R/R NPM1-mutated AML: a closer look
As a key driver mutation, NPM1 mutations directly contribute to the development and progression of acute myeloid leukemia (AML)1-3
-
NPM1 mutations are the most common genetic alteration in newly diagnosed AML, making it the largest AML subgroup in adults3
-
NPM1m AML is associated with poor outcomes following relapse1,4,5
~1 in 3
adults
with AML have
an NPM1
mutation4
Detection of NPM1 mutations at AML diagnosis4,6,7:
Patient
population
AML cases
Adult
~30%
Pediatric
~6%-8%
Several clinical challenges exist when treating
NPM1m AML in the R/R setting
50%
After 1L therapy, ~50% of
adults eventually relapse or
die of progressive disease1,4,5
Limited options for older and/or
high-risk patients who are unfit
for intensive chemotherapy1,4,5,9
1
YEAR
Most patients relapse within
1 year of their first remission8*
1
YEAR
Most patients relapse within
1 year of their first remission8*
Limited options for older and/or
high-risk patients who are unfit
for intensive chemotherapy1,4,5,9
As a heterogeneous disease,
specific co-mutations can further
contribute to a poor prognosis1,5
*Based on a retrospective analysis of relapsing patients with NPM1m AML (n=30/44).
NPM1 mutations are an actionable target in R/R AML
Detecting NPM1 mutations can help optimize use of treatment options and determine a specific course of action10
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)
recommend expedited testing for NPM1 mutations as part of the AML diagnostic workup, with repeat testing at each relapse or progression10
NCCN=National Comprehensive Cancer Network®; NPM1m=mutant nucleophosmin 1; R/R=relapsed/refractory.
R/R KMT2Ar acute leukemia: an urgent clinical need
Acute leukemia with a KMT2A rearrangement (KMT2Ar), including
translocations, are aggressive diseases associated with a poor
prognosis and high relapse rates. KMT2Ar acute leukemia is also
known as “mixed-lineage leukemia rearranged” or MLLr.11,12
-
Rearrangements (including translocations) of the KMT2A gene can occur in AML, ALL, and mixed-phenotype acute leukemia (MPAL) across multiple age groups11
-
The median age at diagnosis for KMT2Ar AML is 52 years—much lower than for AML in general (68 years)13,14
~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 chromosome17
Detection of KMT2Ar at acute leukemia diagnosis11,15,16:
Patient population
AML
cases
ALL
cases
Infant
~35%-60%
~80%
Pediatric
~10%-15%
~5%-6%
Adult
~5%-10%
~5%-15%
KMT2Ar AML rapidly progresses and has high
rates of resistance and relapse13
Based on a recent retrospective analysis13:
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
KMT2A translocations are an actionable target in R/R acute leukemia
-
Early identification of KMT2A translocations is critical given the rapid onset and quick progression of KMT2A-translocated acute leukemia13,18
-
Detecting KMT2A translocations may help optimize use of treatment options and determine a specific course of action
Find information on FDA-authorized tests for the detection
of a KMT2A translocation to determine eligibility for treatment
ALL=acute lymphoblastic leukemia; AML=acute myeloid leukemia; CR=complete remission; CRi=complete remission with incomplete
hematological recovery; KMT2Ar=lysine methyltransferase 2A rearranged; R/R=relapsed/refractory.
Menin-KMT2A complexes: a key driver
NPM1m AML and KMT2A-translocated AML/ALL/MPAL are
acute leukemia subtypes that share a common dependency on the
menin-KMT2A interaction11,19
Menin is a scaffold protein that regulates gene expression, including HOX and MEIS1 genes,
through interactions with transcription factors and chromatin regulators11
-
HOX and MEIS1 are stem cell genes essential for normal hematopoietic development, and play a critical role in leukemia as key regulatory transcription factors linked to cell proliferation and differentiation
NPM1 mutations behave as gatekeepers for leukemogenesis via the menin pathway1,20
In NPM1m AML, menin interacts with wild-type KMT2A21
KMT2A translocations lead to the production of oncogenic fusion proteins that bind with menin17,22,23
In KMT2A-translocated acute leukemia, menin interacts with KMT2A fusion proteins21
Menin-KMT2A interactions:
activation
of a leukemogenic
transcriptional pathway21
Menin-KMT2A interactions have
been shown to1,2,11:
Upregulate HOX/MEIS1 gene expression
Block
hematopoietic cell
differentiation
Increase proliferation
of undifferentiated cells
(leukemogenesis)
The binding of menin with wild-type KMT2A or KMT2A fusion proteins is involved in driving NPM1m AML and KMT2A-translocated acute leukemias, respectively21
ALL=acute lymphoblastic leukemia; AML=acute myeloid leukemia; HOX=homeobox; KMT2A=lysine methyltransferase 2A; KMT2Ar=lysine methyltransferase 2A rearranged; MEIS1=MEIS homeobox-1; MPAL=mixed-phenotype acute leukemia; NPM1m=mutant nucleophosmin 1; R/R=relapsed/refractory.
References: 1. Arellano ML, et al. Blood. 2025;146(9):1065-1077. 2. Uckelmann HJ, et al. Cancer Discov. 2023;13(3):746-765. 3. Falini B, Dillion R. Blood Cancer Discov. 2024;5(1):8-20. 4. Ranieri R, et al. Leukemia. 2022;36(10):2351-2367. 5. Wang R, et al. Front Oncol. 2022;12:972606. 6. Pession A, et al. Blood. 2013;122(2):170-178. 7. Xu LH, et al. Blood Cancer J. 2020;10(1):1. 8. Issa GC, et al. Blood Adv. 2023;7(6):933-942. 9. Candoni A, Coppola G. Hematol Rep. 2024;16(2):244-254. 10. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute Myeloid Leukemia V.3.2026. © National Comprehensive Cancer Network, Inc. 2025. All rights reserved. Accessed January 6, 2026. To view the most recent and complete version of the guideline, go online to NCCN.org. 11. Issa GC, et al. Leukemia. 2021;35:2482-2495. 12. Issa GC, et al. J Clin Oncol. 2025;43(1):75-84. 13. Issa GC, et al. Blood Cancer J. 2021;11:162. 14. Appelbaum FR, et al. Blood. 2006;107:3481-3485. 15. Conneely SE, Rau RE. Cancer Metastasis Rev. 2020;39(1):189-209. 16. Górecki M, et al. Biomedicines. 2023;11:821. 17. Meyer C, et al. Leukemia. 2023;37:988-1005. 18. Nguyen D, et al. Cancer. 2023;129(12):1856-1865. 19. Kühn MWM, et al. Cancer Discov. 2016;6:1166-1181. 20. Sharma N, Liesveld JL. Cancers. 2023;15(4):1177. 21. Revuforj® [Prescribing Information]. Syndax Pharmaceuticals, Inc.; October 2025. 22. Kristov AV, et al. Cancer Cell. 2019;36:660-673.e11. 23. Li X, Song Y. J Hematol Oncol. 2021;14:56.
WARNING: DIFFERENTIATION SYNDROME, QTc PROLONGATION, AND TORSADES DE POINTES
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.
QTc prolongation and Torsades de Pointes have occurred in patients receiving Revuforj. Correct hypokalemia and hypomagnesemia prior to and during treatment. Do not initiate Revuforj in patients with QTcF >450 msec. If QTc interval prolongation occurs, interrupt, reduce, or permanently discontinue Revuforj.
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, rash, and/or hypotension.
In clinical trials, DS occurred in 60 (25%) of 241 patients treated with Revuforj at the recommended dosage for relapsed or refractory acute leukemia. Among those with a KMT2A translocation, DS occurred in 33% of patients with acute myeloid leukemia (AML), 33% of patients with mixed-phenotype acute leukemia (MPAL), and 9% of patients with acute lymphoblastic leukemia (ALL); DS occurred in 18% of patients with NPM1m AML. DS was Grade 3 or 4 in 12% of patients and fatal in 2 patients. The median time to initial onset was 9 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 and Torsades de Pointes: Revuforj can cause QT (QTc) interval prolongation and Torsades de Pointes.
Of the 241 patients treated with Revuforj at the recommended dosage for relapsed or refractory acute leukemia in clinical trials, QTc interval prolongation was reported as an adverse reaction in 86 (36%) patients. QTc interval prolongation was Grade 3 in 15% and Grade 4 in 2%. The heart-rate corrected QT interval (using Fridericia’s method) (QTcF) was greater than 500 msec in 10%, and the increase from baseline QTcF was greater than 60 msec in 24%. Revuforj dose reduction was required for 7% due to QTc interval prolongation. QTc prolongation occurred in 21% of the 34 patients less than 17 years old, 35% of the 146 patients 17 years to less than 65 years old, and 46% of the 61 patients 65 years or older. One patient had a fatal outcome of cardiac arrest, and one patient had non-sustained Torsades de Pointes.
Correct electrolyte abnormalities, including hypokalemia and hypomagnesemia, prior to and throughout 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 9 (4%) patients who received Revuforj, including 4 with sudden death, 2 with differentiation syndrome, 2 with hemorrhage, and 1 with cardiac arrest.
Serious adverse reactions were reported in 184 (76%) patients. The most frequent serious adverse reactions (≥10%) were infection (29%), febrile neutropenia (20%), bacterial infection (15%), differentiation syndrome (13%), and hemorrhage (11%).
The most common adverse reactions (≥20%) including laboratory abnormalities, were phosphate increased (51%), hemorrhage (48%), nausea (48%), infection without identified pathogen (46%), aspartate aminotransferase increased (44%), alanine aminotransferase increased (40%), creatinine increased (38%), musculoskeletal pain (37%), febrile neutropenia (37%), electrocardiogram QT prolonged (36%), potassium decreased (34%), parathyroid hormone intact increased (34%), alkaline phosphatase increased (33%), diarrhea (29%), bacterial infection (27%), triglycerides increased (27%), phosphate decreased (25%), differentiation syndrome (25%), fatigue (24%), edema (24%), viral infection (23%), decreased appetite (20%), and constipation (20%).
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
SPECIFIC 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.
Infertility: based on findings in animals, Revuforj may impair fertility. The effects on fertility were reversible.
Pediatric: monitor bone growth and development in pediatric patients.
Geriatric: no overall differences were observed in the effectiveness of Revuforj between patients who were 65 years and older, and younger patients. Compared to younger patients, the incidences of QTc prolongation and edema were higher in patients 65 years and older.
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.
INDICATIONS
Revuforj® (revumenib) is a menin inhibitor indicated for the treatment of:
-
relapsed or refractory (R/R) acute leukemia with a lysine methyltransferase 2A gene (KMT2A) translocation as determined by an FDA-authorized test in adult and pediatric patients 1 year and older
-
relapsed or refractory acute myeloid leukemia (AML) with a susceptible nucleophosmin 1 (NPM1) mutation in adult and pediatric patients 1 year and older who have no satisfactory alternative treatment options
Please see Full Prescribing Information, including BOXED WARNINGS.
WARNING: DIFFERENTIATION
SYNDROME, QTc
PROLONGATION, AND
TORSADES DE POINTES
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.