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

Panagiotis Baliakas, Sabine Jeromin, Michalis Iskas, Anna Puiggros, Karla Plevova, Florence NguyenKhac, Zadie Davis, Gian Matteo Rigolin, Andrea Visentin, Aliki Xochelli, Julio Delgado, Fanny Baran-Marszak, Evaggelia Stalika, Pau Abrisqueta, Kristina Durechova, George Papaioannou, Virginie Eclache, Maria Dimou, Theodoros Iliakis, Rosa Collado, Michael Doubek, M Jose Calasanz, Neus Ruiz-Xiville, Carolina Moreno, Marie Jarosova, Alexander C. Leeksma, Panayiotis Panayiotidis, Helena Podgornik, Florence Cymbalista, Achilles Anagnostopoulos, Livio Trentin, Niki Stavroyianni, Fred Davi, Paolo Ghia, Arnon P. Kater, Antonio Cuneo, Sarka Pospisilova, Blanca Espinet, Anastasia Athanasiadou, David Oscier, Claudia Haferlach and Kostas Stamatopoulos

Key points

  • 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.

Abstract

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.

  • Submitted September 4, 2018.
  • Accepted December 18, 2018.