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

Abstract

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/m(2), n=113) or low-dose (2 g/m(2), 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).

Figure 1. AML02 treatment schema

After enrollment, patients were randomized to receive daunorubicin (50 mg/m² on days 2, 4, and 6) and etoposide (100 mg/m² on days 2–6) plus either high-dose cytarabine (HDAC, 3 g/m² every 12 hours on days 1, 3, and 5) or low-dose cytarabine (LDAC, 100 mg/m² every 12 hours on days 1–10), constituting the Induction I phase of treatment. Induction II consisted of low-dose cytarabine (100 mg/m² every 12 hours on days 1–8), daunorubicin, and etoposide (ADE) with or without 3 mg/m² gemtuzumab ozogamicin (GO). Standard-risk patients who lacked matched related donors and all low-risk patients received three courses (CI, CII, CIII) of consolidation therapy, whereas standard-risk patients with matched related donors and high-risk patients were eligible to receive hematopoietic stem cell transplantation (HSCT). CI consisted of cytarabine (500 mg/m²/day by continuous infusion for 5 days) and cladribine (9 mg/m² on days 1–5) for patients with t(9;11) and inv(16); cytarabine (3 g/m² every 12 hours on days 1–3) and etoposide (125 mg/m² on days 2–5) for patients with M4 or M5 AML without t(9;11) or inv(16); and cytarabine (3 g/m² every 12 hours on days 1–3) and mitoxantrone (10 mg/m² on days 3–4) for all other patients. CII consisted of cytarabine (3 g/m² every 12 hours on days 1, 2, 8, 9) and L-Asparaginase (6000 Units/m² 3 hours after the 4^th and 8^th doses of cytarabine). CIII included mitoxantrone (10 mg/m² on days 1–3) and cytarabine (1 g/m² every 12 hours on days 1–3).

Figure 2

Patient Flow Chart

Figure 3. Outcome for patients treated in the AML02 study

Upper curves show the probabilities of overall survival and event-free survival; lower curves show the cumulative incidences of relapse and of death unrelated to relapse.

Figure 4. Outcome according to risk group

(A) Probability of event-free survival according to risk group. (B) Probability of overall survival according to risk group.

Figure 5. Cumulative incidence (CI) of relapse or induction failure according to minimal residual disease (MRD)

(A) CI for patients who were positive or negative for MRD after Induction I. (B) CI for patients with negative, low, or high MRD after of Induction I. (C) CI for patients who were positive or negative for MRD after Induction II. (D) CI for patients with negative, low, or high MRD after Induction II.