Articles
A treatment protocol for infants younger than 1 year with
Lancet 2007; 370: 240–50
See Comment page 198
Dutch Childhood Oncology
Group (DCOG; Netherlands)
Erasmus MC-Sophia Children’s
Hospital, Rotterdam,
Netherlands (R Pieters PhD);
Berlin Frankfurt Münster
Germany (BFM-G; Germany,
Switzerland) University Medical
Center Schleswig-Holstein, Kiel,
Germany (Prof M Schrappe MD);
University of Milano-Bicocca,
Department of Clinical Medicine
and Prevention, Italy
(P De Lorenzo PhD,
M G Valsecchi PhD); UK Children’s
Cancer Study Group (UKCCSG;
UK) Great Ormond Street
Hospital for Children, London,
UK (I Hann FRCPCH) and
Sheffield Children’s Hospital,
Sheffield, UK (A Vora FRCPath);
Associazione Italiana
Ematologia Oncologia
Pediatrica (AIEOP; Italy)
University of Milano-Bicocca,
San Gerardo Hospital, Monza
Italy (A Biondi PhD) and Children
Hospital Bambino Gesù, Rome,
Italy (G de Rossi MD); Argentina
Hospital de Pediatría, Buenos
Aires, Argentina (M Felice MD);
Nordic Society of Paediatric
Haematology and Oncology
(NOPHO; Sweden, Denmark,
Norway, Finland, Iceland)
University of Helsinki, Helsinki,
Finland (L Hovi MD); French ALL
Group (FRALLE; France) Hôpital
Saint-Louis, Paris, France
(T LeBlanc MD); Polish Paediatric
Leukaemia and Lymphoma
Study Group (PPLLSG; Poland)
Silesian Medical Academy,
Zabrze, Poland
(T Szczepanski PhD); Children’s
Leukaemia Group (CLG;
Belgium, France, Portugal)
Hôpital Universitaire des
Enfants Reine Fabiola, Brussels,
Belgium (A Ferster MD);
Cooperative study group for
treatment of ALL (COALL;
Germany) University Hospital
Hamburg-Eppendorf,
Hamburg, Germany
(G Janka PhD);
240
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acute lymphoblastic leukaemia (Interfant-99): an
observational study and a multicentre randomised trial
Rob Pieters, Martin Schrappe, Paola De Lorenzo, Ian Hann, Giulio De Rossi, Maria Felice, Liisa Hovi, Thierry LeBlanc, Tomasz Szczepanski,
Alice Ferster, Gritta Janka, Jeffrey Rubnitz, Lewis Silverman, Jan Stary, Myriam Campbell, Chi-Kong Li, Georg Mann, Ram Suppiah, Andrea Biondi,
Ajay Vora, Maria Grazia Valsecchi
Summary
Background Acute lymphoblastic leukaemia in infants younger than 1 year is rare, and infants with the disease have
worse outcomes than do older children. We initiated an international study to investigate the effects of a new hybrid
treatment protocol with elements designed to treat both acute lymphoblastic leukaemia and acute myeloid leukaemia,
and to identify any prognostic factors for outcome in infants. We also did a randomised trial to establish the value of
a late intensification course.
Methods Patients aged 0–12 months were enrolled by 17 study groups in 22 countries between 1999 and 2005. Eligible
patients were stratified for risk according to their peripheral blood response to a 7-day prednisone prophase, and then
given a hybrid regimen based on the standard protocol for acute lymphoblastic leukaemia, with some elements
designed for treatment of acute myeloid leukaemia. Before the maintenance phase, a subset of patients in complete
remission were randomly assigned to receive either standard treatment or a more intensive chemotherapy course
with high-dose cytarabine and methotrexate. The primary outcomes were event-free survival (EFS) for the initial
cohort of patients and disease-free survival (DFS) for the patients randomly assigned to a treatment group. Data were
analysed on an intention-to-treat basis. This trial was registered with ClinicalTrials.gov, number NCT 00015873, and
at controlled-trials.com, number ISRCTN24251487.
Findings In the 482 enrolled patients who underwent hybrid treatment, 260 (58%) were in complete remission at a
median follow-up of 38 (range 1–78) months, and EFS at 4 years was 47·0% (SE 2·6, 95% CI 41∙9–52∙1). Of 445 patients
in complete remission after 5 weeks of induction treatment, 191 were randomised: 95 patients to receive a late
intensification course, and 96 to a control group. At a median follow-up of 42 (range 1–73) months, 60 patients in the
treatment group and 57 controls were disease-free. DFS at 4 years did not differ between the two groups (60·9% [SE 5·2]
for treatment group vs 57·0% [5·5] for controls; p=0·81). During the intensification phase, of 71 patients randomly
assigned to the treatment group, and for whom toxicity data were available, 35 (49%) had infections, 21 (30%) patients
had mucositis, 22 (31%) patients had toxic effects on the liver, and 2 (3%) had neurotoxicity. All types of rearrangements
in the (mixed lineage leukaemia) MLL gene, very high white blood cell count, age of younger than 6 months, and a
poor response to the prednisone prophase were independently associated with inferior outcomes.
Interpretation Patients treated with our hybrid protocol, and especially those who responded poorly to prednisone,
had higher EFS than most reported outcomes for treatment of infant ALL. Delayed intensification of chemotherapy
did not benefit patients.
Introduction cytarabine.13,14 In vivo, small numbers of adults15 and
Acute lymphoblastic leukaemia (ALL) in infants aged infants3 with pro-B ALL phenotypes had better outcomes
younger than 12 months is both rare and biologically after postremission treatment with high-dose cytarabine.
different from acute lymphoblastic leukaemia in older Outcomes for subgroups of infants with acute
children. In infants, this disease is characterised by a high lymphoblastic leukaemia vary with status of the MLL
frequency of abnormalities in chromosome 11q23 that gene, CD10 expression, age at diagnosis, white blood cell
affect the mixed lineage leukaemia (MLL) gene; by a very (WBC) count at presentation, central nervous system
immature B-cell phenotype (pro-B ALL) with no CD10 involvement, coexpression of myeloid markers, and early
expression; and by a high tumour load at presentation.1,2 response to prednisone.1,2 For example, patients who have
Studies in various countries have reported long-term a poor response to prednisone have EFS rate of 15%,
rates of event-free survival (EFS) of 28–45%.3–11 These rates compared with 53% for patients who have a good
are much lower than EFS rates for older children with response to prednisone.5 However, these variables are
acute lymphoblastic leukaemia, which are about 80%.1,2 interdependent, and their relative significance has not
Infant lymphoblasts are more resistant to chemotherapy been clearly established. Also, the various types of MLL
than cells in older children,12,13 but are sensitive in vitro to gene rearrangements could predict different prognoses.7,8,16
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 Articles

St Jude Children’s Research

Hospital (SJCRH; USA) St Jude
36 excluded Children’s Research Hospital,
518 assessed for eligibility
14 did not meet inclusion criteria Memphis, TN, USA
6 did not give consent (J Rubnitz MD); Dana-Farber
16 for other reasons
Cancer Institute (DFCI ALL
1 treated with AML protocol
Consortium; USA, Canada)
3 with Interfant-06 protocol
5 died before consent Dana-Farber Cancer Institute,
291 not randomly assigned 482 enrolled 4 clinical decision Boston, MA, USA
8 risk group or CR status not known 3 unknown reasons (L Silverman MD); Czech
52 events before randomisation Paediatric Haematology (CPH,
36 planned HSCT Czech Republic) University
128 enrolled after randomisation closed Hospital Motol and 2nd Medical
26 clinical decision
School, Charles University
24 did not give consent
17 other reasons 191 randomly assigned Prague, Prague, Czech Republic
(J Stary MD); Programa Infantil
Nacional de Drogas
Antineoplásicas (PINDA; Chile)
Allocation Hospital Roberto del Rio,
Santiago, Chile
96 randomly assigned to receive standard 95 randomly assigned to receive intensified (M Campbell PhD); Prince of
maintenance treatment chemotherapy before maintenance Wales Hospital, The Chinese
87 received allocated intervention phase University of Hong Kong, Hong
9 did not receive allocated intervention 87 received allocated intervention Kong, China (C K Li MD); Berlin
5 refusal by parents 8 did not receive allocated intervention Frankfurt Münster Austria
2 had HSCT 3 refusal by parents (BFM-A; Austria) St Anna
2 unknown reasons 2 had HSCT
Children’s Hospital, Vienna,
3 unknown reasons
Austria (G Mann MD); and
Follow-up Australian and New Zealand
Children’s Haematology
1 lost to follow-up because moved to 3 lost to follow-up for unknown reasons Oncology Group (ANZCHOG;
a foreign country Australia, New Zealand)
Women’s and Children’s
Analysis Hospital Adelaide, Adelaide,
Australia (R Suppiah FRACP)
96 analysed 95 analysed Correspondence to:
0 excluded from analysis 0 excluded from analysis Rob Pieters, Erasmus MC-Sophia
Childrens Hospital, Department
of Paediatric Oncology and
Haematology, Dr Molewaterplein
Figure 1: Trial profile 60, 3015GJ Rotterdam,
AML=acute myeloid leukaemia. CR=complete remission. HSCT=haemopoietic stem cell transplant. HR=high risk. Netherlands
rob.pieters@erasmusmc.nl
National study groups have been unable to accrue the Patients were recruited by the different study groups
numbers needed for analyses with sufficient power, or from May, 1999. Enrolment closed on Jan 1, 2006. All
for randomised comparisons of the effectiveness of study groups had started recruitment of consecutive
treatments. patients by January, 2000. Eligibility criteria for enrolment
We initiated a large collaborative trial, Interfant-99, in the observational study were age 365 days or younger See Online for webtable 1
with three aims. The first was to assess the outcome of a
hybrid treatment schedule in infants younger than
1 year with acute lymphoblastic leukaemia. (This Intensification
Maintenance 1B M2
protocol consisted of elements to treat both acute (VIMARAM)

lymphoblastic and myeloid leukaemia but with no

Standard risk Good Consolidation Reinduction
irradiation and only small amounts of anthracyclines response
Induction
(MARAM) (OCTADD) R Maintenance 1B Maintenance 2

and alkylating agents.) Our second aim was to assess

the efficacy of a late intensification course with Prednisone prophase
high doses of both cytarabine and methotrexate between
reinduction and maintenance phases. Our final aim was High risk Poor Consolidation Reinduction
Induction
(MARAM) R Maintenance 1A Maintenance 2
to identify any clinical and biological factors that might response (OCTADD)
have independent prognostic value.
Intensification
Maintenance 1A M2
(VIMARAM)
Methods
Donor HSCT
Patients
Patients were drawn from 17 study groups in 22 countries: Weeks 1 56 10 12 19 21 25 27 63 69 104
12 original groups and five that joined the collaboration
later (webtable 1). Individual study groups obtained ethics Figure 2: Treatment phases of the hybrid chemotherapy protocol
approval from their own institutions. R=randomisation. M2=maintenance 2. HSCT=haemopoietic stem-cell transplantation.

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Administration Dose Day of trial phase

route
Induction phase (5 weeks)
Prednisone IV or PO 60 mg/m² daily, divided into three doses (lower starting dose for 1–7
patients with high tumour load)
Dexamethasone IV or PO 6 mg/m² daily, divided into three doses 8–28 plus taper for 1 week
Vincristine IV push 1·5 mg/m² 8, 15, 22, 29
Cytarabine IV 75 mg/m² daily in 30 min 8–21
Daunorubicin IV 30 mg/m² in 60 min 8, 9
L-Asparaginase* IV or IM 5000 IU/m² in 1 h 15, 18, 22, 25, 29, 33
Methotrexate IT † 1
Methotrexate and prednisone IT † 29
Cytarabine and prednisone IT † 15
MARAM Consolidation phase (4 weeks)
6-Mercaptopurine PO 25 mg/m² daily 1–14
Methotrexate IV 5000 mg/m² as 24 h infusion 1, 8
Leucovorin rescue PO or IV 15 mg/m² at 36, 42, and 48 h after start of methotrexate
Methotrexate IT †At the end of the 24 h methotrexate infusion 2, 9
Prednisone IT †At the end of the 24 h methotrexate infusion 2, 9
Cytarabine IV 3000 mg/m² as 3 h infusion twice daily with 12 h interval 15, 16, 22, 23
L-Asparaginase* IV or IM 5000 IU/m² daily in 2 h, 3 h after completion of the last cytarabine 16, 23
infusion
OCTADD Reinduction phase (7 weeks)
Dexamethasone PO 6 mg/m² daily, divided into three doses 1–14 plus taper 1 week
6-Tioguanine PO 60 mg/m² daily 1–28 and 36–49
Vincristine IV push 1·5 mg/m² 1, 8, 15, 22
Daunorubicin IV 30 mg/m² in 60 min 1, 8, 15, 22
Cytarabine IV push 75 mg/m² daily 2–5, 9–12, 16–19, and 23–26
Cytarabine and prednisone IT† 1, 15
Cytarabine IV push 75 mg/m² daily 37–40 and 45–48
Cyclophosphamide IV 500 mg/m² in 1 h 36, 49
VIMARAM Intensification phase (4 weeks)
MARAM phase drugs
Vincristine IV push 1·5 mg/m² 1, 8, 15, 22
Maintenance IA phase (three cycles of 14 weeks each)
6-Mercaptopurine PO 50 mg/m² daily
Methotrexate PO 20 mg/m² once weekly
Dexamethasone PO 6 mg/m² daily divided into three doses Weeks 1 and 2
Vincristine IV push 1·5 mg/m² Day 1 of weeks 1 and 2
Methotrexate prednisone IT † Day 1 of cycles 1 and 3
Cytarabine and prednisone IT † Day 1 of cycle 2
Maintenance IB phase (for high risk patients; three cycles of 14 weeks each)
Maintenance 1A phase drugs, and in addition:
Etoposide IV 120 mg/m² in 2 h Day 1 of weeks 8 and 9
Cytarabine IV 1000 mg/m² in 1 h Day 1 of weeks 8 and 9
Maintenance 2 phase (until 104 weeks after diagnosis)
6-Mercaptopurine PO 50 mg/m² daily for 14 weeks
Methotrexate PO 20 mg/m² once weekly for 14 weeks

HSCT=haemopoietic stem-cell transplant. IM=intramuscular. IV=intravenous. PO=by mouth. IT=intrathecal. . *L-Asparaginase (Medac, Hamburg, Germany) or
E coli Asparaginase (Elspar, Merck, West Point, PA, USA) at a dose of 10 000 IU/m². †Intrathecal doses did not depend on body surface area and were fixed for age
categories. Dose for intrathecal prednisone or prednisolone was 6 mg for patients younger than 1 year and 8 mg for those aged 1 year or older; it could be replaced by
hydrocortisone at a dose of 12 mg for those younger than 1 year or 16 mg for older infants. Intrathecal methotrexate was 6 mg for children aged younger than 1 year
and 8 mg for those aged 1 year or older. Intrathecal cytarabine was given at a dose of 15 mg for patients aged younger than 1 year and 20 mg for those aged 1 year
or older.

Table 1: Treatment phases of the hybrid chemotherapy protocol

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with newly diagnosed acute lymphoblastic leukaemia total body irradiation was prohibited because of concerns
(except those with a mature B phenotype); morphological about late neuropsychological toxic effects.
verification of the diagnosis, substantiated by Patients who were alive and in complete remission at
cytochemistry and immunophenotyping (with trephine the end of the reinduction phase (figure 2 and table 1),
biopsies if bone marrow aspiration resulted in a dry tap, and for whom stem-cell transplantation was not planned,
and diagnosis could not be checked by peripheral blood were eligible to participate in the randomised trial
examination); and no previous treatment for leukaemia, (figure 1). Complete remission was defined by testing for
except emergency treatment. Children with central bone marrow with fewer than 5% leukaemic cells and
nervous system involvement or testicular leukaemia at
diagnosis were not excluded.
Enrolled Standard- High-risk Risk p*
A subset of patients who were eligible for the trial of patients risk patients unknown
the late intensification course were randomly assigned patients
between October, 1999, and May, 2004. Total patients 482 (100%) 324 (67%) 151 (31%) 7 (2%)
Female sex 251 (52%) 171 (53%) 77 (51%) 3 (43%) 0·7169
Procedures Age (months) 0·0346
Figure 1 shows the trial profile. Enrolled patients were <3 112 (23%) 62 (19%) 45 (30%) 5 (71%)
stratified into standard-risk and high-risk groups on the 3–6 121 (25%) 82 (25%) 39 (26%) 0
basis of their response to 1 week of daily systemic 6–9 122 (25%) 91 (28%) 29 (19%) 2 (29%)
prednisone (at a dose of 60 mg/m²) and one intrathecal 9–12 127 (26%) 89 (28%) 38 (25%) 0
dose of methotrexate (figure 2). Response was defined as WBC count (cells per L) 0·0001
good, and risk as standard, if the blast count in peripheral
<100×109 211 (44%) 174 (54%) 35 (23%) 2 (29%)
blood at day 8 was less than 1000 cells per µL; a poor
100–300×109 139 (29%) 100 (31%) 38 (25%) 1 (14%)
response was defined as a blast count of equal to or
≥300×109 128 (27%) 49 (151%) 78 (52%) 1 (14%)
greater than 1000 per µL.5,12 We tested 461 patients for
Not known 4 (1%) 1 (0%) 0 3 (43%)
MLL gene rearrangement with split-signal fluorescent
Immunophenotype 0·0001
in-situ hybridisation (FISH), PCR, or both. Absence of
B-lineage: CD10 negative 273 (57%) 182 (56%) 87 (58%) 4 (57%)
MLL rearrangement was defined as a negative split signal
B-lineage: CD10 positive 139 (28%) 105 (32%) 33 (22%) 1 (14%)
for FISH.
B-lineage: CD10 unknown 38 (8%) 26 (8%) 12 (8%) 0
Figure 2 and table 1 show the treatment protocol for
T 18 (4%) 4 (1%) 14 (9%) 0
both the observational study and the randomised trial.
Biphenotypic 3 (1%) 1 (0%) 2 (1%) 0
The protocol was based on a backbone of standard
treatment for acute lymphoblastic leukaemia, consisting AUL 3 (1%) 1 (0%) 2 (1%) 0

of multiagent phases of induction and consolidation Not known 8 (2%) 5 (2%) 1 (1%) 2 (29%)

chemotherapy, followed by extended treatment with 11q23 abnormalities (MLL gene status) 0·2650
antimetabolites (table 1).17 Doses were adjusted according Not known (or not fully 86 (18%) 51 (17%) 23 (15%) 2 (29%)
known)
to patients’ ages at the start of each treatment phase:
MLL germline 82 (17%) 60 (19 %) 22 (15%) 0
children younger than 6 months were given two-thirds
MLL rearrangement 314 (65%) 203 (63%) 106 (70%) 5 (71%)
of the full dose; those aged 6–12 months were given
t(4;11) 166 (53%)‡ 109 (54%)‡ 53 (50%)‡ 4 (80%)‡
three-quarters of the dose; and those older than
t(9;11) 35 (11%)‡ 26 (13%)‡ 8 (8%)‡ 1 (20%)‡
12 months were given the full dose. Total treatment
t(11;19) 64 (20%)‡ 39 (19%)‡ 25 (24%)‡ 0
duration was 104 weeks.
The induction phase consisted of a standard four-drug †Other fusion partner 25 (8%)‡ 14 (7%)‡ 11 (10%)‡ 0

induction for patients with acute lymphoblastic leukaemia, Fusion partner undefined 24 (8%)‡ 15 (7%)‡ 9 (8%)‡ 0
with the addition of low-dose cytarabine (table 1).17 The CNS involvement 0·3818
MARAM phase was a slightly modified consolidation Yes 44 (9%) 26 (8%) 15 (10%) 3 (43%)
course3 that included high-dose cytarabine and high-dose No 365 (76%) 255 (79%) 109 (72%) 1 (14%)
methotrexate. OCTADD was a reinduction block derived Not evaluable or not known 73 (15%) 43 (13%) 27 (18%) 3 (43%)
from the consolidation phase of the Berlin-Frankfurt- Response to 7-day prednisone prophase
Münster (BFM) trials for treatment of acute myeloid Good response 318 (66%) 316 (98%) 2 (1%) 0
leukaemia,18 except that prednisone was replaced by Poor response 138 (29%) 0 138 (91%) 0
dexamethasone. Not evaluable 6 (1%) 2 (1%) 4 (3%) 0
High-risk patients could receive haemopoietic stem-cell Not known 20 (4%) 6 (1%) 7 (5%) 7 (100%)
transplantation at the end of the reinduction phase if a
All data are number (%). AUL=acute undifferentiated leukaemia. CNS=central nervous system. *Difference between the
donor was available for transplantation. The type of risk groups. †The fusion partner of the MLL gene is defined, but differs from that in t(4;11), t(9;11), or t(11;19). ‡Infants
donor and conditioning regimen varied between with this type of MLL gene rearrangement as a proportion of the total number with rearrangements.
participating national groups. The conditioning regimen
Table 2: Patient characteristics by risk group
was with etoposide, busulfan, and cyclophosphamide;

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SR HR NK Total
All translocations 203 106 5 314 (100%)
t (4;11) 109 53 4 166 (53%)
396 patients 314 (79%) patients t (9;11) 26 8 1 35 (11%)
(82% with with MLL rearrangements) t (11;19) 39 25 0 64 (20%)
known MLL
Other defined* 14 11 0 25 (8%)
status)
482 enrolled Undefined 15 9 0 24 (8%)
patients
82 (21%) patients with no MLL rearrangements 60 22 0

65 patients (14% with MLL status not fully known) 48 16 1

21 patients (4% with MLL status unknown) 13 7 1

Figure 3: MLL gene rearrangements

SR=standard risk. HR=high risk. NK=not known. *The fusion partner of the MLL gene is defined, but differs from that in t(4;11), t(9;11), or t(11;19).

haematopoiesis in regeneration, and no evidence of
leukaemic cells elsewhere.
In week 20, after the reinduction phase, treating
physicians obtained written informed consent from all
parents or legal guardians. The data centre of each
participating group checked the eligibility criteria for
each patient and provided the random allocation
schedule, so that treatment arms were balanced within
each group. Every treating physician telephoned their
data centre to obtain a computer-generated random
assignment, based on random permuted blocks, and
stratified by risk group. A blinded study was not possible,
since the intervention was designed to take 4 weeks,
followed by recovery for about 2 weeks. Neither was it
1·0
0·9
0·8
0·7
0·6
55·3 (2·7)
53·8 (3·0)
Survival
EFS
Probability
possible to use placebo controls, since interruption of
chemotherapy for 6 weeks would cause an unacceptable
increase in the risk of leukaemia recurrence.
Treatment protocols for the randomised trial are shown
in figure 2 and table 1. Standard-risk controls were given a
maintenance phase of oral 6-mercaptopurine and
methotrexate, combined with pulses of dexamethasone
and vincristine and intrathecal methotrexate with steroid in
the first three cycles (maintenance 1B). High-risk controls
were given standard maintenance therapy intensified with
pulses of cytarabine and etoposide in the first three cycles
(maintenance 1A). Standard-risk patients who were
randomly assigned to the intervention group were treated
with the intensification (VIMARAM) phase (similar to the
MARAM maintenance block but with the addition of
vincristine),3 followed by a standard maintenance phase
after 2 weeks of recovery (maintenance 1B). High-risk
patients randomly assigned to receive VIMARAM were
given the intensified maintenance treatment after 2 weeks
of recovery (maintenance 1A).
Maximum cumulative doses for standard-risk patients
(including the age-related dose reductions) were
120–165 mg/m² of daunorubicin and 600–1000 mg/m² of

0·5 47·0 (2·6) 46·4 (2·7) cyclophosphamide. Maximum cumulative doses for
0·4 4-year 5-year high-risk patients (including age-related dose reductions)
outcomes outcomes were 120–165 mg/m² of daunorubicin, 600–1000 mg/m²
0·3 of cyclophosphamide, and 480–720 mg/m² of etoposide.
0·2
Patients who were randomly assigned to receive the
intensification phase were given 12 intrathecal injections;
0·1 controls had ten. Patients with overt central nervous
0
system involvement or those with leukaemic cells in their
0 1 2 3 4 5 6 7 cerebrospinal fluid due to contamination with blood
Years after diagnosis received extra intrathecal drugs every week until the
Number at risk 481 350 274 220 186 154 126 99 83 57 38 18 6 1 0 cerebrospinal fluid was clear of leukaemic cells for 2
Deaths in induction 21 .. .. .. .. .. .. .. .. .. .. .. .. .. weeks. Central nervous system involvement was defined
Resistant to induction 11 .. .. .. .. .. .. .. .. .. .. .. .. ..
Relapses 49 51 32 13 9 5 3 0 1 0 0 0 0 0
as more than five cells per µL, with presence of leukaemic
BM 38 40 23 7 5 5 3 0 1 0 0 0 0 0 cells in the cerebrospinal fluid, cranial nerve palsies, or
BM+other 5 7 3 5 3 0 0 0 0 0 0 0 0 0 intracerebral disease on imaging.
Extramedullary 6 4 5 1 1 0 0 0 0 0 0 0 0 0
Deaths in CCR 13 7 3 2 0 0 0 0 0 0 0 0 0 0 Endpoints were early death (during induction);
resistance to induction (ie, no complete remission at the
Figure 4: Outcomes of hybrid treatment with the Interfant-99 protocol
EFS=event-free survival, defined as time from diagnosis to any one of the primary endpoints. BM=bone marrow. end of the induction phase); relapse; death in continuous
CCR=continuous complete remission. *One patient was excluded, since results for the primary endpoint were unknown. complete remission; and second malignancy. The

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Induction Consolidation Reinduction
(MARAM) (OCTADD)
Patients assessed* 342 310 249
Infections 144 (42%) 123 (40%) 59 (24%)
Mucositis 75 (22%) 80 (26%) 19 (8%)
Renal 12 (4%) 3 (1%) 1 (0.4%)
Liver 72 (21%) 65 (21%) 16 (6%)
Neurological 15 (4%) 7 (2%) 6 (2%)
HR=high risk. SR=standard risk. Data are number of patients (%). *We did not obtain toxicity data for all patients and some had not completed treatment at time of analysis.
Table 3: Grade 3 and 4 toxic events by treatment phase
primary outcome measure for the total cohort of patients
was event-free survival (EFS), which was defined as the
time from diagnosis to any one of the primary endpoints.
For patients randomly assigned to a treatment group, the
primary outcome measure was disease-free survival
(DFS), defined as time from randomisation to relapse,
death in continuous complete remission, or second
malignancy. The secondary outcome measure was
survival, defined as time to death from any cause. In EFS,
DFS, and survival, time was censored at the last follow-up
if no events were recorded.
Statistical analysis
The international study operating centre checked and
pooled data into a common database. Blinded yearly
progress reports were circulated to contact people in the
participating groups, and interim analyses were provided
to the data monitoring committee according to the
protocol.
To achieve 80% power to detect a 16% difference in
4-year DFS, with an expected baseline of 50% (two-sided
test, with 5% type-one error), we aimed to recruit
280 patients to our randomised trial. We planned a
recruitment period of 5 years, with interim analyses at 2,
3, and 4 years after the start of recruitment.19 At the third
interim analysis, the data monitoring committee
assessed whether it would be useful to continue the trial.
From interim results, we estimated that enrolment of
additional patients had only a small chance
(6% probability) of achieving the target 16% difference
in the 4-year DFS. Therefore the trial was prematurely
terminated, when we had recruited only 191 patients to
the randomised trial.20 No patients were randomly
assigned after May, 2004. We continued to collect data to
assess outcomes and to identify factors with independent
prognostic value until Jan 1, 2006. The final follow-up
was on Jan 31, 2006. We analysed data with SAS
statistical software (version 8.2).
EFS, DFS, and survival curves were computed with the
Kaplan-Meier estimator, and their SE with the Greenwood
formula. We used the χ² test to assess the association
between patients’ characteristics and risk groups.
DFS and survival curves in the two randomly assigned
treatment groups were compared with the log-rank test.
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Articles
Intensification phase Maintenance 1A Maintenance 1B
(VIMARAM)
71 23 115
35 (49%) 6 (26%) 33 (29%)
21 (30%) 1 (4%) 11 (10%)
1 (1%) 0% 3 (3%)
22 (31%) 5 (22%) 22 (19%)
2 (3%) 0% 2 (2%)
A Cox model, stratified by participating group, was
applied to estimate the treatment effect in terms of
hazard ratio (HR) with 95% CI. The log-rank test was
used to compare outcomes for subgroups identified by
prognostic factors. We used the Cox model on EFS (single
step) and the Wald test for the joint analysis of sex, age,
WBC count, immunophenotype and CD10 expression,
MLL gene status, and prednisone response. All tests were
two sided. The assumption of proportional hazards was
verified by graphical checks.
An unplanned analysis was added to compare the DFS
of patients who received bone marrow transplants with
those who did not. This analysis was adjusted by waiting
time to transplantation, with the inclusion of a
time-dependent indicator for treatment in the Cox model
and the Mantel-Byar test.21 DFS curves were also adjusted.
This trial was registered with ClinicalTrials.gov, number
NCT 00015873, and at controlled-trials.com, number
ISRCTN24251487.
Role of the funding source
The many foundations that collaborated in and supported
this study had no role in study design, data collection,
data analysis, data interpretation, or writing of the report.
All authors had full access to all the data in the study and
had final responsibility for the decision to submit for
publication.
Results
Of 518 consecutive infants registered in the study, 504 met
eligibility criteria and 482 patients were enrolled in the
study cohort (webtable 1 and figure 1). Median follow-up
time from diagnosis was 38 (range 1–78) months. Table 2
shows patient characteristics at baseline, stratified by risk
group. About a tenth of assessed patients in our cohort
had central nervous system involvement. About two-thirds
of the patients had standard risk, and just under a third
were at high risk.
Figure 3 shows that we were not able to establish
whether the MLL gene was rearranged for 21 of
482 enrolled patients. For 65 patients, we did not do split
signal FISH, or PCR for all known MLL translocations.
Of the 396 patients for whom MLL status was fully known,
about a fifth had germline MLL, with no rearrangements.
245
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and 43/64 (67%) of the 64 with t(11;19) were younger than

Univariate analysis Cox regression model*
6 months at diagnosis compared with 11 (31%) of those
Patients Events 4-year EFS† p‡ Estimated p¶
35 with t(9;11) (p=0·0005).
hazard ratio§
Outcomes are described for 474/482 enrolled patients:
Sex 0·60
we did not know whether one patient was in complete
Male 227 109 46·0% (3·7) 1·22 (0·90–65) 0·196 remission, and seven others are not reported because we
Female 247 109 48·4% (3·6) Reference ·· did not know their risk group. Of those seven, three died
Age at diagnosis (months) 0·0001 during the prednisone prophase and four were in
<3 107 69 28·7% (4·7) 3·05 (1·82–5·12) 0·0001 complete remission at last follow-up. 18 (3·8%) died
3–6 120 61 38·8% (5·1) 2·25 (1·35–3·74) 0·002 during induction, and 11 (2·3%) had persistent disease at
6–9 120 49 52·2% (5·2) 1·64 (0·98–2·75) 0·060 the end of induction. At the end of induction,
9–12 127 39 65·3% (4·7) Reference ·· 445/474 (94%) patients were in complete remission
WBC count (cells per L) 0·0001 (312 [97%] standard-risk patients and 133 [88%] high-risk
<100×109 209 75 56·9% (4·0) Reference ·· patients). Four of the 11 patients who did not achieve
100–300×109 137 58 51·8% (4·7) 1·24 (0·83–1·83) 0·297 complete remission were still alive after 14, 17, 34, and
≥300×109 127 85 26·2% (4·4) 1·49 (0·99–2·24) 0·058 52 months from diagnosis, respectively.
Not known 1 0 ·· ·· 445 patients in complete remission were analysed for
Immunophenotype 0·0075 outcome. 260 (58%) of these patients were alive in
B-lineage: CD10 negative 269 140 40·4% (3·4) 0·66 (0·44–0·99) 0·044 complete remission at last follow-up. 163 (34%) patients
B-lineage: CD10 positive 138 50 58·9% (4·6) Reference ·· had relapses: 122 (26%) had bone marrow relapses,
T 18 7 58·5% (12·2) 0·84 (0·29–2·45) 0·751 12 (3%) isolated central nervous system relapses, 23 (5%)
Other 43 20 39·9% (9·2) 0·56 (0·29–1·07) 0·080 combined marrow and extramedullary relapses, and
Not known 6 1 ·· ·· five (1%) other relapses, such as skin or testes. Median
11q23 abnormalities 0·0001 time from first complete remission to relapse was
MLL germline 82 17 74·1% (5·6) Reference ·· 8 months (range 0–50, IQR 4–15). 121 (74%) relapsed
MLL rearranged 308 171 36·9% (3·1) 3·08 (1·73–5·49) 0·0001 patients died; median time to death in these patients was
t(4;11) 161 87 35·8% (4·5) 4 months after relapse (0–39, 2–7). The 42 (26%) relapsed
t(9;11) 34 17 36·1% (9·7) patients who were still alive at the time of analysis
t(11;19) 64 42 33·4% (6·8) survived for a median of 15 months (0–73, 2–7). 25 (5%)
Other 49 25 44·5% (7·6)
patients died in continuous complete remission;
Not known 84 30 59·1% (5·9) ·· ··
18 because of infection, two from multiorgan failure,
Response to prednisone prophase 0·0001
three from complications of haemopoietic stem-cell
transplantation, and two from other causes.
Good response (standard risk) 317 118 56·4 (3·2) Reference ··
Treatment-related death did not differ by age at diagnosis:
Poor response (high risk) 138 89 29·8 (4·3) 1·79 (1·27–2·53) 0·001
6 (5%) of those aged 0–3 months died, compared with
Not known 19 11 ·· ··
6 (5%) aged 3–6 months, 9 (7%) aged 6–9 months, and
Day 15 bone marrow response‡ 0·0001
4 (3%) aged 9–12 months.
<5% leukaemic cells 218 83 54·7% (3·9)
Overall 4-year EFS was 47·0% (SE 2·6, 95% CI 41∙9–
5–25% leukaemic cells 85 40 48·0% (5·8)
52∙1) and survival was 55·3% (2·7, 50∙0–60∙6) (figure 4).
>25% leukaemic cells 46 33 22·5% (6·8)
4-year survival was 56·9% (SE 3·1) for patients enrolled
Not known 125 62 44·5% (4·8)
with the original study groups, and 50·2% (6·1) for
Data are patient numbers, unless otherwise specified. WBC=white blood cell. *The Cox model was fitted on patients in the additional study groups (p=0·04); this was
369 patients for whom all variables were known. Day 15 bone marrow data are not included because of missing data. caused by a higher death rate in induction (7·8% vs 3·6%)
†Data are 4-year EFS (SE). ‡P value for the log-rank test on the difference between subgroups. §Data are HR (95% CI).
¶Calculated with the Wald test for joint analysis of sex, age, WBC, immunophenotype and CD10 expression, MLL gene
and in continuous complete remission (7·8% vs 4·6%) in
status, and prednisone response. the additional study groups than in the original
participating groups.
Table 4: Univariate and multivariate analysis of prognostic factors
Table 3 shows Grade 3 and 4 toxic effects associated
with the hybrid treatment protocol, although we did not
The chromosome translocation t(4;11) was recorded in obtain toxicity data for all patients and some had not
more than half the patients with MLL rearrangements, completed treatment at time of analysis. About two-fifths
t(11;19) in a fifth, and t(9;11) in about a tenth of patients. of patients had infectious complications during or after
Standard-risk and high-risk patients did not have different the induction and consolidation phases, and about a
frequencies of MLL rearrangements (p=0·20). quarter during reinduction and maintenance. A quarter
187 of 205 (91%) infants younger than 6 months for of patients had mucositis during induction and
whom MLL status was known had rearrangements, consolidation phases and less than a tenth during other
compared with 127 of 191 (66%) infants aged 6–12 months treatment phases. Toxic effects on the liver were noted in
(p<0·0001). 108 of 166 (65%) with t(4;11) translocations about a fifth of patients during all treatment phases

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 Articles

except reinduction. Neurotoxicity was seen in a small

number of patients. A
1·0
Variables with significant value as predictors of EFS
on univariate analysis were age at diagnosis, WBC
count, immunophenotype (CD10 expression), MLL gene 0·8
status, and prednisone response. Table 4 shows that a
very high WBC count (more than 300×109 cells per L)
was associated with a poor prognosis, whereas patients 0·6
with a WBC count of 100 to 300×109 cells per L fared

EFS
similarly to those with WBC of less than 100×109 cells
per L. The hazard ratio for any event was more than 0·4
three times higher in the youngest cohort (0–3 months)
and more than twice as high in the 3–6 month cohort Germline MLL (n=82)
than in the oldest cohort (9–12 months). The risk of an 0·2 Other MLL rearrangements (n=49)
t(9,11) MLL rearrangements (n=34)
event in patients with MLL rearrangements was more t(4,11) MLL rearrangements (n=161)
p=0·0001
than three-fold greater than that in patients with t(11,19) MLL rearrangements (n=64)
germline MLL. The increased risk was the same 0
0 1 2 3 4 5 6 7
irrespective of the type of MLL rearrangement (table 4,
Number at risk
figure 5). Germline MLL 82 64 48 32 20 11 2 0
Cox regression analysis, with EFS as endpoint, showed t(4,11) 161 82 54 31 20 8 0 0
that MLL status, age at diagnosis, and prednisone t(11,19) 64 29 19 14 9 3 0 0
t(9,11) 34 17 9 6 4 2 0 0
response at day 8 were independent prognostic factors Other translocations 49 26 17 13 7 3 1 0
(table 4). MLL rearrangement and age younger than
6 months were the strongest predictors for poor B
outcome. 110 (63%) of the 176 patients who had MLL 1·0
rearrangements and were younger than 6 months at
diagnosis had relapses. Within this subgroup, a high
WBC count and poor prednisone response were equally 0·8 74·0 (5·8)
useful for further identification of patients with the
worst prognosis. In patients with MLL rearrangements
who were younger than 6 months of age, 50 (77%) of 0·6

65 high-risk patients, who had a poor prednisone

EFS

44·8 (3·7)
response, had an event, and the 4-year EFS rate was 18%
0·4
(SE 6·4). By contrast, events were recorded in 60 of
111 (54%) patients who had a good prednisone response,
and 4-year EFS was 35% (SE 5·3). In the same group, 0·2
19·8 (6·1)
52 of 73 patients with WBC counts of more than Group 1 (n=75)
300×109 cells per L had relapses, with a 4-year EFS of Group 2 (n=73) p=0·0001
Group 3 (n=221)
20% (6·1), compared with only 58 of 103 patients with 0
WBC counts of less than 300×109 cells per L, with a 4- 0 1 2 3 4 5 6 7
year EFS of 35% (5·3). Time from diagnosis (years)
The 369 patients for whom all variables were known Number at risk
Group 1 75 59 45 31 19 11 2 0
could be divided into three groups on the basis of MLL Group 2 73 26 11 6 4 2 0 0
rearrangement, age, and WBC count. Figure 5 shows Group 3 221 122 85 56 34 14 1 0
that 4-year EFS for 75 (20%) patients with germline MLL
was 74·0% (SE 5·8); 4-year EFS for 73 (20%) patients Figure 5: Outcomes by MLL status, age, and white blood cell count
with all three risk factors (MLL rearrangement, and age EFS=event-free survival, defined as time from diagnosis to any one of the primary endpoints. Group 1: patients
with germline MLL gene. Group 2: patients with MLL gene rearrangement, age <6 months at diagnosis and white
younger than 6 months at diagnosis, and WBC count of blood cell count >300×109 cells per L at diagnosis. Group 3: all other patients.
more than 300×109 cells per L) was 19·8% (SE 3·7); and
4-year EFS for the other 221 (60%) patients was 44·8% chemotherapy plus haemopoietic stem-cell transplantation
(SE 6·1; p<0·0001). HSCT (50·2%, 8·4) when adjusted for waiting time to
37 high-risk patients who were in complete remission transplantation (p=0·19).
after reinduction received stem-cell transplants; another 128 of the 482 enrolled patients were enrolled after
four of these patients received transplants after random randomisation was closed, and 163 were not randomly
allocation, which was a deviation from protocol. 4-year assigned for other reasons (figure 1). By June 1, 2004,
DFS did not significantly differ between high-risk patients 191 patients were randomly assigned: 96 to the control
treated with chemotherapy alone (37·4%, SE 7·2) versus group and 95 to receive intensified treatment. All

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 Articles

1·0
4-year survival was 64·7% (SE 5·5) for infants in the
treatment group, compared with 65·8% (5·4) for controls
(p=0·98). The hazard ratio in the treatment group
0·8
compared with controls was 0·86 (95% CI, 0·61–1·52). A
secondary analysis, adjusted for the specific prognostic
factors we investigated, still did not show any difference
60·9 (5·2)
Disease-free survival

0·6 in outcomes between the two treatment groups (HR

57·0 (5·5) 0·81, 95% CI 0·50–1·32). Four (4%) controls and four
patients given intensified treatment died in continuous
0·4 complete remission, and the number of relapses in the
treatment group was 31 (33%), compared with 34 in
controls (35%). 57 (60%) controls and 60 (63%) patients
0·2 in the treatment group were alive and disease-free at last
Intensified treatment group (n=95)
Control group (n=96) follow-up.
p=0·81
Table 3 shows that substantial grade 3 and 4 toxic effects
0
0 1 2 3 4 5 6 7
were associated with the intensification phase, including
Time from randomisation (years) almost half of patients with infectious complications,
Number at risk almost a third with mucositis, and another third with
Control group 94 71 50 37 26 10 1 0
Treatment group 93 69 50 31 19 6 1 0 toxic effects on the liver.
36 (19%) of the patients randomly assigned to treatment
Figure 6: Randomised trial of treatment with late intensification course groups were from the additional study groups. 28 (23%)
Disease-free survival defined as time from randomisation to relapse, death in continuous complete remission, or
of patients included in the study after random assignment
second malignancy. Two controls and two patients in the group given intensified treatment (VIMARAM) were
excluded because the date of randomisation could not be established. was stopped were from the additional study groups.
4-year DFS for patients enrolled in the original study
group did not differ from patients in the additional study
Date CR EFS or EFS rate (SE) Survival rate (SE) Patients
(year) rate survival enrolled
groups (HR 0·98, 95% CI 0·50–1·91).
timepoint
DFCI (1985–95)3 1997 96% 4 year 54% (11) – 23
Discussion
EFS over 4 years for the 482 infants with acute
Interfant-99 2007 94% 4 year 47% (2·6) 55% (2·7) 482
lymphoblastic leukaemia treated with our hybrid protocol
AIEOP-91/954 2006 96% 5 year 45% (95% CI 31–58) – 52
was 47·0% (SE 2·6); survival was 55·3% (2·7). These
BFM5 1999 95% 6 year 43% (5) 48% (6) 105
outcomes are better than those achieved with most
EORTC-CLCG6 1994 86% 4 year 43% (95% CI 24–62) - 25
previous protocols (table 5). The Dana Farber Cancer
CCG-19537 2006 97% 5 year 42% (9) 45% (6) 115
Institute reported a higher EFS (54%, SE 11), but their
CCG-18838 1999 97% 4 year 39% (4) 51% (4) 135
trial included only 23 patients.3 A brief report from a
CCG-1078 1999 94% 4 year 33% (5) 45% (5) 99
Japanese study22 on infants with acute lymphoblastic
UKALL-929 2002 94% 5 year 33% (95% CI 23–44) 46% (95% CI 35–57) 86
leukaemia reported an overall EFS of 52%, but did not
POG 849310 1997 93% 4 year 28% (5) – 82
provide details about all study participants.
POG alternating 1998 94% 4 year 17% (8) – 33
Outcomes with our hybrid protocol were similar to
drugs11
those from single group studies based on BFM
CR=complete remission. EFS=event-free survival. DFCI=Dana-Farber Cancer Institute (ALL Consortium; USA, Canada). regimens, in which 30–60% of infants were given
AIEOP=Associazione Italiana Ematologia Oncologia Pediatrica (Italy). BFM=Berlin-Frankfurt-Münster (Austria,
intensive high-risk chemotherapy rather than standard
Germany, Switzerland). EORTC-CLG=European Organisation for Research and Treatment of Cancer—Children’s
Leukaemia Cooperative Group (France, Belgium, and Portugal). CCG=Children’s Cancer Group (US). UKALL=Medical treatment for acute lymphoblastic leukaemia.4–6 Patients
Research Council United Kingdom. POG=Paediatric Oncology Group (USA). in our trial who were at standard risk (ie, they
responded well to a prednisone prophase) had similar
Table 5: Outcomes of treatment protocols for acute lymphoblastic leukaemia in infants
outcomes to those reported by the BFM study. EFS for
high-risk patients, who responded poorly to a
participating groups entered at least one patient in the prednisone prophase, was 30% with our trial protocol,
randomised controlled trial (webtable 1). The groups compared with 15% in the BFM study.5 We should
were balanced for sex, age, immunophenotype, MLL point out that our median follow-up was 3·3 years,
status, and prednisone response but only 12 controls compared with 5 years in other studies.5,4 However,
had WBC counts of greater than 300×109 per L compared because 80% of infants with acute lymphoblastic
with 26 in the group given intensified treatment leukaemia have MLL gene rearrangements, and have
See Online for webtable 2 (webtable 2). relapses in the first few years after diagnosis (and
Figure 6 shows that outcomes did not differ for patients while on treatment), only a few late relapses could still
given intensified treatment and controls: 4-year DFS was be noted in the small group of patients in our study
60·9% (SE 5·2) and 57·0% (5·5), respectively (p=0·81,). with MLL germline.

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Our randomised trial showed that patients did not
benefit from a late intensification course with high-dose
cytarabine and high-dose methotrexate. Patients given
late intensification drugs had more toxic effects than
controls, especially infections and mucositis. Most
relapses in infants happened within a year of diag-
nosis. By contrast, in older children most relapses hap-
pened off treatment. This finding suggests that the
delayed intensification in Interfant-99 might have been
scheduled too late to benefit infants who might have
relapses.
Our hybrid treatment protocol did not produce more
toxic effects than previous regimens. The incidence of
deaths in complete remission (5·2%) was similar to
those reported previously (median 4%, range 2–14%).1
Treatment-related deaths were the same in all age-groups
we studied, possibly because drug doses were adjusted
according to age. Agents that are known to cause late
toxic effects, such as anthracyclines, alkylating agents,
and epipodophyllotoxins, were either not given or were
given in very low cumulative doses. We used neither
cranial irradiation, which is known to have severe
neurocognitive sequelae in this age-group,3,23 nor total
body irradiation, which can cause toxic effects such as
neuropsychological effects. The incidence of death in
complete remission differed between study groups in
different countries, suggesting that increased familiarity
with this regimen and improvements in supportive care
might further reduce treatment-related mortality.
Our study protocol differed from protocols designed
to treat older children with acute lymphoblastic
leukaemia because of the inclusion of low-dose and
high-dose cytarabine in sequential courses. Cytarabine
could have improved the outcomes. In-vitro studies have
shown that infant lymphoblasts are highly sensitive to
cytarabine, mainly because of increased expression of
the human equilibrative nucleoside transporter 1
(hENT1).14 However, this membrane transport system
has only been proven to affect sensitivity at low doses of
cytarabine.24,25 The Children’s Cancer Group and
Dana-Farber Cancer Institute have reported that
postinduction intensification courses with high doses of
cytarabine and methotrexate can improve outcome.3,8
Small uncontrolled studies have suggested that haemo-
poietic stem-cell transplantation can benefit infants with
MLL rearrangements.26–28 However, a large retrospective
analysis did not bear this out.29 We recommended that
only high-risk patients in our study should receive stem-
cell transplants. Future studies should assess the
effectiveness of stem-cell transplantation for infants with
acute lymphoblastic leukaemia.
The proportion of patients with central nervous system
involvement was the same or slightly lower than that
published by most study groups. Our findings accord
with other studies that show that about 30% of infants
with acute lymphoblastic leukaemia have a poor response
to prednisone,5 and that about 80% have an MLL
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Articles
rearrangement.1 We recorded the distribution of different
chromosome translocations involved in MLL
rearrangements. The Children’s Cancer Group7
suggested that infants with t(4;11), t(9;11), and t(11;19)
chromosome translocations might have a worse outcome
than infants with other types of MLL gene
rearrangements; however, that study did not analyse
sufficient numbers to generate definite conclusions. Our
study did not identify any association between type of
MLL translocation and outcome.
Our finding that most t(4;11) and t(11;19) translocations
were in very young infants, whereas t(9;11) was seen in
older infants, suggests that t(9;11) develops in a later
phase of development or is associated with a slower
progression to leukaemia. This hypothesis accords with
our previous finding that children with t(9;11)
translocations had more mature immunoglobulin and
T-cell receptor rearrangements than those with t(4;11)
and t(11;19) translocations.30
Both MLL rearrangement and age younger than
6 months were strong independent predictive factors for
poor outcome in infants with acute lymphoblastic
leukaemia. Within subgroups defined by these factors,
poor response to a prednisone prophase and high WBC
count taken individually were equally able to identify
patients with poor prognosis.
We believe that this hybrid treatment protocol will be
used as the standard for continuing international
collaborative studies that aim to further improve
outcomes for acute lymphoblastic leukaemia in infants.
The Interfant-06 treatment protocol compares the
efficacy of two intensification chemotherapy schedules,
which are administered earlier than those used in our
Interfant-99 study (ie, immediately after the induction
therapy). Patients in the Interfant-06 study are now
being stratified according to the prognostic factors
identified in our study.
Currently available drugs will not enable cures for all
infants with acute lymphoblastic leukaemia, particularly
those with MLL rearrangements. Therefore, we will need
innovative strategies directed against novel therapeutic
targets, such as FLT3 inhibitors, demethylating agents,
novel nucleoside analogues, and MCL-1 inhibitors.31
Contributors
RP, MS, and MGV designed and planned the study. RP and MGV wrote
the report. PDL was in charge of data pooling, data checking, and
reporting and analyses. MGV was the study statistician. All authors
coordinated the study in their own countries, and have read and
approved the final version of the report.
Conflict of interest statement
We declare that we have no conflict of interest.
Acknowledgments
The many participating institutes of all study groups are acknowledged
for their support. This study in AIEOP is partially supported by
Associazione Italiana Ricerca sul Cancro: Regional Grant Cod 1105 to AB
and MGV. The international study operating centre is partially supported
by Fondazione Tettamanti and Comitato MM Verga to MGV and PDL.
CPH is supported by grant MSM0021620813 of the Czech Ministry of
Education. BFM-G is supported by Deutsche Krebshilfe.
249
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