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SAN DIEGO -- Nearly two-thirds of patients with relapsed or refractory KMT2A-rearranged acute leukemia responded to an investigational oral menin inhibitor, a phase II trial showed.

Among 57 children and adults in the pivotal study, treatment with single-agent revumenib led to a 63% overall response rate (ORR) and a 23% rate of complete remission or complete remission with partial hematologic recovery (CR/CRh), said Ibrahim Aldoss, MD, of the City of Hope National Medical Center in Duarte, California.

In the CR/CRh responders, 70% attained measurable residual disease (MRD) negativity and the median duration of remission reached 6 months. Moreover, few patients in the overall population discontinued the drug or required dose reductions due to toxicity, he reported at the American Society of Hematology annual meeting here.

"After achieving response, 40% of responders were able to go to allogeneic stem cell transplant, which is really our ultimate goal for someone with relapsed/refractory leukemia," said Aldoss.

Previously described as leukemia with MLL rearrangements, KMT2A-rearranged leukemia can present either as lymphoid or myeloid leukemia and occurs both in children and adults. It's the most common rearrangement in infant leukemia (conferring a poor prognosis), and in total accounts for roughly 10% of all acute leukemias.

"It's a disease with unmet therapeutic needs. These patients have high risk of relapse after transplant and after chemotherapy," said Aldoss, noting that no approved therapy currently targets KMT2A.

KMT2A rearrangements have also been shown to be associated with therapy-related acute myeloid leukemia (AML), which is known to portent adverse outcomes, Jun H. Choi, MD, of NYU Grossman School of Medicine in New York City, told 番茄社区app. "Some data also suggest an increased early death rate in this patient population."

Median overall survival in the trial was 8 months (95% CI 4.1-10.9).

Choi, who was not involved in the study, called the response rate with revumenib promising, given that patients enrolled in the study were without real viable options after failing on multiple lines of therapy.

"More impressive is the high MRD-negativity rate," he said. "Implication is that deep remission is possible with this agent, and combined with a rather high rate of subsequent [hematopoietic stem cell transplant] consolidation, a durable remission is possible in those who are able to be transplanted."

Revumenib is a selective, small molecule inhibitor of the menin-KMT2A binding interaction, a key driver of leukemogenesis. The oral drug is also being evaluated in NPM1-mutated AML, a common mutation that is driven by the same menin-KMT2A interaction, Aldoss noted.

Previous showed revumenib to have a manageable safety profile and durable activity in pretreated patients with KMT2A-rearranged and NPM1-mutated acute leukemias.

Based on the promising phase II results, developer Syndax has initiated a new drug application with FDA for revumenib in KMT2A-rearranged leukemia, said Aldoss.

The study () includes three cohorts: KMT2A-rearranged AML, KMT2A-rearranged acute lymphoblastic leukemia (ALL), and NPM1-mutated AML, the last of which is still enrolling and will be reported on at a later date.

Aldoss presented pooled data from the two KMT2A-rearranged cohorts, which included 57 patients in the efficacy population. These patients had a median age of 34 years; 23% were pediatric cases as the trial enrolled children as young as 30 days old. A majority were female (58%), and three-fourths were white. Most patients had AML (86%), while 12% had ALL and 2% had mixed phenotype acute leukemia.

Co-mutations included FLT3 in 9% of the study population, RAS in 16%, and p53 in 7%. A fourth had primary refractory leukemia; 46% of the participants had received three or more prior lines of treatment, including venetoclax (Venclexta) in 72%; and just under half of the patients had a prior stem cell transplant.

"These are heavily pretreated patients," said Aldoss.

Median follow-up was 6.1 months, and the study was considered a success if the lower bound of the CR/CRh rate surpassed 10%, which it did (95% CI 13-36, P=0.0036). Patients responded quickly to revumenib, with a median time to CR/CRh of 1.9 months.

The composite CR rate reached 44% (95% CI 31-58), which included the 10 patients who achieved a CR (18%) and three who had a CRh (5%), plus an additional 11 patients who achieved a CR with incomplete platelet recovery and one patient who had a CR with incomplete count recovery. More than two-thirds of the patients who had a composite CR attained MRD-negative status.

Another 10 patients (18%) achieved a morphological leukemia-free state, and one patient had a partial response as their best response.

Common treatment-emergent adverse events (AEs) of any grade, from the safety cohort of 94 patients, included nausea (45%), febrile neutropenia (38%), diarrhea (35%), vomiting (31%), differentiation syndrome (28%), hypokalemia (28%), epistaxis (27%), and QTc prolongation (26%), a known toxicity of the drug.

Grade ≥3 treatment-emergent AEs occurred in 92% of patients and included febrile neutropenia (37%), anemia (18%), decreased neutrophils and white blood cell counts (16%), differentiation syndrome (16%), decreased platelets (15%), QTc prolongation (14%), sepsis (12%), and hypokalemia (11%).

Few patients (6%) discontinued revumenib due to treatment-related AEs, said Aldoss, and none discontinued due to differentiation syndrome, QTc prolongation, or cytopenias.

The QTc prolongation rate is moderate, said Choi, but patients will need to be monitored for other concurrent QTc-prolonging medications.

Other ongoing studies are testing revumenib with chemotherapy for relapsed or refractory leukemia (, ), and a planned study will evaluate revumenib in combination with standard treatment for newly diagnosed disease () as well.

"The nice thing about revumenib is the toxicity doesn't overlap with the standard chemotherapy toxicity," said Aldoss.

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