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.

Central European Institute of Technology Masaryk University Brno Czech Republic

Department of Experimental Immunology Cancer Center Amsterdam and Infection and Immunity Institute of Amsterdam Amsterdam The Netherlands

Department of Haematology Royal Bournemouth Hospital Bournemouth United Kingdom

Department of Hematology and Lymphoma and Myeloma Center Amsterdam Academic Medical Center Amsterdam University of Amsterdam Amsterdam The Netherlands

Department of Hematology Hospital Clínic Institut d'Investigacions Biomèdiques August Pi i Sunyer Universitat de Barcelona Barcelona Spain

Department of Hematology University Medical Centre Ljubljana Ljubljana Slovenia; and

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

Department of Internal Medicine Hematology and Oncology University Hospital Brno and Faculty of Medicine Masaryk University Brno Czech Republic

Grup de Recerca Translacional en Neoplàsies Hematològiques Programa de Recerca en Càncer Institut Hospital del Mar d'Investigacions Mèdiques Barcelona Spain

Hematology Department and HCT Unit G Papanicolaou Hospital Thessaloniki Greece

Hematology Department and Sorbonne University Hopital Pitie Salpetriere INSERM U1138 Paris France

Hematology Division Department of Medicine University of Padua Padua Italy

Hematology Section 1st Department of Propedeutic Internal Medicine National and Kapodistrian University of Athens Laikon University Hospital Athens Greece

Hematology Section St Anna University Hospital Ferrara Italy

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

Laboratoire d'hématologie Hopital Avicenne Assistance Publique Hôpitaux de Paris Paris France

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

MLL Munich Leukemia Laboratory Munich Germany

Servei d'Hematologia Hospital Universitari de la Santa Creu i Sant Pau Barcelona Spain

Servei d'Hematología Hospital Vall d'Hebron Barcelona Spain

Servei Laboratori Hematologia ICO Hospital Germans Trias i Pujol Institut de Recerca Contra la Leucèmia Josep Carreras Universitat Autònoma de Barcelona Badalona Spain

Servicio de Genética Citogenética Departamento de Genética Universidad de Navarra Pamplona Spain

Servicio de Hematología Consorcio Hospital General Universitario Valencia Spain

Strategic Research Program in CLL Division of Experimental Oncology IRCCS San Raffaele Scientific Institute and Università Vita Salute San Raffaele Milan Italy

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Blood. 2019 Mar 14;133(11):1168-1170. doi: 10.1182/blood-2019-01-896068. PubMed

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Fabbri G, Dalla-Favera R. The molecular pathogenesis of chronic lymphocytic leukaemia. Nat Rev Cancer. 2016;16(3):145-162. PubMed

Hallek M, Pflug N. Chronic lymphocytic leukemia. Ann Oncol. 2010;21(suppl 7):vii154-vii164. PubMed

Chiorazzi N, Rai KR, Ferrarini M. Chronic lymphocytic leukemia. N Engl J Med. 2005;352(8):804-815. PubMed

Baliakas P, Hadzidimitriou A, Sutton LA, et al. . Clinical effect of stereotyped B-cell receptor immunoglobulins in chronic lymphocytic leukaemia: a retrospective multicentre study. Lancet Haematol. 2014;1(2):e74-e84. PubMed

Baliakas P, Hadzidimitriou A, Agathangelidis A, et al. . Prognostic relevance of MYD88 mutations in CLL: the jury is still out. Blood. 2015;126(8):1043-1044. PubMed PMC

Baliakas P, Iskas M, Gardiner A, et al. . Chromosomal translocations and karyotype complexity in chronic lymphocytic leukemia: a systematic reappraisal of classic cytogenetic data. Am J Hematol. 2014;89(3):249-255. PubMed

Baliakas P, Mattsson M, Stamatopoulos K, Rosenquist R. Prognostic indices in chronic lymphocytic leukaemia: where do we stand how do we proceed? J Intern Med. 2016;279(4):347-357. PubMed

Baliakas P, Puiggros A, Xochelli A, et al. . Additional trisomies amongst patients with chronic lymphocytic leukemia carrying trisomy 12: the accompanying chromosome makes a difference. Haematologica. 2016;101(7):e299-e302. PubMed PMC

Catovsky D, Wade R, Else M. The clinical significance of patients’ sex in chronic lymphocytic leukemia. Haematologica. 2014;99(6):1088-1094. PubMed PMC

Cortese D, Sutton LA, Cahill N, et al. . On the way towards a ‘CLL prognostic index’: focus on TP53, BIRC3, SF3B1, NOTCH1 and MYD88 in a population-based cohort. Leukemia. 2014;28(3):710-713. PubMed

Del Giudice I, Rossi D, Chiaretti S, et al. . NOTCH1 mutations in +12 chronic lymphocytic leukemia (CLL) confer an unfavorable prognosis, induce a distinctive transcriptional profiling and refine the intermediate prognosis of +12 CLL. Haematologica. 2012;97(3):437-441. PubMed PMC

Döhner H, Stilgenbauer S, Benner A, et al. . Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000;343(26):1910-1916. PubMed

Eichhorst B, Hallek M. Prognostication of chronic lymphocytic leukemia in the era of new agents. Hematology Am Soc Hematol Educ Program. 2016;2016:149-155. PubMed PMC

Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK. Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood. 1999;94(6):1848-1854. PubMed

Mansouri L, Cahill N, Gunnarsson R, et al. . NOTCH1 and SF3B1 mutations can be added to the hierarchical prognostic classification in chronic lymphocytic leukemia. Leukemia. 2013;27(2):512-514. PubMed

Parikh SA, Strati P, Tsang M, West CP, Shanafelt TD. Should IGHV status and FISH testing be performed in all CLL patients at diagnosis? A systematic review and meta-analysis. Blood. 2016;127(14):1752-1760. PubMed

Rai KR, Jain P. Chronic lymphocytic leukemia (CLL)—then and now. Am J Hematol. 2016;91(3):330-340. PubMed

Rossi D, Gerber B, Stüssi G. Predictive and prognostic biomarkers in the era of new targeted therapies for chronic lymphocytic leukemia. Leuk Lymphoma. 2017;58(7):1548-1560. PubMed

Wierda WG, O’Brien S, Wang X, et al. . Prognostic nomogram and index for overall survival in previously untreated patients with chronic lymphocytic leukemia. Blood. 2007;109(11):4679-4685. PubMed

Damle RN, Wasil T, Fais F, et al. . Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood. 1999;94(6):1840-1847. PubMed

International CLL-IPI working group An international prognostic index for patients with chronic lymphocytic leukaemia (CLL-IPI): a meta-analysis of individual patient data. Lancet Oncol. 2016;17(6):779-790. PubMed

Baliakas P, Mattsson M, Hadzidimitriou A, et al. . No improvement in long-term survival over time for chronic lymphocytic leukemia patients in stereotyped subsets #1 and #2 treated with chemo(immuno)therapy. Haematologica. 2018;103(4):e158-e161. PubMed PMC

Baliakas P, Moysiadis T, Hadzidimitriou A, et al. . Tailored approaches grounded on immunogenetic features for refined prognostication in chronic lymphocytic leukemia [published online ahead of print 27 September 2018]. Haematologica. doi: 10.3324/haematol.2018.195032. PubMed PMC

Hallek M, Cheson BD, Catovsky D, et al. . iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131(25):2745-2760. PubMed

Puiggros A, Blanco G, Espinet B. Genetic abnormalities in chronic lymphocytic leukemia: where we are and where we go. BioMed Res Int. 2014;2014:435983. PubMed PMC

Dierlamm J, Michaux L, Criel A, Wlodarska I, Van den Berghe H, Hossfeld DK. Genetic abnormalities in chronic lymphocytic leukemia and their clinical and prognostic implications. Cancer Genet Cytogenet. 1997;94(1):27-35. PubMed

Juliusson G, Gahrton G. Chromosome aberrations in B-cell chronic lymphocytic leukemia. Pathogenetic and clinical implications. Cancer Genet Cytogenet. 1990;45(2):143-160. PubMed

Juliusson G, Oscier DG, Fitchett M, et al. . Prognostic subgroups in B-cell chronic lymphocytic leukemia defined by specific chromosomal abnormalities. N Engl J Med. 1990;323(11):720-724. PubMed

Haferlach C, Bacher U. Cytogenetic methods in chronic lymphocytic leukemia. Methods Mol Biol. 2011;730:119-130. PubMed

Gahrton G, Robèrt KH, Friberg K, Zech L, Bird AG. Nonrandom chromosomal aberrations in chronic lymphocytic leukemia revealed by polyclonal B-cell-mitogen stimulation. Blood. 1980;56(4):640-647. PubMed

Dubuc AM, Davids MS, Pulluqi M, et al. . FISHing in the dark: how the combination of FISH and conventional karyotyping improves the diagnostic yield in CpG-stimulated chronic lymphocytic leukemia. Am J Hematol. 2016;91(10):978-983. PubMed

Haferlach C, Dicker F, Schnittger S, Kern W, Haferlach T. Comprehensive genetic characterization of CLL: a study on 506 cases analysed with chromosome banding analysis, interphase FISH, IgV(H) status and immunophenotyping. Leukemia. 2007;21(12):2442-2451. PubMed

Haferlach C, Dicker F, Weiss T, et al. . Toward a comprehensive prognostic scoring system in chronic lymphocytic leukemia based on a combination of genetic parameters. Genes Chromosomes Cancer. 2010;49(9):851-859. PubMed

Puiggros A, Collado R, Calasanz MJ, et al. . Patients with chronic lymphocytic leukemia and complex karyotype show an adverse outcome even in absence of TP53/ATM FISH deletions. Oncotarget. 2017;8(33):54297-54303. PubMed PMC

Rigolin GM, Cibien F, Martinelli S, et al. . Chromosome aberrations detected by conventional karyotyping using novel mitogens in chronic lymphocytic leukemia with “normal” FISH: correlations with clinicobiologic parameters. Blood. 2012;119(10):2310-2313. PubMed

Nguyen-Khac F, Borie C, Callet-Bauchu E, Eclache V, Struski S. Cytogenetics in the management of chronic lymphocytic leukemia: an update by the Groupe francophone de cytogénétique hématologique (GFCH). Ann Biol Clin (Paris). 2016;74(5):561-567. PubMed

Blanco G, Puiggros A, Baliakas P, et al. . Karyotypic complexity rather than chromosome 8 abnormalities aggravates the outcome of chronic lymphocytic leukemia patients with TP53 aberrations. Oncotarget. 2016;7(49):80916-80924. PubMed PMC

Dicker F, Schnittger S, Haferlach T, Kern W, Schoch C. Immunostimulatory oligonucleotide-induced metaphase cytogenetics detect chromosomal aberrations in 80% of CLL patients: a study of 132 CLL cases with correlation to FISH, IgVH status, and CD38 expression. Blood. 2006;108(9):3152-3160. PubMed

Jaglowski SM, Ruppert AS, Heerema NA, et al. . Complex karyotype predicts for inferior outcomes following reduced-intensity conditioning allogeneic transplant for chronic lymphocytic leukaemia. Br J Haematol. 2012;159(1):82-87. PubMed PMC

Rigolin GM, Cavallari M, Quaglia FM, et al. . In CLL, comorbidities and the complex karyotype are associated with an inferior outcome independently of CLL-IPI. Blood. 2017;129(26):3495-3498. PubMed

Rigolin GM, Saccenti E, Guardalben E, et al. . In chronic lymphocytic leukaemia with complex karyotype, major structural abnormalities identify a subset of patients with inferior outcome and distinct biological characteristics. Br J Haematol. 2018;181(2):229-233. PubMed

Badoux XC, Keating MJ, Wang X, et al. . Fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy is highly effective treatment for relapsed patients with CLL. Blood. 2011;117(11):3016-3024. PubMed PMC

Herling CD, Klaumünzer M, Rocha CK, et al. . Complex karyotypes and KRAS and POT1 mutations impact outcome in CLL after chlorambucil-based chemotherapy or chemoimmunotherapy. Blood. 2016;128(3):395-404. PubMed

Takahashi K, Hu B, Wang F, et al. . Clinical implications of cancer gene mutations in patients with chronic lymphocytic leukemia treated with lenalidomide. Blood. 2018;131(16):1820-1832. PubMed PMC

Le Bris Y, Struski S, Guièze R, et al. . Major prognostic value of complex karyotype in addition to TP53 and IGHV mutational status in first-line chronic lymphocytic leukemia. Hematol Oncol. 2017;35(4):664-670. PubMed

Mato AR, Hill BT, Lamanna N, et al. . Optimal sequencing of ibrutinib, idelalisib, and venetoclax in chronic lymphocytic leukemia: results from a multicenter study of 683 patients. Ann Oncol. 2017;28(5):1050-1056. PubMed

Mato AR, Thompson M, Allan JN, et al. . Real-world outcomes and management strategies for venetoclax-treated chronic lymphocytic leukemia patients in the United States. Haematologica. 2018;103(9):1511-1517. PubMed PMC

Roberts AW, Davids MS, Pagel JM, et al. . Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):311-322. PubMed PMC

Thompson PA, O’Brien SM, Wierda WG, et al. . Complex karyotype is a stronger predictor than del(17p) for an inferior outcome in relapsed or refractory chronic lymphocytic leukemia patients treated with ibrutinib-based regimens. Cancer. 2015;121(20):3612-3621. PubMed PMC

Anderson MA, Tam C, Lew TE, et al. . Clinicopathological features and outcomes of progression of CLL on the BCL2 inhibitor venetoclax. Blood. 2017;129(25):3362-3370. PubMed

Swerdlow SH, Campo E, Pileri SA, et al. . The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375-2390. PubMed PMC

Muthusamy N, Breidenbach H, Andritsos L, et al. . Enhanced detection of chromosomal abnormalities in chronic lymphocytic leukemia by conventional cytogenetics using CpG oligonucleotide in combination with pokeweed mitogen and phorbol myristate acetate. Cancer Genet. 2011;204(2):77-83. PubMed PMC

International Standing Committee on Human Cytogenetic Nomenclature ISCN: An International System for Human Cytogenomic Nomenclature. Basel, NY: Karger; 2016.

Peterson JF. The complexities of defining a complex karyotype in hematological malignancies: a need for standardization? Acta Haematol. 2017;138(1):65-66. PubMed

Slovak ML, Kopecky KJ, Cassileth PA, et al. . Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood. 2000;96(13):4075-4083. PubMed

Agathangelidis A, Darzentas N, Hadzidimitriou A, et al. . Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia: a molecular classification with implications for targeted therapies. Blood. 2012;119(19):4467-4475. PubMed PMC

Malcikova J, Tausch E, Rossi D, et al. ; European Research Initiative on Chronic Lymphocytic Leukemia (ERIC)–TP53 network . ERIC recommendations for TP53 mutation analysis in chronic lymphocytic leukemia—update on methodological approaches and results interpretation. Leukemia. 2018;32(5):1070-1080. PubMed PMC

Put N, Konings P, Rack K, et al. ; Belgian Cytogenetic Group for Hemato-Oncology (BCGHO) . Improved detection of chromosomal abnormalities in chronic lymphocytic leukemia by conventional cytogenetics using CpG oligonucleotide and interleukin-2 stimulation: a Belgian multicentric study. Genes Chromosomes Cancer. 2009;48(10):843-853. PubMed

Ibbotson R, Athanasiadou A, Sutton LA, et al. . Coexistence of trisomies of chromosomes 12 and 19 in chronic lymphocytic leukemia occurs exclusively in the rare IgG-positive variant. Leukemia. 2012;26(1):170-172. PubMed

Sellmann L, Gesk S, Walter C, et al. . Trisomy 19 is associated with trisomy 12 and mutated IGHV genes in B-chronic lymphocytic leukaemia. Br J Haematol. 2007;138(2):217-220. PubMed

Rossi D, Khiabanian H, Spina V, et al. . Clinical impact of small TP53 mutated subclones in chronic lymphocytic leukemia. Blood. 2014;123(14):2139-2147. PubMed PMC

Nadeu F, Delgado J, Royo C, et al. . Clinical impact of clonal and subclonal TP53, SF3B1, BIRC3, NOTCH1, and ATM mutations in chronic lymphocytic leukemia. Blood. 2016;127(17):2122-2130. PubMed PMC

Arber DA, Orazi A, Hasserjian R, et al. . The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391-2405. PubMed

Huang SJ, Bergin K, Smith AC, et al. . Clonal evolution as detected by interphase fluorescence in situ hybridization is associated with worse overall survival in a population-based analysis of patients with chronic lymphocytic leukemia in British Columbia, Canada. Cancer Genet. 2017;210:1-8. PubMed

Stilgenbauer S, Sander S, Bullinger L, et al. . Clonal evolution in chronic lymphocytic leukemia: acquisition of high-risk genomic aberrations associated with unmutated VH, resistance to therapy, and short survival. Haematologica. 2007;92(9):1242-1245. PubMed

Wawrzyniak E, Kotkowska A, Blonski JZ, et al. . Clonal evolution in CLL patients as detected by FISH versus chromosome banding analysis, and its clinical significance. Eur J Haematol. 2014;92(2):91-101. PubMed

Lazarian G, Tausch E, Eclache V, et al. . TP53 mutations are early events in chronic lymphocytic leukemia disease progression and precede evolution to complex karyotypes. Int J Cancer. 2016;139(8):1759-1763. PubMed

Gunnarsson R, Isaksson A, Mansouri M, et al. . Large but not small copy-number alterations correlate to high-risk genomic aberrations and survival in chronic lymphocytic leukemia: a high-resolution genomic screening of newly diagnosed patients. Leukemia. 2010;24(1):211-215. PubMed

Kay NE, Eckel-Passow JE, Braggio E, et al. . Progressive but previously untreated CLL patients with greater array CGH complexity exhibit a less durable response to chemoimmunotherapy. Cancer Genet Cytogenet. 2010;203(2):161-168. PubMed PMC

Ouillette P, Collins R, Shakhan S, et al. . Acquired genomic copy number aberrations and survival in chronic lymphocytic leukemia. Blood. 2011;118(11):3051-3061. PubMed PMC

Puiggros A, Puigdecanet E, Salido M, et al. . Genomic arrays in chronic lymphocytic leukemia routine clinical practice: are we ready to substitute conventional cytogenetics and fluorescence in situ hybridization techniques? Leuk Lymphoma. 2013;54(5):986-995. PubMed

Schoumans J, Suela J, Hastings R, et al. . Guidelines for genomic array analysis in acquired haematological neoplastic disorders. Genes Chromosomes Cancer. 2016;55(5):480-491. PubMed

Klintman J, Barmpouti K, Knight SJL, et al. . Clinical-grade validation of whole genome sequencing reveals robust detection of low-frequency variants and copy number alterations in CLL. Br J Haematol. 2018;182(3):412-417. PubMed

Puente XS, Pinyol M, Quesada V, et al. . Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature. 2011;475(7354):101-105. PubMed PMC

Puente XS, Beà S, Valdés-Mas R, et al. . Non-coding recurrent mutations in chronic lymphocytic leukaemia. Nature. 2015;526(7574):519-524. PubMed

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