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

Panagiotis Baliakas, Anastasia Hadzidimitriou, Lesley Ann Sutton, Eva Minga, Andreas Agathangelidis, Michele Nichelatti, Athina Tsanousa, Lydia Scarfò, Zadie Davis, Xiao Jie Yan, Tait Shanafelt, Karla Plevova, Yorick Sandberg, Fie Juhl Vojdeman, Myriam Boudjogra, Tatiana Tzenou, Maria Chatzouli, Charles C. Chu, Silvio Veronese, Anne GardinerLarry Mansouri, Karin E. Smedby, Lone Bredo Pedersen, Kirsten van Lom, Véronique Giudicelli, Hana Skuhrova Francova, Florence Nguyen-Khac, Panagiotis Panagiotidis, Gunnar Juliusson, Lefteris Angelis, Achilles Anagnostopoulos, Marie Paule Lefranc, Monica Facco, Livio Trentin, Mark Catherwood, Marco Montillo, Christian H. Geisler, Anton W. Langerak, Sarka Pospisilova, Nicholas Chiorazzi, David Oscier, Diane F. Jelinek, Nikos Darzentas, Chrysoula Belessi, Frederic Davi, Richard Rosenquist, Paolo Ghia, Kostas Stamatopoulos

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Abstract

Background: About 30% of cases of chronic lymphocytic leukaemia (CLL) carry quasi-identical B-cell receptorimmunoglobulins and can be assigned to distinct stereotyped subsets. Although preliminary evidence suggeststhat B-cell receptor immunoglobulin stereotypy is relevant from a clinical viewpoint, this aspect has never beenexplored 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 immunogeneticdata were available. These patients were followed up in 15 academic institutions throughout Europe (in CzechRepublic, Denmark, France, Greece, Italy, Netherlands, Sweden, and the UK) and the USA, and data were collectedbetween June 1, 2012, and June 7, 2013. We retrospectively assessed the clinical implications of CLL B-cell receptorimmunoglobulin stereotypy, with a particular focus on 14 major stereotyped subsets comprising cases expressingunmutated (U-CLL) or mutated (M-CLL) immunoglobulin heavy chain variable genes. The primary outcome ofour analysis was time to fi rst treatment, defi ned as the time between diagnosis and date of fi rst treatment.Findings: 2878 patients were assigned to a stereotyped subset, of which 1122 patients belonged to one of 14 majorsubsets. Stereotyped subsets showed signifi cant diff erences in terms of age, sex, disease burden at diagnosis,CD38 expression, and cytogenetic aberrations of prognostic signifi cance. Patients within a specifi c subset generallyfollowed the same clinical course, whereas patients in diff erent stereotyped subsets-despite having the sameimmunoglobulin heavy variable gene and displaying similar immunoglobulin mutational status-showedsubstantially diff erent times to fi rst treatment. By integrating B-cell receptor immunoglobulin stereotypy (forsubsets 1, 2, and 4) into the well established Döhner cytogenetic prognostic model, we showed these, whichcollectively account for around 7% of all cases of CLL and represent both U-CLL and M-CLL, constituted separateclinical entities, ranging from very indolent (subset 4) to aggressive disease (subsets 1 and 2).Interpretation: The molecular classifi cation of chronic lymphocytic leukaemia based on B-cell receptorimmunoglobulin stereotypy improves the Döhner hierarchical model and refi nes prognostication beyondimmunoglobulin mutational status, with potential implications for clinical decision making, especially withinprospective clinical trials.

Original languageEnglish (US)
Pages (from-to)e74-e84
JournalThe Lancet Haematology
Volume1
Issue number2
DOIs
StatePublished - Jan 1 2014

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ASJC Scopus subject areas

  • Hematology

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Baliakas, P., Hadzidimitriou, A., Sutton, L. A., Minga, E., Agathangelidis, A., Nichelatti, M., Tsanousa, A., Scarfò, L., Davis, Z., Yan, X. J., Shanafelt, T., Plevova, K., Sandberg, Y., Vojdeman, F. J., Boudjogra, M., Tzenou, T., Chatzouli, M., Chu, C. C., Veronese, S., ... Stamatopoulos, K. (2014). Clinical effect of stereotyped B-cell receptor immunoglobulins in chronic lymphocytic leukaemia: A retrospective multicentre study. The Lancet Haematology, 1(2), e74-e84. https://doi.org/10.1016/S2352-3026(14)00005-2