CBL-MZ is not a single biological entity: evidence from genomic analysis and prolonged clinical follow-up

Abstract

The term "clonal B cell lymphocytosis of marginal zone origin" (CBL-MZ) 1,2 has recently been suggested for asymptomatic individuals whose routine blood count shows a persistent modest lymphocytosis that is usually accompanied by bone marrow involvement. This immunophenotype is suggestive of marginal zone/postgerminal center derivation, but no other features of a chronic B cell lymphoproliferative disorder are found, other than a low-level paraprotein in some cases. Cases with a clonal lymphocyte count ,5 3 10 9 /L would fall within the revised World Health Organization (WHO) category of non-chronic lymphocytic leukemia-type monoclonal B-cell lymphocytosis. In 3 previous series of CBL-MZ consisting of 102, 53, and 16 cases with median follow-ups (FUs) of 60, 34, and 44 months, respectively, 1,3,4 the overall incidence of progression was 15.7%, with the majority (11.1%) developing splenomegaly that frequently did not require treatment. However, it remains unclear whether CBL-MZ is the precursor to 1 or several well-defined WHO entities and what factors predict disease progression. To address this, we performed a genomic analysis of a well-characterized cohort of CBL-MZ cases with long FU and provide evidence to show that CBL-MZ is not a single biological entity.This study includes data from 37 patients with CBL-MZ diagnosed and managed at the Royal Bournemouth Hospital. Clinical, routine laboratory, morphological, immunophenotypic, immunogenetic, and cytogenetic data have been reported on 36 cases using previously described methods.

Systematic Review of Somatic Mutations in Splenic Marginal Zone Lymphoma

“…Other recurrent MYD88 mutations included p.V217F, p.M232T, and p.S219C present in six, four, and three cases respectively. The latter (p.S219C), along with the p.L265P variant, has been identified in a recently recognized entity, termed clonal B-cell lymphocytosis of MZ origin (CBL-MZ) 20,21 , that can sometimes progress to SMZL 22 . The other MYD88 mutations (p.V217F and p.M232T) have been identified in both CLL and DLBCL 23 .…”

Targeted next‐generation sequencing reveals molecular heterogeneity in non‐chronic lymphocytic leukemia clonal B‐cell lymphocytosis

“…2 Immunogenetic analyses of our series showed a great proportion of cases (86.4%) with mutated IGHV genes (identity to germline <100%) and IGHV4-34 was the most used rearrangement, in line with previous studies. 2,5 The extensive gene panel used (138 genes) for targeted NGS analysis in our series revealed no case devoid of molecular lesions, with a total number of 74 somatic mutations in 51 genes. MYD88…”

“…As described elsewhere [2][3][4][5] , non-CLL CBL retain the intrinsic ability to evolve at any time mainly into MZL. We observed only one case who progressed to SLLU after a follow-up of 57 months, showing IGHV4-34 rearrangement and five mutated genes (BIRC3, CXCR4, TRRAP, USH2A, and HIST1H3G).…”

“…1 This entity probably encompasses a heterogeneous group of LPDs with uncertain prognosis, with some cases progressing to a frank lymphoma even after a long follow-up as reported by previous studies. [2][3][4][5] Recently, the term "CBL-MZ" 2,8 has been proposed to highlight the many similarities with MZLs, especially the splenic 9 and nodal 10 subtypes.…”

“…Molecular data about non-CLL CBL are still scanty, with few reports describing the genetic similarities between CBL-MZ and MZLs. 4,5 The main purpose of the present study was to explore the genetic landscape of a well-annotated series of patients with non-CLL CBL, correlating the results with clinical, histological, and immunogenetic features.…”