MYD88 L265P and CXCR4 mutations in lymphoplasmacytic lymphoma identify cases with high disease activity

Abstract

FF and LQ-M contributed equally to this study. SummaryRecurrent mutations in MYD88 have been identified in >90% of lymphoplasmacytic lymphoma (LPL). Recently, WHIM (warts, hypogammaglobulinaemia, infections, myelokathexis) syndrome-like mutations in CXCR4 have been described in 28% of LPL cases, and seem to impact clinical presentation and response to therapy. We investigated the presence of the MYD88 L265P mutation in 90 decalcified, formalin-fixed, paraffin-embedded (FFPE) bone marrow (BM) biopsies, including 51 cases of LPL, 14 cases of B-cell chronic lymphocytic leukaemia (CLL), 13 cases of marginal zone lymphoma (MZL) and 12 normal controls. In addition, the C-terminal domain of CXCR4 was sequenced in LPL cases. MYD88 L265P was found in 49/51 (96%) LPL cases and in 1/13 (7Á6%) MZL (splenic type), whereas all CLL samples remained negative. The two MYD88 wild type LPL cases were associated with cold agglutinin disease. Mutations in CXCR4 were detected in 17/47 (36Á2%) LPL cases, which showed a higher extent of BM infiltration and lower leucocyte counts (P = 0Á02), haemoglobin (P = 0Á05) and platelet counts (P = 0Á01). In conclusion the detection of MYD88 L265P mutation in FFPE samples is reliable and useful for subtyping small B-cell lymphomas in BM biopsies. In addition, the presence of CXCR4 mutations identifies a subgroup of LPL patients with higher disease activity.

Indolent lymphomas in the pediatric population: follicular lymphoma, IRF4/MUM1+ lymphoma, nodal marginal zone lymphoma and chronic lymphocytic leukemia

“…Another interesting finding has been the detection of MYD88 mutations in a subset of young patients with CLL and favorable prognosis [52]. This prompted the panel to perform MYD88 mutation analysis [53], which showed wildtype MYD88 sequence in all three cases (Fig. 6e).…”

How I treat Waldenström macroglobulinemia

“…MYD88 and CXCR4 mutations may impact disease presentation, treatment outcome, and/or survival. [3][4][5][6][7][8][9][10][11][12][13][14] Low tumor burden and serum IgM levels are associated with wild-type MYD88 (MYD88 WT ) disease, whereas MYD88 L265P patients with CXCR4 WHIM mutations have higher bone marrow (BM) disease burden. 13 High serum IgM levels including presentation with hyperviscosity crisis have been observed in patients with CXCR4 WHIM/FS tumor mutation status.…”

“…13 High serum IgM levels including presentation with hyperviscosity crisis have been observed in patients with CXCR4 WHIM/FS tumor mutation status. 11,13 Ibrutinib response (discussed below) is adversely impacted by MYD88 WT and CXCR4 WHIM status. In 1 study, overall survival was lower in patients with MYD88…”

“…MYD88 and CXCR4 WHIM-like somatic mutations are present in .90% and 30% to 35% of WM patients, respectively, but are absent or rare in other IgM secreting B-cell malignancies. [3][4][5][6][7][8][9][10][11][12] More than one half of individuals with IgMsecreting monoclonal gammopathy of unknown significance harbor the MYD88 L265P mutation, suggesting its role as an early oncogenic driver. [4][5][6] Somatic CXCR4 mutations are similar to those found in the germ line of WHIM (warts, hypogammaglobulinemia, infections, myelokathexis) syndrome and nearly always are present in WM patients with MYD88 L265P .…”

High frequency of MYD88 mutations in vitreoretinal B-cell lymphoma: a valuable tool to improve diagnostic yield of vitreous aspirates

“…21 All VRL cases with MYD88 L265 WT and selected VRL with MYD88 L265P were subjected to Sanger sequencing of MYD88 exons 3 and 4 (supplemental Methods). The study was approved by the local ethics committee (105/2013BO2).…”