Rob Pieters, Inge van der Sluis & the Interfant consortium (Princess Maxima Center, Utrecht) — the only global infant-ALL trial network
also called Interfant · Interfant-99 · Interfant-06 · Princess Maxima Center for Pediatric Oncology · Dutch Childhood Oncology Group · DCOG
Infant leukemia is so rare that no single country has enough patients to run a trial. Interfant is the international consortium that solved that, and it controls essentially every infant with this disease who is enrolled in a study anywhere.
The same thing, for a scientist
Interfant is the international collaborative trial programme for acute lymphoblastic leukaemia in infants under one year, coordinated from the Princess Maxima Center for Pediatric Oncology and the Dutch Childhood Oncology Group in Utrecht, with Rob Pieters as principal architect and Maria Grazia Valsecchi (Milano-Bicocca / Monza) as statistical lead. Interfant-99 enrolled through 17 study groups in 22 countries between 1999 and 2005; Interfant-06 comprised 18 national and international study groups; the blinatumomab add-on study, led by Inge van der Sluis, is the first regimen change in decades to show benefit. For a disease of roughly this incidence, Interfant is not one option for patient and sample access - it is effectively the only one.
What they own that no laboratory can generate2 deeper
Patients. Interfant-99 recruited infants aged 0-12 months through 17 study groups in 22 countries over six years 1; Interfant-06 ran through 18 study groups 2. In a disease with an incidence of a few cases per million births, this is the entire accessible population. Any question that needs n in the hundreds of infants can only be answered here.
Outcome data linked to biology. The Interfant-06 analysis defined risk groups on KMT2A status, age and white cell count, tested myeloid- versus lymphoid-style consolidation, and evaluated the role of stem-cell transplantation 2. MRD was measured in 249 KMT2A-rearranged infants at end of induction and end of consolidation and shown to be strongly prognostic, with 6-year disease-free survival of 60.2% for MRD-negative versus 33.8% for MRD-high infants 3.
Diagnostic material with molecular annotation. To run a DNA-based MRD assay on a KMT2A rearrangement, you must first sequence that patient's genomic breakpoint. Interfant did this for 249 infants 3. Those sequences exist.
A working immunotherapy platform in infants. The blinatumomab study added one post-induction course to Interfant-06 chemotherapy in 30 newly diagnosed infants 4, with long-term follow-up at a median of 4.2 years confirming sustained benefit over a historical Interfant-06 comparison cohort 5. That establishes that this consortium can and will test a new agent in infants, which is the gating question for translating anything the lab discovers.
The concrete, low-cost collaboration proposal
This is the single most actionable item in the whole landscape survey, and it is nearly free.
The Interfant-06 MRD paper states that MRD was measured in 249 infants by DNA-based PCR of rearranged KMT2A, immunoglobulin and/or T-cell receptor genes 3. To build a patient-specific KMT2A MRD assay you must know the genomic breakpoint sequence. So the consortium holds, as an operational by-product of MRD monitoring, breakpoint-resolved sequence for a cohort of KMT2A-rearranged infants that is already linked to protocol-standardised outcome data.
Those breakpoints were used as technical targets. As far as this survey found, they have never been analysed as a prognostic or biological variable - breakpoint position within the KMT2A breakpoint cluster region, retained versus lost domain content, microhomology signature at the junction, partner-gene intron - against the outcome data sitting in the same database.
The proposal is therefore: a retrospective analysis of existing sequence against existing outcome data, requiring no new samples, no new patients, no assay development and no laboratory spend. It answers a question the field has asked for twenty years (does the breakpoint matter?), it is publishable on its own, and it is the natural bridge project to Frankfurt, which holds the same kind of sequence at ten times the scale but without the trial-quality outcome linkage.
The realistic obstacles are governance, not science: consortium data-access committees, national consent frameworks across 18 study groups, and whether the breakpoint sequences were retained after the MRD assays were designed. Whether those sequences are still held and retrievable was not verified in this pass and is the first question to ask.
Collaborator, unambiguously
There is no competitive overlap. Interfant runs trials; it does not run a target-discovery programme. Its published bottleneck is explicit: outcomes for KMT2A-rearranged infants have barely moved in decades despite chemotherapy intensification 4, so the consortium needs new biology and new agents more than it needs another chemotherapy schedule.
What a small lab can offer is analysis and hypotheses; what it needs is patients and annotated material. That is a clean trade. The route in is usually through a national member group rather than cold-contacting the coordinating centre.
| group | Interfant international consortium; Rob Pieters (architect), Inge M. van der Sluis (blinatumomab programme), Janine Stutterheim (MRD), Maria Grazia Valsecchi and Paola De Lorenzo (statistics/trial office) |
|---|---|
| institution | Princess Maxima Center for Pediatric Oncology and Dutch Childhood Oncology Group, Utrecht, the Netherlands; statistical centre at Fondazione IRCCS San Gerardo dei Tintori, Monza and University of Milano-Bicocca, Italy; 18 national study groups across Europe, Australia/New Zealand and beyond |
| focus | International clinical trials in infant ALL; risk stratification; MRD methodology in infants; addition of immunotherapy (blinatumomab) to the infant backbone |
| partnering angle | Highest-priority collaboration. Concrete ask: retrospective analysis of the genomic KMT2A breakpoint sequences generated as MRD targets for 249 Interfant-06 infants, tested as a prognostic and biological variable (breakpoint position, retained/lost domain content, junction microhomology, partner intron) against the protocol-standardised outcome data already in the database. No new samples, no new patients, no laboratory spend, no competition with anything they do. |
| relationship | natural collaborator, no overlap, they need biology and we need patients |
key papers — the numbers behind the chart
[
{
"title": "A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomised trial.",
"year": 2007,
"venue": "Lancet",
"pmid": "17658395",
"doi": "10.1016/S0140-6736(07)61126-X",
"title_was_truncated": "Stored title was a strict prefix of the real one (102 of 162 chars). Restored 2026-09-20. This is the listing-truncation trap: idf overlap cannot see it, because a prefix shares all its words with the full title. It was invisible for a second reason too - this citation lives in a data block, which verify-citations.py did not walk until the same day."
},
{
"title": "Outcome of Infants Younger Than 1 Year With ALL Treated With the Interfant-06 Protocol",
"year": 2019,
"venue": "J Clin Oncol",
"pmid": "31283407",
"doi": "10.1200/JCO.19.00261"
},
{
"title": "Clinical Implications of MRD Detection in Infants With KMT2A-Rearranged ALL Treated on Interfant-06",
"year": 2021,
"venue": "J Clin Oncol",
"pmid": "33405950",
"doi": "10.1200/JCO.20.02333"
},
{
"title": "Blinatumomab Added to Chemotherapy in Infant Lymphoblastic Leukemia",
"year": 2023,
"venue": "N Engl J Med",
"pmid": "37099340",
"doi": "10.1056/NEJMoa2214171"
},
{
"title": "Sustained Benefit of Blinatumomab in Infants With KMT2A-Rearranged ALL: Long-Term Outcomes, Toxicity, and Pharmacokinetics.",
"year": 2026,
"venue": "J Clin Oncol",
"pmid": "41505662",
"doi": "10.1200/JCO-25-01806",
"title_was_truncated": "Stored title was a strict prefix of the real one (70 of 123 chars). Restored 2026-09-20. This is the listing-truncation trap: idf overlap cannot see it, because a prefix shares all its words with the full title. It was invisible for a second reason too - this citation lives in a data block, which verify-citations.py did not walk until the same day."
},
{
"title": "MRD and outcome in infant KMT2A-germline ALL on Interfant-06 (167 infants)",
"year": 2021,
"venue": "Eur J Cancer",
"pmid": "34785111",
"doi": "10.1016/j.ejca.2021.10.004"
}
]cohort sizes — the numbers behind the chart
{
"interfant_99_countries": 22,
"interfant_99_study_groups": 17,
"interfant_06_study_groups": 18,
"kmt2a_r_infants_with_mrd_data": 249,
"kmt2a_germline_infants_interfant_06": 167,
"blinatumomab_cohort": 30
}not verified
[ "whether the patient-specific genomic breakpoint sequences generated for MRD assay design in Interfant-06 were archived and are retrievable", "the consortium's current data-access and specimen-request process", "whether an Interfant-21 or successor protocol is open and what its molecular annotation includes" ]
- CD19-directed therapy in KMT2A-r disease has a documented escape route through lineage switch to a CD19-negative myeloid phenotype, so the blinatumomab benefit may be a deferral rather than a cure and may make any later CD19 approach useless.
- Consortium governance is slow: a data request across 18 national study groups with different consent frameworks can take longer than a grant cycle, so a project that depends entirely on Interfant access has schedule risk.
- If breakpoint position turns out not to predict outcome, the negative result is still publishable but removes one of the lab's differentiating angles.
- Do the genomic breakpoint sequences generated as MRD targets for 249 Interfant-06 infants still exist in retrievable form? This single administrative fact decides whether the cheapest high-value project in this graph is possible.
- Does breakpoint position predict outcome independently of age, white cell count and MRD? Nobody has tested it in a trial cohort.
- Does the 60.2% versus 33.8% MRD gradient reflect chemosensitivity or a biologically distinct subgroup? If the latter, the distinguishing feature may be visible in the breakpoint or in the retained fusion domain content.
- Will CD19-directed therapy in infants select for lineage switch, and does adding blinatumomab early change the relapse phenotype rather than the relapse rate?
- E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
Interfant-99 was an international treatment protocol for infants under one year with ALL, enrolling patients aged 0-12 months through 17 study groups in 22 countries between 1999 and 2005, using a hybrid ALL/AML-directed regimen with risk stratification by 7-day prednisone prophase response and a randomised late-intensification question.
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., Valsecchi MG · Lancet 2007What this evidence cannot show
A 2007 protocol; supportive care, MRD methodology and risk assignment have all changed since, so the outcome figures are historical. The randomised component addressed late intensification only, so most of the protocol's content is observational.
Evidence that argues against this (1)
- Interfant-99 is the historical backbone and its results predate every targeted agent now in use, so it functions in this graph as a baseline rather than as current practice. The same consortium's later protocol plus blinatumomab reports substantially better outcomes, which is the comparison that matters. New England Journal of Medicine 2023
- E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
Interfant-06 was an international phase III randomised study comprising 18 national and international study groups, which defined low-, medium- and high-risk groups by KMT2A status, age and white cell count, and tested myeloid-style versus lymphoid-style consolidation and the role of stem-cell transplantation.
Outcome of Infants Younger Than 1 Year With Acute Lymphoblastic Leukemia Treated With the Interfant-06 Protocol: Results From an International Phase III Randomized Study · Pieters R, De Lorenzo P, Ancliffe P, et al., Valsecchi MG · Journal of Clinical Oncology 2019What this evidence cannot show
The consolidation randomisation did not deliver the hoped-for benefit; the value of this trial for an outside collaborator is the cohort and its annotation rather than the therapeutic result.
Evidence that argues against this (1)
- Resolves a not_verified item in this entry and, in doing so, weakens the collaboration case. The entry lists as unverified 'whether an Interfant-21 or successor protocol is open and what its molecular annotation includes'. It is open. Interfant-21 (NCT05327894), 'International Collaborative Treatment Protocol for Infants Under One Year With KMT2A-rearranged Acute Lymphoblastic Leukemia or Mixed Phenotype Acute Leukemia', sponsored by the Princess Maxima Center with the University of Milano-Bicocca and Amgen Europe B.V. as collaborators, has been RECRUITING since 15 December 2022 with an estimated enrolment of 160 and primary completion September 2027. Three registry facts cut against the entry's framing. (1) The only registered interventions are blinatumomab -- there is no menin inhibitor anywhere in the protocol. The world's only global infant-ALL network has therefore committed its current frontline cohort to CD19-directed therapy, not to menin inhibition, while the two North American infant studies (COG AALL2121, NCT05761171; TINI 2, NCT05848687) carry revumenib and ziftomenib respectively. A lab whose thesis is the menin interface is proposing to collaborate with the one infant network that is not testing it. (2) The design is PHASE3, allocation NON_RANDOMIZED, sequential, with risk allocation by age under 6 months, WBC and prednisone response and a primary endpoint of event-free survival. So the successor protocol will again be read against historical Interfant-06 comparators, and the selected-historical-control limitation noted in this entry's E5 is structural to the programme rather than a one-off feature of the 30-infant blinatumomab study. (3) The registry record lists no genomic or breakpoint annotation among the outcome measures, so whether Interfant-21 will generate the breakpoint-resolved data the proposed retrospective needs is still unknown -- and is now a question about a live protocol that could be influenced, rather than an archival question. Caveat: registry records are sponsor-submitted and summarise, not reproduce, the protocol; correlative biology can exist in a protocol without appearing as an outcome measure. Read: full registry record retrieved 2026-09-18. Princess Maxima Center for Pediatric Oncology; University of Milano Bicocca; Amgen Europe B.V. 2026
- E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Within Interfant-06, minimal residual disease was measured in 249 infants with KMT2A-rearranged ALL by DNA-based PCR of rearranged KMT2A, immunoglobulin and/or T-cell receptor genes at end of induction and end of consolidation; end-of-induction MRD predicted outcome, with 6-year disease-free survival of 60.2% (MRD-negative), 45.0% (intermediate) and 33.8% (high).
Clinical Implications of Minimal Residual Disease Detection in Infants With KMT2A-Rearranged Acute Lymphoblastic Leukemia Treated on the Interfant-06 Protocol · Stutterheim J, van der Sluis IM, de Lorenzo P, et al., Pieters R · Journal of Clinical Oncology 2021What this evidence cannot show
The inference that patient-specific genomic breakpoint sequences were generated and retained for these 249 infants follows from the stated use of DNA-based PCR of rearranged KMT2A genes as an MRD target, which requires breakpoint knowledge; the paper does not state that the sequences were archived or are available. That step is an inference, not a verified fact, and must be confirmed with the consortium before the proposal is made.
Evidence that argues against this (1)
- The proposed collaboration -- 'breakpoint position ... tested as a prognostic and biological variable' against outcome -- is not a twenty-year-old untouched question. It was published in 2013, by the Frankfurt group this graph elsewhere describes as cataloguing breakpoints without analysing them. Emerenciano, Meyer, Mansur, Marschalek and Pombo-de-Oliveira studied 545 childhood leukaemia cases aged 24 months or under (385 ALL, 160 AML), determined the genomic breakpoint location in a subset of 30 KMT2A-rearranged cases, and reported 'first evidence that MLL-r patients with poor outcome preferentially displayed chromosomal breakpoints within MLL intron 11', concluding that 'MLL breakpoint localization is of clinical importance and should be considered as a novel outcome predictor'. That changes the proposal in two ways, one bad and one good. Bad: the entry's fourth open question ('Does breakpoint position predict outcome independently of age, white cell count and MRD? Nobody has tested it in a trial cohort') and the corresponding line in this entry's partnering_angle overstate the novelty, and a proposal sent to Interfant that does not cite this paper will look uninformed to people who know it. Good: n=30 with breakpoints localised is small, the analysis was not multivariable against MRD, and the cohort was a single-country referral series rather than a protocol cohort -- so the Interfant proposal is now a well-motivated confirmatory test of a specific published hypothesis (intron 11 versus elsewhere) with a pre-specified direction, which is a stronger design than an open-ended exploration and much easier to get through a consortium's scientific review. Caveats: 30 breakpoint-localised cases is very small; the paper does not report a multivariable model adjusting for age, WBC and MRD; 2013 practice predates Interfant-06 outcome maturity. Read: abstract only. Emerenciano M et al. 2013
- E4established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
van der Sluis and Pieters led the first study to add blinatumomab to Interfant-06 chemotherapy in 30 newly diagnosed infants under one year with KMT2A-rearranged ALL, in a disease with 3-year event-free survival below 40% where outcomes had not improved in decades despite chemotherapy intensification.
Blinatumomab Added to Chemotherapy in Infant Lymphoblastic Leukemia · van der Sluis IM, de Lorenzo P, Kotecha RS, et al., Valsecchi MG, Pieters R · New England Journal of Medicine 2023What this evidence cannot show
Single-arm, n=30, compared against a historical Interfant-06 cohort rather than a concurrent control, so the effect size is not randomised evidence. The primary endpoint was toxicity, not efficacy. **Regraded strong -> established on 2026-09-20** under `concept-the-confidence-grading-rule`: this is the trial's own reported result, which is established as a fact about what the trial found.
Evidence that argues against this (1)
- Thirty infants, single-arm, compared against historical controls. That design cannot separate the drug's effect from improvements in supportive care and MRD-guided management over the intervening years, and the entry should carry the n and the absence of randomisation wherever the result is cited. New England Journal of Medicine 2023
- E5moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
Long-term follow-up of the same 30 infants at a median of 4.2 years (range 3.2-6.0) reported that blinatumomab significantly improved disease-free survival relative to a selected historical Interfant-06 cohort, with toxicity, IVIg/G-CSF use and blinatumomab pharmacokinetics characterised.
Sustained Benefit of Blinatumomab in Infants With KMT2A-Rearranged ALL: Long-Term Outcomes, Toxicity, and Pharmacokinetics · Vieira Martins M, ... van der Sluis IM · Journal of Clinical Oncology 2026What this evidence cannot show
Still n=30 against a selected historical comparison, so selection of the control cohort drives the effect estimate. Blinatumomab targets CD19, and lineage switch to a CD19-negative myeloid phenotype is a documented escape route in KMT2A-r disease, so durability over longer follow-up is the open question.
Evidence that argues against this (1)
- Long-term follow-up of the SAME 30 infants is not independent confirmation — it is the original cohort observed longer, so it removes the worry that the benefit was transient without addressing the worry that the comparison is historical. A median 4.2 years is also short relative to the late-relapse window in infant ALL. Journal of Clinical Oncology 2026
Tier 2 of the analysis needs patient-level Interfant data
Interfant consortium co-authorship on the blinatumomab programme
needs the trial group's cooperation, which makes it a collaboration proposal
Counter to 'no single lab can substitute': COG is the North American relapsed/refractory route only; Interfant-21 (NCT05327894) and TINI 2 (NCT05848687) hold the frontline infant cohorts outside COG
Counter-evidence (NCT05327894): Interfant-21 is recruiting 160 infants with blinatumomab only and registers no menin inhibitor -- the sole global infant-ALL network is not testing the menin interface in the frontline
Counter-evidence (Emerenciano 2013, PMID 23432364): breakpoint position versus outcome in infant leukaemia was published in 2013 by Meyer/Marschalek and colleagues -- intron 11 breakpoints associated with poor outcome in 30 breakpoint-localised cases; the question is under-powered, not untouched
Counter-evidence (NCT05327894): the priority-one partner's open protocol Interfant-21 is blinatumomab-only with no menin arm and a non-randomised design, so the historical-control weakness is structural and the menin question sits elsewhere
the only global infant-ALL trial network; defines the treatment backbone and risk stratification
- related to →Blinatumomab in infant KMT2A-rearranged ALL — the largest single outcome gain in thirty years
first study to add blinatumomab to the infant backbone, with sustained benefit at 4.2 years median follow-up
holds breakpoint-derived MRD data for 249 KMT2A-r infants linked to protocol-standardised outcomes
- related to →Lineage switch as antigen escape from CD19-directed therapy in KMT2A-rearranged leukemia
CD19-directed therapy in infants is exposed to lineage switch, the documented escape route in KMT2A-r disease
the single highest-value gated resource: 249 breakpoint-derived MRD targets linked to protocol outcomes
priority collaboration 1
- ← related toThomas Milne (MRC WIMM, Oxford) — MLL-AF4 target biology, enhancer architecture and PROM1/CD133
joint Oxford-Princess Maxima pinometostat resistance model (Milne, Pieters, Stam)