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Precautions of Revumenib

Differentiation Syndrome

Revumenib may cause fatal or life-threatening differentiation syndrome (DS). Symptoms of DS include fever, dyspnea, hypoxemia, peripheral edema, pericardial or pleural effusion, acute renal failure, rash, and/or hypotension, which have been observed in patients receiving revumenib treatment.

In clinical trials, among 241 patients with relapsed or refractory acute leukemia who received revumenib at the recommended dose, 60 cases (25%) developed DS. Among patients with KMT2A translocation, the incidence of DS was 33% in patients with acute myeloid leukemia (AML), 33% in patients with mixed phenotype acute leukemia (MPAL), and 9% in patients with acute lymphoblastic leukemia (ALL); the incidence of DS was 18% in patients with NPM1-mutated AML. Grade 3 or 4 DS occurred in 12% of patients, including 2 fatal cases. The median time to the first onset of DS was 9 days (range: 3–41 days). Some patients experienced more than one episode of DS. Treatment interruption was required in 7% of patients, and permanent treatment discontinuation was needed in 1% of patients.

Leukocyte count should be reduced to below 25×10⁹/L prior to the initiation of revumenib treatment. If DS is suspected, systemic corticosteroid therapy should be initiated immediately (e.g., dexamethasone 10 mg intravenously every 12 hours for adults; or dexamethasone 0.25 mg/kg per dose intravenously every 12 hours for pediatric patients weighing less than 40 kg) for at least 3 days until signs and symptoms resolve. Supportive measures and hemodynamic monitoring should be implemented until clinical improvement. If severe signs and/or symptoms persist for more than 48 hours after the initiation of systemic corticosteroid therapy, or if life-threatening symptoms (e.g., pulmonary symptoms requiring ventilator support) occur earlier, revumenib treatment should be interrupted. If DS recurs after corticosteroid dose reduction, steroid therapy should be restarted immediately.

QTc Prolongation and Torsades de Pointes

Revumenib may cause QT (QTc) interval prolongation and torsades de pointes.

In clinical trials, among 241 patients with relapsed or refractory acute leukemia who received revumenib at the recommended dose, 86 cases (36%) reported QTc interval prolongation as an adverse reaction. Grade 3 QTc interval prolongation occurred in 15% of patients and grade 4 in 2%. Ten percent of patients had a Fridericia-corrected QT interval (QTcF) exceeding 500 milliseconds, and 24% had a QTcF increase of more than 60 milliseconds from baseline. Dose reduction of revumenib due to QTc interval prolongation was required in 7% of patients. QTc prolongation occurred in 21% of 34 patients under 17 years of age, 35% of 146 patients aged 17 to less than 65 years, and 46% of 61 patients aged 65 years or older. One patient died due to cardiac arrest, and one patient developed non-sustained torsades de pointes.

Electrolyte abnormalities, including hypokalemia and hypomagnesemia, should be corrected before the initiation of revumenib treatment and throughout the treatment course. An electrocardiogram (ECG) should be performed prior to starting revumenib; treatment should not be initiated in patients with a QTcF > 450 milliseconds. ECG monitoring should be conducted at least once weekly during the first 4 weeks of treatment, and at least once monthly thereafter. More frequent ECG monitoring may be necessary for patients with congenital long QT syndrome, congestive heart failure, electrolyte abnormalities, or those taking concomitant medications known to prolong the QTc interval. Concomitant use with drugs known to prolong the QTc interval may increase the risk of QTc interval prolongation.

If QTcF increases to > 480 milliseconds but < 500 milliseconds, revumenib treatment should be interrupted; treatment may be restarted at the same dose twice daily once QTcF returns to ≤ 480 milliseconds.

If QTcF increases to > 500 milliseconds or by > 60 milliseconds from baseline, revumenib treatment should be interrupted; treatment may be restarted at a lower dose level twice daily once QTcF returns to ≤ 480 milliseconds.

Permanent discontinuation of revumenib is recommended for patients who develop ventricular arrhythmias, as well as those who experience QTc interval prolongation accompanied by signs or symptoms of life-threatening arrhythmias.

Embryo-Fetal Toxicity

Revumenib may cause fetal harm when administered to pregnant women. Pregnant women should be informed of the potential risk to the fetus. Females of reproductive potential and males with female partners of reproductive potential should be advised to use effective contraception during revumenib treatment and for 4 months after the last dose.

FDA，2025.10