A South African perspective on MYD88 and CXCR4 variants in lymphoplasmacytic lymphoma or Waldenström macroglobulinaemia

Abstract

Background: Lymphoplasmacytic lymphoma (LPL) is a small mature B-cell neoplasm that primarily involves the bone marrow. When associated with an IgM paraprotein, it is referred to as Waldenström macroglobulinaemia (WM). Variants in the MYD88 and CXCR4 genes are among the most common genetic alterations in LPL. Aim: To determine MYD88 and CXCR4 variant prevalence in South African LPL cases. Setting: National Health Laboratory Service, Charlotte Maxeke Johannesburg Academic Hospital. Methods: Samples were obtained from newly diagnosed, treatment-naïve patients with LPL or WM. MYD88L256P variants were detected using allele-specific oligonucleotide polymerase chain reaction (ASO-PCR), and CXCR4 variants through Sanger sequencing. Clinical and laboratory data were compiled into a database, with statistical analyses performed using GraphPad Prism. Results: Twenty cases of LPL (90% WM) were diagnosed over a 7-year period. The median age of the cohort was 69 years (interquartile range [IQR]: 63–75) with a male predominance. Allele-specific oligonucleotide polymerase chain reaction confirmed MYD88L265P in 80%, and Sanger sequencing confirmed CXCR4 variants in 45%. The group with concurrent MYD88 and CXCR4 variants showed the highest risk stratification scores and the most severe cytopenias. The median overall survival for the cohort was 11.5 months (IQR: 1.9–20.8), with no clear survival difference between CXCR4-mutated and wild-type cases. Survivors tended to be younger and to have lower baseline serum paraprotein levels at presentation. Conclusion: In the South African public healthcare setting, CXCR4 variants are frequent in LPL or WM with high-risk profiles, most common among patients harbouring both MYD88 and CXCR4 variants. Contribution: This study presents the first South African description of LPL genetics.