Daunorubicin - the anthracycline an infant gets before her first birthday, with a measured null in vitro and sixty years of heart downstream
also called daunorubicin · DNR · daunomycin · daunorubicin hydrochloride · Cerubidine · rubidomycin · anthracycline (class)
Daunorubicin is the red drug given on days 8 and 9 of induction and again later. Infant leukaemia cells are no more sensitive to it than any other child's, and every milligram is a permanent withdrawal from a heart that has to last sixty years.
The same thing, for a scientist
Daunorubicin is an anthracycline that intercalates DNA and poisons topoisomerase II, and it generates the same class of TOP2-mediated double-strand break at the KMT2A breakpoint cluster region that makes etoposide leukaemogenic [see `drug-etoposide`, `drug-doxorubicin`]. In Interfant-06 it is **30 mg/m2/dose** on induction days 8-9 (60 mg/m2), **50 mg/m2/dose x 3** in ADE (150 mg/m2) and **30 mg/m2/dose x 4** in OCTADAD (120 mg/m2), omitted from OCTADA in the experimental arm precisely because of cumulative anthracycline dose [E1]. **The KMT2A/infant evidence is a measured null**: no difference between infants and older children for anthracyclines in the MTT assay that returned >580-fold for prednisolone on the same samples [E2]. The nearest thing to a positive is partner- and lineage-specific and it is about doxorubicin, not daunorubicin: t(9;11) AML was more sensitive to cytarabine and doxorubicin than non-11q23 AML [E3]. Against that, romidepsin synergised with daunorubicin in **6 of 6** infant ALL cell lines, the best score in that panel [E4]. The load-bearing fact is the toxicity, and it is quantified in `risk-anthracycline-cardiotoxicity-infant-leukemia`: daunorubicin's late-cardiomyopathy equivalence ratio to doxorubicin is **0.6** (95% CI 0.4-1.0) [E5].
Where it sits, and the cumulative arithmetic
From the protocol document 1:
| block | daunorubicin | cumulative |
|---|---|---|
| remission induction, days 8-9 | 30 mg/m2/dose | 60 mg/m2 |
| ADE (experimental arm), days 1, 3, 5 | 50 mg/m2/dose | 150 mg/m2 |
| OCTADAD part I, days 1, 8, 15, 22 | 30 mg/m2/dose | 120 mg/m2 |
Daunorubicin is omitted from OCTADA in the experimental arm - that is what the missing D denotes - explicitly because those patients already received it in ADE 1. The protocol also requires echocardiography before the first dose and carries a stopping rule on left ventricular shortening fraction 1.
All of this is delivered before the first birthday, at a body-surface-area dose already multiplied by 2/3 or 3/4 1, and the protocol's own guidance for daunorubicin is that when LVSF is repeatedly below 27% the drug is delayed to a later block rather than omitted 1 - a deferral, not a dose reduction.
What is known specifically, which is mostly what is not different
The null is well controlled. Anthracyclines appear in the list of drugs for which 'no differences were found' between 44 infants and 425 older children with common/preB ALL, in an assay that simultaneously returned >580-fold for prednisolone and 12-fold for asparaginase 2. So the instrument was working.
The one positive is about a different anthracycline in a different lineage. Palle et al. found t(9;11) AML more sensitive to doxorubicin (P = 0.005) as well as to cytarabine 3; they did not test daunorubicin separately, and the finding is in AML. Reading it across to daunorubicin in infant ALL requires two substitutions, and this entry does not make them.
The best combination signal in the beat. Romidepsin synergised with daunorubicin in all six infant ALL cell lines tested and significantly enhanced daunorubicin's DNA double-strand-break response at the protein level 4. That is the highest score in a panel where methotrexate and asparaginase were antagonised - but note what it implies: an HDAC inhibitor that amplifies an anthracycline's double-strand breaks in a disease caused by an anthracycline-class double-strand break at the KMT2A locus.
The aetiological shadow
Doxorubicin and etoposide induce cleavage at colocalising positions in the MLL breakpoint cluster region in primary progenitor haematopoietic cells from healthy newborns and adults 6. Daunorubicin is the same pharmacological class acting on the same enzyme, and this graph's whole aetiological account of therapy-related KMT2A-rearranged leukaemia runs through that mechanism [see drug-etoposide].
The honest statement is that daunorubicin has not been separately tested at this locus. Strick et al. name etoposide and doxorubicin; neither the cleavage-mapping literature nor the epidemiology separates daunorubicin. The SFOP case-control study that produced the famous epipodophyllotoxin relative risk of 197 treated anthracycline exposure as a combined category with a threshold of >170 mg/m2 7 - a threshold an Interfant-06 experimental-arm patient crosses before her first birthday.
| target | gene-top2a |
|---|---|
| target note | Schema requires a single target id. Daunorubicin is a DNA intercalator and topoisomerase II poison that does not distinguish TOP2A from TOP2B; gene-top2a is named because it is the isoform associated with the antiproliferative effect, and the KMT2A-locus cleavage attributed to this drug class is TOP2B-dependent (see gene-top2b and drug-etoposide). Treat any isoform-level statement about this drug as naming, not measurement. |
| modality | small molecule, anthracycline; DNA intercalator, topoisomerase II poison, free-radical generator |
| interfant06 position | induction days 8-9 (30 mg/m2/dose, 60 mg/m2 total); ADE days 1/3/5 (50 mg/m2/dose, 150 mg/m2); OCTADAD part I days 1/8/15/22 (30 mg/m2/dose, 120 mg/m2); omitted from OCTADA in the experimental arm because of cumulative anthracycline dose |
| interfant06 cumulative standard arm mg per m2 | 180 |
| infant dose adjustment | x 2/3 under 6 months, x 3/4 from 6 through 12 months |
| late cardiomyopathy equivalence ratio to doxorubicin | 0.6 |
| late cardiomyopathy equivalence ci | 0.4 to 1.0 |
| kmt2a specific evidence | A MEASURED NULL for infant ALL, with a working positive control in the same assay. The only anthracycline positive in KMT2A-rearranged disease is doxorubicin in t(9;11) AML. Best romidepsin synergy score in the infant ALL cell-line panel (6/6). |
| protocol cardiac rule | echocardiography before the first dose; if LVSF is repeatedly below 27% the dose is DELAYED to a later block rather than omitted; at LVSF 27-30% or above, full dose |
key ae
[ "myelosuppression", "mucositis", "alopecia", "severe tissue necrosis on extravasation", "acute arrhythmia", "late dilated cardiomyopathy", "secondary KMT2A-rearranged leukaemia (class effect, not separately quantified for this agent)" ]
resistance
[ "no infant- or KMT2A-specific mechanism identified in this beat", "P-glycoprotein efflux, which was not elevated in infants relative to older children in the cited profile study", "reduced topoisomerase II expression" ]
trials
[ "NCT00550992" ]
- **This is delivered to a heart that must last sixty more years, and the protocol's on-treatment safety test is a shortening fraction, which detects contractile failure after the damage.** 57% of doxorubicin-treated childhood ALL survivors had abnormal afterload or contractility a median of 6.4 years later.
- Daunorubicin belongs to the drug class that causes this disease when given for another one. Amplifying its DNA-damage signal - which is exactly what the best-scoring combination in the infant ALL cell-line panel does - amplifies the mechanism that produces therapy-related KMT2A rearrangement, and nobody has looked for second malignancies in that combination.
- The in-vitro null removes the biological argument for keeping daunorubicin, and the trial design removes the clinical one: Interfant-06 randomised an anthracycline-containing arm against an anthracycline-containing arm. A drug can be both unjustified and unremovable on the available evidence.
- Dexrazoxane protects the heart in children with high-risk ALL without loss of event-free survival, and has never been randomised in infants. Extending it to this population is the obvious move and would be a trial in babies of a drug whose own second-malignancy profile has been questioned.
- The 2/3 dose multiplier under 6 months reduces anthracycline exposure in the youngest patients, who are also the ones at highest independent risk of late cardiotoxicity and the ones with the worst leukaemia outcome. Whichever direction that multiplier is wrong in, it is wrong for the group with the least margin.
- Does daunorubicin cleave the KMT2A breakpoint cluster region? Etoposide and doxorubicin have been mapped there; the anthracycline an infant actually receives has not been tested, and this graph's entire aetiological account assumes the class behaves alike.
- Is the 180 mg/m2 of daunorubicin on the standard arm removable? The randomisation that would have told us compared two anthracycline-containing arms, so Interfant-06 contains no internal information about the anthracycline's contribution.
- What is the cardiomyopathy equivalence ratio in a patient dosed before the first birthday? The Feijen ratios are not age-stratified, and age under four at treatment is an independent risk factor separate from cumulative dose.
- Should romidepsin be scheduled with daunorubicin, given 6/6 synergy, when the mechanism of that synergy is amplified anthracycline-induced double-strand breaks in a disease caused by anthracycline-class double-strand breaks at this exact locus?
- E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
Interfant-06 gives daunorubicin 30 mg/m2/dose IV over 1 hour on induction days 8 and 9, 50 mg/m2/dose in ADE and 30 mg/m2/dose on OCTADAD part I days 1, 8, 15 and 22, with daunorubicin omitted from OCTADA for medium- and high-risk patients randomised to the experimental arm; if left ventricular shortening fraction is repeatedly below 27% daunorubicin is delayed to OCTADA(D) or ADE, and at LVSF of 27-30% or above the normal dose is given; the body-surface-area dose is multiplied by 2/3 under 6 months and 3/4 from 6 through 12 months.
Interfant-06 treatment protocol for infants under 1 year of age with acute lymphoblastic leukaemia - International collaborative treatment protocol, SKION version 01 (April 2006): chapter 5 chemotherapy schedule and chapter 7 modification for toxicity · Interfant-06 study group / SKION (Stichting Kinderoncologie Nederland, Dutch Childhood Oncology Group) · Interfant-06 study protocol document (90 pp.) 2006What 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. The cardiac monitoring schedule in chapter 8.7.3 of this version recommends echocardiography before treatment and before weeks 12 and 15 and states it as a recommendation, not a requirement.
Evidence that argues against this (1)
- A shortening-fraction stopping rule detects contractile failure, which is a late manifestation. In 115 children a median of 6.4 years after doxorubicin for ALL, 57% had abnormalities of left ventricular afterload or contractility, and age under four years at treatment independently predicted increased afterload after adjustment for cumulative dose. An LVSF threshold during therapy is not a test for the toxicity that matters here. Feijen EAM et al. 2019
- E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
No difference in cellular drug resistance was found for anthracyclines between 44 infants with ALL and 425 children over 1 year with common/preB ALL in the MTT assay, in the same experiment that returned more than 580-fold resistance to prednisolone and 12-fold to L-asparaginase.
In vitro drug-resistance profile in infant acute lymphoblastic leukemia in relation to age, MLL rearrangements and immunophenotype. · Ramakers-van Woerden NL, Beverloo HB, Veerman AJ, Camitta BM, Loonen AH, van Wering ER, et al. · Leukemia 2004What this evidence cannot show
A null with a working positive control in the same samples, which is the strongest form available, but still an in-vitro LC50 on bulk blasts. The abstract does not name which anthracycline or anthracyclines were tested, so 'anthracyclines' here is a class result and the entry does not claim it as a daunorubicin-specific measurement. No confidence interval is given, so the bound on the null effect is unknown.
Evidence that argues against this (1)
- An independent assay found t(9;11) AML significantly more sensitive to doxorubicin than non-11q23 AML (P = 0.005), so an anthracycline difference does exist somewhere in the KMT2A-rearranged population. The infant-ALL null and the t(9;11)-AML positive are compatible - different lineage, different partner, different assay - but the class null should not be read as 'anthracycline response is uniform across KMT2A-rearranged disease'. Palle J et al. 2005
- E3moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
In a fluorometric microculture cytotoxicity assay, children with t(9;11) AML (n = 10) were significantly more sensitive to doxorubicin (P = 0.005) as well as to cytarabine (P < 0.001) than children with non-11q23-rearranged AML (n = 108), and the authors propose that this 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 2005What this evidence cannot show
n = 10 in the index group. The anthracycline tested was doxorubicin, not daunorubicin, and the disease was AML, not infant ALL - two substitutions away from this entry's subject. The comparison against 'other 11q23 rearrangements' showed smaller differences, so the effect is partner-specific rather than KMT2A-specific.
Evidence that argues against this (1)
- Better outcomes in t(9;11) AML have alternative explanations that do not require a drug-sensitivity difference, including a distinct cooperating-lesion landscape and a lower relapse rate independent of the induction regimen. In-vitro sensitivity in 10 patients is a plausible but unproven mechanism for a survival difference. Ramakers-van Woerden NL et al. 2004
- E4moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
Romidepsin showed synergy with daunorubicin in all six infant ALL cell lines tested - the highest score in a panel that gave 4 of 6 for vincristine, 3 of 6 for dexamethasone and antagonism in 4 of 6 for methotrexate and L-asparaginase - and significantly enhanced the daunorubicin-induced DNA double-strand-break response measured by phospho-H2A.X.
Romidepsin enhances the efficacy of cytarabine in vivo, revealing histone deacetylase inhibition as a promising therapeutic strategy for KMT2A-rearranged infant acute lymphoblastic leukemia. · Cheung LC, Cruickshank MN, Hughes AM, Singh S, Chua GA, Ford J, et al. · Haematologica 2019What this evidence cannot show
Read from the PMC HTML full text on 2026-09-20; the efetch and Europe PMC abstract fields are empty because this is a Haematologica letter. Six cell lines, Bliss-independence scoring, 2 nM romidepsin with 30 nM daunorubicin for 24 hours; no primary patient samples and no in-vivo arm for this pair - the in-vivo work in that paper used cytarabine.
Evidence that argues against this (1)
- Amplifying an anthracycline's double-strand-break response is not an unambiguously good thing in this disease. The KMT2A breakpoint cluster region is a preferred site of topoisomerase-II-mediated cleavage by exactly this drug class, and therapy-related KMT2A-rearranged leukaemia is the documented consequence. A combination that increases phospho-H2A.X from an anthracycline should be assessed for second-malignancy risk, and that assessment does not exist. Strick R et al. 2000
- E5strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
In a pooled cohort of 28,423 five-year survivors of childhood cancer from the Childhood Cancer Survivor Study, the DCOG-LATER study and the St Jude Lifetime study, with 399 cardiomyopathy cases over a median 20 years of follow-up, the late-cardiomyopathy dose equivalence ratio relative to doxorubicin was 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.
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 2019What this evidence cannot show
Retrospective pooled cohorts treated 1962-2005, cumulative doses abstracted from medical records, endpoint severe/life-threatening/fatal cardiomyopathy by age 40. 4,433 survivors received daunorubicin. Idarubicin events were too rare to estimate. Most of these survivors were not infants, and the ratios are not age-stratified, so applying them to a cohort dosed before its first birthday is an extrapolation.
Evidence that argues against this (1)
- The equivalence ratios are derived for LATE-ONSET cardiomyopathy by age 40 in five-year survivors, from cohorts treated between 1962 and 2005 with historical supportive care and largely without dexrazoxane. Only 265 of 28,423 survivors received mitoxantrone and only 399 cardiomyopathy events occurred in total, so the mitoxantrone confidence interval is wide (6.2-19.1). The authors note the mitoxantrone relationship is better described by a linear exponential than a linear model, which means a single ratio is a simplification. Feijen EAM et al. 2019
- E6strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Doxorubicin and etoposide induce DNA cleavage at colocalising positions within the MLL breakpoint cluster region in primary progenitor haematopoietic cells from healthy newborns and adults, with topoisomerase II identified as the target and religation of the induced cleavage site 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 2000What this evidence cannot show
Cited in this entry only to establish that the anthracycline CLASS cleaves at this locus. Daunorubicin itself was not tested in this paper, and no study this beat found maps daunorubicin cleavage at the KMT2A breakpoint cluster region. Cleavage is not translocation.
Evidence that argues against this (1)
- The epidemiology does not separate daunorubicin from the anthracycline class, and the study that produced the famous dose-response treated anthracycline exposure as a single combined category with the epipodophyllotoxins. So the class mechanism is well demonstrated and the agent-specific risk for daunorubicin is genuinely unknown. Le Deley MC et al. 2003
- E7strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
In a matched case-control study within the Societe Francaise d'Oncologie Pediatrique (61 children with secondary leukaemia or myelodysplasia after a childhood solid tumour, 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).
Risk of secondary leukemia after a solid tumor in childhood according to the dose of epipodophyllotoxins and anthracyclines: a case-control study by the Société Française d'Oncologie Pédiatrique. · Le Deley MC, Leblanc T, Shamsaldin A, Raquin MA, Lacour B, Sommelet D, et al. · J Clin Oncol 2003What this evidence cannot show
Case-control, 61 cases, and anthracycline and epipodophyllotoxin exposures are correlated in these regimens and reported as a combined category in the headline result, so the anthracycline contribution is not separately estimated. The endpoint is secondary leukaemia of any genotype, not KMT2A-rearranged leukaemia. Children with solid tumours, not infants with ALL.
Evidence that argues against this (1)
- A relative risk from a solid-tumour survivor cohort cannot be applied to an infant with KMT2A-rearranged ALL whose competing risk is death from the primary leukaemia within two years. The NCI monitoring programme created for exactly this class of drug was established because premature abandonment was the foreseeable harm, and the same logic applies here. Pieters R et al. 2019
- part of →Interfant-06 — 651 infants, and the definitive answer that myeloid-style consolidation does not help
induction 60 mg/m2, ADE 150 mg/m2, OCTADAD 120 mg/m2
induction, ADE, OCTADAD
induction anthracycline
names this drug in data.affects; late-cardiomyopathy equivalence ratio 0.6 vs doxorubicin
topoisomerase II poison; does not distinguish TOP2A from TOP2B
same TOP2-poisoning class; etoposide and doxorubicin cleave at colocalising positions in the KMT2A BCR, daunorubicin untested there
synergy in 6 of 6 infant ALL cell lines, the highest score in that panel
both measured null against older children in the same MTT experiment
the protocol's stated comparison, contradicted in direction: 10.5 vs 0.6 doxorubicin-equivalents
daunorubicin is the anthracycline actually given; equivalence ratio 0.6 to doxorubicin