Oncofusion

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Drugstrong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.Q51-backbone

Doxorubicin - named in twenty entries of this graph, cuts the KMT2A breakpoint where etoposide does, and appears nowhere in Interfant-06

also called doxorubicin · DOX · DXR · adriamycin · Adriamycin · hydroxydaunorubicin · doxorubicin hydrochloride · anthracycline (class)

Doxorubicin is the anthracycline everyone means when they say 'anthracycline', and it is the yardstick every other one is measured against for heart damage. It is not in the infant leukaemia protocol at all - but it cuts DNA at exactly the spot where this disease's translocation happens.

The same thing, for a scientist

Doxorubicin is the reference anthracycline: a DNA intercalator and topoisomerase II poison against which all late-cardiomyopathy dose equivalences are defined [E1]. **It is not in Interfant-06.** A spike-controlled word count of the full protocol document returns zero for `doxorubicin`, `adriamycin` and the stem `doxo`, in the same instrument that returns 14 for `daunorubicin`, 8 for `mitoxantrone` and 9 for `vincristine` [E2]. The graph nevertheless names it in twenty entries, and it earns an entry for three reasons that are all real. **First, aetiology:** doxorubicin induces site-specific cleavage in the MLL breakpoint cluster region at positions colocalising with etoposide's, in primary progenitor haematopoietic cells from healthy newborns and adults, with religation of the induced site demonstrated [E3]. **Second, the only positive anthracycline sensitivity signal in KMT2A-rearranged disease is doxorubicin's:** t(9;11) AML was significantly more sensitive to doxorubicin (P = 0.005) and cytarabine (P < 0.001) than non-11q23 AML [E4]. **Third, it is the unit of account:** daunorubicin 0.6, epirubicin 0.8 and mitoxantrone 10.5 are all ratios *to doxorubicin* [E1], so every cardiotoxicity number in this beat is stated in doxorubicin.

Go deeper
The bounded absence, with its positive control

This entry's central negative claim is that doxorubicin is not part of Interfant-06 therapy. Because this project has been burned by zeros from broken instruments, the check was run as a spike: the same query shape, on the same document, with five terms known to be present 2.

termoccurrences in the protocol text
daunorubicin (spike)14
DNR (spike)21
vincristine (spike)9
mitoxantrone (spike)8
leucovorin (spike)8
doxorubicin0
adriamycin0
doxo (stem)0
idarubicin0
epirubicin0

Method: 90-page SKION April 2006 PDF, text extracted, lowercased, all whitespace removed before counting because the extractor inserts stray spaces inside words (it renders 'm ethotrexate' and 'recom mended'); a naive substring count on the raw text under-reports. The ClinicalTrials.gov intervention list agrees - doxorubicin is absent there too - but that list also omits dexamethasone, which the protocol prescribes, so the registry is not usable as evidence of absence and only the protocol document is.

Where the graph's twenty mentions come from is therefore worth naming: aetiology, cardiotoxicity equivalence, other protocols, and the Palle t(9;11) AML result. None of them is Interfant-06 therapy, and an entry that let the mention count imply otherwise would be wrong.

Aetiology: the same cut as etoposide

Strick et al. showed that dietary bioflavonoids cause site-specific cleavage in the MLL breakpoint cluster region in primary progenitor haematopoietic cells from healthy newborns and adults, colocalising with the cleavage site induced by etoposide and doxorubicin, with topoisomerase II identified as the target and religation of both the bioflavonoid- and the etoposide-induced site demonstrated 3.

So doxorubicin sits in this graph's causal account of KMT2A rearrangement alongside etoposide - and, unlike daunorubicin, it has actually been tested at the locus. drug-etoposide carries the full aetiological argument including the reasons not to read it as 'avoid these drugs'; all of that applies here.

And the epidemiology puts a number on the anthracycline limb. In the SFOP case-control study, >170 mg/m2 of anthracyclines (or 1.2-6 g/m2 of epipodophyllotoxins) carried a seven-fold higher risk of secondary leukaemia (95% CI 2.6-19) 5. An Interfant-06 standard-arm infant receives 180 mg/m2 of daunorubicin, which is above that threshold in raw milligrams even though the threshold was derived on a mixed anthracycline exposure.

Facts and figures
targetgene-top2a
target noteSchema requires a single target id. Doxorubicin is a DNA intercalator and topoisomerase II poison that does not distinguish TOP2A from TOP2B; the KMT2A-locus cleavage attributed to this class is TOP2B-dependent (see gene-top2b and drug-etoposide). Isoform-level statements about this drug are naming, not measurement.
modalitysmall molecule, anthracycline; DNA intercalator, topoisomerase II poison, free-radical generator
interfant06 positionABSENT. Doxorubicin appears nowhere in the Interfant-06 protocol document (spike-controlled count, see E2). The anthracycline in this protocol is daunorubicin and the anthraquinone is mitoxantrone.
role in this graphaetiological agent at the KMT2A breakpoint cluster region; reference unit for cardiotoxicity equivalence; the one anthracycline with a positive sensitivity signal in a KMT2A-rearranged subtype (t(9;11) AML). NOT an Interfant-06 treatment agent.
late cardiomyopathy equivalence ratio to doxorubicin1
named in graph entries20
named in graph entries noteCount taken 2026-09-20 over all 1,553 node files for the regex 'doxorubicin|adriamycin', case-insensitive, anywhere in the file. A mention count is not evidence of protocol membership and in this case is evidence of the opposite - the mentions are aetiological, cardiotoxicity-equivalence and other-protocol references.
kmt2a specific evidenceGENUINE BUT NOT THERAPEUTIC. Doxorubicin cleaves the MLL breakpoint cluster region at etoposide-colocalising positions in primary newborn progenitors, and t(9;11) AML is significantly more doxorubicin-sensitive than non-11q23 AML. Neither of those is a reason to give it to an infant with KMT2A-rearranged ALL, and the protocol does not.
key ae
[
  "myelosuppression",
  "mucositis",
  "alopecia",
  "severe tissue necrosis on extravasation",
  "late dilated cardiomyopathy (the reference agent for this toxicity)",
  "secondary KMT2A-rearranged acute myeloid leukaemia"
]
resistance
[
  "P-glycoprotein efflux",
  "reduced topoisomerase II expression",
  "no infant- or KMT2A-specific mechanism identified in this beat"
]
trials
[]
How this could bite us back
  • **This entry exists partly to stop a substitution.** Twenty entries name doxorubicin; zero doses of it are given in Interfant-06. Anyone reasoning from graph mention counts to infant exposure will get the wrong drug, and the drugs differ by a factor of 0.6 in the toxicity that matters most.
  • Doxorubicin is in this graph mainly as a cause of the disease. Framing an anthracycline as aetiological in a document read by clinicians risks the harm the NCI created a monitoring programme to prevent - premature abandonment of curative drugs - and the same caution recorded in drug-etoposide applies verbatim.
  • The one positive sensitivity finding is in ten children with t(9;11) AML. Building an anthracycline-intensification argument for infant ALL on it would be reading across a lineage, a partner gene, an age group and a drug.
  • The 170 mg/m2 anthracycline threshold associated with a seven-fold secondary-leukaemia risk is crossed by an Interfant-06 standard-arm infant at 180 mg/m2 of daunorubicin before her first birthday - but the threshold came from a combined anthracycline/epipodophyllotoxin exposure category in children with solid tumours, and quoting it as a limit for this protocol would be a scope error of exactly the kind this graph keeps making.
  • Because doxorubicin is the unit of account, every cardiotoxicity number in this beat inherits its assumptions: a ratio derived from survivors treated between 1962 and 2005, without dexrazoxane, and not stratified by age at treatment - in a population dosed before its first birthday, where age under four is an independent risk factor.
Still open
  1. Twenty entries in this graph name doxorubicin and it is in no infant protocol here. How many of those twenty are using it as a stand-in for 'anthracycline' where the drug actually given was daunorubicin? That substitution is exactly the one the cardiotoxicity equivalence ratios exist to prevent.
  2. Does daunorubicin cleave the KMT2A breakpoint cluster region as doxorubicin does? The drug that was mapped at the locus is not the drug infants receive, and this graph's aetiological account assumes the class behaves alike.
  3. Is t(9;11) AML's doxorubicin sensitivity a partner-gene property that would predict daunorubicin sensitivity in t(9;11) infant ALL? Ten patients, one assay, one lineage - and it is the only anthracycline positive in the whole KMT2A literature this beat searched.
  4. If doxorubicin is the yardstick, what is the doxorubicin-equivalent cumulative exposure of a child treated on Interfant-06 by the age of one, stratified by arm and by the 2/3 or 3/4 age multiplier? The calculation is straightforward and is not published anywhere this beat found.
Every source behind this entry (5)
  1. E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    Doxorubicin is the reference agent for anthracycline and anthraquinone late-cardiomyopathy dose equivalence: in 28,423 five-year survivors of childhood cancer with 399 cardiomyopathy cases over a median 20 years, the equivalence ratios relative to doxorubicin were 0.6 (95% CI 0.4-1.0) for daunorubicin, 0.8 (0.5-2.8) for epirubicin and 10.5 (6.2-19.1) for mitoxantrone, with idarubicin events too rare to estimate.

    Derivation of Anthracycline and Anthraquinone Equivalence Ratios to Doxorubicin for Late-Onset Cardiotoxicity. · Feijen EAM, Leisenring WM, Stratton KL, Ness KK, van der Pal HJH, van Dalen EC, et al. · JAMA Oncol 2019
    PMID 30703192DOI
    What this evidence cannot show

    Retrospective pooled cohorts treated 1962-2005, largely without dexrazoxane. 9,330 survivors received doxorubicin, so the reference arm is the best-populated, but the ratios are not age-stratified and most survivors were not infants. Being the unit of account is a convention as much as a finding.

    Evidence that argues against this (1)
    • The equivalence ratios are for late-onset cardiomyopathy and do not transfer to acute cardiac toxicity, to haematologic toxicity, or to antileukaemic potency, all of which have their own and different ratios. Most oncology groups' substitution rules use the haematologic equivalence, which for mitoxantrone is 4:1 and which these authors state significantly underestimates the cardiomyopathy association. Feijen EAM et al. 2019
  2. E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    Doxorubicin is not part of the Interfant-06 regimen: a whitespace-collapsed, case-insensitive word count over the full 90-page Interfant-06 SKION April 2006 protocol document returns 0 for 'doxorubicin', 0 for 'adriamycin', 0 for the stem 'doxo', 0 for 'idarubicin' and 0 for 'epirubicin', in the same instrument that returns 14 for 'daunorubicin', 21 for 'DNR', 9 for 'vincristine', 8 for 'mitoxantrone' and 8 for 'leucovorin'.

    What this evidence cannot show

    A trial protocol document, not a peer-reviewed publication, and specifically the SKION (Dutch) national version of April 2006; the trial was amended during its course (asparaginase provisions in MARMA and OCTADA(D) among others), so later versions may differ. Doses given are PLANNED doses; delivered cumulative dose per patient is lower wherever a course was omitted, delayed or curtailed by a stopping rule, and the trial report does not publish delivered dose per patient. Retrieved and text-extracted by this beat on 2026-09-20 (90 pages, 194,979 characters); page numbers are the PDF's own. **This is a bounded, spike-controlled absence and not an unbounded one.** Method, 2026-09-20: PDF fetched, text extracted with pypdf (90 pages, 194,979 characters), lowercased, ALL whitespace removed before counting, because the extractor inserts stray spaces inside words and a naive count on the raw text under-reports. Five positive controls were run through the identical query shape on the identical document and all returned non-zero. What this does NOT bound: later protocol versions, national amendments, and relapse or salvage therapy given off protocol, any of which may contain doxorubicin.

    Evidence that argues against this (1)
    • The ClinicalTrials.gov structured intervention list for NCT00550992 also omits doxorubicin, which looks like corroboration and is not usable as such: the same list omits dexamethasone, which the protocol prescribes on induction days 8-28. A registry field that is wrong in one direction gives no information when it is silent. ClinicalTrials.gov 2007
  3. E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    Dietary bioflavonoids cause site-specific DNA cleavage in the MLL breakpoint cluster region in primary progenitor haematopoietic cells from healthy newborns and adults, colocalising with the cleavage site induced by etoposide and doxorubicin, with topoisomerase II identified as the target and religation of the induced cleavage sites demonstrated.

    Dietary bioflavonoids induce cleavage in the MLL gene and may contribute to infant leukemia. · Strick R, Strissel PL, Borgers S, Smith SL, Rowley JD · Proc Natl Acad Sci U S A 2000
    PMID 10758153DOI
    What this evidence cannot show

    Cleavage is not translocation, and the authors' extrapolation from cleavage to maternal diet causing infant leukaemia is a proposal in their discussion rather than a result. The topoisomerase II isoform is not resolved. Doxorubicin's role in this paper is as a comparator cleaving agent, not the study's subject.

    Evidence that argues against this (1)
    • The epidemiological form of the topoisomerase-II-poison hypothesis has been tested and was essentially null: in the Children's Oncology Group case-control study of 240 incident infant acute leukaemias against 255 controls, a maternal dietary topoisomerase-II-inhibitor index showed little evidence of association overall or by subtype, and maternal fruit and vegetable intake was inversely associated with risk. That study is cited in full in drug-etoposide. Le Deley MC et al. 2003
  4. E4moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

    In a fluorometric microculture cytotoxicity assay across 132 children with AML, those with t(9;11) (n = 10) were significantly more sensitive to doxorubicin (P = 0.005) and to cytarabine (P < 0.001) than children with non-11q23-rearranged AML (n = 108); children with other 11q23 rearrangements (n = 14) differed less, and the authors propose that high cellular sensitivity to cytarabine and doxorubicin may explain the good treatment results in t(9;11) AML.

    Cellular drug sensitivity in MLL-rearranged childhood acute leukaemia is correlated to partner genes and cell lineage. · Palle J, Frost BM, Forestier E, Gustafsson G, Nygren P, Hellebostad M, et al. · Br J Haematol 2005
    PMID 15813846DOI
    What this evidence cannot show

    n = 10 in the index group and the result is in AML, not infant ALL. The comparison that matters for this beat - doxorubicin sensitivity in KMT2A-rearranged infant B-ALL - was not made in this or any study this beat found, and the infant-ALL MTT profile returned a null for anthracyclines as a class.

    Evidence that argues against this (1)
    • In the infant ALL comparison, anthracyclines showed NO difference between 44 infants and 425 older children with common/preB ALL in an assay that returned >580-fold for prednisolone on the same samples. So the anthracycline sensitivity signal in KMT2A-rearranged disease is confined to t(9;11) AML and does not appear in the lymphoid infant disease this graph is mainly about. Ramakers-van Woerden NL et al. 2004
  5. E5strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    In the SFOP matched case-control study of 61 children with secondary leukaemia or myelodysplasia after a childhood solid tumour against 196 controls, exposure to more than 170 mg/m2 of anthracyclines, or 1.2-6 g/m2 of epipodophyllotoxins, carried a seven-fold higher risk of secondary leukaemia (95% CI 2.6-19), while alkylating agents and radiotherapy did not raise risk.

    PMID 12637473DOI
    What this evidence cannot show

    Anthracycline and epipodophyllotoxin exposures are correlated in these regimens and are reported as a combined exposure category in the headline result, so the anthracycline contribution is not separately estimable and the 170 mg/m2 threshold should not be read as a doxorubicin-specific limit. Endpoint is secondary leukaemia of any genotype. Children with solid tumours, not infants with ALL.

    Evidence that argues against this (1)
    • The NCI Cancer Therapy Evaluation Program set up its monitoring plan for exactly this class of agent because concern over case reports risked premature abandonment of curative drugs, and its first analysis put the 6-year treatment-related AML/MDS rate at low cumulative dose at 3.2%, within the range already reported for alkylator regimens containing no topoisomerase II poison. A threshold crossed is not a harm demonstrated. Le Deley MC et al. 2003
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