Minimal residual disease-directed therapy for childhood acute myeloid leukaemia: results of the AML02 multicentre trial

doi:10.1016/S1470-2045(10)70090-5

The Lancet Oncology

Volume 11, Issue 6, June 2010, Pages 543-552

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https://doi.org/10.1016/S1470-2045(10)70090-5 Get rights and content

Summary

Background

We sought to improve outcome in patients with childhood acute myeloid leukaemia (AML) by applying risk-directed therapy that was based on genetic abnormalities of the leukaemic cells and measurements of minimal residual disease (MRD) done by flow cytometry during treatment.

Methods

From Oct 13, 2002, to June 19, 2008, 232 patients with de-novo AML (n=206), therapy-related or myelodysplasia-related AML (n=12), or mixed-lineage leukaemia (n=14) were enrolled at eight centres. 230 patients were assigned by block, non-blinded randomisation, stratified by cytogenetic or morphological subtype, to high-dose (18 g/m², n=113) or low-dose (2 g/m², n=117) cytarabine given with daunorubicin and etoposide (ADE; induction 1). The primary aim of the study was to compare the incidence of MRD positivity of the high-dose group and the low-dose group at day 22 of induction 1. Induction 2 consisted of ADE with or without gemtuzumab ozogamicin (GO anti-CD33 monoclonal antibody); consolidation therapy included three additional courses of chemotherapy or haematopoietic stem-cell transplantation (HSCT). Levels of MRD were used to allocate GO and to determine the timing of induction 2. Both MRD and genetic abnormalities at diagnosis were used to determine the final risk classification. Low-risk patients (n=68) received five courses of chemotherapy, whereas high-risk patients (n=79), and standard-risk patients (n=69) with matched sibling donors, were eligible for HSCT (done for 48 high-risk and eight standard-risk patients). All 230 randomised patients were analysed for the primary endpoint. Other analyses were limited to the 216 patients with AML, excluding those with mixed-lineage leukaemia. This trial is closed to accrual and is registered with ClinicalTrials.gov, number NCT00136084.

Findings

Complete remission was achieved in 80% (173 of 216 patients) after induction 1 and 94% (203 of 216) after induction 2. Induction failures included two deaths from toxic effects and ten cases of resistant leukaemia. The introduction of high-dose versus low-dose cytarabine did not significantly lower the rate of MRD-positivity after induction 1 (34% vs 42%, p=0·17). The 6-month cumulative incidence of grade 3 or higher infection was 79·3% (SE 4·0) for patients in the high-dose group and 75·5% (4·2) for the low-dose group. 3-year event-free survival and overall survival were 63·0% (SE 4·1) and 71·1% (3·8), respectively. 80% (155 of 193) of patients achieved MRD of less than 0·1% after induction 2, and the cumulative incidence of relapse for this group was 17% (SE 3). MRD of 1% or higher after induction 1 was the only significant independent adverse prognostic factor for both event-free (hazard ratio 2·41, 95% CI 1·36–4·26; p=0·003) and overall survival (2·11, 1·09–4·11; p=0·028).

Interpretation

Our findings suggest that the use of targeted chemotherapy and HSCT, in the context of a comprehensive risk-stratification strategy based on genetic features and MRD findings, can improve outcome in patients with childhood AML.

Funding

National Institutes of Health and American Lebanese Syrian Associated Charities (ALSAC).

Introduction

With improvements in risk-directed therapy and supportive care, event-free survival (EFS) for children with acute lymphoblastic leukaemia (ALL) now approaches 90%.¹ By contrast, EFS for children with acute myeloid leukaemia (AML) ranges from 49% to 62%.2, 3, 4 Improving clinical results in AML requires not only the development of new drugs and better supportive care, but also a more precise application of risk-directed therapy.

It is well known that genetic abnormalities of leukaemic blasts are associated with clinical outcome in patients with AML.⁵ Methods for detecting minimal residual disease (MRD) allow much more precise assessments of early reduction in leukaemic burden than were possible in the past, and the results of these tests are powerful and independent predictors of relapse in adults and children with AML.6, 7, 8, 9, 10 We therefore designed a multicentre study, AML02, that relied on presenting genetic features and sequential assessment of MRD to establish the final risk assignment and treatment of children with AML. Additionally, because earlier studies suggested that higher doses of cytarabine during induction therapy might be associated with lower relapse rates,11, 12, 13 we investigated whether high-dose cytarabine (18 g/m²) would lead to better results than a lower dose (2 g/m²). Gemtuzumab ozogamicin (GO) was given to patients with poor early response, and those with high-risk features were eligible for haematopoietic stem-cell transplantation (HSCT).

Section snippets

Patients

From October 13, 2002, to June 19, 2008, 232 children with de-novo AML (n=206), therapy-related or myelodysplastic syndromes (MDS)-related AML (n=12), or mixed-lineage leukaemia (n=14) were enrolled in the AML02 trial at eight centres. Mixed-lineage leukaemia was defined as described in the WHO 2008 classification.14, 15 Age at diagnosis ranged from 2 days to 21·4 years (median 9·1 years). Patients with acute promyelocytic leukaemia or Down's syndrome were excluded. The protocol was approved by

Results

Of the 232 eligible patients, 230 (216 with AML and 14 with mixed lineage leukaemia) were randomised to receive high-dose cytarabine (n=113) or low-dose cytarabine (n=117; figure 2). Two patients were not randomised because of physician choice or parent refusal. Presenting features of the randomised patients are shown in table 1, and were much the same in the two groups, with the exception of WBC count and the proportion of patients with normal karyoptype.

On day 22 of remission-induction

Discussion

In this multicentre study of risk-adapted therapy based on genetic features and sequential MRD measurements, patients with AML achieved a 3-year EFS of 63% and an overall survival of 71%. These results represent substantial gains over the outcomes of trials done in the USA, including St Jude AML97²⁶ (44% and 50%), the Pediatric Oncology Group Study 9421²⁷ (36% and 54%), and the Children's Cancer Group 2961³ (42% and 52%). Our results also compared favourably with results reported by the Medical

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Fast track — ArticlesMinimal residual disease-directed therapy for childhood acute myeloid leukaemia: results of the AML02 multicentre trial

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Patients

Results

Discussion

Blood

Blood

Blood

Blood

Blood

Blood

J Chronic Dis

Lancet

Blood

Blood

Blood

Blood

Blood

Treating childhood acute lymphoblastic leukemia without cranial irradiation

N Engl J Med

Less toxicity by optimizing chemotherapy, but not by addition of granulocyte colony-stimulating factor in children and adolescents with acute myeloid leukemia: results of AML-BFM 98

J Clin Oncol

Risk-stratified therapy and the intensive use of cytarabine improves the outcome in childhood acute myeloid leukemia: the AML99 trial from the Japanese Childhood AML Cooperative Study Group

J Clin Oncol

Independent prognostic factors for AML outcome

Hematology Am Soc Hematol Educ Program

Determination of minimal residual disease in leukaemia patients

Br J Haematol

Fast track — Articles
Minimal residual disease-directed therapy for childhood acute myeloid leukaemia: results of the AML02 multicentre trial