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

• Published in: Blood 2019-03, Vol.133 (11), p.1205-1216
• Main Authors: Baliakas, Panagiotis, Jeromin, Sabine, Iskas, Michalis, Puiggros, Anna, Plevova, Karla, Nguyen-Khac, Florence, Davis, Zadie, Rigolin, Gian Matteo, Visentin, Andrea, Xochelli, Aliki, Delgado, Julio, Baran-Marszak, Fanny, Stalika, Evangelia, Abrisqueta, Pau, Durechova, Kristina, Papaioannou, George, Eclache, Virginie, Dimou, Maria, Iliakis, Theodoros, Collado, Rosa, Doubek, Michael, Calasanz, M. Jose, Ruiz-Xiville, Neus, Moreno, Carolina, Jarosova, Marie, Leeksma, Alexander C., Panayiotidis, Panayiotis, Podgornik, Helena, Cymbalista, Florence, Anagnostopoulos, Achilles, Trentin, Livio, Stavroyianni, Niki, Davi, Fred, Ghia, Paolo, Kater, Arnon P., Cuneo, Antonio, Pospisilova, Sarka, Espinet, Blanca, Athanasiadou, Anastasia, Oscier, David, Haferlach, Claudia, Stamatopoulos, Kostas
• Format: Article
• Language: English
• Subjects: Aged; Biomarkers, Tumor - genetics; Chromosome Aberrations; Cytogenetics - methods; Female; Follow-Up Studies; Humans; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Leukemia, Lymphocytic, Chronic, B-Cell - mortality; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Life Sciences; Lymphoid Neoplasia; Male; Medicin och hälsovetenskap; Middle Aged; Mutation; Prognosis; Retrospective Studies; Somatic Hypermutation, Immunoglobulin - genetics; Survival Rate; Tumor Suppressor Protein p53 - genetics
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2018-09-873083

Recent evidence suggests that complex karyotype (CK) defined by the presence of ≥3 chromosomal aberrations (structural and/or numerical) identified by using chromosome-banding analysis (CBA) may be relevant for treatment decision-making in chronic lymphocytic leukemia (CLL). However, many challenges toward the 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 outcomes, 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 immunoglobulin heavy variable genes. Thus, they contrasted with 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 immunoglobulin heavy variable gene somatic hypermutation status, we propose a novel hierarchical model in which patients with high-CK exhibit the worst prognosis, whereas those with mutated CLL lacking CK or TP53abs, as well as CK with +12,+19, show the longest overall survival. Thus, 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, independent of other biomarkers. Prospective clinical validation is warranted before ultimately incorporating high-CK in risk stratification of CLL. •Complex karyotype defined by the presence of ≥3 chromosomal abnormalities should not be axiomatically considered unfavorable in CLL.•High cytogenetic complexity with ≥5 chromosomal aberrations emerges as prognostically adverse, independently of other biomarkers. [Display omitted]