Page 173 - Educacional Ponenecias Congreso SEHH-STH 2020

Importance of the karyotype in chronic lymphocytic leukemia (CLL)
Blanca Espinet1,2, Anna Puiggros1,2, Silvia Ramos2
1 Laboratori de Citogenètica Molecular. Servei de Patologia. Hospital del Mar. Barcelona; 2 Programa de Recerca en Càncer, Institut Mar d’Investigacions Mèdiques (IMIM). Barcelona
❯ Acknowledgements
The authors want to thank members of Grupo Cooperativo Español de Citogenética Hematológica (GCECGH), Grupo Español de Leucemia Linfática Crónica (GELLC) and European Research Initiative on Chronic Lymphocytic Leukemia (ERIC) for their contribution to several cooperative projects on complex karyotype and genomic complexity. Cooperative studies have been performed in part thanks to Gilead Sciences Fellowship GLD17/00282 and 2017/SGR437 from Generalitat de Catalunya.
❯ Introduction
Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western countries, with a median age at diagnosis of 70 years. Its clinical course is highly variable, ranging from very indolent cases to patients with aggressive disease and rapid progression. This heterogeneity has important consequences for the clinical follow-up, therapeutic strategies and patients’ survival(1). The presence of deletions of 17p13 region (involving TP53), usually detected by fluorescence in situ hybridization (FISH), and TP53 mutations as well as the mutational status of the variable region of the immunoglobulin heavy chain (IGHV) gene represent the most important prognostic/predictive markers which allow the stratification of patients into different risk groups in the era of chemoimmunotherapy(2). Nevertheless, new mechanism-based therapeutic agents have been developed in CLL. In the last years, two inhibitors of the signaling pathway of the B-cell receptor (BCR), named ibrutinib and idelalisib, as well as the BCL2 inhibitor venetoclax, have been approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA)(3,4). These new
drugs have improved the outcomes of CLL patients and have been able to overcome or at least attenuate the adverse impact of TP53 deletions or mutations as well as the unmutated IGHV (U-IGHV) status(5,6).
Even though the prognostic value of TP53 and IGHV is well established, several studies have highlighted the prognostic and predictive value of complex karyotype (CK) in CLL. Different cooperative studies have been conducted to analyze the clinical impact of CK(7-10). Besides, the presence of CK has been included in clinical trials in order to elucidate its prognostic/ predictive value, especially with the use of new therapeutic modalities.
The aim of this talk is to review the cytogenetic/ cytogenomic techniques that allow to detect genomic complexity, to show cooperative studies which deal with the definition of complex karyotype and to discuss the prognostic value of CK in the management of CLL.
❯ Chromosome banding analysis (CBA)
Chromosome banding analysis (CBA) allows the detection of numerical and structural aberrations in the karyotype. Initial cytogenetic studies in CLL were highly limited by the low mitotic rate of tumor B-cells in culture. Traditional B-cell mitogens, such as pokeweed mitogen, 12-O-tetradecanoly-phorpol-13- acetate (TPA), and lipopolysaccharide were not very effective, with detection of abnormal clones in only 40-50% of cases(11). Indeed, interphase FISH analysis –with the centromeric probe of chromosome 12 and locus specific probes for 13q14, 11q23 (ATM) and 17p13 (TP53)– was implemented as the gold standard for cytogenetic risk stratification of CLL patients(12). Nonetheless, the detection of abnormalities by FISH was limited to the probes used and underestimated the true complexity and heterogeneity of chromosomal
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