Interfant-99 — the first global infant ALL protocol, and the first negative answer on myeloid intensification
also called Interfant-99 · NCT00015873 · ISRCTN24251487
Interfant-99 was the first time doctors worldwide treated babies with leukemia on one shared plan, so the results could actually be compared. It showed that adding extra AML-style chemotherapy at the end of treatment did not help at all.
The same thing, for a scientist
Interfant-99 enrolled 482 infants under 1 year with ALL across 17 study groups in 22 countries (1999-2005) onto a hybrid ALL/AML backbone, and randomised those in CR after the 5-week induction to an intensified late-intensification course or not. Four-year EFS for the whole cohort was 47.0% (SE 2.6; 95% CI 41.9-52.1). The randomised question was negative: 4-year DFS 60.9% (SE 5.2) with intensification versus 57.0% (SE 5.5) without, p=0.81. KMT2A rearrangement of any type, very high WBC, age under 6 months and poor prednisone response were each independently associated with inferior outcome.
Design and what the randomisation asked
Infant ALL is rare enough that no single country can run a definitive trial, which is why Interfant exists. The protocol used a hybrid backbone: an ALL-type induction and framework with AML-type elements folded in, on the reasoning that KMT2A-rearranged infant leukemia sits biologically between the two lineages.
Of 445 infants in complete remission after the 5-week induction, 191 were randomised (95 to the additional intensification course, 96 to control) 1. That randomisation fraction — 191 of 445 — is itself informative: more than half of eligible infants were not randomised, which limits generalisability and is typical of how hard these trials are to run.
Results, stated only as far as the primary source supports
| Endpoint | Value |
|---|---|
| Patients enrolled | 482 |
| 4-year EFS, whole cohort (ITT) | 47.0% (SE 2.6; 95% CI 41.9-52.1) |
| 4-year DFS, intensification arm | 60.9% (SE 5.2), n=95 |
| 4-year DFS, control arm | 57.0% (SE 5.5), n=96 |
| p (randomised comparison) | 0.81 |
| In CR at median follow-up 38 months | 260/482 (58%) |
Toxicity during the randomised intensification phase, among the 71 patients with follow-up data: infections 49%, hepatotoxicity 31%, mucositis 30%, neurotoxicity 3% 1.
Numbers this graph deliberately does not state: the induction CR rate, 4-year overall survival with its confidence interval, EFS split by KMT2A-rearranged versus germline as explicit percentages, hazard ratios with CIs for the four prognostic factors, and the induction/toxic death count. None of these appear in the primary abstract and the full text could not be retrieved. They are quotable only from the tables, which we have not read. Do not import them from a review.
Why this trial is the reference point for everything after it
Interfant-99 established the four-variable risk model that Interfant-06 then formalised (KMT2A status, age under 6 months, WBC, prednisone response), and it established the negative result that intensification of conventional cytotoxic therapy does not rescue KMT2A-rearranged infants. Every subsequent strategy — FLT3 inhibition in AALL0631, hypomethylation in AALL15P1, blinatumomab, menin inhibitors — exists because this door was closed first.
| nct | NCT00015873 |
|---|---|
| isrctn | ISRCTN24251487 |
| phase | Observational cohort with an embedded multicentre randomised comparison |
| status | Completed (enrolment 1999-2005) |
| n | 482 |
| n randomised | 191 |
| population | Infants <1 year with newly diagnosed ALL |
| pediatric eligible | true |
| open now | false |
| readout | Negative for late intensification; established the four-factor infant ALL risk model |
arms
[
{
"name": "Additional late intensification course",
"n": 95,
"dfs_4y_pct": 60.9,
"se": 5.2
},
{
"name": "No additional intensification",
"n": 96,
"dfs_4y_pct": 57,
"se": 5.5
}
]primary result
{
"efs_4y_pct": 47,
"se": 2.6,
"ci95": [
41.9,
52.1
],
"randomised_p": 0.81
}prognostic factors
[ "any KMT2A rearrangement", "very high WBC", "age <6 months", "poor prednisone prophase response" ]
- Essential-function toxicity: infection during intensification affected 49% of the randomised patients with follow-up data, in a population whose immune system is immature at baseline.
- Late effects: anthracycline and alkylator exposure in the first year of life is a major driver of cardiac and growth late effects in survivors, and intensification adds that exposure without adding survival.
- Compensation: the negative result is the clinical demonstration that KMT2A-rearranged infant leukemia is not chemo-sensitivity-limited, so escalating cytotoxic dose is a dead lever.
- What were the actual KMT2A-rearranged versus germline EFS percentages? They are repeatedly quoted in reviews but we could not verify them from the primary paper, and this graph should hold the verified number.
- Was the non-randomised majority (254 of 445 in CR) systematically different from the randomised 191? If sicker infants were not randomised, the negative intensification result may understate harm rather than show equipoise.
- Why did an AML-flavoured intensification fail in a leukemia whose defining lesion is lineage-ambiguous? The answer is presumably that lineage plasticity is not the same as drug-class sensitivity, but nobody has shown that directly.
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Interfant-99 enrolled 482 infants under 1 year with ALL in 22 countries; 4-year EFS was 47.0% (SE 2.6; 95% CI 41.9-52.1); of 445 in CR after induction, 191 were randomised to late intensification (95) or not (96) with 4-year DFS 60.9% (SE 5.2) versus 57.0% (SE 5.5), p=0.81; KMT2A rearrangement, very high WBC, age under 6 months and poor prednisone response were independently associated with inferior outcome.
A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomised trial · Pieters R, Schrappe M, De Lorenzo P, et al. · Lancet 2007What this evidence cannot show
All figures above are taken from the primary abstract; the full text is paywalled and was not retrieved, so hazard ratios, confidence intervals on DFS, the induction CR rate, overall survival and the toxic death rate are NOT asserted here. Only 191 of 445 eligible infants were randomised, so the randomised comparison is underpowered relative to the cohort size and subject to selection. The '58% in complete remission at median follow-up 38 months' figure is disease status at last follow-up, not an induction CR rate; it is frequently misquoted as one.
Evidence that argues against this (1)
- The generalised reading of this result - that intensifying conventional chemotherapy cannot help KMT2A-rearranged infants - is contradicted by the JPLSG MLL-10 trial, which put high-dose cytarabine into EARLY intensification (rather than late) under a three-tier risk stratification and reported 3-year EFS of 66.2% (SE 5.6) for KMT2A-rearranged infants and 94.4% (SE 5.4) for the intermediate-risk group, roughly 20 points above the Interfant series. Interfant-99 randomised a LATE course in patients already in CR; MLL-10 argues the timing, not the principle, was what failed. Counterweight: MLL-10 was a single-country, non-randomised, 90-patient study and the comparison with Interfant is historical. Tomizawa D et al. 2020
- E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.trial_registry
Interfant-99 is registered on ClinicalTrials.gov as NCT00015873 and on the ISRCTN registry as ISRCTN24251487.
Interfant-99 trial registration · Dutch Childhood Oncology Group and Interfant consortium · ClinicalTrials.gov 2007What this evidence cannot show
Registration numbers are taken from the primary publication's abstract; the registry record itself was not independently opened for this node.
Evidence that argues against this (1)
- The registration record understates this trial by more than a quarter and has never carried results. Raw ClinicalTrials.gov v2 API, retrieved 2026-09-19: NCT00015873 lists enrolment 350 as ESTIMATED, hasResults FALSE, last update 2014-02-14. The trial's own publication reports 482 ENROLLED patients who underwent the hybrid treatment, of whom 445 were in complete remission after five weeks of induction and 191 were randomised (95 to late intensification, 96 control). Anyone reading the registry for Interfant-99's size would be out by 132 patients, and the ISRCTN cross-reference does not fix that. Pieters R et al. 2007
- ← related toLeukaemia diagnosed in the first month of life: a different presentation and a different prognosis
30 congenital ALL patients treated uniformly on Interfant-99
482 infants, 4-year EFS 47.0%, model uses 'all types of MLL rearrangement' as one covariate
the predecessor whose prognostic factors built this risk model, and whose outcomes it did not improve on
- ← related toWhich MRD timepoint drives which decision in infant ALL, and how good the evidence for each is
the first infant MRD timepoint analysis, three MRD-defined groups
no per-partner EFS in the published abstract; full text not open access
- ← related toInterfant-06 — 651 infants, and the definitive answer that myeloid-style consolidation does not help
successor; outcome did not improve on Interfant-99
randomised late intensification: 4-year DFS 60.9% vs 57.0%, p=0.81
Interfant-99 used prednisone response alone; its subgroup analysis defined the Interfant-06 criteria