EHA-SWG 2017 | Rare Lymphomas: Biology of WM

On March 11^th, at the EHA-SWG Rare Lymphomas Scientific Meeting 2017 in Barcelona, Spain, Marie José Kersten chaired a scientific session on ‘Waldenström’s Macroglobulinemia’. The first presentation of this session was by Roger Owen, from the St. James’s Institute of Oncology, Leeds, UK, on the topic of ‘Biology of WM’. Below are the key highlights from this presentation:

• WM patients frequently have mutations in key genes such as MYD88 and CXCR4
• MYD88
  • MYD88 L265P mutation was identified in 91% of WM patients initially
  • Not all WM patients have the MYD88 L265P mutation
  • MYD88 L265P mutation results in activation of IRAK and BTK, leading to NFkB signaling and tumor cell growth
  • Other mutations have been found to be recurring within WM patients e.g. CXCR4, ARID1A, etc. suggesting subclonal mutations within WM patients

• CXCR4
  • CXCR4 mutations in ~30–40% WM pts with MYD88 mutation
  • C-terminus of CXCR4 ligates with SDF1a (CXCL12) and is involved in signaling
  • Nonsense and frame-shift mutations in CXCR4 are similar to those seen in WHIM syndrome
  • CXCR4 mutations also present in ~33% of IgM monoclonal gammopathy of undetermined significance (MGUS)
• Both MYDS88 and CXCR4 are markers of poor clinical prognosis in WM

• WT MYD88 L265P pts have lower IgM and a poorer response to ibrutinib
• Other MYD88 mutations include BTK^Cys481 mutations, associated with ibrutinib resistance and CXCR4 mutations in WM
• WM B-cells have been shown to have a specific immunophenotype

• Conclusions included the importance of flow cytometry to define WM, and the role of MYD88 point mutation screening