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Drugestablished confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.Q6-therapeutics

Revumenib (SNDX-5613, Revuforj) — first approved menin–KMT2A interface inhibitor

also called SNDX-5613 · Revuforj · revumenib citrate · SNDX-50613

Revumenib is a pill that pries apart the handshake between the KMT2A fusion protein and a partner protein called menin, which the leukaemia needs in order to stay immature. It became the first drug of its kind approved by the FDA, in November 2024, for children over one year old and adults whose KMT2A-rearranged leukaemia has come back.

The same thing, for a scientist

Revumenib is an orally bioavailable, selective small-molecule inhibitor of the menin–KMT2A protein–protein interaction, built on a 2,7-diazaspiro[3.5]nonane (spirocyclic) scaffold bearing an N-ethyl-N-isopropyl benzamide and an ethanesulfonamide-cyclohexyl tail (C32H47FN6O4S, free base MW 630.83; marketed as the monocitrate monohydrate). It occupies the KMT2A MBM1-binding pocket on menin, displacing both wild-type KMT2A and KMT2A fusion proteins, collapsing the HOXA9/MEIS1 self-renewal program and releasing blasts into terminal differentiation. FDA approved 2024-11-15 for R/R acute leukaemia with a KMT2A translocation in patients 1 year and older (AUGMENT-101, NCT04065399), and 2025-10-24 for R/R NPM1-mutant AML 1 year and older. It carries a boxed warning for differentiation syndrome and for QTc prolongation/Torsades de Pointes; it is a CYP3A4 substrate, and the label dose is halved when a strong CYP3A4 inhibitor is co-administered.

Go deeper
What it binds and how1 deeper

Revumenib is a protein–protein interaction (PPI) inhibitor, not a kinase or enzyme-active-site inhibitor. Menin has a deep central cavity that normally accepts the MBM1 motif (RWRFP, residues ~6–10) of the KMT2A N-terminus — a motif retained in every KMT2A fusion because the breakpoints all lie downstream of it. Revumenib binds that cavity and competitively blocks the KMT2A/KMT2A-fusion docking site 1. Because the fusion protein depends on menin for chromatin targeting of the HOXA9/MEIS1 locus, this single displacement is enough to shut off the self-renewal program. The FDA label states the mechanism as blocking the interaction of both wild-type KMT2A and KMT2A fusion proteins with menin 3 — a point that matters for on-target toxicity, since the drug cannot distinguish fusion from wild-type.

Why NPM1-mutant AML responds too

Cytoplasmic-mislocalised mutant NPM1 leaves a chromatin-bound residue that co-occupies the same menin–KMT2A-dependent HOXA/MEIS1 enhancers. Menin inhibition therefore also collapses the NPM1-mutant program, which is why a single agent covers two genetically distinct diseases (~10% of acute leukaemias KMT2A-r, up to 30% of AML NPM1m) 1. The NPM1m indication was approved 2025-10-24 on a 23.1% CR+CRh rate (95% CI 13.5–35.2), median duration 4.5 months 5, with the phase-2 NPM1m cohort publication reporting CR+CRh 23.4% and ORR 46.9% in 64 efficacy-evaluable adults 6.

Approval status — verified from FDA primary sources

2024-11-15 — FDA approved revumenib (Revuforj, Syndax) for "relapsed or refractory 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" 23. Priority review; breakthrough and orphan designations. NDA 218944.

2025-10-24 — FDA approved a second indication: "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" 53.

Note the age floor of 1 year in both indications. The pivotal trial enrolled from age 30 days and the youngest treated patient was 1.3 years 4, so the great majority of infant KMT2A-r ALL — diagnosed at a median of ~5 months — sits outside the label. This is the single biggest clinical gap for the infant-ALL population this lab cares about.

Efficacy — the numbers, with n
Populationn (efficacy)CR+CRhORRMedian DoRSource
Phase 1, R/R acute leukaemia (KMT2A-r or NPM1m)6030%——Nature 2023 1
Phase 2 KMT2A-r (interim, JCO)57 (94 treated)22.8% (95% CI 12.7–35.8), p=0.003663.2%—JCO 2025 4
Phase 2 KMT2A-r (label, longer follow-up)10421.2% (95% CI 13.8–30.3)—6.4 moFDA 2
Phase 2 NPM1m6423.4% (p=0.0014)46.9%4.7 moBlood 2025 6

Two caveats a reader must hold. First, CR+CRh of ~21–23% is a real but modest bar — the comparator is a population with a median OS measured in 2–3 months, and the registration null hypothesis was only 10%. Second, MRD clearance was deep in responders: 15 of 22 evaluable responders (68.2%) had no detectable residual disease 4, and 14% of transfusion-dependent patients converted to transfusion independence 2. The drug's realistic role today is a bridge to transplant, not a cure: 5 of 30 NPM1m responders (16.7%) proceeded to HSCT 6.

Dosing and the CYP3A4 trap

Twice daily, orally, in 28-day cycles 3:

WeightNo strong CYP3A4 inhibitorWith strong CYP3A4 inhibitor
40 kg or more270 mg BID160 mg BID
Under 40 kg160 mg/m² BID95 mg/m² BID

Revumenib is a CYP3A4 substrate; co-administration with cobicistat raised AUC and Cmax ~2.5-fold 7. The pivotal phase 2 was in fact run with a mandated strong CYP3A4 inhibitor at 163 mg (95 mg/m² if <40 kg) every 12 h 4 — a deliberate PK-boosting strategy. For paediatric oncology this is a practical hazard: azoles (posaconazole, voriconazole) are near-universal antifungal prophylaxis in this population, so essentially every child on revumenib needs the reduced dose and QTc vigilance simultaneously.

Toxicity — boxed warning and the two dose-limiting problems

The label carries a boxed warning for (i) differentiation syndrome, which can be fatal, and (ii) QTc prolongation and Torsades de Pointes 3.

  • Differentiation syndrome: 60/241 patients (25%) across the pooled safety population; grade 3–4 in 12%; fatal in 2 patients. Strikingly lineage-dependent — 33% in KMT2A-r AML, 33% in MPAL, but only 9% in ALL, and 18% in NPM1m AML 3. In the KMT2A-r registration safety set (n=135) DS was reported at 29% 8. This is mechanistically on-target — it is the drug working.
  • QTc prolongation: 86/241 (36%) any grade, grade 3 15%, grade 4 2%; QTcF >500 ms in 10%; >60 ms rise from baseline in 24%; one fatal cardiac arrest and one non-sustained Torsades 3. Asymptomatic QT prolongation was the only dose-limiting toxicity in phase 1 1.
  • Other events at 20% or more: raised phosphate, haemorrhage, nausea, infection, transaminase and creatinine rise, febrile neutropenia, musculoskeletal pain, raised intact PTH 3. The raised phosphate and PTH signal is interesting and under-discussed: menin is the MEN1 tumour-suppressor whose loss causes parathyroid adenomas, so perturbing menin pharmacologically in the parathyroid axis is a plausible on-target endocrine effect worth watching in children who may be on drug for years.
Resistance already reported in the clinic

On-target MEN1 binding-site mutations (M327I, G331R, G331D, T349M and others) emerge under revumenib pressure and confer resistance — see resistance-men1-interface-mutations. Crucially, these mutations are not uniformly cross-resistant across the drug class: ziftomenib retains activity against T349M and low-nanomolar potency against G331R, while M327I and G331D remain resistant to it 9. That asymmetry is the basis for a sequencing/alternation strategy (see hyp-mutation-guided-menin-inhibitor-alternation).

Facts and figures
chembl IDCHEMBL4650827
chembl salt IDCHEMBL6068395
targetgene-men1
target interactionmenin–KMT2A (MBM1) protein–protein interface
modalitysmall molecule (oral, reversible PPI inhibitor)
chemical class2,7-diazaspiro[3.5]nonane spirocyclic pyrimidine-ether benzamide with ethanesulfonamide-cyclohexyl tail
molecular formulaC32H47FN6O4S
mw freebase da630.83
alogp4.68
ro5 violations1
marketed formrevumenib citrate (monocitrate monohydrate), tablets
usan stem-menib (inhibitor of the menin-MLL/KMT2A interaction)
statusFDA approved 2024-11-15 (R/R acute leukaemia with KMT2A translocation, 1 year and older); second indication approved 2025-10-24 (R/R NPM1-mutant AML, 1 year and older)
nda218944
sponsorSyndax Pharmaceuticals
pediatric label floor1 year — excludes most infant KMT2A-r ALL (median age at diagnosis ~5 months)
efficacy
phase 2 KMT2A-r (JCO inte…57.0phase 2 KMT2A-r (JCO interim): 57phase 1 R/R KMT2A-r or NP…60.0phase 1 R/R KMT2A-r or NPM1m: 60phase 2 NPM1m64.0phase 2 NPM1m: 64phase 2 KMT2A-r (label, n…104.0phase 2 KMT2A-r (label, n=104): 104
dosing
{
  "route": "oral",
  "schedule": "every 12 hours, continuous 28-day cycles",
  "ge_40kg_no_cyp3a4i_mg": 270,
  "ge_40kg_with_cyp3a4i_mg": 160,
  "lt_40kg_no_cyp3a4i_mg_m2": 160,
  "lt_40kg_with_cyp3a4i_mg_m2": 95
}
trials
[
  "NCT04065399"
]
efficacy — the numbers behind the chart
[
  {
    "population": "phase 1 R/R KMT2A-r or NPM1m",
    "n": 60,
    "cr_crh_pct": 30
  },
  {
    "population": "phase 2 KMT2A-r (JCO interim)",
    "n": 57,
    "cr_crh_pct": 22.8,
    "orr_pct": 63.2
  },
  {
    "population": "phase 2 KMT2A-r (label, n=104)",
    "n": 104,
    "cr_crh_pct": 21.2,
    "median_dor_months": 6.4
  },
  {
    "population": "phase 2 NPM1m",
    "n": 64,
    "cr_crh_pct": 23.4,
    "orr_pct": 46.9,
    "median_dor_months": 4.7
  }
]
boxed warning
[
  "differentiation syndrome (can be fatal)",
  "QTc prolongation and Torsades de Pointes"
]
key ae
[
  "differentiation syndrome 25% (G3-4 12%, 2 deaths)",
  "QTc prolongation 36% (QTcF>500ms 10%)",
  "febrile neutropenia",
  "hyperphosphataemia",
  "raised intact PTH",
  "transaminitis",
  "haemorrhage"
]
resistance
[
  "MEN1 M327I",
  "MEN1 G331R",
  "MEN1 G331D",
  "MEN1 T349M",
  "RAS-pathway co-mutation",
  "non-genetic transcriptional adaptation"
]
How this could bite us back
  • On-target MEN1 pocket mutations (M327I/G331R/G331D/T349M) arise under monotherapy pressure and were essentially predictable from the binding mode — monotherapy is a mutation-selection machine.
  • The drug cannot distinguish fusion KMT2A from wild-type KMT2A, so every therapeutic effect is bought with inhibition of an essential normal complex; the hyperphosphataemia/raised-PTH signal may be the early clinical readout of that.
  • Differentiation syndrome is the mechanism working, so it cannot be engineered away by better selectivity — only by managed ramp-up, prophylaxis and cytoreduction.
  • QTc prolongation collides with the azole antifungals and CYP3A4 inhibitors that paediatric leukaemia patients almost always receive, compressing the usable therapeutic window exactly in the population of interest.
  • CR+CRh of ~21% means about 4 in 5 patients do not get a deep remission; treating revumenib as a solved problem would misallocate effort away from combinations and the infant-specific questions.
Still open
  1. Does revumenib work in true infants (under 12 months), where the leukaemia arises in a fetal-liver-derived progenitor with a different chromatin state — and is the 1-year label floor a data gap or a real biological boundary?
  2. Differentiation syndrome is 33% in KMT2A-r AML but only 9% in ALL. Is the lower ALL rate evidence that the lymphoid KMT2A-r program is less menin-dependent for differentiation, and does that predict shallower responses in infant ALL?
  3. Given that the label mechanism explicitly includes displacement of wild-type KMT2A from menin, what is the cumulative endocrine and haematopoietic cost of years of menin blockade in a surviving child?
Every source behind this entry (9)
  1. E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    Revumenib is a selective oral inhibitor of the menin–KMT2A interaction that produced a 30% CR/CRh rate in the first-in-human phase 1 trial of R/R KMT2A-rearranged or NPM1-mutant acute leukaemia, with asymptomatic QT prolongation as the only dose-limiting toxicity.

    The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia · Issa GC, Aldoss I, DiPersio J, Cuglievan B, Stone R, Arellano M, Thirman MJ, Patel MR, Dickens DS, Shenoy S, Shukla N, Kantarjian H, Armstrong SA, Perner F, Perry JA, Rosen G, Bagley RG, Meyers ML, Ordentlich P, Gu Y, Kumar V, Smith S, McGeehan GM, Stein EM · Nature 2023
    PMID 36922593DOI
    What this evidence cannot show

    Phase 1, single-arm, no control; efficacy population enriched for evaluable patients; heavily pretreated cohort so response durability is hard to read; sponsor (Syndax) co-authored.

    Evidence that argues against this (1)
    • The same trial programme's later, larger phase 2 analysis gave a lower CR+CRh rate (21–23%), indicating the phase 1 30% figure was optimistic. Issa GC et al. 2024
  2. E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.regulatory

    FDA approved revumenib on 2024-11-15 for relapsed or refractory acute leukaemia with a KMT2A translocation in adult and paediatric patients 1 year and older, based on 104 patients with a 21.2% CR+CRh rate and 6.4-month median duration.

    FDA approves revumenib for relapsed or refractory acute leukemia with a KMT2A translocation · US Food and Drug Administration · FDA Oncology (Cancer) Approval Notifications 2024
    What this evidence cannot show

    Regulatory summary, not a peer-reviewed analysis; single-arm evidence base with no randomised comparator. CITATION TYPE CORRECTED 2026-09-20: this was stored as `type: news`. It is an FDA approval announcement on fda.gov, which is a PRIMARY regulatory record, not a news report of one. Retyped to `regulatory`. URL fetched and the page title and approval date confirmed against the claim in the same session.

    Evidence that argues against this (1)
    • The 21.2% CR+CRh in the approval is a property of the relapsed/refractory MONOTHERAPY setting, not of the drug. In newly diagnosed NPM1m or KMT2A-r AML in patients 60 years and older, azacitidine + venetoclax + revumenib gave a composite CR rate of 81.4% (95% CI 66.6-91.6; KMT2A-r 88.9%) and ORR 88.4%, with no patient refractory after 1-2 cycles and 37/37 evaluated patients MRD-negative by central flow. Quoting the label figure as 'revumenib's response rate' misdescribes what was measured. Zeidner JF et al. 2025
  3. E3established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    The current REVUFORJ label specifies both KMT2A-translocation and NPM1-mutation indications, weight-based twice-daily dosing halved with strong CYP3A4 inhibitors, and a boxed warning for differentiation syndrome (25%, grade 3-4 12%, 2 fatal) and QTc prolongation (36% any grade, QTcF >500 ms in 10%).

    REVUFORJ (revumenib) tablets — full prescribing information (label, revised 2025) · Syndax Pharmaceuticals / US FDA · DailyMed / Drugs@FDA (NDA 218944) 2025
    What this evidence cannot show

    Pooled safety population (n=241) mixes KMT2A-r and NPM1m, adults and children, so subgroup rates are approximate; label rates reflect trial-setting monitoring and may differ in routine practice.

    Evidence that argues against this (2)
    • The pooled label adverse-event rates do not transport to the settings in which revumenib is actually being developed. In the phase 1 azacitidine/venetoclax/revumenib combination (n=43), dosed deliberately on top of a strong CYP3A4-inhibitor azole, QTcF prolongation occurred in 19/43 (44%) - higher than the label's pooled 36% - while differentiation syndrome was lower at 8/43 (19%); neither required permanent discontinuation. A single pooled percentage for a drug given in at least three different regimens is an average of dissimilar populations. Zeidner JF et al. 2025
    • QTc prolongation is NOT a menin-inhibitor class effect and must not be read as on-mechanism. The registration-enabling phase 2 of the second approved menin inhibitor, ziftomenib (KOMET-001, n=92), reports a safety profile with an explicit 'lack of clinically significant QTc prolongation', alongside differentiation syndrome at 25% (15% grade 3, no grade 4-5). Differentiation syndrome tracks the mechanism across both agents; QTc does not, so revumenib's boxed QT warning is a property of this chemotype and is potentially engineerable away, contrary to how the class is often described. Wang ES et al. 2025
  4. E4strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    In the registration-enabling phase 2 KMT2A-r portion of AUGMENT-101, 94 patients (median age 37, range 1.3–75 years) were treated; CR+CRh was 22.8% in 57 efficacy-evaluable patients, ORR 63.2%, and 68.2% of evaluable responders had no detectable residual disease.

    Menin Inhibition With Revumenib for KMT2A-Rearranged Relapsed or Refractory Acute Leukemia (AUGMENT-101) · Issa GC, Aldoss I, Thirman MJ, DiPersio J, Arellano M, Blachly JS, Mannis GN, Perl A, Dickens DS, McMahon CM, Traer E, Zwaan CM, Grove CS, Stone R, Shami PJ, Mantzaris I, Greenwood M, Shukla N, Cuglievan B, Kovacsovics T, et al. · Journal of Clinical Oncology 2024
    PMID 39121437DOI
    What this evidence cannot show

    Interim analysis at a prespecified stop; single-arm; 22 clinical sites in 5 countries; youngest treated patient 1.3 years despite 30-day eligibility floor, so infant data are essentially absent.

    Evidence that argues against this (1)
    • The 22.8% CR+CRh bounds a heavily pretreated population rather than the agent. In serial patient-derived xenografts from two patients with multiply relapsed KMT2A::AFF1 ALL, late samples were markedly LESS sensitive to menin inhibition than earlier samples from the same patient, although none of the patients had ever received a menin inhibitor - so a substantial share of 'refractoriness' in an R/R registration cohort is upfront resistance acquired from prior chemotherapy. Critically, transcriptomic analysis showed sustained on-target suppression of canonical menin-inhibitor target genes in the resistant cells, so target engagement is preserved while response is lost: a pharmacodynamic readout would have called these responders. Mahdavi L et al. 2026
  5. E5established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.regulatory

    FDA approved revumenib on 2025-10-24 for relapsed or refractory AML with a susceptible NPM1 mutation in patients 1 year and older, on a CR+CRh of 23.1% (95% CI 13.5–35.2) with median duration 4.5 months.

    FDA approves revumenib for relapsed or refractory acute myeloid leukemia with a susceptible NPM1 mutation · US Food and Drug Administration · FDA Oncology (Cancer) Approval Notifications 2025
    What this evidence cannot show

    Single-arm; NPM1m cohort was overwhelmingly adult (median age 63, only 1 patient under 18), so the paediatric extension of the indication is by extrapolation rather than data. CITATION TYPE CORRECTED 2026-09-20: this was stored as `type: news`. It is an FDA approval announcement on fda.gov, which is a PRIMARY regulatory record, not a news report of one. Retyped to `regulatory`. URL fetched and the page title and approval date confirmed against the claim in the same session.

    Evidence that argues against this (1)
    • A second, independently developed menin inhibitor produced essentially the same modest numbers in the same indication, which bounds how much of the 23.1% is attributable to revumenib specifically: in KOMET-001 phase 2 (n=92, median age 69), ziftomenib gave CR/CRh 22% (95% CI 14-32), ORR 33%, median response duration 4.6 months and median OVERALL SURVIVAL 6.6 months (95% CI 3.6-8.6). A median OS under seven months is the number that should be read beside a CR+CRh rate in the low twenties; neither approval carries a randomised comparator. Wang ES et al. 2025
  6. E6strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    In the phase 2 NPM1-mutant cohort of AUGMENT-101 (84 treated, 64 efficacy-evaluable adults; 75% prior venetoclax), CR+CRh was 23.4% and ORR 46.9% with median CR+CRh duration 4.7 months; 5 of 30 responders went to HSCT.

    Menin inhibition with revumenib for NPM1-mutated relapsed or refractory acute myeloid leukemia: the AUGMENT-101 study · Arellano ML, Thirman MJ, DiPersio JF, Heiblig M, Stein EM, Schuh AC, Zucenka A, de Botton S, Grove CS, Mannis GN, Papayannidis C, Perl AE, Issa GC, Aldoss I, et al. · Blood 2025
    PMID 40332046DOI
    What this evidence cannot show

    Median age 63; only one patient under 18 years, so no paediatric inference; 75% had prior venetoclax, which selects for a biology that may not match frontline patients.

    Evidence that argues against this (1)
    • This entry's caveat - that 75% prior venetoclax exposure 'selects for a biology that may not match frontline patients' - is contradicted by the only prespecified test of it in the class. In KOMET-001 phase 2, prespecified subgroup analyses found CR/CRh comparable regardless of previous therapy, INCLUDING venetoclax, and regardless of comutation type. Prior venetoclax is therefore not established as the variable that depresses menin-inhibitor response; prior therapy INTENSITY may be (see the E4 counter-evidence), which is a different and testable claim. Wang ES et al. 2025
  7. E7strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.database

    Revumenib AUC and Cmax increase approximately 2.5-fold with concomitant strong CYP3A4 inhibition (cobicistat), which is why the label halves the dose in that setting.

    REVUFORJ (revumenib) tablets — Clinical Pharmacology (section 12.3), initial US approval 2024 · Syndax Pharmaceuticals / US FDA · Drugs@FDA label 218944s000 2024
    What this evidence cannot show

    Drug-interaction study in a limited population; the paediatric PK of the reduced dose with azole antifungals is less well characterised.

    Evidence that argues against this (1)
    • Framing CYP3A4 inhibition as an interaction to be MITIGATED inverts how the programme actually uses it. The registration phase 2 dosed revumenib at 163 mg (95 mg/m2 under 40 kg) every 12 h WITH a mandated strong CYP3A4 inhibitor, and the frontline triplet study likewise dosed 113 or 163 mg q12h explicitly 'in combination with strong cytochrome P450 inhibitor azoles', identifying no maximum tolerated dose. Azole boosting is the intended dosing paradigm, not a deviation from it - which means there is essentially no azole-free clinical exposure dataset in children to compare the reduced dose against, and the practical hazard runs the other way from the label's framing: stopping the azole un-boosts the patient. Zeidner JF et al. 2025
  8. E8moderate confidence 3 of 5: One strong study, or several smaller consistent ones.review

    In the KMT2A-r registration dataset, grade 3/4 differentiation syndrome occurred in 13% and grade 3/4 QT prolongation in 12%, with differentiation syndrome overall in 29% of 135 patients in the safety population.

    Revumenib for Relapsed or Refractory Acute Leukemia With a KMT2A Translocation · Lynch EJ, Faro SJE, Lindstrom AM, Sethi NA, Wang WY, Seligson ND · Annals of Pharmacotherapy 2025
    PMID 40437770DOI
    What this evidence cannot show

    Narrative drug review, not primary data; numbers are re-reported from trial publications and the label and differ slightly from the pooled 241-patient label figures.

    Evidence that argues against this (2)
    • These re-reported numbers disagree with the primary publication of the same dataset. The AUGMENT-101 phase 2 KMT2A-r paper reports grade 3 or higher differentiation syndrome in 16.0% and grade 3 or higher QTc prolongation in 13.8% of the 94 treated patients - not 13% and 12%. A narrative review's transcription of trial numbers should not be cited in place of the trial. Issa GC et al. 2025
    • Independent secondary syntheses of the same trials do not agree with each other either. A scoping review covering all six clinical-stage menin inhibitors through December 2024 reports revumenib MRD-negative rates of 70-90% and puts ziftomenib differentiation syndrome in KMT2A-r patients at 30%, and records MEN1 resistance mutations emerging as early as two treatment cycles. Where two secondary sources differ, the primary trial report and the label are the only defensible citations for a rate. Dali SA et al. 2025
  9. E9moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

    MEN1 mutations selected by revumenib are not uniformly cross-resistant to other menin inhibitors: ziftomenib retained antileukaemic activity against T349M and low-nanomolar potency (GI50 25 nM or less) against G331R, while M327I and G331D were resistant.

    Discovery and preclinical activity of the menin-KMT2A inhibitor ziftomenib in acute leukemia models · Miao H, Wu T, Purohit T, Chen D, Klossowski S, Borkin D, Clegg B, Ray J, Park S, Stevens R, Kim E, Kempinska K, Cierpicki T, Grembecka J, et al. · Blood 2026
    PMID 41849234DOI
    What this evidence cannot show

    Engineered cell lines and crystallography, not patient data; no clinical evidence yet that switching menin inhibitors at MEN1-mutant relapse recovers response.

    Evidence that argues against this (2)
    • MEN1 pocket mutation is not the dominant resistance route, so a mutation-guided alternation strategy addresses a minority of failures. In multiply relapsed KMT2A::AFF1 ALL never exposed to a menin inhibitor, resistance arose with SUSTAINED on-target transcriptional response and no MEN1 pocket mutation; RAS-pathway and TP53 comutations emerged but neither was sufficient to induce resistance in vitro, and KMT2C/KMT2D loss was implicated in one patient. Switching between menin inhibitors cannot rescue a leukaemia whose resistance is downstream of, or orthogonal to, the pocket. Mahdavi L et al. 2026
    • A second pocket-independent mechanism has been reported: TP53 inactivation confers resistance to revumenib in AML. PREPRINT, not peer-reviewed as of 2026-09 (PubMed returns only the bioRxiv record); cited here to bound the cross-resistance claim, not to establish the mechanism. D'Souza J et al. 2025
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