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
N1 - Funding Information:
T.D. Shanafelt reports receiving commercial research grants from AbbVie, Celgene, Cephalon, Genentech, GlaxoSmithKline, Hospira, Janssen, Pharma-cyclics and Polypenon E International. D. Rossi reports receiving commercial research grants from Abbvie and Gilead and is a consultant/advisory board member for Abbvie, Gilead, and Janssen. F.J. Vojdeman reports receiving other commercial research support from Gilead and Roche. J. Bahlo reports receiving speakers bureau honoraria from Roche and has received travel grants and honoraria (speaker activity at a scientific meeting) from Roche. P. Panagiotidis reports receiving speakers bureau honoraria from Gilead, Janssen, and Roche. M. Montillo reports receiving speakers bureau honoraria from Gilead and Janssen and is a consultant/advisory board member for Abbvie, Gilead, and Janssen. C.U. Niemann reports receiving commercial research grants from Abbvie and is a consultant/advisory board member for Abbvie, Gilead, Janssen, and Roche. A.W. Langerak reports receiving commercial research grants from Roche-Genentech. E. Campo holds ownership interest (including patents) in NanoString Technologies, is a consultant/advisory board member for Bayer and Gilead, and served as an Opinion Expert for Gilead and prepared a report for a trial. A. Hadzidimitriou reports receiving commercial research grants from Janssen and Novartis. K. Stamatopoulos reports receiving commercial research grants from Janssen and Novartis. No potential conflicts of interest were disclosed by the other authors.
Funding Information:
This work was supported in part by H2020 "AEGLE, An analytics framework for integrated and personalized healthcare services in Europe", by the EU; H2020 No. 692298 project "MEDGENET, Medical Genomics and Epigenomics
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.
UR - http://www.scopus.com/inward/record.url?scp=85029456308&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85029456308&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-16-3100
DO - 10.1158/1078-0432.CCR-16-3100
M3 - Article
C2 - 28536306
AN - SCOPUS:85029456308
VL - 23
SP - 5292
EP - 5301
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 17
ER -