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Clinical effect of stereotyped B-cell receptor immunoglobulins in chronic lymphocytic leukaemia: a retrospective multicentre study

Baliakas, Panagiotis; Hadzidimitriou, Anastasia; Sutton, Lesley-Ann; Minga, Eva; Agathangelidis, Andreas; Nichelatti, Michele; Tsanousa, Athina; Scarfo, Lydia; Davis, Zadie and Yan, Xiao-Jie, et al. (2014) In Lancet Haematology 1(2). p.74-84
Abstract
Background About 30% of cases of chronic lymphocytic leukaemia (CLL) carry quasi-identical B-cell receptor immunoglobulins and can be assigned to distinct stereotyped subsets. Although preliminary evidence suggests that B-cell receptor immunoglobulin stereotypy is relevant from a clinical viewpoint, this aspect has never been explored in a systematic manner or in a cohort of adequate size that would enable clinical conclusions to be drawn. Methods For this retrospective, multicentre study, we analysed 8593 patients with CLL for whom immunogenetic data were available. These patients were followed up in 15 academic institutions throughout Europe (in Czech Republic, Denmark, France, Greece, Italy, Netherlands, Sweden, and the UK) and the USA,... (More)
Background About 30% of cases of chronic lymphocytic leukaemia (CLL) carry quasi-identical B-cell receptor immunoglobulins and can be assigned to distinct stereotyped subsets. Although preliminary evidence suggests that B-cell receptor immunoglobulin stereotypy is relevant from a clinical viewpoint, this aspect has never been explored in a systematic manner or in a cohort of adequate size that would enable clinical conclusions to be drawn. Methods For this retrospective, multicentre study, we analysed 8593 patients with CLL for whom immunogenetic data were available. These patients were followed up in 15 academic institutions throughout Europe (in Czech Republic, Denmark, France, Greece, Italy, Netherlands, Sweden, and the UK) and the USA, and data were collected between June 1, 2012, and June 7, 2013. We retrospectively assessed the clinical implications of CLL B-cell receptor immunoglobulin stereotypy, with a particular focus on 14 major stereotyped subsets comprising cases expressing unmutated (U-CLL) or mutated (M-CLL) immunoglobulin heavy chain variable genes. The primary outcome of our analysis was time to first treatment, defined as the time between diagnosis and date of first treatment. Findings 2878 patients were assigned to a stereotyped subset, of which 1122 patients belonged to one of 14 major subsets. Stereotyped subsets showed significant differences in terms of age, sex, disease burden at diagnosis, CD38 expression, and cytogenetic aberrations of prognostic significance. Patients within a specific subset generally followed the same clinical course, whereas patients in different stereotyped subsets-despite having the same immunoglobulin heavy variable gene and displaying similar immunoglobulin mutational status-showed substantially different times to first treatment. By integrating B-cell receptor immunoglobulin stereotypy (for subsets 1, 2, and 4) into the well established Dohner cytogenetic prognostic model, we showed these, which collectively account for around 7% of all cases of CLL and represent both U-CLL and M-CLL, constituted separate clinical entities, ranging from very indolent (subset 4) to aggressive disease (subsets 1 and 2). Interpretation The molecular classification of chronic lymphocytic leukaemia based on B-cell receptor immunoglobulin stereotypy improves the Dohner hierarchical model and refines prognostication beyond immunoglobulin mutational status, with potential implications for clinical decision making, especially within prospective clinical trials. (Less)
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Lancet Haematology
volume
1
issue
2
pages
74 - 84
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Elsevier
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  • wos:000362070200008
  • scopus:84921885631
ISSN
2352-3026
DOI
10.1016/S2352-3026(14)00005-2
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English
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yes
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f374ae41-a195-4b3a-8fea-479fca71a585 (old id 8227283)
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2015-12-01 07:06:19
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@article{f374ae41-a195-4b3a-8fea-479fca71a585,
  abstract     = {Background About 30% of cases of chronic lymphocytic leukaemia (CLL) carry quasi-identical B-cell receptor immunoglobulins and can be assigned to distinct stereotyped subsets. Although preliminary evidence suggests that B-cell receptor immunoglobulin stereotypy is relevant from a clinical viewpoint, this aspect has never been explored in a systematic manner or in a cohort of adequate size that would enable clinical conclusions to be drawn. Methods For this retrospective, multicentre study, we analysed 8593 patients with CLL for whom immunogenetic data were available. These patients were followed up in 15 academic institutions throughout Europe (in Czech Republic, Denmark, France, Greece, Italy, Netherlands, Sweden, and the UK) and the USA, and data were collected between June 1, 2012, and June 7, 2013. We retrospectively assessed the clinical implications of CLL B-cell receptor immunoglobulin stereotypy, with a particular focus on 14 major stereotyped subsets comprising cases expressing unmutated (U-CLL) or mutated (M-CLL) immunoglobulin heavy chain variable genes. The primary outcome of our analysis was time to first treatment, defined as the time between diagnosis and date of first treatment. Findings 2878 patients were assigned to a stereotyped subset, of which 1122 patients belonged to one of 14 major subsets. Stereotyped subsets showed significant differences in terms of age, sex, disease burden at diagnosis, CD38 expression, and cytogenetic aberrations of prognostic significance. Patients within a specific subset generally followed the same clinical course, whereas patients in different stereotyped subsets-despite having the same immunoglobulin heavy variable gene and displaying similar immunoglobulin mutational status-showed substantially different times to first treatment. By integrating B-cell receptor immunoglobulin stereotypy (for subsets 1, 2, and 4) into the well established Dohner cytogenetic prognostic model, we showed these, which collectively account for around 7% of all cases of CLL and represent both U-CLL and M-CLL, constituted separate clinical entities, ranging from very indolent (subset 4) to aggressive disease (subsets 1 and 2). Interpretation The molecular classification of chronic lymphocytic leukaemia based on B-cell receptor immunoglobulin stereotypy improves the Dohner hierarchical model and refines prognostication beyond immunoglobulin mutational status, with potential implications for clinical decision making, especially within prospective clinical trials.},
  author       = {Baliakas, Panagiotis and Hadzidimitriou, Anastasia and Sutton, Lesley-Ann and Minga, Eva and Agathangelidis, Andreas and Nichelatti, Michele and Tsanousa, Athina and Scarfo, Lydia and Davis, Zadie and Yan, Xiao-Jie and Shanafelt, Tait and Plevova, Karla and Sandberg, Yorick and Vojdeman, Fie Juhl and Boudjogra, Myriam and Tzenou, Tatiana and Chatzouli, Maria and Chu, Charles C. and Veronese, Silvio and Gardiner, Anne and Mansouri, Larry and Smedby, Karin E. and Pedersen, Lone Bredo and van Lom, Kirsten and Giudicelli, Veronique and Francova, Hana Skuhrova and Nguyen-Khac, Florence and Panagiotidis, Panagiotis and Juliusson, Gunnar and Angelis, Lefteris and Anagnostopoulos, Achilles and Lefranc, Marie-Paule and Facco, Monica and Trentin, Livio and Catherwood, Mark and Montillo, Marco and Geisler, Christian H. and Langerak, Anton W. and Pospisilova, Sarka and Chiorazzi, Nicholas and Oscier, David and Jelinek, Diane F. and Darzentas, Nikos and Belessi, Chrysoula and Davi, Frederic and Rosenquist, Richard and Ghia, Paolo and Stamatopoulos, Kostas},
  issn         = {2352-3026},
  language     = {eng},
  number       = {2},
  pages        = {74--84},
  publisher    = {Elsevier},
  series       = {Lancet Haematology},
  title        = {Clinical effect of stereotyped B-cell receptor immunoglobulins in chronic lymphocytic leukaemia: a retrospective multicentre study},
  url          = {http://dx.doi.org/10.1016/S2352-3026(14)00005-2},
  volume       = {1},
  year         = {2014},
}