In acute myeloid leukemia (AML) the subset with complex karyotype (CK) is traditionally regarded as the worst prognostic group. However, ≥ 3, ≥ 4, or ≥ 5 abnormalities have been variably used for its definition. Recently, monosomal karyotype (MSK) was suggested to indicate an even inferior outcome. We tested which definition fits best to identify the most unfavorable subgroup. After excluding patients with t(15;17)/PML-RARA, t(8;21)/RUNX1-RUNX1T1, inv (16)/t(16;16)/CBFB-MYH11, and normal karyotype, 824 patients with AML with cytogenetic abnormalities were analyzed. Patients with MSK or CK defined as ≥ 3, ≥ 4, or ≥ 5 abnormalities showed an inferior overall survival compared with the respective remaining patients not fulfilling these criteria (for all, P < .001). Hazard ratios were 1.93, 1.68, 1.94, and 1.92. CK ≥ 4 as a single parameter identified the largest proportion of patients with very poor risk. However, combining CK ≥ 4 and MSK detected an even larger number of patients with very unfavorable outcome (261 of 824; 31.7%).
"This observation was confirmed by the Southwest Oncology Group (SWOG), Groupe Ouest Est d'Etude des Leuc emies 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). "
[Show abstract][Hide abstract] ABSTRACT: Genetic profiling in acute myeloid leukaemia (AML) is a moving target. Only 4 years ago, AML was re-classified, based on karyotypic abnormalities. However, numerous important new mutations and other genetic abnormalities that were not considered in this classification have been identified. Current cytogenetic-based classification is limited by the substantial number of intermediate-risk patients in whom the preferred therapy is debatable. In addition, the majority of AML patients co-express multiple mutations and cannot be easily categorized into predefined homogenous groups. The tremendous progress in mass sequencing allows parallel identification of multiple genetic aberrations in large cohorts. Thus, a new concept of genetic profiling has arisen. Genes and proteins biologically interact with each other; therefore, it should not be surprising that mutations in different genes interact. Prognosis is determined by the composition of mutations and aberrations in leukaemic stem cells. As a consequence, clinical decisions no longer rely on scant genetic data and require comprehensive genetic evaluation. Some non-genetic parameters are also important and should be incorporated into the clinical decision algorithm. Genetic interaction-based profiles are challenging and recent studies demonstrate an improvement in prognostic predictions with this model. Thus, genetic profiling is likely to have a major therapeutic impact, at least for intermediate-risk cytogenetics.
British Journal of Haematology 12/2012; 160(3). DOI:10.1111/bjh.12135 · 4.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Clonal cytogenetic abnormalities are a major risk factor for relapse after hematopoietic cell transplantation (HCT) for myelodysplastic syndrome (MDS). We determined the impact of the recently established 5-group cytogenetic classification of MDS on outcome after HCT. Results were compared with the impact of the International Prognostic Scoring System (IPSS) 3 cytogenetic risk groups, and the additional effect of a monosomal karyotype was assessed. The study included data on 1007 patients, 1-75 years old (median 45 years), transplanted from related (n = 547) or unrelated (n = 460) donors. Various conditioning regimens were used, and marrow, peripheral blood, or cord blood served as stem cell source. Both IPSS and 5-group cytogenetic risk classifications were significantly associated with post-HCT relapse and mortality, but the 5-group classification discriminated more clearly among the lowest- and highest-risk patients. A monosomal karyotype tended to further increase the rates of relapse and mortality, even after considering the IPSS or 5-group classifications. In addition, the pathologic disease category correlated with both relapse and mortality. Mortality was also impacted by patient age, donor type, conditioning regimen, platelet count, and etiology of MDS. Although mortality declined significantly in recent years, novel strategies are needed to overcome the barrier of high-risk cytogenetics.
[Show abstract][Hide abstract] ABSTRACT: An increasing number of cytogenetic and molecular genetic aberrations have been identified in acute myeloid leukaemia (AML), highlighting the biological heterogeneity of the disease. Moreover, the characterisation of specific molecular abnormalities provides the basis for targeted therapies, such as all trans retinoic acid (ATRA) and arsenic trioxide treatment in acute promyelocytic leukaemia or tyrosine kinase inhibitors in AML with FLT3 mutations. Several cytogenetic and molecular genetic changes have been shown to be prognostically relevant and have been acknowledged in the latest WHO classification of AML as separate entities. A detailed marker assessment at diagnosis is crucial for risk-stratification of AML patients, allowing the identification of those at high risk of relapse, who may benefit from early allogeneic stem cell transplantation. Finally, molecular markers are important for the detection of minimal residual disease after initial therapy and during long-term follow-up, which enables a more tailored treatment approach for individual AML patients.
International journal of hematology 07/2012; 96(2):153-63. DOI:10.1007/s12185-012-1123-9 · 1.92 Impact Factor
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