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, Véronique Giudicelli, Marie-Paule Lefranc, Panagiotis Panagiotidis, Gunnar Juliusson, Achilles Anagnostopoulos, Ioannis Vlahavas, Darko Antic, Livio Trentin, Marco Montillo, Carsten Niemann, Hartmut Döhner, 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

We sought to investigate if B cell receptor immunoglobulin (BcR IG) stereotypy is associated with particular clinicobiological features amongst 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.<br /> <p>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.</p> Results:We identified shared and subset-specific patterns of somatic hypermutation (SHM) amongst 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 CLLs. 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 to the IgM/D subsets #29 and #201 (median TTFT: 11 and 12 years, respectively).<br /><br />Conclusions:Our findings support the notion that BcR IG stereotypy further refines prognostication in CLL, superseding the immunogenetic distinction based solely on SHM load. Additionally, the observed distinct genetic aberration landscapes and clinical heterogeneity suggests that not all M-CLL cases are equal, prompting further research into the underlying biological background with the ultimate aim of tailored patient management.