No menin-inhibitor or DOT1L-inhibitor trial has ever named this fusion - and the DOT1L trials excluded it by construction
also called PICALM::MLLT10 trial eligibility
We checked the eligibility rules of every major menin-blocking drug trial and both DOT1L-blocking drug trials. None mentions CALM-AF10. Worse, the DOT1L trials required an '11q23' chromosome break, which this fusion does not have - so the drug that should work here was never given to these patients.
The same thing, for a scientist
Read from the raw ClinicalTrials.gov v2 API on 2026-09-20. **Menin inhibitors:** AUGMENT-101 (revumenib) names KMT2A, NPM1 and NUP98 [E1]; KOMET-001 (ziftomenib) names KMT2A and NPM1 [E2]; cAMeLot-1 (bleximenib) names KMT2A, NPM1 and NUP98 [E3]; the enzomenib study names KMT2A/MLLr and NPM1 [E4]. **PICALM, MLLT10 and CALM-AF10 appear in none of them.** **But AUGMENT-101 cohort 2D is open by mechanism, not by gene**: 'R/R acute leukemia with a genetic mutation expected to lead to HOX/MEIS upregulation (for example, KMT2Ar, NPM1m, and NUP98r)' [E1] - wording a PICALM::MLLT10 patient satisfies. **DOT1L inhibitors are the sharper finding.** Both pinometostat phase 1 studies required **'rearrangement involving the MLL gene, including reciprocal chromosomal translocations involving 11q23'** [E5][E6]. **PICALM is at 11q14**, so t(10;11)(p13;q14) is not an 11q23 rearrangement and a CALM-AF10 patient was not eligible. The preclinical case for DOT1L inhibition is strongest in AF10 fusions, and the clinical test was run in the disease where it is weakest. A third study, pinometostat with standard chemotherapy in newly diagnosed KMT2A-rearranged AML, was **terminated because the study agent was no longer available**, not for efficacy or safety [E7].
The actionable sentence
A relapsed PICALM::MLLT10 patient today is formally eligible for AUGMENT-101 cohort 2D on a HOX/MEIS criterion, and formally ineligible for every DOT1L-inhibitor study ever run, which is the exact inverse of what the preclinical data support. If a single fact from this beat should reach a clinician, it is that one.
Search bound
ClinicalTrials.gov full-record search, 2026-09-20: PICALM returns 2 studies, both cognitive/neurological (the Alzheimer's locus). MLLT10 returns 1 study - NCT06221683, a paediatric AML molecular-subtyping induction study in which MLLT10 appears as a subtyping term, not as a targeted-agent eligibility criterion. CALM-AF10 and "CALM-AF10" return 0. AF10 is unusable as a query term: it returns atrial-fibrillation studies, because AF is atrial fibrillation in the registry's corpus.
| nct | NCT04065399 |
|---|---|
| phase | survey of phase 1/2 menin-inhibitor and DOT1L-inhibitor studies |
| status | mixed; see per-trial evidence |
| n | 0 |
| readout | Zero trials name PICALM, MLLT10 or CALM-AF10 in eligibility. AUGMENT-101 cohort 2D is open by HOX/MEIS mechanism and would admit a PICALM::MLLT10 patient. Both pinometostat studies required an 11q23/MLL rearrangement, which excludes t(10;11)(p13;q14). |
| registry search bound | ClinicalTrials.gov full-record search 2026-09-20: PICALM = 2 studies (both neurological), MLLT10 = 1 (NCT06221683, a molecular-subtyping induction study), CALM-AF10 = 0. AF10 is unusable as a query token because AF means atrial fibrillation in this registry. |
| actionable | A relapsed PICALM::MLLT10 patient is formally eligible for AUGMENT-101 cohort 2D and was never eligible for any DOT1L-inhibitor study. |
arms
[ "revumenib NCT04065399", "ziftomenib NCT04067336", "bleximenib NCT04811560", "enzomenib NCT04988555", "pinometostat NCT01684150", "pinometostat NCT02141828", "pinometostat + chemotherapy NCT03724084 (terminated, agent unavailable)" ]
- Enrolling a CALM-AF10 patient on a HOX/MEIS criterion exposes them to differentiation syndrome and QTc risk on the strength of an untested mechanistic assumption.
- The 'DOT1L inhibition failed' narrative is being carried into this disease where the drug was never given. An absence of testing is not a negative result.
- Has any PICALM::MLLT10 patient actually been enrolled on AUGMENT-101 cohort 2D? The registry records eligibility, never enrolled genotypes, and the answer would be the first clinical datum on menin sensitivity in this fusion.
- Would a sponsor open a DOT1L-inhibitor arm restricted to AF10 fusions - KMT2A::MLLT10 plus PICALM::MLLT10 - given that the preclinical case is strongest exactly there and has never been tested?
- Is NCT06221683's MLLT10 term a KMT2A::MLLT10 term or a PICALM::MLLT10 term? The registry record does not distinguish them, and they are different diseases.
- E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.trial_registry
AUGMENT-101 (NCT04065399, revumenib, phase 1/2, recruiting) names KMT2A rearrangement, NUP98 rearrangement and NPM1 mutation in eligibility, and cohort 2D enrols R/R acute leukaemia with a genetic mutation expected to lead to HOX/MEIS upregulation; PICALM, MLLT10 and CALM-AF10 appear nowhere in the criteria.
A Study of Revumenib in R/R Leukemias Including Those With an MLL/KMT2A Gene Rearrangement or NPM1 Mutation (AUGMENT-101) · ClinicalTrials.gov 2026What this evidence cannot show
Read from the raw v2 API rather than the MCP wrapper, per the brief. Registry text is a protocol summary; the operative inclusion decision is made by the site investigator against the full protocol, which is not public.
Evidence that argues against this (1)
- Registry eligibility text is a protocol summary; the operative inclusion decision is made against the full protocol, which is not public, and cohort 2D's 'for example' list is explicitly non-exhaustive. A PICALM::MLLT10 patient's eligibility is therefore an inference from wording rather than a statement by the sponsor. ClinicalTrials.gov 2026
- E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.trial_registry
KOMET-001 (NCT04067336, ziftomenib, phase 1/2, active not recruiting) names KMT2A and NPM1 in eligibility and does not name MLLT10, PICALM or CALM-AF10.
First in Human Study of Ziftomenib in Relapsed or Refractory Acute Myeloid Leukemia (KOMET-001) · ClinicalTrials.gov 2026What this evidence cannot show
Raw v2 API, 2026-09-20.
Evidence that argues against this (1)
- PUBLISHED CONFLICTING RESULT about what these eligibility lists record. They track where dependency was demonstrated before the protocol was written, and that set has grown: NUP98-rearranged AML is a menin-MLL1 dependency - VTP50469 active at an IC50 similar to KMT2A-rearranged and NPM1c cells, MLL1 and the fusion evicted from chromatin together, survival prolonged in NUP98-NSD1 and NUP98-JARID1A xenografts - and a later menin-inhibitor protocol duly names NUP98. So the absence of PICALM::MLLT10 from KOMET-001 records the absence of a preclinical dependency paper, not a judgement that the fusion is menin-independent. The mechanism that would put it on a list is 'somebody runs the mouse experiment', and that is a cheap experiment. Heikamp EB et al. 2022
- E3established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.trial_registry
cAMeLot-1 (NCT04811560, bleximenib, phase 1/2, recruiting) names KMT2A, NPM1 and NUP98 and does not name MLLT10, PICALM or CALM-AF10.
A Phase 1/2 Study of Bleximenib in Participants With Acute Leukemia (cAMeLot-1) · ClinicalTrials.gov 2026What this evidence cannot show
Raw v2 API, 2026-09-20.
Evidence that argues against this (1)
- PUBLISHED CONFLICTING RESULT, and it is the sharpest one available on this entry. The closest genotype to PICALM::MLLT10 that has been tested against a menin inhibitor IS menin-sensitive: in patient-derived xenografts of KMT2A-rearranged leukaemias with high-risk fusion partners, three AMLs with MLLT10 and MLLT4 partners were SENSITIVE to menin inhibition. MLLT10 - the partner that supplies the DOT1L recruitment in CALM-AF10 - therefore sits inside a menin-dependent leukaemia. What differs between KMT2A::MLLT10 and PICALM::MLLT10 is the 5' partner, so the reason PICALM::MLLT10 is absent from these lists is a claim about PICALM, and nobody has shown that swapping the 5' partner removes the menin dependency. Mahdavi L et al. 2026
- E4established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.trial_registry
The enzomenib (DSP-5336) study NCT04988555, phase 1/2, recruiting, names KMT2A/MLLr and NPM1 and does not name MLLT10, PICALM or CALM-AF10.
A Phase 1/2 Study of Enzomenib (DSP-5336) in Patients With Acute Leukemia · ClinicalTrials.gov 2026What this evidence cannot show
Raw v2 API, 2026-09-20.
Evidence that argues against this (1)
- SOURCE-SCOPE DEFEATER: a named genotype in a protocol does not guarantee reported data, so an unnamed one carries even less. The registration-enabling phase 2 of the furthest-advanced menin inhibitor restricted its efficacy analysis to patients with CENTRALLY CONFIRMED KMT2A rearrangement - 57 evaluable of 94 treated - and reported the NPM1 cohort as separate and still ongoing. A trial that names two genotypes and reports one is evidence about enrolment logistics and central confirmation, not about which leukaemias the sponsor believes are menin-dependent. Building a claim about PICALM::MLLT10's standing in the field on which strings appear in three eligibility documents reads more into them than they will hold. Issa GC et al. 2025
- E5established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.trial_registry
The paediatric pinometostat study NCT02141828 required 'rearrangement involving the MLL gene, including reciprocal chromosomal translocations involving 11q23 by FISH, cytogenetic analysis, PCR or NGS, OR partial tandem duplication of MLL'.
A Phase 1 Dose Escalation and Expanded Cohort Study of EPZ-5676 in the Treatment of Children With Relapsed/Refractory Leukemias Bearing a Rearrangement of the MLL Gene · ClinicalTrials.gov 2026What this evidence cannot show
Raw v2 API, 2026-09-20. The exclusion of PICALM::MLLT10 is an inference from the band: PICALM is at 11q14 and KMT2A at 11q23, so a t(10;11)(p13;q14) case does not satisfy an 11q23 criterion and does not carry an MLL rearrangement. It is a strong inference, not a statement in the protocol.
Evidence that argues against this (1)
- MLLT10 is not entirely absent from the registry: NCT06221683, a paediatric AML induction study using molecular subtyping and MRD, names MLLT10 among its subtyping terms. It is not a targeted-agent eligibility criterion and the record does not distinguish KMT2A::MLLT10 from PICALM::MLLT10, but the token is in trial vocabulary. ClinicalTrials.gov 2026
- E6established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.trial_registry
The adult pinometostat study NCT01684150 likewise enrolled patients with MLL rearrangement including 11q23 or PTD into its expanded cohort.
A Phase 1, Open-Label, Dose-Escalation and Expanded Cohort, Continuous Intravenous Infusion Study of EPZ-5676 in Subjects With Advanced Hematologic Malignancies · ClinicalTrials.gov 2026What this evidence cannot show
Raw v2 API, 2026-09-20. Completed.
Evidence that argues against this (1)
- PUBLISHED CONFLICTING RESULT on how much the exclusion cost. The eligible arm of that study did not do well: across all dose levels 2 of 51 patients achieved complete remission, both with t(11;19), no maximum tolerated dose was established in dose escalation, and the authors describe the clinical activity as modest while noting the pharmacodynamic reduction in H3K79 methylation was achieved. A patient excluded from a trial that produced a 4% CR rate in the population selected for the mechanism has lost very little, and the entry's framing - that the DOT1L trials excluded this fusion by construction - is correct as a fact and overstated as a grievance. Stein EM et al. 2018
- E7established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.trial_registry
NCT03724084, pinometostat with standard chemotherapy in newly diagnosed KMT2A-rearranged AML, was terminated with whyStopped 'Other - Study agent no longer available'.
Pinometostat With Standard Chemotherapy in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia With MLL Gene Rearrangement · ClinicalTrials.gov 2026What this evidence cannot show
The whyStopped field is not returned by the MCP Clinical_Trials tool and was read from the raw API. Supply failure, not an efficacy or safety signal - which matters, because the clinical story of DOT1L inhibition is routinely summarised as 'it did not work'.
Evidence that argues against this (1)
- PUBLISHED CONFLICTING RESULT: the registry field and the efficacy record are not independent, so 'supply failure, not efficacy' is true and incomplete. The phase 1 that preceded this study reported complete remission in 2 of 51 adults and characterised the activity as modest, having confirmed target engagement by reduced H3K79 methylation. A sponsor discontinuing supply of an agent with demonstrated pharmacodynamics and modest clinical activity is making a decision informed by that record. Quoting 'Study agent no longer available' as a correction to 'it did not work' is right about what the registry says and should not be read as evidence that the efficacy story was better than reported. Stein EM et al. 2018
- related to →PICALM::MLLT10 (CALM-AF10), t(10;11)(p13;q14) - the DOT1L-dependent HOXA fusion that contains no KMT2A
no trial names this fusion; the DOT1L trials excluded it by band
AUGMENT-101 cohort 2D is open by HOX/MEIS mechanism
- related to →Pinometostat (EPZ-5676) — the DOT1L inhibitor, and the most instructive failure in this field
11q23 eligibility excluded t(10;11)(p13;q14) from both phase 1 studies
KOMET-001 names KMT2A and NPM1 only
cAMeLot-1 names KMT2A, NPM1 and NUP98 only
names KMT2A/MLLr and NPM1 only
cohort 2D encodes the rival hypothesis and could falsify this one
KMT2A::MLLT10 patient-derived xenografts are SENSITIVE to menin inhibition, so MLLT10 in a fusion is compatible with menin dependence and the exclusion is about the 5' partner