Complex karyotype (CK) identified by chromosome-banding analysis (CBA) has shown prognostic value in chronic lymphocytic leukemia (CLL). Genomic arrays offer high-resolution genome-wide detection of copy-number alterations (CNAs) and could therefore be well equipped to detect the presence of a CK. Current knowledge on genomic arrays in CLL is based on outcomes of single center studies, in which different cutoffs for CNA calling were used. To further determine the clinical utility of genomic arrays for CNA assessment in CLL diagnostics, we retrospectively analyzed 2293 arrays from 13 diagnostic laboratories according to established standards. CNAs were found outside regions captured by CLL FISH probes in 34% of patients, and several of them including gains of 8q, deletions of 9p and 18p (p<0.01) were linked to poor outcome after correction for multiple testing. Patients (n=972) could be divided in three distinct prognostic subgroups based on the number of CNAs. Only high genomic complexity (high-GC), defined as ≥5 CNAs emerged as an independent adverse prognosticator on multivariable analysis for time to first treatment (Hazard ratio: 2.15, 95% CI: 1.36-3.41; p=0.001) and overall survival (Hazard ratio: 2.54, 95% CI: 1.54-4.17; p<0.001; n=528). Lowering the size cutoff to 1 Mb in 647 patients did not significantly improve risk assessment. Genomic arrays detected more chromosomal abnormalities and performed at least as well in terms of risk stratification compared to simultaneous chromosome banding analysis as determined in 122 patients. Our findings highlight genomic array as an accurate tool for CLL risk stratification.

Amsterdam University Medical Centers University of Amsterdam

Amsterdam University Medical Centers University of Amsterdam The Netherlands

Amsterdam University Medical Centers Vrije Universiteit Amsterdam The Netherlands

Cancer Genomics Academic Unit of Cancer Sciences University of Southampton

Cancer Genomics Academic Unit of Cancer Sciences University of Southampton Southampton UK

CEITEC University Hospital Brno and Faculty of Medicine Masaryk University Brno Czech Republic

Cytogenetics department St Vincent Hospital Melbourne Victoria Australia

Department of Oncology Pathology Karolinska Institutet Stockholm

Department of Oncology Pathology Karolinska Institutet Stockholm Sweden

Dept of Clinical Genetics Amsterdam University Medical Centers Univ of Amsterdam The Netherlands

Dept of Experimental Oncology IRCCS Ospedale San Raffaele Università Vita Salute Milan

Dept of Genetics University Medical Center Groningen University of Groningen The Netherlands

Dept of Immunology Genetics and Pathology Science for Life Laboratory Uppsala University Sweden

Dept of Molecular Medicine and Surgery Karolinska Institutet Stockholm Sweden

Dept of Molecular Pathology Royal Bournemouth Hospital Bournemouth UK

Division of Clinical Genetics Dept of Laboratory Medicine Lund University Lund Sweden

Hematology Amsterdam University Medical Centers University of Amsterdam The Netherlands

Hospital del Mar Barcelona

IBSAL IBMCC Centro de Investigación del Cancer Universidad de Salamanca CSIC Spain

Institut Universitaire du Cancer de Toulouse Oncopole Toulouse France

Institute of Applied Biosciences Center for Research and Technology Hellas Thessaloniki Greece

Laboratori de Citogenetica Molecular Servei de Patologia Hospital del Mar Barcelona Spain

MLL Munich Leukemia Laboratory Munich Germany

Oncogenomic laboratory Dept of Hematology Lausanne University Hospital Switzerland

Radboud University Medical Center Dept of Human Genetics Nijmegen The Netherlands

Service d'Hematologie Biologique Hopital Pitié Salpetriere APHP Paris France

St Vincent Hospital Melbourne Peter MacCallum Cancer Center University of Melbourne Australia

University Hospital Brno and Faculty of Medicine Masaryk University Brno Czech Republic

University Hospital Brno Masaryk University Brno Czech Republic

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Haematologica. 2021 Jan 01;106(1):7-9. doi: 10.3324/haematol.2020.264689. PubMed

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