ASH Annual Meeting & Exposition. Abstract LBA-5. Presented December 12, 2023.