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CLL cells are endowed with a plethora of communication systems facilitating microenvironmental interactions, key amongst which is the B-cell receptor (BcR). The pivotal role of the BcR in CLL onset and progression is amply supported by recent clinical studies documenting the remarkable therapeutic efficacy of BcR signaling inhibitors even among heavily pretreated, relapsed/refractory patients. These exciting developments complement earlier immunogenetic evidence that CLL development and evolution is not stochastic but rather driven by extrinsic stimuli, especially stimulation by antigen.

A strong case for antigen involvement is made by the distinction of CLL patients in two categories with markedly different behavior and outcome based on the presence or not of somatic hypermutation (SHM) in the immunoglobulin heavy variable (IGHV) genes of the clonotypic BcR. In particular, patients with no or few SHMs in their IGHV genes (“unmutated” CLL, U-CLL) experience a significantly more aggressive disease than those with a significant SHM load (“mutated” CLL, M-CLL).

IGHV gene mutational status is one of the most robust prognostic markers in CLL, readily identifiable at diagnosis and independent of clinical stage or other biomarkers. More importantly, it remains stable over time, thus contrasting all other well-established prognostic markers, including genomic aberrations, which are influenced by or reflect disease evolution. Furthermore, IGHV gene mutational status has a strong predictive value for response to treatment e.g. U-CLL displays shorter progression-free survival after chemoimunotherapy with the FCR regimen compared to M-CLL.

Considering the above, it is not surprising that immunogenetic analysis of CLL has held much interest for both biological and clinical/prognostic purposes, leading to the amassment of a considerable body of information about BcR IGs in CLL and their molecular configuration, unprecedented in the field of lymphoid malignancies.

Given the importance of the determination of IGHV mutational status for clinical decision making, ERIC, the European Research Initiative on CLL, has taken several initiatives for promoting good practices and standardized approaches while also ensuring the widest possible dissemination both in Europe and throughout the world.