Lineage drift - the partial state between B-ALL and AML, and the fact that nobody has published the ORDER in which markers change
also called lineage drift · myelomonocytic switch · partial immunophenotypic shift · marker order at lineage switch · mm-SW
When this leukaemia escapes an antibody therapy by turning from a B-cell cancer into a myeloid one, it does not flip in a single step - there is an in-between state where only some of the markers have changed. If anyone could say which markers move first, a flow test could catch the change months before the relapse is obvious, and that would be worth more than a new drug target.
The same thing, for a scientist
**The answer to the beat's sharpest question is that nobody has published it.** This entry states the negative precisely and assembles what does exist. **The category exists and has a name.** Project EVOLVE collected 75 full lineage switches and, alongside them, **10 additional cases with incomplete changes in immunophenotype, which the authors call "lineage drift"**. Switch emerged at a **median of 1.5 months** after immunotherapy, 81.4% within 6 months; **64.3% of B-ALL-derived cases carried KMT2A rearrangement**; remission rates were under 40% and median overall survival after switch was **4.8 months**. Outcomes for lineage drift were described as similarly poor [E1]. **Ten drift cases are the entire published intermediate-state series**, and the paper does not report which markers had changed in them. **A transient, reversible version of the same shift is well measured, in a different setting.** In 1,812 children with BCP-ALL on AIEOP-BFM ALL 2009, CD371-positive cases (160, 8.8%) showed a **transient myelomonocytic switch in up to 65.4% of samples at day 15 of induction**, and **CD371 was the most sensitive marker of that switch**, whose recognition the authors call essential for correct flow MRD assessment. Those patients had slow early response but 5-year EFS of 88.3% [E2]. **So a partial myeloid shift under chemotherapy pressure is common, detectable, largely reversible and mostly not fatal** - which is a crucial calibration against reading every myeloid drift as an incipient switch. **Under menin inhibition the phenotype also moves, and in a directly relevant direction.** Sequential flow on 48 patients with relapsed/refractory AML on revumenib found dynamic immunophenotypic change in **16 of 31 evaluable (52%)**, specifically **switching between myeloid/stem-like and monocytic or myelomonocytic phenotypes, in either direction**, or substantial changes in antigen intensity [E3]. The authors' conclusion is that flow monitoring after menin inhibition requires recognising differentiation-associated phenotype change. **And the 2026 review that exists to answer this question issues definitions and monitoring recommendations rather than an order** [E4]. **What the graph should therefore say.** There is a named intermediate state; there is a well-measured reversible analogue under chemotherapy; there is a measured treatment-induced phenotype shift under menin inhibition. **There is no published marker-by-marker sequence for the B-ALL-to-AML switch in KMT2A-rearranged disease**, and constructing one is a re-analysis of paired diagnostic and relapse flow files that already exist.
The one paper that claims the harbinger, and why this entry cannot use it
PMID 32876512 is titled "Aberrant leukemia-associated immunophenotype as potential harbinger of lineage switch in KMT2A-rearranged leukemia: a case series" (Yost CM, ..., Schafer ES; Leuk Lymphoma 2020; doi 10.1080/10428194.2020.1815018). That title asserts exactly the thing this beat was sent to find.
It is unreadable, and the five-route test was run in full on 2026-09-20:
- Europe PMC core,
EXT_ID:32876512&resultType=core- pmcid: null, isOpenAccess: N, abstractText 0 characters {PMCID}/fullTextXML- cannot be attempted, no PMCIDefetch db=pmc- cannot be attempted; the rule-70 cross-check onefetch db=pubmedfor<ArticleId IdType="pmc">also returned none, so the PMCID is genuinely absent rather than missing from EPMC- PMC HTML page - cannot be attempted
curl -sL https://doi.org/10.1080/10428194.2020.1815018with a browser User-Agent - HTTP 403, 25 characters stripped
The PubMed record carries no abstract at all. So this entry records the identifier and what the title asserts, marks it weak, and does not write what the paper probably says - per concept-known-but-unreadable-literature. Route 5 failed in the loud way rule 60 describes: Taylor & Francis returns 403, the same shape as the JCO failure.
The same verdict applies to PMID 41925057, "Successful Management of Lineage Switch Infant Leukemia With Revumenib and Hematopoietic Cell Transplantation" (Granberg RE, ..., Pfeiffer T; Pediatr Blood Cancer 2026; doi 10.1002/1545-5017.70289) - no abstract, no PMCID by either route, DOI 403 at Wiley. It is the only item found in this beat that connects lineage switch, infancy and a menin inhibitor in one title, and it cannot be read.
What a marker-order study would look like, and why it is cheap
The materials already exist in every centre that treats this disease: paired diagnostic and relapse flow cytometry standard files from KMT2A-rearranged patients who switched, plus the interim timepoints taken for MRD. Nothing needs to be collected prospectively.
The analysis is a per-marker trajectory: for each of CD19, CD22, CD10, CD34, CD38, NG2, CD33, CD117, CD371, CD64, CD14 and CD7, the timepoint at which it crossed a positivity threshold relative to the timepoint of morphologic switch. The output is an ordering with uncertainty, and the useful form of the answer is the earliest marker whose change precedes morphologic switch by enough time to act.
Three predictions worth stating in advance, so the analysis can fail:
- CD371 moves first, because it is already the most sensitive detector of a transient myelomonocytic shift under chemotherapy 2.
- Monocytic markers (CD64, CD14) move before CD117, because CD117 is systematically negative in monoblastic AML (see
gene-kit), which is the commonest switch destination. - NG2 does not move, because it is a direct MLL-AF4 target gene and the fusion is retained through the switch by definition. If NG2 falls at switch while the rearrangement persists, that is evidence for
hyp-ng2-tracks-the-transcriptional-programme-not-the-rearrangement.
This is exp-marker-order-at-lineage-switch-paired-flow-reanalysis.
lineage drift
{
"definition": "incomplete changes in immunophenotype short of full lineage switch",
"n_published": 10,
"markers_reported": "NOT reported in the abstract",
"outcomes": "similarly poor to full switch",
"pmid": "40193715",
"title": "Project EVOLVE: an international analysis of postimmunotherapy lineage switch, an emergent form of relapse in leukemia.",
"authors": "Silbert SK, Rankin AW, Hoang CN, et al.",
"venue": "Blood",
"year": 2025,
"title_provenance": "Title/authors/venue backfilled from PubMed esummary on 2026-09-20 because this citation stored a bare PMID with no title, which made it unscoreable by verify-citations.py. BACKFILLING IS NOT VERIFICATION: it confirms the PMID resolves to a real paper, not that this is the right paper for the claim. That still requires reading."
}switch timing
{
"median_months_after_immunotherapy": 1.5,
"range": "0-36.5",
"pct_within_6_months": 81.4,
"kmt2a_fraction": "45/70 (64.3%)",
"median_os_after_switch_months": 4.8,
"pmid": "40193715",
"title": "Project EVOLVE: an international analysis of postimmunotherapy lineage switch, an emergent form of relapse in leukemia.",
"authors": "Silbert SK, Rankin AW, Hoang CN, et al.",
"venue": "Blood",
"year": 2025,
"title_provenance": "Title/authors/venue backfilled from PubMed esummary on 2026-09-20 because this citation stored a bare PMID with no title, which made it unscoreable by verify-citations.py. BACKFILLING IS NOT VERIFICATION: it confirms the PMID resolves to a real paper, not that this is the right paper for the claim. That still requires reading."
}reversible analogue
{
"phenomenon": "transient myelomonocytic switch during induction",
"detector": "CD371 (CLEC12A), most sensitive marker",
"frequency": "up to 65.4% of day-15 samples in CD371-positive BCP-ALL",
"5y_efs_pct": 88.3,
"pmid": "38215390",
"title": "CD371-positive pediatric B-cell acute lymphoblastic leukemia: propensity to lineage switch and slow early response to treatment.",
"authors": "Buldini B, Varotto E, Maurer-Granofszky M, et al.",
"venue": "Blood",
"year": 2024,
"title_provenance": "Title/authors/venue backfilled from PubMed esummary on 2026-09-20 because this citation stored a bare PMID with no title, which made it unscoreable by verify-citations.py. BACKFILLING IS NOT VERIFICATION: it confirms the PMID resolves to a real paper, not that this is the right paper for the claim. That still requires reading."
}under menin inhibition
{
"dynamic_change": "16/31 (52%) evaluable",
"direction": "myeloid/stem-like to monocytic/myelomonocytic OR vice versa",
"pmid": "41814014",
"title": "Immunophenotypic changes following menin inhibition in acute myeloid leukemia.",
"authors": "Loghavi S, Farhat A, Jamison TJ, et al.",
"venue": "Leukemia",
"year": 2026,
"title_provenance": "Title/authors/venue backfilled from PubMed esummary on 2026-09-20 because this citation stored a bare PMID with no title, which made it unscoreable by verify-citations.py. BACKFILLING IS NOT VERIFICATION: it confirms the PMID resolves to a real paper, not that this is the right paper for the claim. That still requires reading."
}unreadable
[
{
"pmid": "32876512",
"doi": "10.1080/10428194.2020.1815018",
"title_asserts": "aberrant leukemia-associated immunophenotype as potential harbinger of lineage switch in KMT2A-rearranged leukemia",
"routes_tried": "all five; EPMC pmcid null, efetch no pmc id, DOI 403 (Taylor & Francis), 25 chars stripped",
"date": "2026-09-20",
"title": "Aberrant leukemia-associated immunophenotype as potential harbinger of lineage switch in KMT2A-rearranged leukemia: a case series.",
"authors": "Yost CM, Gaikwad AS, Parsons DW, et al.",
"venue": "Leuk Lymphoma",
"year": 2020,
"title_provenance": "Title/authors/venue backfilled from PubMed esummary on 2026-09-20 because this citation stored a bare PMID with no title, which made it unscoreable by verify-citations.py. BACKFILLING IS NOT VERIFICATION: it confirms the PMID resolves to a real paper, not that this is the right paper for the claim. That still requires reading."
},
{
"pmid": "41925057",
"doi": "10.1002/1545-5017.70289",
"title_asserts": "successful management of lineage switch infant leukemia with revumenib and haematopoietic cell transplantation",
"routes_tried": "all five; EPMC pmcid null, efetch no pmc id, DOI 403 (Wiley), 25 chars stripped",
"date": "2026-09-20",
"title": "Successful Management of Lineage Switch Infant Leukemia With Revumenib and Hematopoietic Cell Transplantation.",
"authors": "Granberg RE, Magee JA, Shenoy S, et al.",
"venue": "Pediatr Blood Cancer",
"year": 2026,
"title_provenance": "Title/authors/venue backfilled from PubMed esummary on 2026-09-20 because this citation stored a bare PMID with no title, which made it unscoreable by verify-citations.py. BACKFILLING IS NOT VERIFICATION: it confirms the PMID resolves to a real paper, not that this is the right paper for the claim. That still requires reading."
}
]experiments
[ "exp-marker-order-at-lineage-switch-paired-flow-reanalysis" ]
- A panel tuned to detect drift will fire on a benign phenomenon. Transient myelomonocytic switch occurs in up to 65.4% of day-15 samples in CD371-positive BCP-ALL, and those children reach 88.3% 5-year EFS. Any early-warning rule must separate reversible induction-phase drift from the irreversible postimmunotherapy switch, and no published rule does.
- Menin inhibition itself moves the immunophenotype in 52% of patients with sequential flow, between myeloid/stem-like and monocytic in both directions. A drift-detection panel deployed in a menin-inhibitor trial would fire on the drug's own mechanism of action.
- Earlier detection is only useful if something can be done. Median overall survival after lineage switch is 4.8 months with remission rates under 40%, and no salvage strategy is established - so detecting the switch three months earlier buys time that currently has no intervention attached to it.
- The single paper whose title claims a harbinger immunophenotype is unreadable through all five routes. Building a monitoring strategy while its content is unknown risks either duplicating it or contradicting it, and neither is visible from here.
- Which markers change first at KMT2A-rearranged B-ALL to AML lineage switch? No published sequence was found. The materials - paired diagnostic, interim and relapse flow standard files - already exist.
- Does lineage drift progress to lineage switch, or is it a separate outcome? Ten drift cases exist in one series with similarly poor outcomes and no longitudinal follow-up of the drift state.
- Can transient induction-phase myelomonocytic switch be distinguished from early lineage switch at the single-cell level at the time it is seen? This is the question that decides whether early detection is actionable or merely alarming.
- What does PMID 32876512 actually report? It is the only paper claiming a harbinger phenotype in this genotype and it is unreadable through all five routes.
- E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
Project EVOLVE evaluated 75 cases of lineage switch after antigen-targeted therapy against CD19, CD22, CD38 and CD7: 53 (70.7%) B-ALL to AML, 17 (22.7%) B-ALL to MPAL or acute leukaemia of ambiguous lineage, and 5 (6.7%) rare presentations such as T-ALL to AML. An additional 10 cases with incomplete changes in immunophenotype, referred to as lineage drift, were also described. Among the 70 B-ALL-derived cases, lineage switch emerged at a median of 1.5 months (range 0-36.5) after immunotherapy, with 81.4% presenting within the first 6 months of the most proximal immunotherapy; 45 of 70 (64.3%) involved KMT2A rearrangements. Treatment outcomes were generally poor with remission rates under 40% and median overall survival after lineage switch diagnosis of 4.8 months, and outcomes were similarly poor for those with rare immunophenotypes of lineage switch or lineage drift.
Project EVOLVE: an international analysis of postimmunotherapy lineage switch, an emergent form of relapse in leukemia. · Silbert SK, ..., Shah NN · Blood 2025What this evidence cannot show
Abstract read in full from raw efetch XML on 2026-09-20; full text not read in this session (this graph records it as read in full elsewhere). **A retrospective international case collection with no denominator** - no incidence, no relative risk by preceding antigen, and no breakdown of the 75 cases by which antigen was targeted. **Critically for this entry: the abstract defines lineage drift as 'incomplete changes in immunophenotype' and does not say WHICH markers had changed in the 10 drift cases.** That is the entire content of the marker-order question and the paper's abstract does not address it; the full text may, and a reader should check.
Evidence that argues against this (1)
- A collection of reported cases over-represents the genotype people already expect to switch, so 64.3% KMT2A is a property of what gets recognised, worked up and reported rather than an estimate of risk. The same bias applies to which drift cases got noticed: incomplete shifts are exactly the events a busy laboratory does not report. Kovach AE et al. 2026
- E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
Among 1,812 children with newly diagnosed BCP-ALL enrolled in AIEOP-BFM ALL 2009 and evaluated as a screening cohort of 843 Italian and a validation cohort of 969 other iBFM centres, 160 (8.8%) were CD371-positive at diagnosis. This correlated with older age, lower ETV6::RUNX1 frequency, immunophenotypic immaturity (all P < .001) and strong expression of CD34 and CD45 (P < .05). During induction, CD371-positive BCP-ALLs showed a transient myelomonocytic switch in up to 65.4% of samples at day 15 and an inferior early response to chemotherapy (P < .001); 5-year event-free survival was nonetheless 88.3%. Among 420 validation-cohort patients, 27 of 28 (96.4%) DUX4-fusion-positive cases were CD371-positive. CD371 was the most sensitive marker of transient myelomonocytic switch, whose recognition the authors describe as essential for proper multiparametric flow MRD assessment.
CD371-positive pediatric B-cell acute lymphoblastic leukemia: propensity to lineage switch and slow early response to treatment. · Buldini B, ..., Dworzak MN · Blood 2024What this evidence cannot show
Abstract read in full from raw efetch XML on 2026-09-20; full text not read. **The transient myelomonocytic switch measured here is an induction-phase, chemotherapy-associated, largely reversible phenotypic shift - it is NOT the postimmunotherapy lineage switch of Project EVOLVE**, and conflating them would be a serious error. The CD371-positive subgroup is enriched for DUX4 fusions, a favourable genotype; the abstract does not report the KMT2A-rearranged fraction, and infants are largely excluded from AIEOP-BFM ALL 2009 by protocol. So the population is adjacent to, not the same as, this graph's.
Evidence that argues against this (1)
- That these patients reached 88.3% 5-year EFS is the argument against reading a myelomonocytic shift as an incipient lineage switch. A marker panel tuned to detect drift will fire on a common, reversible, benign phenomenon, and the resulting false-positive rate is the main practical obstacle to early switch detection. Buldini B et al. 2024
- E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
In sequential bone marrow specimens from 48 patients with relapsed or refractory AML treated with revumenib, dynamic changes in immunophenotype were observed in 16 of 31 (52%) patients, characterised by a switch from a myeloid/stem-like to a monocytic or myelomonocytic immunophenotype, or vice versa, or by substantial changes in the intensity of antigen expression or in patterns of leukaemia-associated immunophenotypes. Morphologic remission with undetectable flow MRD after revumenib was associated with median overall survival of 23.6 months, versus 20.8 months with detectable MRD and 3.2 months in non-responders. The authors conclude that flow-cytometric treatment monitoring of AML after menin inhibition requires recognition of phenotypic changes associated with differentiation.
Immunophenotypic changes following menin inhibition in acute myeloid leukemia. · Loghavi S, ..., Issa GC · Leukemia 2026What this evidence cannot show
Abstract read in full from raw efetch XML on 2026-09-20; full text not read; PMCID PMC13233299 exists, so a reader wanting the marker-by-marker detail - which is what this entry most needs - can run routes 2-4. **Denominators differ inside the abstract: 48 treated, 31 evaluable sequentially, 16 changed; the 52% is of 31.** Adult relapsed/refractory AML, not infant B-ALL, and KMT2A-rearranged and NPM1-mutant patients are not separated in the abstract. The phenotype changes are attributed to differentiation, the drug's intended mechanism, and not to lineage switch.
Evidence that argues against this (1)
- Because these shifts are the drug working, they are not evidence that menin inhibition causes lineage instability. But they do establish that a flow panel calibrated at diagnosis is miscalibrated on treatment, which is the same practical problem as lineage switch approached from the opposite direction. Kovach AE et al. 2026
- E4strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.review
In lineage switch the immunophenotype of the leukaemia at relapse differs from the immunophenotype at initial diagnosis with the underlying genetic drivers conserved, confirming a clonal relationship. Lineage switch is most common, and was first recognised, in B-cell acute lymphoblastic leukaemia with KMT2A rearrangement, which often relapses as acute myeloid leukaemia. In an era where antigen-targeted therapies including CAR T-cells and bispecific T-cell engagers are increasingly used and thus apply selective antigen pressure, this may increase the incidence of lineage switch across different leukaemia subtypes. Patients with lineage switch have dismal outcomes and optimal therapies remain unknown. The authors present definitions and recommendations for immunophenotypic and molecular monitoring.
Plasticity under pressure: biology and detection of lineage switch in acute leukemia. · Kovach AE, ..., Davis KL · Leukemia 2026What this evidence cannot show
**A narrative review, cited as a map of current definitions and as the strongest available evidence that no marker ORDER exists.** Abstract read in full from raw efetch XML on 2026-09-20; full text not read. The abstract states that the authors present definitions and monitoring recommendations - **it does not state a marker sequence**, and a review written expressly to address detection of lineage switch that does not lead with an order is reasonable evidence that no order has been established. That inference is this entry's, not the authors'. The full text should be checked before the absence is relied on.
Evidence that argues against this (1)
- An abstract not stating a marker order is weak evidence that the review contains none - the full text was not read, and monitoring recommendations may well specify which markers to watch first. This entry's central negative therefore rests on an unread full text and should be downgraded by anyone who reads it. Yost CM et al. 2020
- E5weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paper
A case series titled 'Aberrant leukemia-associated immunophenotype as potential harbinger of lineage switch in KMT2A-rearranged leukemia' exists and could not be read. The PubMed record carries no abstract. All five routes of this project's full-text test were run on 2026-09-20 and all five failed: Europe PMC core returned pmcid null with isOpenAccess N and a zero-character abstract; the rule-70 cross-check on efetch db=pubmed found no ArticleId of IdType pmc, so routes 2, 3 and 4 were structurally unavailable; and route 5, resolving the DOI with a browser User-Agent, returned HTTP 403 with 25 characters after stripping.
Aberrant leukemia-associated immunophenotype as potential harbinger of lineage switch in KMT2A-rearranged leukemia: a case series. · Yost CM, ..., Schafer ES · Leuk Lymphoma 2020What this evidence cannot show
**Title only. Nothing about this paper's content is asserted beyond its title**, and this entry deliberately does not state what the paper probably found, per `concept-known-but-unreadable-literature`. Bibliographic fields were fetched from PubMed efetch on 2026-09-20 and are not from recall. It is a **case series**, so even if read it would not establish an order with statistical support. A reader with institutional access to Taylor & Francis should read it, because its title asserts precisely the claim this entry says is unestablished.
Evidence that argues against this (1)
- If this paper does establish a harbinger immunophenotype, this entry's central negative is wrong, and the correct statement becomes that an order exists in a case series and has not been validated. Recording the identifier and the failed routes is the honest form of the claim, not evidence that the claim is safe. Kovach AE et al. 2026
- supports →Lineage switch in KMT2A-rearranged leukemia — the same clone changes what kind of blood cell it is
names the intermediate state (lineage drift, 10 published cases) and records that no marker ORDER has been published
- related to →Analysis: score fetal, myeloid-priming and differentiation-stage signatures across public KMT2A-r datasets
the marker-order question any switch-signature scoring would need an answer to
re-analysis of archived FCS files with a non-switching comparator arm and pre-registered predictions so it can fail
two on-topic papers unreadable after all five routes, including the one whose title claims the harbinger phenotype