FDA approves revumenib for select acute leukemias with KMT2A defect
Called Revuforj, oral therapy for children and adults with AML, ALL, and MPAL
The U.S. Food and Drug Administration (FDA) has approved revumenib, now called Revuforj, as an oral therapy for children and adults, ages 1 year and older, with hard-to-treat acute leukemias caused by a KMT2A gene translocation.
Syndax, the therapy’s developer, expects that tablets of Revuforj (110 mg and 160 mg) will be available in the U.S. this month. The company also anticipates 25 mg tablets being available by mid-2025 for patients weighing less than 40 kg (about 88 pounds). Until then, these patients can acquire an oral solution of Revuforj through an expanded access program.
“The approval of Revuforj is a remarkable achievement that reflects the dedication and tenacity of everyone involved, especially the patients and clinicians who participated in our trial,” Michael A. Metzger, CEO of Syndax, said in a company press release.
Acute leukemias with this gene translocation can be difficult to treat
Acute leukemias are caused by genetic defects in hematopoietic stem cells that give rise to all types of blood cells, and they are marked by the rapid growth of abnormal blood cells. Acute leukemia types include acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and mixed-phenotype acute leukemia (MPAL).
Some adults and many children with acute leukemias have a KMT2A translocation, a type of DNA rearrangement that occurs when part of one chromosome breaks and joins a different chromosome.
Acute leukemias with this defect can be resistant to treatment (refractory) and are associated with poor outcomes, the company noted. For example, more than half of patients with KMT2A acute leukemias will relapse after receiving conventional first-line therapies, with a median survival of less than one year. With three or more lines of treatment, median survival is less than three months, and 5% achieve complete remission.
KMT2A translocation leads to the abnormal production of proteins that bind to a protein called menin, driving the development of blood cancer.
Revuforj is designed to block the interaction between KMT2A-encoded proteins and menin, intending to slow the development of associated acute leukemias.
“The FDA approval of the first menin inhibitor is a major breakthrough for patients with  R/R [relapse/refractory] acute leukemia with a KMT2A translocation, a genetic alteration associated with a very poor prognosis,” said Ghayas C. Issa, MD, an associate professor of leukemia at the University of Texas MD Anderson Cancer Center.
21% of patients in clinical trial achieved complete cancer remission
Approval was based on an analysis of 104 patients with relapsed or refractory acute leukemia with a KMT2A defect participating in the ongoing Phase 1/2 AUGMENT-101 trial (NCT04065399). All enrolled had either AML, ALL, or MPAL.
Data showed that 22 patients (21%) achieved complete remission or complete remission with partial blood cell recovery. The median time to either outcome was 1.9 months, and the median duration of these effects was 6.4 months.
Following treatment, 24 patients (23%) underwent hematopoietic stem cell transplantation (HSCT), a procedure that replaces cancer cells with healthy blood cells.
These findings were consistent with a previous Phase 2 interim analysis of 57 KMT2A acute leukemia patients, including 13 children, treated with Revuforj in the AUGMENT-101 trial. The analysis recently was published in the Journal of Clinical Oncology.
“The significant clinical benefit and robust efficacy seen with Revuforj represents a substantial improvement over what has been historically observed in these patients with previously available therapies and has the potential to be an important new treatment option for patients,” Issa said.
Revuforj’s safety data was based on 135 KMT2A acute leukemia patients treated in AUGMENT-101. The most common adverse reactions, those in at least 20% of patients, included bleeding, nausea, muscle pain, infection, elevations in liver enzymes, fever with a low immune neutrophil count, diarrhea, decreased appetite, constipation, and fatigue. Adverse reactions leading to a dose reduction occurred in 10% of patients, and treatment discontinuation in 12%.
The treatment’s FDA label also carries a boxed warning for differentiation syndrome, a group of severe reactions to drugs used to treat two kinds of acute leukemia, AML and acute promyelocytic leukemia.
Revuforj tablets are to be taken twice daily without food or while eating a low-fat meal, the label states.
Revuforj also being tested for AML due to an abnormal NPM1 protein
AUGMENT-101 also included people with hard-to-treat AML associated with a gene mutation causing an abnormal form of the NPM1 protein. Recent top-line data showed similar response rates (23%) to Revuforj as those with KMT2A acute leukemia, as reported in a separate company press release. Additional trials testing Revuforj in combination with standard-of-care in KMT2A acute leukemia and mutant NPM1 AML patients, including those newly diagnosed, are ongoing.
“We are well-prepared to launch Revuforj this month and we are committed to rapidly advancing the development of Revuforj across the treatment continuum for KMT2A-rearranged acute leukemias and mutant NPM1 AML,” Metzger said.
The FDA previously granted breakthrough designations to revumenib for treating adults and children with hard-to-treat acute leukemia harboring a KMT2A rearrangement. It also granted fast track status for the same induction and mutant NPM1 AML, as well as orphan drug designation for treating AML, ALL, and acute leukemias of ambiguous lineage. These designations, overall, help to speed the development and approval consideration of investigational therapies.
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