Minimal residual disease-directed therapy for childhood acute myeloid leukaemia

Results of the AML02 multicentre trial

Jeffrey E. Rubnitz, Hiroto Inaba, Gary Dahl, Raul C. Ribeiro, W. Paul Bowman, Jeffrey Taub, Stanley Pounds, Bassem I. Razzouk, Norman J. Lacayo, Xueyuan Cao, Soheil Meshinchi, Barbara Degar, Gladstone Airewele, Susana C. Raimondi, Mihaela Onciu, Elaine Coustan-Smith, James R. Downing, Wing Leung, Ching Hon Pui, Dario Campana

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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/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).

Original languageEnglish (US)
Pages (from-to)543-552
Number of pages10
JournalThe Lancet Oncology
Volume11
Issue number6
DOIs
StatePublished - Jun 1 2010

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Residual Neoplasm
Acute Myeloid Leukemia
Multicenter Studies
Therapeutics
Hematopoietic Stem Cell Transplantation
Leukemia
Cytarabine
Drug Therapy
Incidence
Charities
Daunorubicin
Survival
Poisons
National Institutes of Health (U.S.)
Etoposide
Random Allocation
Cytogenetics
Disease-Free Survival
Siblings
Flow Cytometry

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Rubnitz, J. E., Inaba, H., Dahl, G., Ribeiro, R. C., Bowman, W. P., Taub, J., ... Campana, D. (2010). Minimal residual disease-directed therapy for childhood acute myeloid leukaemia: Results of the AML02 multicentre trial. The Lancet Oncology, 11(6), 543-552. https://doi.org/10.1016/S1470-2045(10)70090-5

Minimal residual disease-directed therapy for childhood acute myeloid leukaemia : Results of the AML02 multicentre trial. / Rubnitz, Jeffrey E.; Inaba, Hiroto; Dahl, Gary; Ribeiro, Raul C.; Bowman, W. Paul; Taub, Jeffrey; Pounds, Stanley; Razzouk, Bassem I.; Lacayo, Norman J.; Cao, Xueyuan; Meshinchi, Soheil; Degar, Barbara; Airewele, Gladstone; Raimondi, Susana C.; Onciu, Mihaela; Coustan-Smith, Elaine; Downing, James R.; Leung, Wing; Pui, Ching Hon; Campana, Dario.

In: The Lancet Oncology, Vol. 11, No. 6, 01.06.2010, p. 543-552.

Research output: Contribution to journalArticle

Rubnitz, JE, Inaba, H, Dahl, G, Ribeiro, RC, Bowman, WP, Taub, J, Pounds, S, Razzouk, BI, Lacayo, NJ, Cao, X, Meshinchi, S, Degar, B, Airewele, G, Raimondi, SC, Onciu, M, Coustan-Smith, E, Downing, JR, Leung, W, Pui, CH & Campana, D 2010, 'Minimal residual disease-directed therapy for childhood acute myeloid leukaemia: Results of the AML02 multicentre trial', The Lancet Oncology, vol. 11, no. 6, pp. 543-552. https://doi.org/10.1016/S1470-2045(10)70090-5
Rubnitz, Jeffrey E. ; Inaba, Hiroto ; Dahl, Gary ; Ribeiro, Raul C. ; Bowman, W. Paul ; Taub, Jeffrey ; Pounds, Stanley ; Razzouk, Bassem I. ; Lacayo, Norman J. ; Cao, Xueyuan ; Meshinchi, Soheil ; Degar, Barbara ; Airewele, Gladstone ; Raimondi, Susana C. ; Onciu, Mihaela ; Coustan-Smith, Elaine ; Downing, James R. ; Leung, Wing ; Pui, Ching Hon ; Campana, Dario. / Minimal residual disease-directed therapy for childhood acute myeloid leukaemia : Results of the AML02 multicentre trial. In: The Lancet Oncology. 2010 ; Vol. 11, No. 6. pp. 543-552.
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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/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).",
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T1 - Minimal residual disease-directed therapy for childhood acute myeloid leukaemia

T2 - Results of the AML02 multicentre trial

AU - Rubnitz, Jeffrey E.

AU - Inaba, Hiroto

AU - Dahl, Gary

AU - Ribeiro, Raul C.

AU - Bowman, W. Paul

AU - Taub, Jeffrey

AU - Pounds, Stanley

AU - Razzouk, Bassem I.

AU - Lacayo, Norman J.

AU - Cao, Xueyuan

AU - Meshinchi, Soheil

AU - Degar, Barbara

AU - Airewele, Gladstone

AU - Raimondi, Susana C.

AU - Onciu, Mihaela

AU - Coustan-Smith, Elaine

AU - Downing, James R.

AU - Leung, Wing

AU - Pui, Ching Hon

AU - Campana, Dario

PY - 2010/6/1

Y1 - 2010/6/1

N2 - 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).

AB - 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).

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