Elsevier

The Lancet

Volume 370, Issue 9583, 21–27 July 2007, Pages 240-250
The Lancet

Articles
A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomised trial

https://doi.org/10.1016/S0140-6736(07)61126-XGet rights and content

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

Acute lymphoblastic leukaemia (ALL) in infants aged younger than 12 months is both rare and biologically different from acute lymphoblastic leukaemia in older children. In infants, this disease is characterised by a high frequency of abnormalities in chromosome 11q23 that affect the mixed lineage leukaemia (MLL) gene; by a very immature B-cell phenotype (pro-B ALL) with no CD10 expression; and by a high tumour load at presentation.1, 2 Studies in various countries have reported long-term rates of event-free survival (EFS) of 28–45%.3, 4, 5, 6, 7, 8, 9, 10, 11 These rates are much lower than EFS rates for older children with acute lymphoblastic leukaemia, which are about 80%.1, 2

Infant lymphoblasts are more resistant to chemotherapy than cells in older children,12, 13 but are sensitive in vitro to cytarabine.13, 14 In vivo, small numbers of adults15 and infants3 with pro-B ALL phenotypes had better outcomes after postremission treatment with high-dose cytarabine. Outcomes for subgroups of infants with acute lymphoblastic leukaemia vary with status of the MLL gene, CD10 expression, age at diagnosis, white blood cell (WBC) count at presentation, central nervous system involvement, coexpression of myeloid markers, and early response to prednisone.1, 2 For example, patients who have a poor response to prednisone have EFS rate of 15%, compared with 53% for patients who have a good response to prednisone.5 However, these variables are interdependent, and their relative significance has not been clearly established. Also, the various types of MLL gene rearrangements could predict different prognoses.7, 8, 16 National study groups have been unable to accrue the numbers needed for analyses with sufficient power, or for randomised comparisons of the effectiveness of treatments.

We initiated a large collaborative trial, Interfant-99, 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 protocol consisted of elements to treat both acute lymphoblastic and myeloid leukaemia but with no irradiation and only small amounts of anthracyclines and alkylating agents.) Our second aim was to assess the efficacy of a late intensification course with high doses of both cytarabine and methotrexate between reinduction and maintenance phases. Our final aim was to identify any clinical and biological factors that might have independent prognostic value.

Section snippets

Patients

Patients were drawn from 17 study groups in 22 countries: 12 original groups and five that joined the collaboration later (webtable 1). Individual study groups obtained ethics approval from their own institutions.

Patients were recruited by the different study groups from May, 1999. Enrolment closed on Jan 1, 2006. All study groups had started recruitment of consecutive patients by January, 2000. Eligibility criteria for enrolment in the observational study were age 365 days or younger with

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

Discussion

EFS over 4 years for the 482 infants with acute lymphoblastic leukaemia treated with our hybrid protocol was 47·0% (SE 2·6); survival was 55·3% (2·7). These outcomes are better than those achieved with most previous protocols (table 5). The Dana Farber Cancer Institute reported a higher EFS (54%, SE 11), but their trial included only 23 patients.3 A brief report from a Japanese study22 on infants with acute lymphoblastic leukaemia reported an overall EFS of 52%, but did not provide details

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