Higher-order connections between stereotyped subsets: implications for improved patient classification in CLL

Andreas Agathangelidis 1, Anastasia Chatzidimitriou 1 2, Katerina Gemenetzi 1 3, Veronique Giudicelli 4, Maria Karypidou 1, Karla Plevova 5 6, Zadie Davis 7, Xiao-Jie Yan 8, Sabine Jeromin 9, Christof Schneider 10, Lone Bredo Pedersen 11, Renee C Tschumper 12, Lesley-Ann Sutton 2, Panagiotis Baliakas 13, Lydia Scarfò 14, Ellen J van Gastel 15, Marine Armand 16, Eugen Tausch 17, Bella Biderman 18, Constance Baer 9, Davide Bagnara 19, Alba Navarro 20 21, Anne Langlois de Septenville 16, Valentina Guido 22, Gerlinde Mitterbauer-Hohendanner 23, Aleksandar Dimovski 24, Christian Brieghel 11, Sarah Lawless 25, Manja Meggendorfer 9, Kamila Brazdilova 5 6, Matthias Ritgen 26, Monica Facco 27 28, Cristina Tresoldi 29, Andrea Visentin 27 28, Andrea Patriarca 30, Mark Catherwood 25, Lisa Bonello 31, Andrey Sudarikov 18, Katrina Vanura 23, Maria Roumelioti 32, Hana Skuhrova Francova 5, Theodoros Moysiadis 1, Silvio Veronese 22, Krzysztof Giannopoulos 33, Larry Mansouri 2, Teodora Karan-Djurasevic 34, Raphael Sandaltzopoulos 3, Csaba Bödör 35, Franco Fais 19 36, Arnon P Kater 37, Irina Panovska 38, Davide Rossi 39, Salem Alshemmari 40, Panagiotis Panagiotidis 32, Paul Costeas 41 42, Blanca Espinet 43, Darko Antic 44, Letizia Foroni 45, Marco Montillo 22, Livio Trentin 27 28, Niki Stavroyianni 46, Gianluca Gaidano 30, Paola Francia di Celle 31, Carsten Niemann 11, Elias Campo 20 21 47, Achilles Anagnostopoulos 45, Christiane Pott 26, Kirsten Fischer 48, Michael Hallek 49, David Oscier 7, Stephan Stilgenbauer 17, Claudia Haferlach 9, Diane Jelinek 50, Nicholas Chiorazzi 8, Sarka Pospisilova 5 6, Marie-Paule Lefranc 4, Sofia Kossida 4, Anton W Langerak 15, Chrysoula Belessi 51, Frederic Davi 15, Richard Rosenquist 2 52, Paolo Ghia 14, Kostas Stamatopoulos 1 2


 

Affiliations

11 March 2021

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doi: 10.1182/blood.2020007039

Abstract

Chronic lymphocytic leukemia (CLL) is characterized by the existence of subsets of patients with (quasi)identical, stereotyped B-cell receptor (BcR) immunoglobulins. Patients in certain major stereotyped subsets often display remarkably consistent clinicobiological profiles, suggesting that the study of BcR immunoglobulin stereotypy in CLL has important implications for understanding disease pathophysiology and refining clinical decision-making. Nevertheless, several issues remain open, especially pertaining to the actual frequency of BcR immunoglobulin stereotypy and major subsets, as well as the existence of higher-order connections between individual subsets. To address these issues, we investigated clonotypic IGHV-IGHD-IGHJ gene rearrangements in a series of 29 856 patients with CLL, by far the largest series worldwide. We report that the stereotyped fraction of CLL peaks at 41% of the entire cohort and that all 19 previously identified major subsets retained their relative size and ranking, while 10 new ones emerged; overall, major stereotyped subsets had a cumulative frequency of 13.5%. Higher-level relationships were evident between subsets, particularly for major stereotyped subsets with unmutated IGHV genes (U-CLL), for which close relations with other subsets, termed "satellites," were identified. Satellite subsets accounted for 3% of the entire cohort. These results confirm our previous notion that major subsets can be robustly identified and are consistent in relative size, hence representing distinct disease variants amenable to compartmentalized research with the potential of overcoming the pronounced heterogeneity of CLL. Furthermore, the existence of satellite subsets reveals a novel aspect of repertoire restriction with implications for refined molecular classification of CLL.

Conflict of interest statement

Conflict-of-interest disclosure: S.V. has received honoraria from Bayer, AstraZeneca, and Janssen; A.K. has received research funding from AbbVie, Roche/Genentech, Janssen, and AstraZeneca. D.R. has received honoraria from AbbVie, AstraZeneca, Gilead, Janssen, Verastem, and research grants from AbbVie, Gilead, Janssen, and Cellestia. S.A. has received educational grants from Johnson & Johnson, AbbVie, and Roche. K. Giannopoulos has received honoraria from AbbVie, Janssen, and Roche. L.T. has received honoraria from AbbVie, Roche, Janssen, and Shire. A.V. has received honoraria from Janssen and AbbVie. G.G. has received honoraria from AbbVie, Janssen, Sunesis, and AstraZeneca for advisory boards or speaker’s bureau services. C.N. has received research support, consultancy fees, and/or travel grants from AbbVie, Gilead, Janssen, Roche, CSL Behring, Genmab, Sunesis, and Acerta/AstraZeneca outside this work. K.F. has received honoraria from Roche and AbbVie, and Roche travel grants. S.S. has received honoraria and research support from AbbVie, AstraZeneca, Celgene, Gilead, GlaxoSmithKline, Hoffmann La-Roche, Janssen, and Novartis. R.R. has received honoraria from AbbVie, Illumina, Janssen, and Roche. P.G. has received honoraria from AbbVie, Acerta, BeiGene, Gilead, Janssen, Sunesis, and reseach funding from AbbVie, Gilead, Janssen, Novartis, and Sunesis. K.S. has received honoraria and research support from AbbVie, Janssen, AstraZeneca, and Gilead. The remaining authors declare no competing financial interests.

References

https://pubmed.ncbi.nlm.nih.gov/

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