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Full Prescribing Information

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Important Safety Information

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Revuforj is a menin inhibitor indicated for the treatment of relapsed or refractory acute leukemia with a
lysine methyltransferase 2A gene (KMT2A) translocation in adult and pediatric patients 1 year and older.

R/R KMT2Ar AML & ALL

R/R KMT2Ar acute leukemia: an urgent clinical need for targeted therapy

Acute leukemias with a KMT2A rearrangement (KMT2Ar), including translocations, are aggressive diseases associated with a very poor prognosis and high relapse rates. KMT2Ar acute leukemia is also known as “mixed-lineage leukemia rearranged” or MLLr.1

  • Rearrangements (including translocations) of the KMT2A gene can occur in AML, ALL, and mixed-phenotype acute leukemia (MPAL) across multiple age groups1

  • The median age at diagnosis for KMT2Ar AML is 52 years—much lower than for AML in general (68 years)2,3

Detection of KMT2Ar at acute leukemia diagnosis:

Patient
population

AML cases1,4

ALL cases1,5

Baby icon

Infant

~35%-60%

~80%

Child icon

Pediatric

~10%-15%

~5%-6%

Adult icon

Adult

~5%-10%

~5%-15%

KMT2Ar is detected in ~8% of adult MPAL cases1

KMT2Ar AML rapidly progresses and has high
rates of resistance and relapse2:

82%

RELAPSE

Up to 82% of adult patients
relapse within the first year
following second-line therapy

9%

CR + CRi

Only 9% of adult patients
achieve CR or CRi following
third-line or later therapy

ALL=acute lymphoblastic leukemia; AML=acute myeloid leukemia; CR=complete remission; CRi=complete remission with incomplete hematologic recovery; KMT2Ar=lysine methyltransferase 2A rearranged; R/R=relapsed/refractory.

KMT2A translocations: an actionable biomarker in R/R disease

Early identification of KMT2A gene rearrangements is critical given the rapid onset and quick progression of KMT2Ar AML and ALL2,6

  • Request and confirm with your pathologist that KMT2Ar is included when testing at diagnosis and relapse

  • Detecting KMT2Ar, particularly KMT2A translocations, can help determine a specific course of action and identify R/R patients who may benefit from a targeted treatment

    • ~95% of patients with KMT2Ar acute leukemia have a KMT2A translocation, a type of rearrangement that occurs when part of one chromosome breaks and fuses to a different chromosome7

KMT2Ar dectection in AML & ALL

KMT2A rearrangements can be detected by standard cytogenetic testing, such as fluorescence in situ hybridization (FISH), and may appear as1,2:

KMT2Ar

MLLr

11q23

A reliance on menin-KMT2A complexes1

  • KMT2Ar AML and ALL are dependent on menin interactions with KMT2A (MLL1) fusion proteins

Common translocations and oncogenic fusion partners involved in driving KMT2Ar acute leukemia (AML, ALL, and MPAL)1,2,7:

Alteration

KMT2A translocations may appear as:

KMT2Ar
(KMT2A rearranged)

MLLr
(mixed-lineage
leukemia rearranged)

11q23
chromosomal
translocations affecting
the KMT2A (MLL) gene

Cytogenetic
abnormality

t(9;11)(p21;q23)

t(6;11)(q27;q23)

t(11;19)(q23;p13.1)

t(11;19)(q23;p13.3)

t(11;19)(q23;p13)

t(10;11)(p12;q23)

t(4;11)(q21;q23)

Common
fusion genes

KMT2A-MLLT3

KMT2A-MLLT4

KMT2A-ELL

KMT2A–MLLT1

KMT2A-EEN

KMT2A-MLLT10

KMT2A-MLLT2

The following are NOT a KMT2A translocation:

KMT2A partial tandem duplication (KMT2A-PTD), KMT2A deletion, and KMT2A amplification

Revuforj is the first and only FDA-approved menin inhibitor for the treatment of adult and pediatric patients 1 year and older with any lineage of relapsed/refractory acute leukemia with a KMT2A translocation

NEXT: MOA

ALL=acute lymphoblastic leukemia; AML=acute myeloid leukemia; KMT2A=lysine methyltransferase 2A; KMT2Ar=lysine methyltransferase 2A rearranged; MLL1=mixed-lineage leukemia protein-1; MPAL=mixed-phenotype acute leukemia; R/R=relapsed/
refractory.

References: 1. Issa GC, et al. Leukemia. 2021;35:2482-2495. 2. Issa GC, et al. Blood Cancer J. 2021;11:162. 3. Appelbaum FR, et al. Blood. 2006;107:3481-3485.
4. Conneely SE, Rau RE. Cancer Metastasis Rev. 2020;39(1):189-209. 5. Górecki M, et al. Biomedicines. 2023;11:821. 6. Nguyen D, et al. Cancer. 2023;129(12):1856-1865. 7. Meyer C, et al. Leukemia. 2023;37:988-1005.

IMPORTANT SAFETY
INFORMATION AND INDICATION

WARNING: DIFFERENTIATION SYNDROME

Differentiation syndrome, which can be fatal, has occurred with Revuforj. Signs and symptoms may include fever, dyspnea, hypoxia, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, hypotension, and renal dysfunction. If differentiation syndrome is suspected, immediately initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution.

WARNINGS AND PRECAUTIONS

Differentiation syndrome: Revuforj can cause fatal or life-threatening differentiation syndrome (DS). Symptoms of DS, including those seen in patients treated with Revuforj, include fever, dyspnea, hypoxia, peripheral edema, pleuropericardial effusion, acute renal failure, and/or hypotension. In clinical trials, DS occurred in 39 (29%) of 135 patients treated with Revuforj. DS was Grade 3 or 4 in 13% of patients and fatal in one. The median time to onset was 10 days (range 3-41 days). Some patients experienced more than 1 DS event. Treatment interruption was required for 7% of patients, and treatment was withdrawn for 1%.


Reduce the white blood cell count to less than 25 Gi/L prior to starting Revuforj. If DS is suspected, immediately initiate treatment with systemic corticosteroids (e.g., dexamethasone 10-mg IV every 12 hours in adults or dexamethasone 0.25-mg/kg/dose IV every 12 hours in pediatric patients weighing less than 40 kg) for a minimum of 3 days and until resolution of signs and symptoms. Institute supportive measures and hemodynamic monitoring until improvement. Interrupt Revuforj if severe signs and/or symptoms persist for more than 48 hours after initiation of systemic corticosteroids, or earlier if life-threatening symptoms occur such as pulmonary symptoms requiring ventilator support. Restart steroids promptly if DS recurs after tapering corticosteroids.


QTc interval prolongation: In the clinical trials, QTc interval prolongation was reported as an adverse reaction in 39 (29%) of 135 patients treated with Revuforj. QTc interval prolongation was Grade 3 in 12% of patients. The heart-rate corrected QT interval (using Fridericia’s method) (QTcF) was greater than 500 msec in 8%, and the increase from baseline QTcF was greater than 60 msec in 18%. Revuforj dose reduction was required for 5% of patients due to QTc interval prolongation. QTc prolongation occurred in 16% of the 31 patients less than 17 years old, 33% of the 88 patients 17 years to less than 65 years old, and in 50% of the 16 patients 65 years or older.


Correct electrolyte abnormalities, including hypokalemia and hypomagnesemia, prior to treatment with Revuforj. Perform an electrocardiogram (ECG) prior to initiation of Revuforj, and do not initiate Revuforj in patients with QTcF >450 msec. Perform an ECG at least once weekly for the first 4 weeks and at least monthly thereafter. In patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval, more frequent ECG monitoring may be necessary. Concomitant use with drugs known to prolong the QTc interval may increase the risk of QTc interval prolongation.

  • Interrupt Revuforj if QTcF increases >480 msec and <500 msec, and restart Revuforj at the same dose twice daily after the QTcF interval returns to ≤480 msec
  • Interrupt Revuforj if QTcF increases >500 msec or by >60 msec from baseline, and restart Revuforj twice daily at the lower-dose level after the QTcF interval returns to ≤480 msec
  • Permanently discontinue Revuforj in patients with ventricular arrhythmias and in those who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia

Embryo-fetal toxicity: Revuforj can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with Revuforj and for 4 months after the last dose of Revuforj.


ADVERSE REACTIONS

Fatal adverse reactions occurred in 4 (3%) patients who received Revuforj, including 2 with differentiation syndrome, 1 with hemorrhage, and 1 with sudden death.


Serious adverse reactions were reported in 99 (73%) patients. The most frequent serious adverse reactions (≥5%) were infection (24%), febrile neutropenia (19%), bacterial infection (17%), differentiation syndrome (12%), hemorrhage (9%), and thrombosis (5%).


The most common adverse reactions (≥20%) including laboratory abnormalities, were hemorrhage (53%), nausea (51%), phosphate increased (50%), musculoskeletal pain (42%), infection (41%), aspartate aminotransferase increased (37%), febrile neutropenia (35%), alanine aminotransferase increased (33%), parathyroid hormone intact increased (33%), bacterial infection (31%), diarrhea (30%), differentiation syndrome (29%), electrocardiogram QT prolonged (29%), phosphate decreased (25%), triglycerides increased (25%), potassium decreased (24%), decreased appetite (24%), constipation (23%), edema (23%), viral infection (23%), fatigue (22%), and alkaline phosphatase increased (21%).


DRUG INTERACTIONS

Drug interactions can occur when Revuforj is concomitantly used with:

  • Strong CYP3A4 inhibitors: reduce Revuforj dose

  • Strong or moderate CYP3A4 inducers: avoid concomitant use with Revuforj

  • QTc-prolonging drugs: avoid concomitant use with Revuforj. If concomitant use is unavoidable, obtain ECGs when initiating, during concomitant use, and as clinically indicated. Withhold Revuforj if the QTc interval is >480 msec.
    Restart Revuforj after the QTc interval returns to ≤480 msec


SPECIAL POPULATIONS

Lactation: advise lactating women not to breastfeed during treatment with Revuforj and for 1 week after the last dose.


Pregnancy and testing: Revuforj can cause fetal harm when administered to a pregnant woman. Verify pregnancy status in females of reproductive potential within 7 days prior to initiating Revuforj.


Pediatric: monitor bone growth and development in pediatric patients.


Geriatric: compared to younger patients, the incidences of QTc prolongation and edema were higher in patients 65 years and older.


Infertility: based on findings in animals, Revuforj may impair fertility. The effects on fertility were reversible.


To report SUSPECTED ADVERSE REACTIONS, contact Syndax Pharmaceuticals at 1-888-539-3REV or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.


INDICATION

Revuforj® (revumenib) is a menin inhibitor indicated for the treatment of relapsed or refractory acute leukemia with a lysine methyltransferase 2A gene (KMT2A) translocation in adult and pediatric patients 1 year and older.


Please see Full Prescribing Information, including BOXED WARNING.

IMPORTANT SAFETY
INFORMATION AND INDICATION

IMPORTANT SAFETY
INFORMATION AND INDICATION

WARNING: DIFFERENTIATION SYNDROME

Differentiation syndrome, which can be fatal, has occurred with Revuforj. Signs and symptoms may include fever, dyspnea, hypoxia, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, hypotension, and renal dysfunction. If differentiation syndrome is suspected, immediately initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution.