Karyotypic abnormalities are the first and most widely established genetic prognostic markers in AML. Numerous cytogenetic changes have been recognized in AML, with varying prognostic significance. The role of a specific cytogenetic aberration in leukaemogenesis is a productive field for research; yet, unique biological mechanisms were discovered for only few recurrent aberrations [e.g., t(15;17), t(8:21), MLL translocations (Kakizuka et al, 1991; Schoch et al, 2003; Prebet et al, 2009)]. Patient outcome has been known to be associated with specific cytogenetic aberrations for more than 25 years. In the last 15 years major cooperative leukaemia research groups around the world have assessed the cytogenetic prognostic value in large uniformly treated cohorts. The UK Medical Research Council (MRC) 10 trial (Grimwade et al, 1998) included 1966 patients younger than 55 years of age, most of them with de-novo AML. Evaluation of the prognostic value of each recurrent cytogenetic aberration, led to a general classification of three cytogenetic risk groups (favourable, intermediate and adverse). Similar results were reported by the US intergroup study in 609 patients younger than 56 years (Slovak et al, 2000), and by the Cancer and Leukaemia Group B (CALGB) in 1213 adult patients of all ages (Byrd et al, 2002) (Fig 1). The MRC11 trial, which included 1065 patients older than 55 years of age, a Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON) study that included patients older than 60 years and an Eastern Cooperative Oncology Group (ECOG) study of patients older than 55 years all confirmed that karyotypes define biologically distinguished diseases and validate their prognostic value for all age groups (Grimwade et al, 2001; Rowe et al, 2004; van der Holt et al, 2007). Due to insufficient numbers of patients on studies, multiple rare aberrations were grouped together and analysed as a group. Efforts have been made to sort data regarding specific rare but recurrent aberrations from cooperative group databases. Breems et al (2008) first reported that monosomal karyotype (excluding sex chromosomes) has an extremely poor prognosis, even more so than a complex karyotype. This observation was confirmed by the Southwest Oncology Group (SWOG), Groupe Ouest Est d'Etude des Leucémies et Autres Maladies du Sang (GOELAMS), the German-Austrian AML Study Group (Medeiros et al, 2010; Perrot et al, 2011; Kayser et al, 2012) and the Japan Adult Leukaemia Study Group (Yanada et al, 2012) in various age groups and following different protocols. Combination of a monosomal karyotype and multiply complexed karyotype (≥4) appears to confer the poorest prognosis (Haferlach et al, 2012a). A commendably exhaustive effort to explore the value of rare cytogenetic aberrations has been conducted by the MRC, with data on 5876 AML patients (Grimwade et al, 2010a) (Fig 2). This study confirmed the very poor prognosis of monosomy and discriminated t(3;5) without additional adverse features, to be considered not as poor as other chromosome 3 aberrations. Nevertheless, this very large study led to reassignment of only 299 patients (275 cases moved from intermediate to adverse and 24 conversely).
Figure 2. Detailed karyotype analysis in AML. De-tailed cytogenetic aberrations among young adults with AML, reported in the MRC 10, 12 and 15 trials. MRC, Medical Research Council; NCRI, National Cancer Research Institute. This research was originally published in Blood. Grimwade et al (2010a), © the American Society of Hematology.
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Cytogenetics predict for success of intensive induction, relapse rate and overall survival (Table 1) and therefore, play a pivotal role in clinical decisions. However existing clinical data regarding cytogenetics are mainly observational and their clinical utilization is mostly confined to the assignment of post-remission therapy. Cytogenetics have no direct impact on the initial induction regimen chosen, except perhaps in older adults with very unfavourable cytogenetics where the dismal outlook could influence a decision to elect for alternative therapies (Estey, 2011). Decisions regarding post-remission therapy may be made following completion of induction or, as in the UK, after the first cycle of induction, especially in those patients who have an incomplete response. In addition, the cytogenetic intermediate risk group, which includes up to 70% of AML patients, is very heterogeneous and therefore hardly predictive of specific outcome. Long-term survival of intermediate-risk cytogenetics in young adults is about 35–40%. Considering the high morbidity and mortality associated with allogeneic stem cell transplantation (allo-SCT), intermediate-risk AML patients in first remission require a better predictive tool to guide the best post-remission regimen. Currently, only the very best or the poorer cytogenetic markers can reasonably guide clinical decisions as a single genetic parameter. For most AML patients, the intermediate-risk group is far too heterogeneous; a more refined genetic or immunological profile is required.