TY - JOUR
T1 - Clinical effect of stereotyped B-cell receptor immunoglobulins in chronic lymphocytic leukaemia
T2 - A retrospective multicentre study
AU - Baliakas, Panagiotis
AU - Hadzidimitriou, Anastasia
AU - Sutton, Lesley Ann
AU - Minga, Eva
AU - Agathangelidis, Andreas
AU - Nichelatti, Michele
AU - Tsanousa, Athina
AU - Scarfò, Lydia
AU - Davis, Zadie
AU - Yan, Xiao Jie
AU - Shanafelt, Tait
AU - Plevova, Karla
AU - Sandberg, Yorick
AU - Vojdeman, Fie Juhl
AU - Boudjogra, Myriam
AU - Tzenou, Tatiana
AU - Chatzouli, Maria
AU - Chu, Charles C.
AU - Veronese, Silvio
AU - Gardiner, Anne
AU - Mansouri, Larry
AU - Smedby, Karin E.
AU - Pedersen, Lone Bredo
AU - van Lom, Kirsten
AU - Giudicelli, Véronique
AU - Francova, Hana Skuhrova
AU - Nguyen-Khac, Florence
AU - Panagiotidis, Panagiotis
AU - Juliusson, Gunnar
AU - Angelis, Lefteris
AU - Anagnostopoulos, Achilles
AU - Lefranc, Marie Paule
AU - Facco, Monica
AU - Trentin, Livio
AU - Catherwood, Mark
AU - Montillo, Marco
AU - Geisler, Christian H.
AU - Langerak, Anton W.
AU - Pospisilova, Sarka
AU - Chiorazzi, Nicholas
AU - Oscier, David
AU - Jelinek, Diane F.
AU - Darzentas, Nikos
AU - Belessi, Chrysoula
AU - Davi, Frederic
AU - Rosenquist, Richard
AU - Ghia, Paolo
AU - Stamatopoulos, Kostas
N1 - Funding Information:
This study was supported in part by the ENosAI project (code 09SYN-13-880), co-funded by the EU and the General Secretariat for Research and Technology of Greece; the KRIPIS action, funded by the General Secretariat for Research and Technology of Greece; Associazione Italiana per la Ricerca sul Cancro (AIRC; Investigator Grant and Special Program Molecular Clinical Oncology–5 per mille #9965), Milan, Italy, and Ricerca Finalizzata 2010 (RF-2010-2318823)–Italian Ministry of Health; AIRC Regional Project with Fondazione CARIPARO and CARIVERONA; Regione Veneto on Chronic Lymphocytic Leukemia; the Nordic Cancer Union; the Swedish Cancer Society; the Swedish Research Council; the Lion's Cancer Research Foundation, Uppsala, Sweden; and Selander's Foundation, Uppsala, Sweden; grants CEITEC MU (CZ.1.05/1.1.00/02.0068) and SuPReMMe (CZ.1.07/2.3.00/20.0045). AAg is recipient of a fellowship by Associazione Italiana per la Ricerca sul Cancro AIRC (triennial fellowship “Guglielmina Lucatello e Gino Mazzega”). This study was partly supported by the National Cancer Institute, NIH, USA (grant RO1 CA081554 to NC; and grant CA136591 to DFJ).
PY - 2014/11
Y1 - 2014/11
N2 - 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 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 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 collected between 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 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 Döhner 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 Döhner hierarchical model and refines prognostication beyond immunoglobulin mutational status, with potential implications for clinical decision making, especially within prospective clinical trials.
AB - 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 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 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 collected between 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 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 Döhner 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 Döhner hierarchical model and refines prognostication beyond immunoglobulin mutational status, with potential implications for clinical decision making, especially within prospective clinical trials.
UR - http://www.scopus.com/inward/record.url?scp=84921885631&partnerID=8YFLogxK
U2 - 10.1016/S2352-3026(14)00005-2
DO - 10.1016/S2352-3026(14)00005-2
M3 - Article
C2 - 27030157
AN - SCOPUS:84921885631
SN - 2352-3026
VL - 1
SP - e74-e84
JO - The Lancet Haematology
JF - The Lancet Haematology
IS - 2
ER -