The first published complete remission of NUP98-rearranged AML on a menin inhibitor (icovamenib/BMF-219, n=1)
also called BMF-219 NUP98 case report · icovamenib NUP98-NSD1 CR · COVALENT-101 NUP98 patient
A 39-year-old man whose leukaemia came back after a bone-marrow transplant was given a menin-blocking drug and went into complete remission within three months, with no detectable disease left. Six months later the leukaemia returned, carrying a handful of new mutations that had nothing to do with the drug's target.
The same thing, for a scientist
A single published case from the COVALENT-101 dose-escalation study: a 39-year-old man with **NUP98::NSD1** AML, relapsed after allogeneic transplant, treated with the **covalent** menin inhibitor icovamenib (BMF-219) 500 mg once daily on continuous 28-day cycles [E1]. Course: suspected **grade 3 differentiation syndrome at C1D15** with peribronchial ground-glass opacities, treated with prednisone; **partial response at C2D1** (blasts 13% → 6%); **complete remission at C3D1** (0% blasts, normal female donor karyotype, recovering haematopoiesis); **MRD-negative by C4D1**; dose escalated to 650 mg toward the end of cycle 6; **progression and discontinuation at C7D8** [E1]. The paper states plainly that before it, *"clinical proof has not been described so far, to our knowledge"* for menin inhibition in NUP98-rearranged AML [E1]. Two things make this worth a node despite n=1. First, the **differentiation syndrome is on-target pharmacology**, which is the strongest available evidence that menin inhibition engaged the NUP98 fusion's transcriptional programme in a human being. Second, the **NGS at discontinuation** shows NUP98-NSD1 retained alongside CEBPA (VAF 30%), KRAS G13D (34.1%), NRAS G13D (6.2%), WT1 (45.4%) and a RUNX1 VUS (46.7%) [E1] — escape via RAS-pathway co-mutation, **not** via a MEN1 binding-site mutation.
Why n=1 is load-bearing here and usually is not
A single case cannot estimate a response rate and this entry does not try. What it can do is settle an existence question, and the existence question was genuinely open: the authors state that clinical proof of menin inhibition in NUP98-rearranged AML had not been described 1. A complete remission with MRD negativity, preceded by a grade 3 differentiation syndrome, is a mechanistically coherent on-target response rather than a coincidence of timing — differentiation syndrome is the class toxicity of agents that release a differentiation block, and releasing a differentiation block is exactly what menin inhibition is proposed to do to a HOXA-driven fusion.
The honest limit: one patient, one drug, no control, and the drug is not one of the three agents whose trials name NUP98 in eligibility.
The escape route, and why it matters for the family analogy
At discontinuation the marrow carried NUP98-NSD1 plus CEBPA, KRAS G13D, NRAS G13D, WT1 and a RUNX1 variant of uncertain significance 1. Two RAS-pathway mutations at once, at very different variant allele fractions (34.1% and 6.2%), reads as convergent subclonal selection on RAS signalling.
This is a different escape shape from the one the SAVE trial reports for the same class (emergent menin-binding-site mutations in 13%; see trial-save-revumenib-nup98-subgroup) and from the MEN1 interface mutations catalogued in resistance-men1-interface-mutations. Both routes are presumably available. For a beat whose question is whether NUP98 and KMT2A families converge on one target, the useful observation is that the resistance biology may not converge even where the dependency does: a fusion that drives a HOXA programme through a partner-specific chromatin mechanism may have a different set of bypasses available to it.
The co-mutation caveat, stated by the same paper
The case report itself raises the complication that matters most for predicting who responds 1:
"Heikamp et al. showed responsiveness of a NUP98-NSD1 patient-derived xenograft model that was also WT1 mutant, while another NUP98-NSD1 AML patient-derived xenograft model containing mutations in WT1, ASXL1, IDH1, BCORL1 and FLT3-ITD did not respond. Of note, Rasouli and colleagues showed that menin inhibitor monotherapy was sufficient to suppress NUP98-rearranged AML with co-occurring FLT3-ITD and WT1 mutations; however, co-administration of a menin inhibitor with an FLT3 inhibitor enhanced the antileukemic effect."
So within the preclinical NUP98-NSD1 literature there is already a non-responding PDX, and the two published PDX series disagree about whether FLT3-ITD co-mutation blocks response. That disagreement is unresolved and is the reason hyp-nup98-menin-response-is-comutation-gated exists in this beat.
| age at dx | 39 years (adult; NUP98::NSD1 is commoner in children and young adults) |
|---|---|
| sex | male; transplanted from a female donor, so donor karyotype 46,XX is the remission marker |
| fusion | fusion-nup98-nsd1 |
| drug | icovamenib (BMF-219), covalent menin inhibitor, COVALENT-101 |
| dose | 500 mg PO once daily, continuous 28-day cycles; escalated to 650 mg once daily late in cycle 6 |
| course | C1D15 suspected grade 3 differentiation syndrome (peribronchial ground-glass opacities, prednisone); C2D1 partial response, blasts 13% to 6%; C3D1 complete remission, 0% blasts, 46,XX donor karyotype; C4D1 MRD-negative, NGS without detectable mutations; C7D8 progression and discontinuation |
| outcome | complete remission achieved and lost within seven cycles |
| resistance mechanism class | RAS-pathway and transcription-factor co-mutation, NOT a MEN1 binding-site mutation |
| source type | case report |
| consent note | published case report; no PHI beyond what the journal printed |
presentation
[ "primary NUP98::NSD1-positive AML with leukocytosis (WBC 317.6 x10^9/L)", "anaemia (Hb 7.1 g/dL)", "thrombocytopenia", "relapse after allogeneic haematopoietic stem cell transplant" ]
resistance at progression
[ "NUP98-NSD1 retained", "CEBPA VAF 30%", "KRAS G13D VAF 34.1%", "NRAS G13D VAF 6.2%", "WT1 VAF 45.4%", "RUNX1 VUS VAF 46.7%" ]
- Progression at cycle 7 with a RAS-pathway subclone means a NUP98-directed menin programme must plan for RAS escape from the outset; a MEN1-interface-mutation resistance assay would have missed this patient's relapse entirely.
- Grade 3 differentiation syndrome at C1D15 in the first published NUP98 responder is a warning for a paediatric population with high HOXA output and high tumour burden at relapse.
- The only published NUP98 complete remission came from a drug outside the three trials that name NUP98, so the evidence base and the eligible-drug list do not overlap; a clinician acting on this case cannot act on it with an approved agent.
- Were the KRAS/NRAS G13D subclones present below detection at baseline, or acquired under menin inhibition? The paper reports NGS at discontinuation but a baseline deep-sequencing comparison would separate selection from acquisition.
- Does RAS-pathway escape dominate in NUP98-rearranged disease while MEN1 interface mutation dominates in KMT2A-rearranged disease, or is that an artefact of n=1 versus a 42-patient trial? A pooled resistance-genotype comparison across both families is the analysis nobody has run.
- Is covalent menin inhibition (icovamenib) mechanistically different from reversible inhibition (revumenib, ziftomenib) in a NUP98 context, and does that explain why the only published CR came from the covalent agent?
- Given the post-transplant setting, how much of the remission was drug and how much was a restored graft-versus-leukaemia effect following differentiation?
- E1moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
A 39-year-old man with post-transplant relapsed NUP98::NSD1 AML treated with icovamenib (BMF-219) 500 mg daily achieved complete remission at C3D1 and MRD negativity by C4D1, after grade 3 differentiation syndrome at C1D15, and progressed at C7D8 with emergent CEBPA, KRAS G13D, NRAS G13D, WT1 and RUNX1 variants.
Complete remission of NUP98 fusion-positive acute myeloid leukemia with the covalent menin inhibitor BMF-219, icovamenib · Carraway HE, Nakitandwe J, Cacovean A, et al. · Haematologica 110(4):1041-1046 2025What this evidence cannot show
n = 1, uncontrolled, from a dose-escalation study; the full text was read in this session from PMC11959225. Eight of the eleven authors are affiliated to the sponsor of the drug. The patient was post-allogeneic-transplant, so a graft-versus-leukaemia contribution to the remission cannot be excluded, and the dose was escalated mid-course, which confounds the duration. Confidence is 'moderate' rather than 'strong' because a single uncontrolled case supports an existence claim only.
Evidence that argues against this (2)
- The same paper records that a NUP98-NSD1 PDX carrying WT1, ASXL1, IDH1, BCORL1 and FLT3-ITD mutations did NOT respond to menin inhibition in the founding preclinical study, so responsiveness in NUP98-rearranged disease is not uniform even in models, and a single responding patient may be the favourable tail of a co-mutation-gated distribution. Heikamp EB et al. 2022
- The prospective SAVE trial subsequently reported the shortest CR/CRh duration of any genotype in its NUP98-rearranged subgroup (5.9 months), which is the population-level context this single durable-sounding remission should be read against; the case patient himself progressed within seven cycles. Issa GC et al. 2026
- E2moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
Menin inhibitor monotherapy suppressed NUP98-rearranged AML with co-occurring FLT3-ITD and WT1 mutations, and adding an FLT3 inhibitor enhanced the effect.
The MLL-Menin Interaction is a Therapeutic Vulnerability in NUP98-rearranged AML · Rasouli M, et al. · HemaSphere 7(8):e935 2023What this evidence cannot show
Cited here as reported by the case report's discussion and by its own abstract; the primary figures were not read in this session. Xenograft work, small numbers of PDX models, and the comparison with the non-responding model in the founding study is across laboratories and not head to head.
Evidence that argues against this (1)
- The founding study's non-responding NUP98-NSD1 PDX carried FLT3-ITD among its co-mutations, which is the opposite conclusion about the same co-lesion. The two reports are not reconciled anywhere in the literature read here, and no experiment has tested FLT3-ITD as a response modifier prospectively. Carraway HE et al. 2025
- treated by →NUP98::NSD1, t(5;11)(q35;p15.5)
first published CR in NUP98-rearranged AML on a menin inhibitor
grade 3 differentiation syndrome as on-target pharmacology in a NUP98 patient
escape was by RAS-pathway co-mutation, not a MEN1 binding-site mutation
FLT3-ITD co-mutation as a disputed response modifier in NUP98-NSD1 PDX
500 mg daily, COVALENT-101
RAS-pathway escape in the only published NUP98 complete remission