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.

Argentina Hospital de Pediatría Buenos Aires Argentina

Associazione Italiana Ematologia Oncologia Pediatrica University of Milano Bicocca San Gerardo Hospital Monza Italy

Australian and New Zealand Children's Haematology Oncology Group Women's and Children's Hospital Adelaide Adelaide Australia

Berlin Frankfurt Münster Austria St Anna Children's Hospital Vienna Austria

Berlin Frankfurt Münster Germany University Medical Center Schleswig Holstein Kiel Germany

Children Hospital Bambino Gesù Rome Italy

Children's Leukaemia Group Hôpital Universitaire des Enfants Reine Fabiola Brussels Belgium

Cooperative study group for treatment of ALL University Hospital Hamburg Eppendorf Hamburg Germany

Czech Paediatric Haematology University Hospital Motol and 2nd Medical School Charles University Prague Prague Czech Republic

Dana Farber Cancer Institute Dana Farber Cancer Institute Boston MA USA

Dutch Childhood Oncology Group Erasmus MC Sophia Children's Hospital Rotterdam Netherlands

French ALL Group Hôpital Saint Louis Paris France

Nordic Society of Paediatric Haematology and Oncology University of Helsinki Helsinki Finland

Polish Paediatric Leukaemia and Lymphoma Study Group Silesian Medical Academy Zabrze Poland

Prince of Wales Hospital The Chinese University of Hong Kong Hong Kong China

Programa Infantil Nacional de Drogas Antineoplásicas Hospital Roberto del Rio Santiago Chile

Sheffield Children's Hospital Sheffield UK

St Jude Children's Research Hospital St Jude Children's Research Hospital Memphis TN USA

UK Children's Cancer Study Group Great Ormond Street Hospital for Children London UK

University of Milano Bicocca Department of Clinical Medicine and Prevention Italy

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Lancet. 2007 Jul 21;370(9583):198-200. doi: 10.1016/S0140-6736(07)61101-5. PubMed

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ClinicalTrials.gov
NCT00015873

ISRCTN
ISRCTN24251487