Oncofusion

start / graph / disease-kmt2a-r-all

Diseasestrong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.Q-nonelongation-partners

KMT2A-rearranged acute lymphoblastic leukaemia

also called KMT2A-r ALL · MLL-rearranged ALL · 11q23/KMT2A-rearranged ALL

Acute lymphoblastic leukaemia in which the KMT2A gene on chromosome 11 has broken and joined another gene. It is the defining lesion of leukaemia in babies under one year old, and it responds far worse to standard treatment than other childhood ALL.

The same thing, for a scientist

KMT2A-rearranged ALL is defined by a chromosomal rearrangement of KMT2A at 11q23.3 producing an in-frame fusion to one of more than a hundred partner genes. It is the dominant genotype of infant ALL and carries substantially worse outcomes than KMT2A-germline ALL: in Interfant-06, 651 infants had 6-year event-free survival of 46.1% (SE 2.1) and overall survival 58.2% (SE 2.0), with KMT2A rearrangement the strongest prognostic factor for EFS, ahead of age, white-cell count and prednisone response; the high-risk group (KMT2A-rearranged, older than 6 months, WBC at least 300 x 10^9/L or poor prednisone response) had 6-year EFS of 20.9% (SE 3.4) [E1]. The partner distribution is strongly lineage-biased: in 3401 genomically characterised KMT2A-rearranged patients the lymphoid cases are dominated by AFF1, MLLT1, MLLT3, MLLT10 and EPS15, while the cytoskeletal and septin partners are almost entirely myeloid, contributing only three lymphoid patients between them [E2]. This entry is a minimal canonical node written so that non-elongation-partner entries can resolve their lineage edges; it is not a full disease review and the coordinator should expect a fuller version from a clinical beat.

Go deeper
Why this node exists in this folder

The canonical id list includes disease-kmt2a-r-all but no entry had been written when this beat needed it, so a minimal, fully cited version was created here per the standing instruction, using the canonical id so edges resolve. It should be superseded by a proper clinical entry rather than extended piecemeal.

Partner distribution is a lineage question

Across 3401 genomically characterised patients, ALL cases cluster on a small set of partners: AFF1 (1262 patients in total, 477 of them infant ALL), MLLT1 (460 total, 234 infant ALL), MLLT3, MLLT10 and EPS15 2. The septin partners contribute almost nothing lymphoid — SEPTIN6 and SEPTIN9 have zero ALL cases across 33 patients, SEPTIN5 one, SEPTIN11 two — and ABI1 has none 2. Whatever determines lineage in KMT2A-rearranged leukaemia, partner identity tracks it strongly, and the non-elongation partners sit on the myeloid side of that split.

Response to menin inhibition

Revumenib is approved and active in relapsed or refractory KMT2A-rearranged acute leukaemia across lineages, with a CR+CRh of 22.8% in the AUGMENT-101 efficacy population 3. In vitro, KMT2A-rearranged ALL and AML respond differently in kind, not just in degree: ALL samples show rapid dose-dependent induction of leukaemic cell death while AML responses are much slower and promote myeloid differentiation, and revumenib synergises with the DOT1L inhibitor pinometostat in KMT2A-rearranged ALL 4. That lineage difference is a caution for any claim that menin dependence is uniform.

Facts and figures
who classacute lymphoblastic leukaemia with KMT2A rearrangement
defining lesionin-frame fusion of KMT2A (11q23.3) to one of >100 partner genes
node scopeMINIMAL canonical node written by the non-elongation-partners beat so that partner entries could resolve lineage edges. Not a full clinical review; expected to be superseded.
non elongation partner lymphoid cases
SEPTIN60.000SEPTIN6: 0SEPTIN90.000SEPTIN9: 0SEPTIN20.000SEPTIN2: 0ABI10.000ABI1: 0SEPTIN51.000SEPTIN5: 1SEPTIN112.000SEPTIN11: 2
dominant partners lymphoid
[
  "AFF1",
  "MLLT1",
  "MLLT3",
  "MLLT10",
  "EPS15"
]
non elongation partner lymphoid cases — the numbers behind the chart
{
  "SEPTIN6": 0,
  "SEPTIN9": 0,
  "SEPTIN5": 1,
  "SEPTIN11": 2,
  "SEPTIN2": 0,
  "ABI1": 0
}
outcome
{
  "cohort": "Interfant-06, infants <1 year, n=651",
  "efs_6yr_pct": 46.1,
  "efs_6yr_se": 2.1,
  "os_6yr_pct": 58.2,
  "os_6yr_se": 2,
  "high_risk_efs_6yr_pct": 20.9,
  "high_risk_efs_6yr_se": 3.4
}
drugs
[
  "drug-revumenib",
  "drug-blinatumomab"
]
How this could bite us back
  • Outcome varied by 10-12% between regions within a single protocol, which means any biological explanation of KMT2A-r ALL prognosis is competing with a care-delivery explanation of similar magnitude.
  • Menin-inhibitor kinetics differ between KMT2A-rearranged ALL and AML, and partner distribution differs between the two lineages, so lineage and partner are confounded in every dataset currently available.
Still open
  1. Does partner identity predict lineage causally, or does cell of origin determine which partner is available for rearrangement? The septin partners' near-absence from ALL is a clean natural experiment nobody has framed that way.
  2. Are the two lymphoid SEPTIN11 cases and the one SEPTIN5 case genuine B- or T-lineage disease, or mixed-phenotype presentations classified as ALL?
Every source behind this entry (4)
  1. E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper

    In Interfant-06, 651 infants younger than 1 year with ALL had 6-year event-free survival of 46.1% (SE 2.1) and overall survival 58.2% (SE 2.0); KMT2A rearrangement was the strongest prognostic factor for EFS, followed by age, white-cell count and prednisone response; the high-risk KMT2A-rearranged group had 6-year EFS of 20.9% (SE 3.4); and early intensification with myeloid-type chemotherapy did not improve outcome over the lymphoid-type course IB (6-year DFS 39.3% vs 36.8%, log-rank p=0.47).

    PMID 31283407DOI
    What this evidence cannot show

    Infants under 1 year only; the outcome figures do not generalise to older children or adults with KMT2A-rearranged ALL. Only 46% of high-risk patients intended for transplant received it, because many had early events, so the HR figure reflects an intention-to-treat population with substantial early attrition.

    Evidence that argues against this (1)
    • Outcome varied by region within the same protocol — 6-year EFS was 49.4% in West European/North American groups against a trial-wide 46.1%, a 10-12% gap versus other countries — so a substantial part of the prognosis attributed to biology is attributable to care delivery. Pieters R et al. 2019
  2. E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper

    In 3401 genomically characterised KMT2A-rearranged acute leukaemia patients, the lymphoid cases concentrate on a small set of partners (AFF1 n=1262 total with 477 infant ALL; MLLT1 n=460 with 234 infant ALL; MLLT3, MLLT10 and EPS15 next), while the septin partners contribute almost no lymphoid disease — SEPTIN6 (n=19) and SEPTIN9 (n=14) have zero ALL cases in any age class, SEPTIN5 one and SEPTIN11 two — and ABI1 (n=8) has none.

    The KMT2A recombinome of acute leukemias in 2023. · Meyer C, Larghero P, Almeida Lopes B, et al. · Leukemia 2023
    PMID 37019990DOI
    What this evidence cannot show

    Read from Table 1 of the PMC full text. A referral cohort, not population incidence; lineage assignment follows the referring centre's diagnosis and mixed-phenotype cases are classified inconsistently.

    Evidence that argues against this (1)
    • Lineage assignment in KMT2A-rearranged leukaemia is genuinely unstable: infant ALL is characterised by coexpression of myeloid markers, and lineage switch at relapse is documented, so a partner-lineage correlation drawn from diagnostic labels is softer than the table makes it look. Pieters R et al. 2019
  3. E3established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper

    In AUGMENT-101, revumenib monotherapy in relapsed or refractory KMT2A-rearranged acute leukaemia met its primary endpoint with CR+CRh of 22.8% (95% CI 12.7 to 35.8) in a 57-patient efficacy population and an overall response rate of 63.2%, with responses across a broad age range from 1 to 75 years and efficacy observed across subgroups including lineage and KMT2A translocation partner in exploratory analyses with limited sample sizes.

    PMID 39121437DOI
    What this evidence cannot show

    Relapsed/refractory population, heavily pretreated (median 2 prior lines, 45.6% with at least 3), 71.9% with prior venetoclax. Subgroup analyses including lineage are exploratory and underpowered.

    Evidence that argues against this (1)
    • The trial reports composition by cytogenetic translocation, and 22.8% of the efficacy population had an unknown fusion partner, so partner-stratified and lineage-stratified conclusions from it cannot be checked after the fact. Meyer C et al. 2023
  4. E4strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    In vitro, KMT2A-rearranged ALL samples show rapid dose-dependent induction of leukaemic cell death on revumenib while KMT2A-rearranged AML responses are much slower and promote myeloid differentiation; acquired resistance in KMT2A-rearranged ALL arises either through MEN1 mutation or independently of it; and revumenib synergises significantly with the DOT1L inhibitor pinometostat in KMT2A-rearranged ALL.

    PMID 38892207DOI
    What this evidence cannot show

    In vitro on patient samples and lines; the lineage comparison is not matched for partner, so some of the ALL/AML difference could be partner composition rather than lineage.

    Evidence that argues against this (1)
    • The confound is not hypothetical: partner distribution differs sharply by lineage — ALL is dominated by AFF1 and MLLT1 while AML carries the septin, AFDN and ELL partners — so an apparent lineage effect on menin-inhibitor kinetics is partly a partner effect, and neither study design separates them. Meyer C et al. 2023
Connected to