Targeted therapies overcome the poor prognosis of stereotyped Subset#2 chronic lymphocytic leukemia : a real-world multicentric study

The outcome of patients with chronic lymphocytic leukemia (CLL) is known to be influenced by the mutational status of the immunoglobulin heavy-chain variable (IGHV) region [1].In the past decade, it has been shown that a large part of CLL share B-cell receptor (BCR) sequence homologies, defining subsets of patients with similar clinical outcome [2].The CLL Subset#2 (S#2), defined by the presence of the stereotyped IGHV3-21-derived rearrangement, with a short third complementarity-determining region (CDR3), has been linked to unfavorable prognosis.This translates in shorter time to first treatment, independently of other prognostic factors such as IGHV mutational status or genetic alterations [3,4].Despite S#2 being the most prevalent subset, few studies have investigated treatment responses and progression-free survival (PFS) in this context.Chemoimmunotherapy (CIT) is unsatisfactory in this group of patients [5,6], but responses to targeted therapies (TT) have not been investigated.The aim of this study was to evaluate the outcome of patients with S#2 compared to patients with other IGHV3-21 subsets in the era of TT.A retrospective multicentric study was conducted across 31 French Innovative Leukemia Organization (FILO-CLL) affiliated centers in France, including patients diagnosed between 1998 and 2023.The study was declared to the Health data Hub according to French legislation.Patients identified with a productive IGHV3-21 rearrangement, available clinical and survival data, and no opposition to the study, were included.S#2, not-Subset#2 (nS#2) and IGHV mutational status were categorized according to the recommendations of the European Research Initiative on CLL (ERIC) [7].Treatment strategies were CIT, Bruton Tyrosine Kinase inhibitors (BTKi), and B-Cell Lymphoma 2 inhibitors (BCL2i).Survival analysis, according to ERIC recommendations [7], considered borderline IGHV status as mutated.Time to first treatment (TTFT) and subsequent PFS analysis were performed using Kaplan-Meier estimation and log-rank test (R software, CRAN).Potential confounders, including age, sex, mutated (mIGHV) and unmutated (uIGHV) status, complex karyotype (CK) (3 abnormalities), high-CK (HCK) (5 abnormalities) and TP53

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Journal
Leukemia
Published
2025-04-01
DOI
https://doi.org/10.1038/s41375-025-02555-0
Primary Topic
Chronic Lymphocytic Leukemia Research
Type
article
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article

Targeted therapies overcome the poor prognosis of stereotyped Subset#2 chronic lymphocytic leukemia : a real-world multicentric study

Isabelle Plantier, Audrey Bidet, Elsa Maître, Grégory Lazarian et al.
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Leukemia
Chronic Lymphocytic Leukemia Research
article

Targeted therapies overcome the poor prognosis of stereotyped Subset#2 chronic lymphocytic leukemia : a real-world multicentric study

Isabelle Plantier, Audrey Bidet, Elsa Maître, Grégory Lazarian, Émilie Montaut, Jehan Dupuis, Éric Delabesse, Stéphanie Poulain, Kamel Laribi, Yannick Le Bris, Caroline Algrin, Florence Lachenal, Cécile Tomowiak, Romain Guièze, Sophie Dupire, Pascale Cornillet‐Lefèbvre, Édouard Cornet, Jérôme Cornillon, Anne‐Sophie Michallet, H Barbier, Anne Desmares, Pierre Feugier, Marie C. Béné, Bernard Drénou, Stéphane Leprêtre, Marie‐Hélène Delfau‐Larue, Sylvain Carras, Anne Quinquenel, Anne Murati, Julia Hieulle, Luca Inchiappa, Stéphanie Tardy, Lucile Bussot, Aline Clavert, Adrien Caillet, Xavier Troussard, Cédric Pastoret, Sarah Huet, Damien Roos‐Weil, Pierre Sujobert, Bruno Villemagne, Anne Lok, Pascale Flandrin‐Gresta, Emmanuelle Ferrant, Loïc Ysebaert, Frédéric Davi, Sarah Barbieux, Marie Sarah Dilhuydy, Doriane Richard, Lysiane Molina, Caroline Dartigeas, Morgane Nudel Ortmans, Céline Lechat
article en

Abstract

The outcome of patients with chronic lymphocytic leukemia (CLL) is known to be influenced by the mutational status of the immunoglobulin heavy-chain variable (IGHV) region [1].In the past decade, it has been shown that a large part of CLL share B-cell receptor (BCR) sequence homologies, defining subsets of patients with similar clinical outcome [2].The CLL Subset#2 (S#2), defined by the presence of the stereotyped IGHV3-21-derived rearrangement, with a short third complementarity-determining region (CDR3), has been linked to unfavorable prognosis.This translates in shorter time to first treatment, independently of other prognostic factors such as IGHV mutational status or genetic alterations [3,4].Despite S#2 being the most prevalent subset, few studies have investigated treatment responses and progression-free survival (PFS) in this context.Chemoimmunotherapy (CIT) is unsatisfactory in this group of patients [5,6], but responses to targeted therapies (TT) have not been investigated.The aim of this study was to evaluate the outcome of patients with S#2 compared to patients with other IGHV3-21 subsets in the era of TT.A retrospective multicentric study was conducted across 31 French Innovative Leukemia Organization (FILO-CLL) affiliated centers in France, including patients diagnosed between 1998 and 2023.The study was declared to the Health data Hub according to French legislation.Patients identified with a productive IGHV3-21 rearrangement, available clinical and survival data, and no opposition to the study, were included.S#2, not-Subset#2 (nS#2) and IGHV mutational status were categorized according to the recommendations of the European Research Initiative on CLL (ERIC) [7].Treatment strategies were CIT, Bruton Tyrosine Kinase inhibitors (BTKi), and B-Cell Lymphoma 2 inhibitors (BCL2i).Survival analysis, according to ERIC recommendations [7], considered borderline IGHV status as mutated.Time to first treatment (TTFT) and subsequent PFS analysis were performed using Kaplan-Meier estimation and log-rank test (R software, CRAN).Potential confounders, including age, sex, mutated (mIGHV) and unmutated (uIGHV) status, complex karyotype (CK) (3 abnormalities), high-CK (HCK) (5 abnormalities) and TP53

LeukemiaVol. 39(5)
Centre National de la Recherche Scientifique (FR), Inserm (FR), Université Paris-Est Créteil (FR), Université de Lille (FR), Centre Hospitalier Universitaire de Grenoble (FR), Centre Hospitalier Universitaire de Bordeaux (FR), Université de Poitiers (FR), Sorbonne Université (FR), Centre Hospitalier de Roubaix (FR), Centre Hospitalier Universitaire de Besançon (FR), Lille’s Cardiology Hospital (FR), Université Sorbonne Paris Nord (FR), Centre Hospitalier Universitaire de Tours (FR), Assistance Publique – Hôpitaux de Paris (FR), Institut universitaire du cancer de Toulouse Oncopole (FR), Centre Hospitalier Régional et Universitaire de Nancy (FR), Hospices Civils de Lyon (FR), Centre Léon Bérard (FR), Centre Hospitalier Universitaire de Reims (FR), Roche (France) (FR), Institut de Cancérologie de Bourgogne (FR), Centre Hospitalier Universitaire d'Angers (FR), Centre Hospitalier Universitaire de Caen Normandie (FR), Hôpitaux Universitaires Paris-Ouest (FR), Pitié-Salpêtrière Hospital (FR), Int'Air Medical (France) (FR), Centre Hospitalier du Mans (FR), Centre Hospitalier Universitaire de Clermont-Ferrand (FR), Hôpital Avicenne (FR), Hôpitaux Universitaires Henri-Mondor (FR), Centre Hospitalier Annecy Genevois (FR), Centre Hospitalier Départemental Vendée (FR), Institut Paoli-Calmettes (FR), Groupe Hospitalier de la Région de Mulhouse et Sud Alsace (FR), Centre Hospitalier Universitaire de Rennes (FR), Centre Hospitalier Universitaire de Saint-Étienne (FR), Onco Lille (FR), Institut Mondor de Recherche Biomédicale (FR), Centre Henri Becquerel, Université Grenoble Alpes (FR), Université de Reims Champagne-Ardenne (FR), Université de Caen Normandie (FR)
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