Revumenib (Revuforj®): A Comprehensive Monograph on the First-in-Class Menin Inhibitor for the Treatment of Acute Leukemias

I. Executive Summary

Revumenib, marketed under the brand name Revuforj®, is a first-in-class, orally bioavailable, small-molecule antineoplastic agent that functions as a potent and selective menin inhibitor.[1] Its development marks a significant advancement in the targeted therapy of acute leukemias characterized by specific genetic alterations. The drug is designed to disrupt the critical protein-protein interaction between menin and the lysine methyltransferase 2A (KMT2A, also known as MLL) protein or its oncogenic fusion variants. This interaction is a key driver of leukemogenesis in acute leukemias harboring

KMT2A gene rearrangements (KMT2Ar) or mutations in the nucleophosmin 1 (NPM1) gene (NPM1m).[1]

On November 15, 2024, the U.S. Food and Drug Administration (FDA) granted approval to Revumenib for the treatment of adult and pediatric patients aged one year and older with relapsed or refractory (R/R) acute leukemia featuring a KMT2A translocation.[7] This regulatory milestone was based on the compelling efficacy and safety data from the pivotal Phase I/II AUGMENT-101 clinical trial. In a heavily pretreated population of patients with KMT2Ar acute leukemia, Revumenib monotherapy demonstrated clinically meaningful and durable responses. The trial met its primary endpoint with a complete remission (CR) plus CR with partial hematologic recovery (CR+CRh) rate of 21.2% and an overall response rate (ORR) exceeding 60%.[10]

The safety profile of Revumenib is considered manageable, though it includes significant risks that require careful clinical oversight. The drug's prescribing information includes a boxed warning for Differentiation Syndrome (DS), a potentially fatal on-target toxicity. Another major risk is QTc interval prolongation, necessitating baseline and routine electrocardiogram (ECG) monitoring.[1]

Revumenib represents a paradigm shift in the treatment of these genetically defined leukemias, moving away from broad cytotoxic chemotherapy towards a targeted, differentiation-based therapeutic strategy. It provides a novel and much-needed option for patients with limited or no effective alternatives and serves as a crucial bridge to potentially curative allogeneic hematopoietic stem cell transplantation (HSCT) for a significant proportion of responders.[12]

II. Introduction: The Menin-KMT2A Axis as a Therapeutic Target in Acute Leukemia

The development of Revumenib is rooted in a deep understanding of the molecular drivers of specific high-risk acute leukemias. For decades, patients with acute leukemias harboring rearrangements of the KMT2A gene have faced a grim prognosis. These genetic aberrations, previously known as mixed-lineage leukemia (MLL) fusions, are present in approximately 5-10% of acute myeloid leukemia (AML) cases and 10% of acute lymphoblastic leukemia (ALL) cases, and are particularly prevalent and aggressive in infant ALL and therapy-related AML.[2] Similarly, while mutations in the

NPM1 gene are often associated with a more favorable prognosis in AML, a substantial number of these patients ultimately relapse, requiring effective salvage therapies.[2] Combined, these two genetic subtypes account for a significant portion of acute leukemias, representing a major unmet clinical need.[2]

At the core of the pathogenesis of these diseases lies a critical dependency on the interaction between the nuclear scaffold protein menin, encoded by the tumor suppressor gene MEN1, and the KMT2A protein or its fusion products.[5] In KMT2Ar leukemias, the N-terminal portion of KMT2A, which contains the menin-binding domain, is fused to one of over 100 different partner proteins.[2] This aberrant fusion protein is recruited by menin to specific chromatin locations, where it drives the transcriptional upregulation of a specific set of leukemogenic genes. The most critical of these are members of the

HOX gene family, particularly HOXA9, and their essential cofactor MEIS1.[1] The sustained, high-level expression of these genes is essential for maintaining hematopoietic stem and progenitor cells in an undifferentiated, self-renewing state. This leads to a profound block in cellular differentiation, locking the cells in a proliferative, blast-like phase and ultimately resulting in overt leukemia.[1] A similar dependency on the menin-KMT2A interaction has also been identified in NPM1-mutated AML.[2]

This deep mechanistic understanding provided a clear therapeutic rationale: disrupting the menin-KMT2A protein-protein interaction could serve as a highly targeted strategy to dismantle the core oncogenic machinery of these leukemias. Preclinical research robustly demonstrated that this interaction was an "Achilles' heel" for these cancer cells. Genetically or pharmacologically preventing menin from binding to KMT2A led to the collapse of the leukemogenic transcriptional program. The expression of HOX and MEIS1 genes was rapidly downregulated, which in turn released the differentiation block.[1] This action forces the malignant blasts to resume their normal maturation process, undergo terminal differentiation, and ultimately enter apoptosis.[5]

This mechanism represents a fundamental departure from the traditional cytotoxic approach to cancer treatment. Rather than aiming to directly kill rapidly dividing cells, the primary goal of menin inhibition is to induce cellular maturation—to effectively "normalize" the malignant cells and push them down their natural developmental path toward senescence and death. This therapeutic philosophy of "differentiation therapy" is not merely a semantic distinction; it directly explains the most significant and unique on-target toxicity associated with Revumenib. The very process that drives its therapeutic efficacy—the rapid and widespread differentiation of leukemic cells—can, when overly robust, manifest as the life-threatening complication known as Differentiation Syndrome.[1] This direct link between the desired mechanism and a key toxicity is a defining characteristic of highly specific targeted agents and presents a distinct set of clinical management challenges compared to conventional chemotherapy. Revumenib (formerly SNDX-5613) was engineered as a potent, selective, and orally bioavailable small molecule designed to precisely fit into the menin binding pocket, thereby physically displacing the KMT2A protein and disrupting the oncogenic complex.[6] Its successful clinical development serves as a landmark proof-of-concept for targeting this specific protein-protein interaction in oncology.

III. Drug Identification and Physicochemical Properties

Revumenib is a synthetic organic small molecule with a complex chemical structure. Its identity is defined by a range of nomenclature, registry numbers, and structural identifiers that are essential for its precise characterization in research, clinical, and regulatory contexts.

Nomenclature and Classification

• [Generic Name]: Revumenib [8]
• [Brand Name]: Revuforj® [8]
• [Developmental Code Name]: SNDX-5613 [18]
• [Drug Type]: Small Molecule [4]
• [Pharmacological Class]: Antineoplastic Agent; Menin Inhibitor; Protein-Protein Interaction Inhibitor [3]

Chemical and Structural Data

The primary active form of the drug is the free base, though various salt forms have been developed for research and formulation purposes.

• [Chemical Formula]: C32​H47​FN6​O4​S [18]
• [Molecular Weight]: 630.82 g/mol [18]
• [IUPAC Name]: N-ethyl-2-[7-[[4-(ethylsulfonylamino)cyclohexyl]methyl]-2,7-diazaspiro[3.5]nonan-2-yl]pyrimidin-5-yl]oxy-5-fluoro-N-propan-2-ylbenzamide [19]
• [SMILES Notation]: CCN(C(C)C)C(=O)c1cc(F)ccc1Oc1cncnc1N1CC2(C1)CCN(C[C@H]1CC[C@@H](CC1)NS(=O)(=O)CC)CC2 [18]
• [International Chemical Identifier (InChI) Key]: FRVSRBKUQZKTOW-YOCNBXQISA-N [19]

Physical and Chemical Properties

• [Solubility]: Revumenib is soluble in organic solvents such as dimethyl sulfoxide (DMSO) and ethanol.[19]
• [Storage]: For long-term stability, it is recommended to be stored at -20 °C, protected from light and moisture.[19]

Table 1 below provides a consolidated list of key identifiers for Revumenib across various chemical and drug databases.

Table 1: Revumenib Key Identifiers and Chemical Properties
Identifier Type	Value(s)
CAS Number	2169919-21-3 (free base) 18
DrugBank ID	DB18515 20
PubChem CID	132212657 20
UNII (FDA)	LZ0M43NNF2 (free base) 20
ChEMBL ID	ChEMBL4650827 20
KEGG ID	D12728 20
ChemSpider ID	95502909 20
Molecular Formula	C32​H47​FN6​O4​S 18
Molecular Weight	630.82 g/mol 18
Topological Polar Surface Area	116.35 Ų 23
XLogP3	4.69 23

IV. Mechanism of Action and Preclinical Pharmacology

Revumenib exerts its antineoplastic effects through a highly specific and targeted molecular mechanism, functioning as a best-in-class inhibitor of a critical protein-protein interaction that drives leukemogenesis.

Molecular Target and Binding Affinity

The primary molecular target of Revumenib is the nuclear scaffold protein menin.[4] It is not an enzyme inhibitor but rather a protein-protein interaction (PPI) inhibitor. It was specifically designed to bind with high affinity and selectivity to a hydrophobic pocket on the surface of menin that is normally occupied by the N-terminal region of the KMT2A protein (or its fusion variants).[6] Preclinical biochemical assays have quantified this potent interaction, demonstrating a binding affinity constant (

Ki​) of 0.149 nM.[18] In cell-based assays, Revumenib effectively disrupts the menin-KMT2A complex with a half-maximal inhibitory concentration (

IC50​) in the low nanomolar range, typically between 10 and 20 nM.[18]

Downstream Signaling and Cellular Effects

The therapeutic action of Revumenib is a direct consequence of its ability to disrupt the menin-KMT2A complex. The downstream cascade of events proceeds as follows:

1. [Disruption of the Oncogenic Complex]: In KMT2Ar or NPM1m leukemia cells, the menin-KMT2A complex is essential for tethering the KMT2A fusion protein to chromatin at specific gene loci, most notably the promoters of HOX genes (e.g., HOXA9, HOXA10) and their cofactor MEIS1.[1]
2. [Transcriptional Reprogramming]: By binding to menin, Revumenib physically displaces the KMT2A fusion protein from the complex.[1] This prevents the recruitment of the transcriptional machinery required for HOX and MEIS1 gene expression, leading to their rapid and significant downregulation.[1]
3. [Release of Differentiation Block]: The sustained overexpression of HOX and MEIS1 is what maintains the leukemic cells in an immature, blast-like state. The downregulation of these key oncogenic drivers effectively "switches off" the leukemic program, thereby releasing the block on hematopoietic differentiation.[1]
4. [Induction of Maturation and Apoptosis]: Freed from the differentiation arrest, the leukemic blasts are induced to undergo terminal myeloid differentiation. This process of maturation is incompatible with uncontrolled proliferation and ultimately leads to cell cycle arrest and apoptosis, thus eliminating the malignant cell population.[5]

Preclinical Efficacy

The proposed mechanism of action has been extensively validated in preclinical models. In vitro studies using KMT2Ar leukemia cell lines confirmed that treatment with Revumenib leads to a dose-dependent downregulation of HOXA9 and MEIS1 mRNA and protein levels.[19] This was accompanied by morphological and immunophenotypic changes consistent with myeloid differentiation.

In vivo efficacy was demonstrated in aggressive, disseminated xenograft mouse models using the MOLM-13 (KMT2A-AF9) human AML cell line. Oral administration of Revumenib (SNDX-5613) resulted in a significant reduction in leukemic burden in the bone marrow and peripheral blood, leading to a substantial survival benefit compared to vehicle-treated controls.[18] Furthermore, the drug has shown potent activity in patient-derived xenograft (PDX) mouse models, which are considered more representative of human disease. In PDX models derived from patients with either KMT2Ar or NPM1m leukemia, Revumenib treatment effectively reduced disease burden and increased survival, providing strong preclinical evidence for its efficacy in both genetically defined patient populations.[21]

V. Clinical Pharmacology: Pharmacokinetics and Pharmacodynamics

The clinical pharmacology of Revumenib describes its absorption, distribution, metabolism, and excretion (pharmacokinetics, PK), as well as its dose- and concentration-dependent effects on the body (pharmacodynamics, PD). A central feature of its profile is its extensive metabolism by the cytochrome P450 3A4 (CYP3A4) enzyme system, which profoundly influences its dosing, drug interaction potential, and safety.

A. Pharmacokinetics

• [Absorption]: Revumenib is administered orally. Following oral administration, it is rapidly absorbed, with the time to reach maximum plasma concentration (Tmax​) occurring at approximately 1 hour post-dose.[4] The drug can be administered without regard to food, or with a low-fat meal (approximately 400 calories with <25% fat content), which does not significantly affect its absorption.[25]
• [Distribution]: Revumenib has a moderate volume of distribution, with a geometric mean apparent volume of distribution (Vd​) of 78 L.[4] It is highly bound (90%) to plasma proteins, primarily albumin, which restricts its distribution into tissues but maintains a circulating reservoir of the drug.[4]
• [Metabolism]: The drug undergoes extensive metabolism, with approximately 86% of an administered dose being metabolized before excretion.[4] The primary enzyme responsible for this metabolism is CYP3A4, with minor contributions from CYP2C8 and other unspecified hepatic enzymes.[4] This heavy reliance on a single metabolic pathway is a critical clinical consideration. The primary circulating metabolite, designated M1, is not therapeutically active but is pharmacologically active, contributing to the drug's effect on the QTc interval.[4]
• [Excretion]: The metabolites and remaining parent drug are eliminated from the body through both renal and fecal routes. Approximately 49% of an administered dose is recovered in the feces (with 7% as the unchanged parent drug), and 27% is recovered in the urine (also with 7% as unchanged parent drug).[4]
• [Half-Life and Clearance]: The pharmacokinetic profile of Revumenib is dramatically altered by the co-administration of strong CYP3A4 inhibitors. This interaction is not a minor perturbation but a fundamental shift in the drug's disposition that mandates clinical intervention. In the absence of a strong CYP3A4 inhibitor, Revumenib has a short terminal half-life (t1/2​) of 3.6 hours and a high apparent clearance (CL) of 27 L/h, indicating rapid elimination. However, when co-administered with a strong CYP3A4 inhibitor, the metabolic pathway is blocked, causing the half-life to more than double to 7.5 hours and the clearance to decrease by approximately 75% to 7 L/h.[4] This substantial increase in drug exposure directly elevates the risk of concentration-dependent toxicities.

The profound impact of CYP3A4 modulation is the central pillar of Revumenib's practical pharmacology. It dictates not only the mandatory dose adjustments outlined in the prescribing information but also the stringent warnings against co-administration with CYP3A4 inducers, which would risk sub-therapeutic exposure and loss of efficacy.[14] This metabolic vulnerability is the direct cause of its most significant drug-drug interactions and is inextricably linked to the management of its primary dose-limiting toxicity, QTc prolongation.

Table 2: Summary of Key Pharmacokinetic Parameters of Revumenib
Parameter	Value (without strong CYP3A4 inhibitor)	Value (with strong CYP3A4 inhibitor)
Dose	276 mg	163 mg (twice daily)
Tmax​ (Time to Peak Concentration)	~1 hour	Not specified
Cmax​ (Peak Concentration)	2052 ng/mL	Not specified
AUC0−12h​ (Area Under the Curve)	10150 ng·h/mL	Not specified
Vd​ (Apparent Volume of Distribution)	78 L	Not specified
Plasma Protein Binding	90% (primarily albumin)	90% (primarily albumin)
t1/2​ (Terminal Half-life)	3.6 hours	7.5 hours
CL (Apparent Clearance)	27 L/h	7 L/h
Data derived from.4

B. Pharmacodynamics

The pharmacodynamic effects of Revumenib are directly related to its plasma concentration. While a comprehensive exposure-response relationship for efficacy has not been fully characterized, a clear relationship has been established for a key safety parameter.

• [Exposure-QTc Relationship]: Revumenib exhibits a concentration-dependent increase in the QTc interval on the electrocardiogram.[4] This effect is a critical safety consideration and represents the drug's primary dose-limiting toxicity. The inactive M1 metabolite also contributes to this QTc-prolonging effect, complicating the risk profile, especially when metabolic pathways are altered by interacting drugs.[4] This pharmacodynamic property necessitates careful cardiac monitoring and avoidance of other QTc-prolonging medications in patients receiving Revumenib.[25]

VI. Clinical Evidence: Efficacy in Relapsed/Refractory Acute Leukemias

The clinical development of Revumenib has been anchored by the pivotal AUGMENT-101 trial (NCT04065399), a Phase I/II, open-label, multicenter study designed to evaluate its safety and efficacy in patients with R/R acute leukemias harboring specific genetic markers.[15] The trial's robust results, particularly in the KMT2A-rearranged cohort, formed the basis for its FDA approval.

A. Efficacy in KMT2A-Rearranged (KMT2Ar) Acute Leukemia

This cohort was the primary focus for regulatory approval and included a heavily pretreated and poor-prognosis patient population. The participants had a median of two prior lines of therapy, with 44% having received three or more. Over half (51%) had previously failed an allogeneic HSCT, and 63% had been treated with venetoclax, underscoring the refractory nature of their disease.[27] The study enrolled both adult and pediatric patients with various KMT2Ar leukemia subtypes, including AML (82%), ALL (13%), and mixed-phenotype acute leukemia (MPAL).[27]

The trial was stopped early after a pre-specified interim analysis of 57 patients met the threshold for efficacy, a strong indicator of the drug's significant clinical activity.[12] Subsequent analyses on the full efficacy population of 97-104 patients confirmed these findings.

• [Primary Efficacy Outcomes]:
• [Complete Remission (CR) + CR with Partial Hematologic Recovery (CRh)]: The primary endpoint of CR+CRh rate was consistently met, reported at 21.2% to 23% across different data cuts.[10] This rate significantly exceeded the pre-defined null hypothesis for clinical activity in this patient population.[17]
• [Overall Response Rate (ORR)]: The ORR, a broader measure of clinical benefit that includes less stringent remissions (e.g., CR with incomplete platelet recovery, morphological leukemia-free state), was robust at 63-64%.[12]
• [Composite Complete Remission (CRc)]: The CRc rate, which includes CR, CRh, CR with incomplete platelet recovery (CRp), and CR with incomplete hematologic recovery (CRi), was 42.3%.[27]
• [Durability, Depth, and Clinical Impact of Response]:
• [Duration of Response (DoR)]: The responses achieved were durable, with a median duration of CR+CRh of 6.4 months.[8] Longer-term follow-up of the initial responders showed a median DoR of 13.0 months, highlighting the potential for sustained benefit.[27]
• [Time to Response]: The onset of action was rapid, with a median time to achieve CR or CRh of just 1.9 to 2.0 months.[8]
• [Measurable Residual Disease (MRD) Negativity]: A critical indicator of a deep and high-quality remission, MRD negativity was achieved in a high proportion of responders. Among evaluable patients who achieved CR+CRh, 61-70% became MRD-negative.[12]
• [Bridge to Transplant]: The clinical success of Revumenib in this setting is not solely measured by remission rates or duration but by its ability to alter the trajectory of the disease for these patients. Historically, patients with such advanced, refractory leukemia have a median overall survival of only 2.4 months and are rarely candidates for further curative-intent therapy.[28] Revumenib-induced remissions were deep enough to allow a substantial proportion of responders (34-39%) to proceed to a potentially curative allogeneic HSCT.[12] This outcome redefines the therapeutic goal in this setting, transforming the drug's role from one of mere palliation to a critical "bridge-to-cure" for patients who previously had no viable path forward. Some patients were even able to resume Revumenib as post-transplant maintenance therapy to reduce the risk of relapse.[12]

Table 3: Summary of Efficacy Outcomes in the KMT2Ar Cohort of AUGMENT-101
Efficacy Endpoint	Result (Efficacy Population n=97-104)
CR + CRh Rate	21.2% - 23% 10
Overall Response Rate (ORR)	63% - 64% 12
Composite CR (CRc) Rate	42.3% 27
Median Duration of CR+CRh	6.4 months (95% CI: 2.7, NE) 10
Median Time to CR/CRh	1.9 months (range: 0.9, 5.6) 11
MRD Negativity in CR+CRh Responders	61% - 70% 17
Responders Proceeding to HSCT	34% - 39% 12

B. Efficacy in NPM1-Mutated (NPM1m) Acute Myeloid Leukemia

A separate expansion cohort of the AUGMENT-101 trial evaluated Revumenib in patients with R/R NPM1-mutated AML, demonstrating that the drug's activity extends beyond KMT2Ar leukemias.[15]

• [Response Rates and Survival]: In a cohort of 64-77 patients, the CR+CRh rate was approximately 23-26%, with an ORR of 47%.[15] In this heavily pretreated population, the median duration of response was 4.7 months, and the median overall survival was 4 months.[15]
• [Influence of Co-mutations]: An exploratory analysis suggested that the genomic context may influence response to Revumenib. The presence of an IDH1 co-mutation was significantly associated with achieving a CR+CRh, whereas a STAG2 mutation was associated with nonresponse, although these findings require confirmation in larger datasets.[15]

Table 4: Summary of Efficacy Outcomes in the NPM1m Cohort of AUGMENT-101
Efficacy Endpoint	Result (Efficacy Population n=64-77)
CR + CRh Rate	23.4% - 26% 15
Overall Response Rate (ORR)	46.9% 15
Median Duration of Response (DoR)	4.7 months 15
Median Overall Survival (mOS)	4.0 months 15
Responders Proceeding to HSCT	16.7% 15

C. Emerging Data from Combination Studies

The promising activity of Revumenib as a monotherapy has prompted investigation into its use in combination with other standard-of-care agents to deepen responses and improve outcomes. Several clinical trials are actively exploring these combinations.[32] Preliminary results from the SAVE trial, which combines Revumenib with venetoclax and the oral hypomethylating agent decitabine/cedazuridine, have been particularly encouraging. In patients with R/R AML, this all-oral triplet regimen demonstrated a very high ORR of 82% and a CR/CRh rate of 48%, suggesting strong synergistic activity.[29]

VII. Safety and Tolerability Profile

The safety profile of Revumenib has been characterized primarily through the AUGMENT-101 trial. While the drug is associated with significant and potentially severe toxicities, it is generally considered to have a manageable profile, evidenced by low rates of treatment discontinuation due to treatment-related adverse events (TRAEs), which were reported to be between 5% and 6.4%.[12] However, Grade 3 or higher adverse events (AEs) are very common, occurring in over 90% of patients, necessitating vigilant monitoring and proactive management.[15]

A. Common and Serious Adverse Reactions

The most frequently reported adverse reactions (occurring in ≥20% of patients) of any grade include hemorrhage, nausea, increased serum phosphate, musculoskeletal pain, various infections, febrile neutropenia, diarrhea, edema, and vomiting. Common laboratory abnormalities include elevations in liver transaminases (AST and ALT) and increased intact parathyroid hormone.[1]

Table 5: Incidence of Common (≥20%) and Grade ≥3 Adverse Reactions in AUGMENT-101 (Safety Population N=94-116)
Adverse Reaction	Any Grade (%)	Grade ≥3 (%)
Hemorrhage (including Epistaxis)	53%	Not specified
Nausea	45-51%	<5%
Febrile Neutropenia	35-38%	35-39%
Musculoskeletal Pain	42%	Not specified
Diarrhea	35%	<5%
Edema	32%	<5%
Differentiation Syndrome	19-29%	11-16%
QTc Prolongation	26-43%	14-20%
Infection (Bacterial, Viral)	41%	Not specified
Vomiting	31%	<5%
Laboratory Abnormalities
Phosphate Increased	50%	Not specified
Aspartate Aminotransferase (AST) Increased	37%	2%
Alanine Aminotransferase (ALT) Increased	33%	4%
Neutropenia / Neutrophil Count Decreased	30%	15-29%
Thrombocytopenia / Platelet Count Decreased	23%	16-21%
Anemia	22%	18-20%
Hypokalemia	28%	11%
Data compiled from.1

B. Boxed Warning and Major Risks of Concern

Two major toxicities require special attention due to their potential severity: Differentiation Syndrome and QTc interval prolongation.

• [Differentiation Syndrome (DS)]: Revumenib carries a [boxed warning] for DS, which can be life-threatening or fatal.[1]
• [Incidence]: DS of any grade occurs in 16-29% of patients, with Grade 3 or higher events reported in 11-16% of patients.[1] Fatal DS has been reported.[13]
• [Pathophysiology]: This is a direct, on-target consequence of the drug's mechanism of action. The rapid induction of differentiation and proliferation of myeloid precursor cells leads to a systemic inflammatory response, cytokine release, and tissue infiltration by maturing cells.
• [Clinical Presentation]: The syndrome is characterized by a constellation of signs and symptoms, including fever, dyspnea, hypoxia, unexplained weight gain, peripheral edema, hypotension, acute renal dysfunction, and radiographic evidence of pulmonary infiltrates or pleural/pericardial effusions.[1]
• [Management]: Prompt recognition and intervention are critical. If DS is suspected, systemic corticosteroids (e.g., dexamethasone 10 mg IV every 12 hours) must be initiated immediately, along with supportive care and hemodynamic monitoring. For severe or life-threatening symptoms, or symptoms persisting for more than 48 hours after starting corticosteroids, Revumenib therapy should be interrupted.[1]
• [QTc Interval Prolongation]:
• [Incidence]: Prolongation of the QTc interval on the ECG is a common finding, occurring in 25-43% of patients. Grade 3 or higher events (QTc >500 ms or change from baseline >60 ms) are seen in 14-20% of patients.[1]
• [Mechanism]: This is a direct pharmacodynamic effect of both the parent drug and its primary metabolite, M1.[4] The risk is concentration-dependent and is exacerbated by factors that increase drug exposure (e.g., CYP3A4 inhibitors) or other QTc-prolonging conditions.
• [Management]: A rigorous monitoring and management strategy is required. This includes correcting any pre-existing electrolyte abnormalities (hypokalemia, hypomagnesemia) before starting treatment. A baseline ECG is mandatory, and treatment should not be initiated in patients with a QTcF >450 ms. ECGs must be monitored at least weekly for the first four weeks of therapy and at least monthly thereafter. More frequent monitoring is necessary for patients with risk factors or those on concomitant QTc-prolonging drugs. Dose interruption or reduction is mandated for significant QTc prolongation, and the drug should be permanently discontinued for life-threatening arrhythmias like Torsades de Pointes.[14]

VIII. Practical Considerations for Clinical Use

The safe and effective use of Revumenib in the clinical setting requires strict adherence to specific guidelines regarding dosing, administration, management of drug interactions, and a comprehensive monitoring plan.

A. Dosing and Administration

• [Route and Schedule]: Revumenib is administered orally, twice daily. Patients should be instructed to take their doses at approximately the same times each day to maintain steady-state concentrations.[25]
• [Relation to Food]: The medication can be taken either in a fasted state or with a low-fat meal (defined as approximately 400 calories with less than 25% of calories from fat).[25]
• [Administration Instructions]: Tablets should be swallowed whole. For patients who cannot swallow tablets, they may be crushed, mixed with water, and administered immediately, with the full dose needing to be taken within two hours.[25]
• [Dosage]: The recommended dosage is dependent on the patient's body weight and, most critically, on the concomitant use of strong CYP3A4 inhibitors. The standard recommended phase II dose was 270 mg every 12 hours, but this is reduced to 160 mg every 12 hours if given with a strong CYP3A4 inhibitor.[15] Clinicians must consult the official prescribing information for the precise weight-based dosing tables.[25]

B. Drug-Drug Interactions

Revumenib's heavy reliance on CYP3A4 for metabolism makes it highly susceptible to clinically significant drug-drug interactions.

• [Strong CYP3A4 Inhibitors]: Co-administration significantly increases Revumenib plasma concentrations and the risk of toxicities, particularly QTc prolongation. The dose of Revumenib [must be reduced] when used concomitantly with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir).[14]
• [Strong or Moderate CYP3A4 Inducers]: Co-administration significantly decreases Revumenib plasma concentrations, which may result in a loss of efficacy. Concomitant use with these agents (e.g., rifampin, carbamazepine, phenytoin, St. John's Wort) [should be avoided].[14]
• [QTc-Prolonging Drugs]: Due to Revumenib's intrinsic QTc-prolonging effect, concomitant use of other drugs known to prolong the QTc interval (e.g., certain antiarrhythmics, antipsychotics, macrolide antibiotics, fluoroquinolones) [should be avoided]. If co-administration is unavoidable, more frequent ECG monitoring is required.[14] There are over 500 drugs known to interact with Revumenib, with a large number classified as major interactions.[38]

C. Required Monitoring and Pre-Treatment Screening

A comprehensive screening and monitoring plan is essential for patient safety.

• [Pre-Treatment Screening]:
• [Genetic Confirmation]: Confirm the presence of a KMT2A translocation in bone marrow or peripheral blood cells.[25]
• [Leukocyte Count]: Ensure the patient's white blood cell (WBC) count is less than 25×109/L prior to initiation. Cytoreductive therapy (e.g., hydroxyurea) may be required.[14]
• [Cardiac Evaluation]: Perform a baseline ECG. Do not initiate therapy in patients with a corrected QT interval (QTcF) >450 ms.[14]
• [Electrolytes]: Assess and correct any electrolyte abnormalities, particularly hypokalemia and hypomagnesemia.[14]
• [Baseline Labs]: Obtain complete blood count (CBC), and assess liver enzymes and renal function.[25]
• [Pregnancy Status]: Verify pregnancy status in females of reproductive potential within 7 days prior to starting therapy.[14]
• [Ongoing Monitoring During Therapy]:
• [ECG]: Monitor at least once weekly for the first 4 weeks of treatment, and at least monthly thereafter.[14]
• [Electrolytes, CBC, Liver Enzymes]: Monitor monthly throughout the course of therapy.[14]

Table 6: Recommended Dose Adjustments and Management of Key Toxicities
Scenario	Management Action
Concomitant Strong CYP3A4 Inhibitor	Reduce Revumenib dosage as per prescribing information.25
Concomitant Strong/Moderate CYP3A4 Inducer	Avoid concomitant use.14
Suspected Differentiation Syndrome (DS)	Immediately initiate systemic corticosteroids (e.g., dexamethasone) and provide hemodynamic support. Interrupt Revumenib for severe/life-threatening symptoms.25
QTcF >480-500 ms	Interrupt Revumenib. Correct electrolytes. Restart at the same dose once QTcF ≤480 ms.25
QTcF >500 ms (Grade 3)	Interrupt Revumenib. Correct electrolytes. Restart at a reduced dose level once QTcF ≤480 ms.25
QTc Prolongation with Life-Threatening Arrhythmia	Permanently discontinue Revumenib.25
Grade ≥3 Non-Hematologic Toxicity	Interrupt Revumenib until recovery to Grade ≤1. Restart at same or reduced dose depending on recurrence.25

IX. Regulatory and Development Status

Revumenib's path to market was characterized by an expedited regulatory process, reflecting both the significant unmet medical need it addresses and the strength of its supporting clinical data.

A. U.S. Food and Drug Administration (FDA) Approval

• [Approval Date]: Revumenib was approved by the U.S. FDA on [November 15, 2024].[7]
• [Approved Indication]: The drug is indicated for the treatment of relapsed or refractory (R/R) acute leukemia with a lysine methyltransferase 2A gene (KMT2A) translocation in adult and pediatric patients 1 year of age and older.[8]
• [Regulatory Pathway]: The New Drug Application (NDA) for Revumenib received multiple expedited program designations from the FDA, including [Fast Track Designation], [Breakthrough Therapy Designation], and [Orphan Drug Designation].[7] The application was also granted [Priority Review] and was reviewed under the [Real-Time Oncology Review (RTOR)] pilot program, which allows for earlier and more interactive engagement between the sponsor and the FDA. This highly streamlined process resulted in an approval six weeks ahead of the scheduled Prescription Drug User Fee Act (PDUFA) goal date.[9] This confluence of every available expedited pathway is a powerful regulatory signal. It indicates that the agency viewed the data as exceptionally compelling and straightforward, and recognized the therapy as a substantial improvement over available options for a serious condition, thereby justifying the use of every tool to accelerate its availability to patients.

B. Companion Diagnostics

To ensure appropriate patient selection, the FDA concurrently approved the [CytoCell KMT2A Breakapart FISH Probe Kit PDx] as a companion diagnostic. This test is used to detect the KMT2A gene rearrangements in leukemia cells that are required for a patient to be eligible for treatment with Revumenib.[39]

C. Global Regulatory Status

As of late 2024, Revumenib's regulatory approval was limited to the United States.

• [European Medicines Agency (EMA)]: No Marketing Authorisation Application (MAA) has been submitted to the EMA. Therefore, Revumenib is not currently approved for use in the European Union. However, it has received an Orphan Designation from the European Commission for the treatment of AML, which provides incentives for its development.[9]
• [United Kingdom (MHRA)]: Similarly, no application for approval had been submitted to the UK's Medicines and Healthcare products Regulatory Agency as of late 2024.[41]
• [Patient Access Programs]: For patients in regions where Revumenib is not yet approved, access may be possible on a case-by-case basis through mechanisms such as Expanded Access Programs (also known as Compassionate Use) or Named Patient Import regulations, which require a prescription from a treating physician.[41]

D. Future Directions and Pipeline Expansion

The clinical development of Revumenib is ongoing, with the goal of expanding its approved indications.

• [NPM1-Mutated AML]: Based on the positive efficacy data from the NPM1m cohort of the AUGMENT-101 trial, a supplemental New Drug Application (sNDA) has been submitted to the FDA for the treatment of R/R NPM1-mutant AML. The FDA has granted this sNDA Priority Review, with a PDUFA goal date of October 25, 2025.[31] Approval in this indication would significantly broaden the eligible patient population for Revumenib.

X. Synthesis and Future Outlook

Revumenib (Revuforj®) represents a landmark achievement in the field of precision oncology and a significant therapeutic breakthrough for patients with high-risk acute leukemias. Its development and approval have not only provided a new treatment option but have also validated the menin-KMT2A axis as a critical and druggable dependency in genetically defined subsets of leukemia. This success serves as a powerful proof-of-concept for targeting protein-protein interactions, a class of targets long considered "undruggable," opening new avenues for drug discovery in oncology and beyond.

In the current treatment landscape, Revumenib is positioned as an essential salvage therapy for patients with R/R KMT2Ar acute leukemia who have exhausted conventional options. Its most profound immediate impact lies in its demonstrated ability to serve as a bridge to potentially curative allogeneic HSCT. By inducing deep, MRD-negative remissions in a significant fraction of these otherwise unsalvageable patients, Revumenib fundamentally alters the therapeutic possibilities and offers a tangible chance for long-term survival. The pending approval for NPM1-mutated AML is poised to substantially expand its clinical utility, addressing another large population of patients with unmet needs.

The future of menin inhibition is likely to evolve rapidly along several key trajectories:

• [Combination Therapies]: While effective as a monotherapy, the true potential of Revumenib may be realized in rational combination regimens. The highly promising early data from the SAVE trial, combining Revumenib with venetoclax and a hypomethylating agent, suggest that synergistic combinations can lead to even higher and deeper response rates.[29] Future trials will explore combinations with other targeted agents, such as FLT3 or IDH inhibitors, tailored to the specific co-mutational profile of a patient's leukemia.
• [Advancement to Earlier Lines of Therapy]: The logical next step in development is to move Revumenib from the relapsed/refractory setting into earlier lines of treatment. Clinical trials are already underway evaluating its integration with standard induction and consolidation chemotherapy for newly diagnosed patients with KMT2Ar or NPM1m leukemia.[35] Success in this setting could redefine the frontline standard of care for these genetic subtypes, potentially improving cure rates and reducing the need for salvage therapies.
• [Maintenance and MRD Eradication]: The ability of Revumenib to induce deep, MRD-negative remissions makes it an attractive candidate for post-remission or post-HSCT maintenance therapy to prevent relapse.[15] Furthermore, its use as a pre-emptive therapy for patients who are in remission but show signs of rising MRD levels is being actively investigated as a strategy to intercept relapse before it becomes clinically apparent.[42]
• [Addressing Acquired Resistance]: As with all targeted therapies, the development of acquired resistance is an anticipated challenge. Future research must focus on elucidating the molecular mechanisms by which leukemia cells evade menin inhibition. This knowledge will be crucial for developing next-generation menin inhibitors or designing combination strategies that can prevent or overcome resistance, ensuring the long-term durability of this therapeutic approach.

In conclusion, Revumenib is more than just a new drug; it is the vanguard of a new therapeutic class that embodies the principles of precision medicine. It offers a novel mechanism of action, a tangible clinical benefit, and renewed hope for patients with some of the most aggressive forms of acute leukemia. Its continued clinical development and integration into the treatment paradigm will be critical in defining its ultimate, and likely expanding, role in hematologic oncology.

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