uu.seUppsala University Publications
Change search
ReferencesLink to record
Permanent link

Direct link
Clinical effect of stereotyped B-cell receptor immunoglobulins in chronic lymphocytic leukaemia: a retrospective multicentre study
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala Univ, Sci Life Lab, Dept Immunol Genet & Pathol, Uppsala, Sweden.;G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. CERTH, Inst Appl Biosci, Thessaloniki, Greece..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
CERTH, Inst Appl Biosci, Thessaloniki, Greece..
Show others and affiliations
2014 (English)In: LANCET HAEMATOLOGY, ISSN 2352-3026, Vol. 1, no 2, E74-E84 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2014. Vol. 1, no 2, E74-E84 p.
National Category
Cancer and Oncology
URN: urn:nbn:se:uu:diva-265949DOI: 10.1016/S2352-3026(14)00005-2ISI: 000362070200008OAI: oai:DiVA.org:uu-265949DiVA: diva2:866904
EU, European Research CouncilSwedish Research CouncilSwedish Cancer Society
Available from: 2015-11-04 Created: 2015-11-04 Last updated: 2016-04-21Bibliographically approved
In thesis
1. Reappraising prognosis in chronic lymphocytic leukemia
Open this publication in new window or tab >>Reappraising prognosis in chronic lymphocytic leukemia
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Chronic lymphocytic leukemia (CLL) exhibits remarkable clinical heterogeneity likely reflecting the underlying biological heterogeneity. The genetic landscape of CLL has been recently enriched with mutations within a number of genes proposed as novel prognostic markers. Mounting evidence also supports the pivotal role of the clonotypic B-cell receptor immunoglobulin (BcR IG) in the natural history of CLL. Interestingly, almost 30% of all CLL patients can be assigned to different patient subsets, each defined by expression of a distinct stereotyped BcR IG. Whether stereotyped subsets exhibit distinct clinical behavior is still an issue of debate. The aim of this thesis was to evaluate the prognostic relevance of recurrent gene mutations and to assess the clinicobiological associations and clinical impact of BcR IG stereotypy in CLL. In a cohort of 3490 patients, NOTCH1, SF3B1 and TP53 mutations were enriched within clinically aggressive cases carrying unmutated IGHV genes (U-CLL), frequently co-occurring with trisomy 12, del(11q) and del(17p), respectively. Of note, SF3B1 mutations increased in parallel with increasing timespan between diagnosis and mutational screening. NOTCH1 mutations, SF3B1 mutations and TP53 abnormalities (TP53abs, deletions and/or mutations) correlated with shorter time-to-first-treatment among early stage cases, while in multivariate analysis, only SF3B1 mutations and TP53abs retained independent significance. In a series of 8593 CLL patients, stereotyped subsets showed marked differences in demographics, clinical presentation, cytogenetic aberrations and gene mutational spectrum. Patients within a specific subset generally followed similar clinical courses, whereas patients in different stereotyped subsets—even when displaying similar IG somatic hypermutation status— experienced significantly different clinical outcome. In particular, subset #2 (IGHV3-21/IGLV3-21), the largest overall, was found to exhibit (i) a remarkably high incidence of SF3B1 mutations (44%), alluding to subset-biased acquisition of genomic aberrations, in the context of particular antigenic stimulation; and, (ii) a dismal clinical outcome, distinct from the remaining IGHV3-21 CLL. Our findings strongly support the adverse clinical impact of SF3B1 mutations in CLL in addition to TP53abs. BcR IG stereotypy also emerges as prognostically relevant, further highlighting that an immunogenetic sub-classification of CLL based on BcR IG configuration could refine patient risk stratification. 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 59 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1199
CLL, prognosis
National Category
Medical and Health Sciences
Research subject
Medical Genetics
urn:nbn:se:uu:diva-280943 (URN)978-91-554-9519-0 (ISBN)
Public defence
2016-05-11, Rudbecksalen, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Available from: 2016-04-18 Created: 2016-03-16 Last updated: 2016-04-21

Open Access in DiVA

No full text

Other links

Publisher's full text

Search in DiVA

By author/editor
Baliakas, PanagiotisMansouri, LarryRosenquist Barndell, Richard
By organisation
Experimental and Clinical OncologyScience for Life Laboratory, SciLifeLabDepartment of Immunology, Genetics and Pathology
Cancer and Oncology

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 282 hits
ReferencesLink to record
Permanent link

Direct link