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MK in EORTC/GIMEMA AML-10&12
ty that can be detected by conventional cytogenetics.5 In younger AML patients, the karyotype of leukemic cells has remained one of the main prognostic factors.5,6 Specifically, patients can be classified into a favorable, intermediate or adverse group.5,6 This classification not only provides information on prognosis, but also influ- ences the choice of post-remission treatment.5,7 In 2008, Breems et al. identified a group of cytogenetic abnormal- ities, termed monosomal karyotype (MK), which was associated with a particularly poor prognosis.8 MK is defined as the presence of two or more autosomal mono- somies, or a single monosomy in the presence of struc- tural abnormalities.8,9
The aim of this study was to determine the impact of the type of remission-induction chemotherapy and allo- geneic hematopoietic stem cell transplantation (HSCT) in younger AML patients with a MK, using the data from the European Organization for Research and Treatment on Cancer/Gruppo Italiano Malattie Ematologiche dell'Adulto (EORTC/GIMEMA) AML-10 and AML-12 phase III multi- center trials.
Methods
Study design
In the EORTC Leukemia Group/GIMEMA AML-10 trial,2 patients 15-60 years old were randomized to receive either daunorubicin (50 mg/m2), mitoxantrone (12 mg/m2), or idarubicin (10 mg/m2) on days 1, 3 and 5 in addition to standard-dose cytara- bine (25 mg/m2 bolus followed by 100 mg/m2 given as a continu- ous infusion daily for 10 days) and etoposide (100 mg/m2 on days 1-5) for induction chemotherapy.
In the EORTC Leukemia Group/GIMEMA AML-12 trial,1 patients 15-60 years old were randomized between standard-dose cytarabine induction: daunorubicin (50 mg/m2 per day on days 1, 3, and 5) plus etoposide (50 mg/m2 per day on days 1-5) plus 10 days of cytarabine (100 mg/m2 per day as a continuous intra- venous infusion) and high-dose cytarabine induction: daunoru- bicin (50 mg/m2 on days 1, 3, and 5) plus etoposide (50 mg/m2 per day on days 1-5) plus cytarabine (3,000 mg/m2 every 12 h as a 3 h intravenous infusion on days 1, 3, 5, and 7).
In both trials, a second cycle of induction was administered to patients who achieved a partial response. Patients who achieved a CR or a CR with incomplete blood count recovery (CRi) after one or two courses of induction chemotherapy received consolidation chemotherapy with the same anthracycline as in the induction course plus intermediate-dose cytarabine (500 mg/m2 every 12 h as a 2 h intravenous infusion on days 1-6). Younger patients (<46 years in AML-10 and <50-60 years in AML-12) were then sched- uled to undergo allogeneic HSCT in first CR/CRi if they had an HLA-identical family donor (in both trials) or if they had an unre- lated donor and needed two induction courses to achieve a CR/CRi or had chromosome abnormalities involving 3q, 5, 7, 11q23, t(6;9), t(9;22) or complex abnormalities (in the AML-12 trial). Patients without a donor were scheduled to undergo autol- ogous HSCT in first CR/CRi.
Ethics approval and consent to participation
This is a retrospective analysis limited to data from patients included in phase III multicenter prospective trials (either the EORTC/GIMEMA AML-10 or the EORTC/GIMEMA AML-12). Both prospective phase III trials were approved by the internal review boards of EORTC and GIMEMA and the ethical commit- tee of each participating institution, and were conducted in accor-
dance with the Declaration of Helsinki. All patients signed the respective informed consent form.
Cytogenetic assessment
Cytogenetic examinations were performed at diagnosis. Cytogenetic data were centrally reviewed.2 For the current analy- sis, cytogenetics were centrally re-reviewed, described according to International System for Cytogenetic Nomenclature (ISCN)10 and classified using the refined UK Medical Research Council (MRC) classification.6 MK was defined as the presence of two or more autosomal monosomies or a single monosomy in the pres- ence of structural abnormalities, as introduced by Breems et al.8
Statistical analyses
The duration of overall survival (OS) was calculated from the date of randomization until death. The Kaplan-Meier method was used to estimate the OS rates.11 Confidence intervals for the 5-year OS rates were obtained using the normal approximation of the distribution of log[-log(survival)] and the Greenwood variance for- mula.12 The confidence interval of the median OS from CR/CRi was estimated based on the Brookmeyer and Crowley method.13 Log-rank tests and Cox models were used to compare OS between groups.14 Logistic regression was used to assess associa- tions with CR/CRi achievement after induction. The analysis was stratified (in the case of survival analysis) or adjusted (in the case of logistic regression) by protocol when it included data from two trials. Multivariate Cox and logistic regression models were per- formed to assess the associations of MK and adverse MRC risk group with outcomes, adjusting for known prognostic factors. A Fisher exact test was used to investigate the association between two categorical variables. All reported P-values are two-sided. SAS 9.4 software (SAS Institute Inc. Cary, NC, USA) was used for the statistical analyses.
Results
Patients
In the AML-10 trial, 2,157 patients were randomized to receive daunorubicin, mitoxantrone or idarubicin. The current analyses were performed in a subgroup of 911 patients for whom cytogenetic data were available and who did not have t(8;21), inv(16) or t(15;17); 696 of them were classified in the MRC intermediate cytogenetic risk group and 215 in the adverse group. Out of the 911 patients, 93 had a MK (5 with intermediate-risk cytoge- netics and 88 with adverse risk) (Table 1, Figure 1). In the AML-12 trial, 1,942 patients were randomized between high-dose cytarabine or standard-dose cytarabine. The current analyses were performed in a subgroup of 1,079 patients for whom cytogenetic data were available and who did not have t(8;21), inv(16) or t(15;17); 896 of them were classified in the MRC intermediate cytogenetic risk group and 182 in the adverse-risk group (information was missing for 1 patient). Out of these 1,079 patients, 95 had a MK (4 with intermediate-risk cytogenetics and 91 with adverse-risk) (Table 1, Figure 1). The patients’ median fol- low up was 10.8 years in the whole population, 16.6 years among those in the AML-10 study and 9.9 years among AML-12 patients.
Monosomal karyotype is an independent poor prognostic factor in young acute myeloid leukemia patients
The impact of MK on AML outcomes was assessed by comparing outcomes of patients without MK and without
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