Chronic lymphocytic leukemia with mutated IGHV4-34 receptors: Shared and distinct immunogenetic features and clinical outcomes

Aliki Xochelli; Panagiotis Baliakas; Ioannis Kavakiotis; Andreas Agathangelidis; Lesley Ann Sutton; Eva Minga; Stavroula Ntoufa; Eugen Tausch; Xiao Jie Yan; Tait Shanafelt; Karla Plevova; Myriam Boudjogra; Davide Rossi; Zadie Davis; Alba Navarro; Yorick Sandberg; Fie Juhl Vojdeman; Lydia Scarfo; Niki Stavroyianni; Andrey Sudarikov; Silvio Veronese; Tatiana Tzenou; Teodora Karan-Djurasevic; Mark Catherwood; Dirk Kienle; Maria Chatzouli; Monica Facco; Jasmin Bahlo; Christiane Pott; Lone Bredo Pedersen; Larry Mansouri; Karin E. Smedby; Charles C. Chu; Veronique Giudicelli; Marie Paule Lefranc; Panagiotis Panagiotidis; Gunnar Juliusson; Achilles Anagnostopoulos; Ioannis Vlahavas; Darko Antic; Livio Trentin; Marco Montillo; Carsten Niemann; Hartmut Dohner; Anton W. Langerak; Sarka Pospisilova; Michael Hallek; Elias Campo; Nicholas Chiorazzi; Nikos Maglaveras; David Oscier; Gianluca Gaidano; Diane F. Jelinek; Stephan Stilgenbauer; Ioanna Chouvarda; Nikos Darzentas; Chrysoula Belessi; Frederic Davi; Anastasia Hadzidimitriou; Richard Rosenquist; Paolo Ghia; Kostas Stamatopoulos

doi:10.1158/1078-0432.CCR-16-3100

Chronic lymphocytic leukemia with mutated IGHV4-34 receptors: Shared and distinct immunogenetic features and clinical outcomes

Aliki Xochelli, Panagiotis Baliakas, Ioannis Kavakiotis, Andreas Agathangelidis, Lesley Ann Sutton, Eva Minga, Stavroula Ntoufa, Eugen Tausch, Xiao Jie Yan, Tait Shanafelt, Karla Plevova, Myriam Boudjogra, Davide Rossi, Zadie Davis, Alba Navarro, Yorick Sandberg, Fie Juhl Vojdeman, Lydia Scarfo, Niki Stavroyianni, Andrey SudarikovSilvio Veronese, Tatiana Tzenou, Teodora Karan-Djurasevic, Mark Catherwood, Dirk Kienle, Maria Chatzouli, Monica Facco, Jasmin Bahlo, Christiane Pott, Lone Bredo Pedersen, Larry Mansouri, Karin E. Smedby, Charles C. Chu, Veronique Giudicelli, Marie Paule Lefranc, Panagiotis Panagiotidis, Gunnar Juliusson, Achilles Anagnostopoulos, Ioannis Vlahavas, Darko Antic, Livio Trentin, Marco Montillo, Carsten Niemann, Hartmut Dohner, Anton W. Langerak, Sarka Pospisilova, Michael Hallek, Elias Campo, Nicholas Chiorazzi, Nikos Maglaveras, David Oscier, Gianluca Gaidano, Diane F. Jelinek, Stephan Stilgenbauer, Ioanna Chouvarda, Nikos Darzentas, Chrysoula Belessi, Frederic Davi, Anastasia Hadzidimitriou, Richard Rosenquist, Paolo Ghia, Kostas Stamatopoulos

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Abstract

Purpose: We sought to investigate whether B cell receptor immunoglobulin (BcR IG) stereotypy is associated with particular clinicobiological features among chronic lymphocytic leukemia (CLL) patients expressing mutated BcR IG (M-CLL) encoded by the IGHV4-34 gene, and also ascertain whether these associations could refine prognostication. Experimental Design: In a series of 19,907 CLL cases with available immunogenetic information, we identified 339 IGHV4-34-expressing cases assigned to one of the four largest stereotyped M-CLL subsets, namely subsets #4, #16, #29 and #201, and investigated in detail their clinicobiological characteristics and disease outcomes. Results: We identified shared and subset-specific patterns of somatic hypermutation (SHM) among patients assigned to these subsets. The greatest similarity was observed between subsets #4 and #16, both including IgG-switched cases (IgG-CLL). In contrast, the least similarity was detected between subsets #16 and #201, the latter concerning IgM/D-expressing CLL. Significant differences between subsets also involved disease stage at diagnosis and the presence of specific genomic aberrations. IgG subsets #4 and #16 emerged as particularly indolent with a significantly (P < 0.05) longer time-to-first-treatment (TTFT; median TTFT: not yet reached) compared with the IgM/D subsets #29 and #201 (median TTFT: 11 and 12 years, respectively). Conclusions: Our findings support the notion that BcR IG stereotypy further refines prognostication in CLL, superseding the immunogenetic distinction based solely on SHM load. In addition, the observed distinct genetic aberration landscapes and clinical heterogeneity suggest that not all M-CLL cases are equal, prompting further research into the underlying biological background with the ultimate aim of tailored patient management.

Original language	English (US)
Pages (from-to)	5292-5301
Number of pages	10
Journal	Clinical Cancer Research
Volume	23
Issue number	17
DOIs	https://doi.org/10.1158/1078-0432.CCR-16-3100
State	Published - Sep 1 2017

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General Medicine

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10.1158/1078-0432.CCR-16-3100

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Xochelli, A., Baliakas, P., Kavakiotis, I., Agathangelidis, A., Sutton, L. A., Minga, E., Ntoufa, S., Tausch, E., Yan, X. J., Shanafelt, T., Plevova, K., Boudjogra, M., Rossi, D., Davis, Z., Navarro, A., Sandberg, Y., Vojdeman, F. J., Scarfo, L., Stavroyianni, N., ... Stamatopoulos, K. (2017). Chronic lymphocytic leukemia with mutated IGHV4-34 receptors: Shared and distinct immunogenetic features and clinical outcomes. Clinical Cancer Research, 23(17), 5292-5301. https://doi.org/10.1158/1078-0432.CCR-16-3100

Xochelli, A, Baliakas, P, Kavakiotis, I, Agathangelidis, A, Sutton, LA, Minga, E, Ntoufa, S, Tausch, E, Yan, XJ, Shanafelt, T, Plevova, K, Boudjogra, M, Rossi, D, Davis, Z, Navarro, A, Sandberg, Y, Vojdeman, FJ, Scarfo, L, Stavroyianni, N, Sudarikov, A, Veronese, S, Tzenou, T, Karan-Djurasevic, T, Catherwood, M, Kienle, D, Chatzouli, M, Facco, M, Bahlo, J, Pott, C, Pedersen, LB, Mansouri, L, Smedby, KE, Chu, CC, Giudicelli, V, Lefranc, MP, Panagiotidis, P, Juliusson, G, Anagnostopoulos, A, Vlahavas, I, Antic, D, Trentin, L, Montillo, M, Niemann, C, Dohner, H, Langerak, AW, Pospisilova, S, Hallek, M, Campo, E, Chiorazzi, N, Maglaveras, N, Oscier, D, Gaidano, G, Jelinek, DF, Stilgenbauer, S, Chouvarda, I, Darzentas, N, Belessi, C, Davi, F, Hadzidimitriou, A, Rosenquist, R, Ghia, P & Stamatopoulos, K 2017, 'Chronic lymphocytic leukemia with mutated IGHV4-34 receptors: Shared and distinct immunogenetic features and clinical outcomes', Clinical Cancer Research, vol. 23, no. 17, pp. 5292-5301. https://doi.org/10.1158/1078-0432.CCR-16-3100

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title = "Chronic lymphocytic leukemia with mutated IGHV4-34 receptors: Shared and distinct immunogenetic features and clinical outcomes",

abstract = "Purpose: We sought to investigate whether B cell receptor immunoglobulin (BcR IG) stereotypy is associated with particular clinicobiological features among chronic lymphocytic leukemia (CLL) patients expressing mutated BcR IG (M-CLL) encoded by the IGHV4-34 gene, and also ascertain whether these associations could refine prognostication. Experimental Design: In a series of 19,907 CLL cases with available immunogenetic information, we identified 339 IGHV4-34-expressing cases assigned to one of the four largest stereotyped M-CLL subsets, namely subsets #4, #16, #29 and #201, and investigated in detail their clinicobiological characteristics and disease outcomes. Results: We identified shared and subset-specific patterns of somatic hypermutation (SHM) among patients assigned to these subsets. The greatest similarity was observed between subsets #4 and #16, both including IgG-switched cases (IgG-CLL). In contrast, the least similarity was detected between subsets #16 and #201, the latter concerning IgM/D-expressing CLL. Significant differences between subsets also involved disease stage at diagnosis and the presence of specific genomic aberrations. IgG subsets #4 and #16 emerged as particularly indolent with a significantly (P < 0.05) longer time-to-first-treatment (TTFT; median TTFT: not yet reached) compared with the IgM/D subsets #29 and #201 (median TTFT: 11 and 12 years, respectively). Conclusions: Our findings support the notion that BcR IG stereotypy further refines prognostication in CLL, superseding the immunogenetic distinction based solely on SHM load. In addition, the observed distinct genetic aberration landscapes and clinical heterogeneity suggest that not all M-CLL cases are equal, prompting further research into the underlying biological background with the ultimate aim of tailored patient management.",

author = "Aliki Xochelli and Panagiotis Baliakas and Ioannis Kavakiotis and Andreas Agathangelidis and Sutton, {Lesley Ann} and Eva Minga and Stavroula Ntoufa and Eugen Tausch and Yan, {Xiao Jie} and Tait Shanafelt and Karla Plevova and Myriam Boudjogra and Davide Rossi and Zadie Davis and Alba Navarro and Yorick Sandberg and Vojdeman, {Fie Juhl} and Lydia Scarfo and Niki Stavroyianni and Andrey Sudarikov and Silvio Veronese and Tatiana Tzenou and Teodora Karan-Djurasevic and Mark Catherwood and Dirk Kienle and Maria Chatzouli and Monica Facco and Jasmin Bahlo and Christiane Pott and Pedersen, {Lone Bredo} and Larry Mansouri and Smedby, {Karin E.} and Chu, {Charles C.} and Veronique Giudicelli and Lefranc, {Marie Paule} and Panagiotis Panagiotidis and Gunnar Juliusson and Achilles Anagnostopoulos and Ioannis Vlahavas and Darko Antic and Livio Trentin and Marco Montillo and Carsten Niemann and Hartmut Dohner and Langerak, {Anton W.} and Sarka Pospisilova and Michael Hallek and Elias Campo and Nicholas Chiorazzi and Nikos Maglaveras and David Oscier and Gianluca Gaidano and Jelinek, {Diane F.} and Stephan Stilgenbauer and Ioanna Chouvarda and Nikos Darzentas and Chrysoula Belessi and Frederic Davi and Anastasia Hadzidimitriou and Richard Rosenquist and Paolo Ghia and Kostas Stamatopoulos",

note = "Publisher Copyright: {\textcopyright} 2017 AACR.",

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doi = "10.1158/1078-0432.CCR-16-3100",

language = "English (US)",

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pages = "5292--5301",

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TY - JOUR

T1 - Chronic lymphocytic leukemia with mutated IGHV4-34 receptors

T2 - Shared and distinct immunogenetic features and clinical outcomes

AU - Xochelli, Aliki

AU - Baliakas, Panagiotis

AU - Kavakiotis, Ioannis

AU - Agathangelidis, Andreas

AU - Sutton, Lesley Ann

AU - Minga, Eva

AU - Ntoufa, Stavroula

AU - Tausch, Eugen

AU - Yan, Xiao Jie

AU - Shanafelt, Tait

AU - Plevova, Karla

AU - Boudjogra, Myriam

AU - Rossi, Davide

AU - Davis, Zadie

AU - Navarro, Alba

AU - Sandberg, Yorick

AU - Vojdeman, Fie Juhl

AU - Scarfo, Lydia

AU - Stavroyianni, Niki

AU - Sudarikov, Andrey

AU - Veronese, Silvio

AU - Tzenou, Tatiana

AU - Karan-Djurasevic, Teodora

AU - Catherwood, Mark

AU - Kienle, Dirk

AU - Chatzouli, Maria

AU - Facco, Monica

AU - Bahlo, Jasmin

AU - Pott, Christiane

AU - Pedersen, Lone Bredo

AU - Mansouri, Larry

AU - Smedby, Karin E.

AU - Chu, Charles C.

AU - Giudicelli, Veronique

AU - Lefranc, Marie Paule

AU - Panagiotidis, Panagiotis

AU - Juliusson, Gunnar

AU - Anagnostopoulos, Achilles

AU - Vlahavas, Ioannis

AU - Antic, Darko

AU - Trentin, Livio

AU - Montillo, Marco

AU - Niemann, Carsten

AU - Dohner, Hartmut

AU - Langerak, Anton W.

AU - Pospisilova, Sarka

AU - Hallek, Michael

AU - Campo, Elias

AU - Chiorazzi, Nicholas

AU - Maglaveras, Nikos

AU - Oscier, David

AU - Gaidano, Gianluca

AU - Jelinek, Diane F.

AU - Stilgenbauer, Stephan

AU - Chouvarda, Ioanna

AU - Darzentas, Nikos

AU - Belessi, Chrysoula

AU - Davi, Frederic

AU - Hadzidimitriou, Anastasia

AU - Rosenquist, Richard

AU - Ghia, Paolo

AU - Stamatopoulos, Kostas

PY - 2017/9/1

Y1 - 2017/9/1

N2 - Purpose: We sought to investigate whether B cell receptor immunoglobulin (BcR IG) stereotypy is associated with particular clinicobiological features among chronic lymphocytic leukemia (CLL) patients expressing mutated BcR IG (M-CLL) encoded by the IGHV4-34 gene, and also ascertain whether these associations could refine prognostication. Experimental Design: In a series of 19,907 CLL cases with available immunogenetic information, we identified 339 IGHV4-34-expressing cases assigned to one of the four largest stereotyped M-CLL subsets, namely subsets #4, #16, #29 and #201, and investigated in detail their clinicobiological characteristics and disease outcomes. Results: We identified shared and subset-specific patterns of somatic hypermutation (SHM) among patients assigned to these subsets. The greatest similarity was observed between subsets #4 and #16, both including IgG-switched cases (IgG-CLL). In contrast, the least similarity was detected between subsets #16 and #201, the latter concerning IgM/D-expressing CLL. Significant differences between subsets also involved disease stage at diagnosis and the presence of specific genomic aberrations. IgG subsets #4 and #16 emerged as particularly indolent with a significantly (P < 0.05) longer time-to-first-treatment (TTFT; median TTFT: not yet reached) compared with the IgM/D subsets #29 and #201 (median TTFT: 11 and 12 years, respectively). Conclusions: Our findings support the notion that BcR IG stereotypy further refines prognostication in CLL, superseding the immunogenetic distinction based solely on SHM load. In addition, the observed distinct genetic aberration landscapes and clinical heterogeneity suggest that not all M-CLL cases are equal, prompting further research into the underlying biological background with the ultimate aim of tailored patient management.

AB - Purpose: We sought to investigate whether B cell receptor immunoglobulin (BcR IG) stereotypy is associated with particular clinicobiological features among chronic lymphocytic leukemia (CLL) patients expressing mutated BcR IG (M-CLL) encoded by the IGHV4-34 gene, and also ascertain whether these associations could refine prognostication. Experimental Design: In a series of 19,907 CLL cases with available immunogenetic information, we identified 339 IGHV4-34-expressing cases assigned to one of the four largest stereotyped M-CLL subsets, namely subsets #4, #16, #29 and #201, and investigated in detail their clinicobiological characteristics and disease outcomes. Results: We identified shared and subset-specific patterns of somatic hypermutation (SHM) among patients assigned to these subsets. The greatest similarity was observed between subsets #4 and #16, both including IgG-switched cases (IgG-CLL). In contrast, the least similarity was detected between subsets #16 and #201, the latter concerning IgM/D-expressing CLL. Significant differences between subsets also involved disease stage at diagnosis and the presence of specific genomic aberrations. IgG subsets #4 and #16 emerged as particularly indolent with a significantly (P < 0.05) longer time-to-first-treatment (TTFT; median TTFT: not yet reached) compared with the IgM/D subsets #29 and #201 (median TTFT: 11 and 12 years, respectively). Conclusions: Our findings support the notion that BcR IG stereotypy further refines prognostication in CLL, superseding the immunogenetic distinction based solely on SHM load. In addition, the observed distinct genetic aberration landscapes and clinical heterogeneity suggest that not all M-CLL cases are equal, prompting further research into the underlying biological background with the ultimate aim of tailored patient management.

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U2 - 10.1158/1078-0432.CCR-16-3100

DO - 10.1158/1078-0432.CCR-16-3100

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AN - SCOPUS:85029456308

SN - 1078-0432

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EP - 5301

JO - Clinical Cancer Research

JF - Clinical Cancer Research

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Chronic lymphocytic leukemia with mutated IGHV4-34 receptors: Shared and distinct immunogenetic features and clinical outcomes

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