{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T10:29:16Z","timestamp":1794047356388,"version":"4.8.0"},"reference-count":42,"publisher":"Ferrata Storti Foundation (Haematologica)","issue":"6","license":[{"start":{"date-parts":[[2020,5,15]],"date-time":"2020-05-15T00:00:00Z","timestamp":1589500800000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/legalcode"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["haematol"],"abstract":"<jats:p>Mutations of the IGH variable region in patients with chronic lymphocytic leukemia (CLL) are associated with a favorable prognosis.  Cytogenetic complexity (&gt;3 unrelated aberrations) and translocations have been associated with an unfavorable prognosis.  While mutational status of IGHV is stable, cytogenetic aberrations frequently evolve.  However, the relationships of these features as prognosticators at diagnosis are unknown.  We examined the CpG-stimulated metaphase cytogenetic features detected within one year of diagnosis of CLL and correlated these features with outcome and other clinical features including IGHV.  Of 329 untreated patients, 53 (16.1%) had a complex karyotype (16.1%), and 85 (25.8%) had a translocation.  Median time to first treatment (TFT) was 47 months. In univariable analyses, significant risk factors for shorter TFT (p3.5, log-transformed WBC, unmutated IGHV, complex karyotype, translocation, and FISH for trisomy 8, del(11q) and del(17p).  In multivariable analysis, there was significant effect modification of IGHV status on the relationship between translocation and TFT (p=0.002).  In IGHV mutated patients, those with a translocation had over 3.5 times higher risk of starting treatment than those without a translocation (p<\/jats:p>","DOI":"10.3324\/haematol.2018.212571","type":"journal-article","created":{"date-parts":[[2020,5,15]],"date-time":"2020-05-15T12:24:21Z","timestamp":1589545461000},"page":"1608-1615","source":"Crossref","is-referenced-by-count":11,"title":["Prognostic significance of translocations in the presence of mutated IGHV and of cytogenetic complexity at diagnosis of chronic lymphocytic leukemia"],"prefix":"10.3324","volume":"106","author":[{"family":"Nyla A. Heerema","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Natarajan Muthusamy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Qiuhong Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Amy S. Ruppert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Heather Breidenbach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Leslie A. Andritsos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Michael R. Grever","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Kami J. Maddocks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Jennifer Woyach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Farrukh Awan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Meixiao Long","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Amber Gordon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Caitlin Coombes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"John C. Byrd","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1856","published-online":{"date-parts":[[2020,5,15]]},"reference":[{"key":"26005","doi-asserted-by":"crossref","unstructured":"Byrd JC, Gribben JG, Peterson BL. Select high-risk genetic features predict earlier progression following chemoimmunotherapy with fludarabine and rituximab in chronic lymphocytic leukemia: justification for risk-adapted therapy. J Clin Oncol. 2006; 24(3):437-443.","DOI":"10.1200\/JCO.2005.03.1021"},{"key":"26006","doi-asserted-by":"crossref","unstructured":"Oscier DG, Gardiner AC, Mould SJ. Multivariate analysis of prognostic factors in CLL: clinical stage, IGVH gene mutational status, and loss or mutation of the p53 gene are independent prognostic factors. Blood. 2002; 100(4):1177-1184.","DOI":"10.1182\/blood.V100.4.1177.h81602001177_1177_1184"},{"key":"26007","doi-asserted-by":"crossref","unstructured":"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.","DOI":"10.1182\/blood.V94.6.1848.418k05_1848_1854"},{"key":"26008","doi-asserted-by":"crossref","unstructured":"Haferlach C, Dicker F, Weiss T. 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.","DOI":"10.1002\/gcc.20794"},{"key":"26009","doi-asserted-by":"crossref","unstructured":"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.","DOI":"10.1038\/sj.leu.2404935"},{"key":"26010","doi-asserted-by":"crossref","unstructured":"Woyach JA, Ruppert AS, Guinn D. BTK(C481S)-mediated resistance to ibrutinib in chronic lymphocytic leukemia. J Clin Oncol. 2017; 35(13):1437-1443.","DOI":"10.1200\/JCO.2016.70.2282"},{"key":"26011","doi-asserted-by":"crossref","unstructured":"Woyach JA, Lozanski G, Ruppert AS. Outcome of patients with relapsed or refractory chronic lymphocytic leukemia treated with flavopiridol: impact of genetic features. Leukemia. 2012; 26(6):1442-1444.","DOI":"10.1038\/leu.2011.375"},{"key":"26012","doi-asserted-by":"crossref","unstructured":"Jaglowski SM, Ruppert AS, Heerema NA. Complex karyotype predicts for inferior outcomes following reduced-intensity conditioning allogeneic transplant for chronic lymphocytic leukaemia. Br J Haematol. 2012; 159(1):82-87.","DOI":"10.1111\/j.1365-2141.2012.09239.x"},{"key":"26013","doi-asserted-by":"crossref","unstructured":"Baliakas P, Iskas M, Gardiner A. Chromosomal translocations and karyotype complexity in chronic lymphocytic leukemia: a systematic reappraisal of classic cytogenetic data. Am J Hematol. 2014; 89(3):249-255.","DOI":"10.1002\/ajh.23618"},{"key":"26014","doi-asserted-by":"crossref","unstructured":"Rogers KA, Huang Y, Ruppert AS. A single-institution retrospective cohort study of first-line R-EPOCH chemoimmunotherapy for Richter syndrome demonstrating complex chronic lymphocytic leukaemia karyotype as an adverse prognostic factor. Br J Haematol. 2018; 180(2):259-266.","DOI":"10.1111\/bjh.15035"},{"key":"26015","doi-asserted-by":"crossref","unstructured":"Rigolin GM, Formigaro L, Cavallari M. An extensive molecular cytogenetic characterization in high-risk chronic lymphocytic leukemia identifies karyotype aberrations and TP53 disruption as predictors of outcome and chemorefractoriness. Oncotarget. 2017; 8(17):28008-28020.","DOI":"10.18632\/oncotarget.15883"},{"key":"26016","doi-asserted-by":"crossref","unstructured":"Rigolin GM, Cavallari M, Quaglia FM. In CLL, comorbidities and the complex karyotype are associated with an inferior outcome independently of CLL-IPI. Blood. 2017; 129(26):3495-3498.","DOI":"10.1182\/blood-2017-03-772285"},{"key":"26017","doi-asserted-by":"crossref","unstructured":"Le Bris Y, Struski S, Gui\u00e8ze R. 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.","DOI":"10.1002\/hon.2349"},{"key":"26018","doi-asserted-by":"crossref","unstructured":"Cavallari M, Cavazzini F, Bardi A. Biological significance and prognostic\/predictive impact of complex karyotype in chronic lymphocytic leukemia. Oncotarget. 2018; 9(76):34398-34412.","DOI":"10.18632\/oncotarget.26146"},{"key":"26019","doi-asserted-by":"crossref","unstructured":"Baliakas P, Jeromin S, Iskas M. Cytogenetic complexity in chronic lymphocytic leukemia: definitions, associations, and clinical impact. Blood. 2019; 133(11):1205-1216.","DOI":"10.1182\/blood-2018-09-873083"},{"key":"26020","doi-asserted-by":"crossref","unstructured":"Rigolin GM, del Giudice I, Formigaro L. Chromosome aberrations detected by conventional karyotyping using novel mitogens in chronic lymphocytic leukemia: clinical and biologic correlations. Genes Chromosomes Cancer. 2015; 54(12):818-826.","DOI":"10.1002\/gcc.22293"},{"key":"26021","doi-asserted-by":"crossref","unstructured":"Mayr C, Speicher MR, Kofler DM. Chromosomal translocations are associated with poor prognosis in chronic lymphocytic leukemia. Blood. 2006; 107(2):742-751.","DOI":"10.1182\/blood-2005-05-2093"},{"key":"26022","doi-asserted-by":"crossref","unstructured":"Van Den Neste E, Robin V, Francart J. Chromosomal translocations independently predict treatment failure, treatment-free survival and overall survival in B-cell chronic lymphocytic leukemia patients treated with cladribine. Leukemia. 2007; 21(8):1715-1722.","DOI":"10.1038\/sj.leu.2404764"},{"key":"26023","doi-asserted-by":"crossref","unstructured":"Rigolin GM, Saccenti E, Guardalben E. 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.","DOI":"10.1111\/bjh.15174"},{"key":"26024","doi-asserted-by":"crossref","unstructured":"Herling CD, Klaum\u00fcnzer M, Rocha CK. Complex karyotypes and KRAS and POT1 mutations impact outcome in CLL after chlorambucil-based chemotherapy or chemoimmunotherapy. Blood. 2016; 128(3):395-404.","DOI":"10.1182\/blood-2016-01-691550"},{"key":"26025","doi-asserted-by":"crossref","unstructured":"Decker T, Schneller F, Kronschnabl M. Immunostimulatory CpG-oligonucleotides induce functional high affinity IL-2 receptors on B-CLL cells: costimulation with IL- 2 results in a highly immunogenic phenotype. Exp Hematol. 2000; 28(5):558-568.","DOI":"10.1016\/S0301-472X(00)00144-2"},{"key":"26026","doi-asserted-by":"crossref","unstructured":"Decker T, Schneller F, Sparwasser T. Immunostimulatory CpG-oligonucleotides cause proliferation, cytokine production, and an immunogenic phenotype in chronic lymphocytic leukemia B cells. Blood. 2000; 95(3):999-1006.","DOI":"10.1182\/blood.V95.3.999.003k10_999_1006"},{"key":"26027","doi-asserted-by":"crossref","unstructured":"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.","DOI":"10.1182\/blood-2006-02-005322"},{"key":"26028","doi-asserted-by":"crossref","unstructured":"Muthusamy N, Breidenbach H, Andritsos L. 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.","DOI":"10.1016\/j.cancergen.2010.12.006"},{"key":"26029","doi-asserted-by":"crossref","unstructured":"Put N, Konings P, Rack K. 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.","DOI":"10.1002\/gcc.20691"},{"key":"26030","doi-asserted-by":"crossref","unstructured":"Struski S, Gervais C, Helias C. Stimulation of B-cell lymphoproliferations with CpG-oligonucleotide DSP30 plus IL-2 is more effective than with TPA to detect clonal abnormalities. Leukemia. 2009; 23(3):617-619.","DOI":"10.1038\/leu.2008.252"},{"key":"26031","doi-asserted-by":"crossref","unstructured":"Haferlach C, Jeromin S, Nadarajah N. Cytogenetic and molecular genetic clonal evolution in CLL is associated with an unmutated IGHV status and frequently leads to a combination of loss of 17p and TP53 mutation. Blood. 2016; 128(22):3213-3213.","DOI":"10.1182\/blood.V128.22.3213.3213"},{"key":"26032","doi-asserted-by":"crossref","unstructured":"Stilgenbauer S, Sander S, Bullinger L. 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.","DOI":"10.3324\/haematol.10720"},{"key":"26033","doi-asserted-by":"crossref","unstructured":"Hallek M, Cheson BD, Catovsky D. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018; 131(25):2745-2760.","DOI":"10.1182\/blood-2017-09-806398"},{"key":"26034","doi-asserted-by":"crossref","unstructured":"Pepper C, Buggins AG, Jones CH. Phenotypic heterogeneity in IGHV-mutated CLL patients has prognostic impact and identifies a subset with increased sensitivity to BTK and PI3Kinhibition. Leukemia. 2015; 29(3):744-747.","DOI":"10.1038\/leu.2014.308"},{"key":"26035","doi-asserted-by":"crossref","unstructured":"Baumann T, Delgado J, Santacruz R. CD49d (ITGA4) expression is a predictor of time to first treatment in patients with chronic lymphocytic leukaemia and mutated IGHV status. Br J Haematol. 2016; 172(1):48-55.","DOI":"10.1111\/bjh.13788"},{"key":"26036","doi-asserted-by":"crossref","unstructured":"Gattei V, Bulian P, Del Principe MI. Relevance of CD49d protein expression as overall survival and progressive disease prognosticator in chronic lymphocytic leukemia. Blood. 2008; 111(2):865-873.","DOI":"10.1182\/blood-2007-05-092486"},{"key":"26037","doi-asserted-by":"crossref","unstructured":"Del Giudice I, Mauro FR, De Propris MS. White blood cell count at diagnosis and immunoglobulin variable region gene mutations are independent predictors of treatment- free survival in young patients with stage A chronic lymphocytic leukemia. Haematologica. 2011; 96(4):626-630.","DOI":"10.3324\/haematol.2010.028779"},{"key":"26038","doi-asserted-by":"crossref","unstructured":"Dohner H, Stilgenbauer S, Benner A. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000; 343(26):1910-1916.","DOI":"10.1056\/NEJM200012283432602"},{"key":"26039","doi-asserted-by":"crossref","unstructured":"Foa R, Del Giudice I, Guarini A, Rossi D, Gaidano G. Clinical implications of the molecular genetics of chronic lymphocytic leukemia. Haematologica. 2013; 98(5):675-685.","DOI":"10.3324\/haematol.2012.069369"},{"key":"26040","doi-asserted-by":"crossref","unstructured":"Lin TS, Ruppert AS, Johnson AJ. Phase II study of flavopiridol in relapsed chronic lymphocytic leukemia demonstrating high response rates in genetically high-risk disease. J Clin Oncol. 2009; 27(35):6012-6018.","DOI":"10.1200\/JCO.2009.22.6944"},{"key":"26041","doi-asserted-by":"crossref","unstructured":"Zenz T, Eichhorst B, Busch R. TP53 mutation and survival in chronic lymphocytic leukemia. J Clin Oncol. 2010; 28(29):4473-4479.","DOI":"10.1200\/JCO.2009.27.8762"},{"key":"26042","doi-asserted-by":"crossref","unstructured":"Stephens DM, Ruppert AS, Weirda WG. Externally validated predictive clinical model for untreated del(17p13.1) chronic lymphocytic leukemia patients. Am J Hematol. 2015; 90(11):967-969.","DOI":"10.1002\/ajh.24125"},{"key":"26043","doi-asserted-by":"crossref","unstructured":"Tam CS, Shanafelt TD, Wierda WG. De novo deletion 17p13.1 chronic lymphocytic leukemia shows significant clinical heterogeneity: the M. D. Anderson and Mayo Clinic experience. Blood. 2009; 114(5):957-964.","DOI":"10.1182\/blood-2009-03-210591"},{"key":"26044","doi-asserted-by":"crossref","unstructured":"Van Dyke DL, Werner L, Rassenti LZ. The Dohner fluorescence in situ hybridization prognostic classification of chronic lymphocytic leukaemia (CLL): the CLL Research Consortium experience. Br J Haematol. 2016; 173(1):105-113.","DOI":"10.1111\/bjh.13933"},{"key":"26045","doi-asserted-by":"crossref","unstructured":"Yu L, Kim HT, Kasar S. Survival of del17p CLL depends on genomic complexity and somatic mutation. Clin Cancer Res. 2017; 23(3):735-745.","DOI":"10.1158\/1078-0432.CCR-16-0594"},{"key":"26046","doi-asserted-by":"crossref","unstructured":"Liu G, Parant JM, Lang G. Chromosome stability, in the absence of apoptosis, is critical for suppression of tumorigenesis in Trp53 mutant mice. Nat Genet. 2004; 36(1):63-68.","DOI":"10.1038\/ng1282"}],"container-title":["Haematologica"],"original-title":[],"link":[{"URL":"https:\/\/haematologica.org\/article\/download\/9754\/70883","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/haematologica.org\/article\/download\/9754\/70884","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/haematologica.org\/article\/download\/9754\/70883","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T09:57:07Z","timestamp":1794045427000},"score":1,"resource":{"primary":{"URL":"https:\/\/haematologica.org\/article\/view\/9754"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,15]]},"references-count":42,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,6,1]]}},"URL":"https:\/\/doi.org\/10.3324\/haematol.2018.212571","relation":{},"ISSN":["1592-8721","0390-6078"],"issn-type":[{"value":"1592-8721","type":"electronic"},{"value":"0390-6078","type":"print"}],"subject":[],"published":{"date-parts":[[2020,5,15]]}}}