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Blood. 2019 Jan 2. pii: blood-2018-09-873083. doi: 10.1182/blood-2018-09-873083. [Epub ahead of print]

Cytogenetic complexity in chronic lymphocytic leukemia: definitions, associations and clinical impact.

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Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Sweden.
MLL Munich Leukemia Laboratory, Munich, Germany.
Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece.
Laboratori de Citogenetica Molecular, Servei de Patologia, Hospital del Mar, Barcelona, Spain.
Central European Institute of Technology (CEITEC), Masaryk University, Brno, Czech Republic.
Hematology Department and Sorbonne University, Hopital Pitie-Salpetriere, INSERM U1138, Paris, France.
Department of Haematology, Royal Bournemouth Hospital, United Kingdom.
Hematology Section, St. Anna University Hospital, Ferrara, Italy.
Hematology Division, Department of Medicine, University of Padua, Italy.
Institute of Applied Biosciences, Center for Research and Technology Hellas, Thessaloniki, Greece.
Department of Hematology, Hospital Clinic, IDIBAPS, Universitat de Barcelona, Barcelona, Spain.
Laboratoire d'hematologie, Hopital Avicenne, AP-HP, France.
Servei d'Hematologia, Hospital Vall d'Hebron, Barcelona, Spain.
Department of Internal Medicine - Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic.
Hematology Section, First Department of Propedeutic Internal Medicine, National and Kapodistrian University of Athens, Laikon University Hospital, Athens, Greece.
Servicio de Hematologia, Consorcio Hospital General Universitario, Valencia, Spain.
Servicio de Genetica Citogenetica, Departamento de Genetica, Universidad de Navarra, Pamplona, Spain.
Servei Laboratori Hematologia, ICO-Hospital Germans Trias i Pujol, Institut de Recerca Contra la Leucemia Josep Carreras (IJC), Universitat Autonoma de Barcelona, Badalona, Spain.
Servei d'Hematologia, Hospital Universitari de la Santa Creu i Sant Pau, Barcelona, Spain.
Department of Hematology & Lymphoma and Myeloma Center Amsterdam, Academic Medical Center Amsterdam, University of Amsterdam, and Cancer Center Amsterdam and Infection & Immunity Institute of Amsterdam, Netherlands.
Department of Hematology, University Medical Centre Ljubljana, Slovenia.
Strategic Research Program in CLL, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute and Universita Vita-Salute San Raffaele, Milan, Italy.
Institute of Applied Biosciences, Center for Research and Technology Hellas, Thessaloniki, Greece;


Recent evidence suggests that complex karyotype (CK) defined by the presence of ≥3 chromosomal aberrations (structural and/or numerical) identified by chromosome banding analysis (CBA) may be relevant for treatment decision-making in chronic lymphocytic leukemia (CLL). However, many challenges towards routine clinical application of CBA remain. In a retrospective study of 5290 patients with available CBA data, we explored both clinicobiological associations and the clinical impact of CK in CLL. We found that patients with ≥5 abnormalities, defined as high-CK, exhibit uniformly dismal clinical outcome, independently of clinical stage, TP53 aberrations (deletion of chromosome 17p and or TP53 mutations, TP53abs) and the expression of somatically hypermutated (M-CLL) or unmutated (U-CLL) immunoglobulin heavy variable genes (IGHV). Thus, they contrasted CK cases with 3 or 4 aberrations (low-CK and intermediate-CK, respectively) who followed aggressive disease courses only in the presence of TP53abs. At the other end of the spectrum, patients with CK and +12,+19 displayed an exceptionally indolent profile. Building upon CK, TP53abs and IGHV gene somatic hypermutation status, we propose a novel hierarchical model where patients with high-CK exhibit the worst prognosis, while M-CLL lacking CK or TP53abs as well as CK with +12,+19 show the longest overall survival. In conclusion, CK should not be axiomatically considered unfavorable in CLL, representing a heterogeneous group with variable clinical behavior. High-CK with ≥5 chromosomal aberrations emerges as prognostically adverse, independently of other biomarkers. Prospective clinical validation is warranted before finally incorporating high-CK in risk stratification of CLL.

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