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 Gardiner; Larry 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

doi:10.1016/S2352-3026(14)00005-2

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

Abstract

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 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.

FUNDING: European Union; General Secretariat for Research and Technology of Greece; AIRC; Italian Ministry of Health; AIRC Regional Project with Fondazione CARIPARO and CARIVERONA; Regione Veneto on Chronic Lymphocytic Leukemia; Nordic Cancer Union; Swedish Cancer Society; Swedish Research Council; and National Cancer Institute (NIH).

Original language	English
Journal	The Lancet. Haematology
Volume	1
Issue number	2
Pages (from-to)	e74-84
ISSN	2352-3026
DOIs	https://doi.org/10.1016/S2352-3026(14)00005-2
Publication status	Published - Nov 2014

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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), e74-84. https://doi.org/10.1016/S2352-3026(14)00005-2

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, FJ, Boudjogra, M, Tzenou, T, Chatzouli, M, Chu, CC, Veronese, S, Gardiner, A, Mansouri, L, Smedby, KE, Pedersen, LB, van Lom, K, Giudicelli, V, Francova, HS, Nguyen-Khac, F, Panagiotidis, P, Juliusson, G, Angelis, L, Anagnostopoulos, A, Lefranc, M-P, Facco, M, Trentin, L, Catherwood, M, Montillo, M, Geisler, CH, Langerak, AW, Pospisilova, S, Chiorazzi, N, Oscier, D, Jelinek, DF, Darzentas, N, Belessi, C, Davi, F, Rosenquist, R, Ghia, P & Stamatopoulos, K 2014, 'Clinical effect of stereotyped B-cell receptor immunoglobulins in chronic lymphocytic leukaemia: a retrospective multicentre study', The Lancet. Haematology, vol. 1, no. 2, pp. e74-84. https://doi.org/10.1016/S2352-3026(14)00005-2

@article{ce4359ade3524550add7df936cbdf7a5,

title = "Clinical effect of stereotyped B-cell receptor immunoglobulins in chronic lymphocytic leukaemia: a retrospective multicentre study",

abstract = "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 D{\"o}hner 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 D{\"o}hner hierarchical model and refines prognostication beyond immunoglobulin mutational status, with potential implications for clinical decision making, especially within prospective clinical trials.FUNDING: European Union; General Secretariat for Research and Technology of Greece; AIRC; Italian Ministry of Health; AIRC Regional Project with Fondazione CARIPARO and CARIVERONA; Regione Veneto on Chronic Lymphocytic Leukemia; Nordic Cancer Union; Swedish Cancer Society; Swedish Research Council; and National Cancer Institute (NIH).",

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

year = "2014",

month = nov,

doi = "10.1016/S2352-3026(14)00005-2",

language = "English",

volume = "1",

pages = "e74--84",

journal = "The Lancet. Haematology",

issn = "2352-3026",

publisher = "Lancet Publishing Group",

number = "2",

}

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

PY - 2014/11

Y1 - 2014/11

N2 - 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 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.FUNDING: European Union; General Secretariat for Research and Technology of Greece; AIRC; Italian Ministry of Health; AIRC Regional Project with Fondazione CARIPARO and CARIVERONA; Regione Veneto on Chronic Lymphocytic Leukemia; Nordic Cancer Union; Swedish Cancer Society; Swedish Research Council; and National Cancer Institute (NIH).

AB - 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 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.FUNDING: European Union; General Secretariat for Research and Technology of Greece; AIRC; Italian Ministry of Health; AIRC Regional Project with Fondazione CARIPARO and CARIVERONA; Regione Veneto on Chronic Lymphocytic Leukemia; Nordic Cancer Union; Swedish Cancer Society; Swedish Research Council; and National Cancer Institute (NIH).

U2 - 10.1016/S2352-3026(14)00005-2

DO - 10.1016/S2352-3026(14)00005-2

M3 - Journal article

C2 - 27030157

SN - 2352-3026

VL - 1

SP - e74-84

JO - The Lancet. Haematology

JF - The Lancet. Haematology

IS - 2

ER -

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

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