Prevalence and Clinical Significance of the MYD88 (L265P) Somatic Mutation in Patients with Waldenström Macroglobulinemia, IgM-Monoclonal Gammopathy of Undetermined Significance or Other Mature B-Cell Neoplasms.
Authors: Varettoni Marzia , Arcaini Luca , Zibellini Silvia , Boveri Emanuela , Rattotti Sara , Riboni Roberta , Corso Alessandro , Orlandi Ester , Bonfichi Maurizio , Gotti Manuel , Pascutto Cristiana , Mangiacavalli Silvia , Morello Lucia , Guerrera Maria Luisa , Croci Giorgio , Fiaccadori Valeria , Paulli Marco , Cazzola Mario 
Published: October 2019

Abstract
Abstract 2667
Waldenström Macroglobulinemia (WM) is a B-cell lymphoproliferative disorder characterized by bone marrow infiltration by lymphoplasmacytic lymphoma associated with a monoclonal component of IgM type in the serum. WM is often preceded by an IgM monoclonal gammopathy of undetermined significance (IgM-MGUS). The cumulative probability of progression of IgM-MGUS to WM or to other lymphoproliferative disorders is approximately 1.5% per year. Other mature B-cell neoplasms such as splenic marginal zone lymphoma (SMZL) and B-cell chronic lymphoproliferative disorders (B-CLPD) can carry an IgM monoclonal component and should therefore be considered in differential diagnosis with WM.
In a study based on parallel sequencing of the whole genome of lymphoplasmacytic cells and paired normal tissue from WM patients, Treon et al (Blood. 2011;118:Abstract 300) have identified a highly recurrent somatic mutation with oncogenic activity in the myeloid differentiation primary response (MYD88) gene, leading to a change from leucine to proline at position 265 of the aminoacid sequence [MYD88 (L265P)]. Targeted Sanger resequencing showed MYD88 (L265P) in 90% of WM patients, but only in a minority of patients with IgM-MGUS or other mature B-cell neoplasms such as SMZL.
We developed an allele-specific PCR for the MYD88 (L265P) mutation, and studied 58 patients with WM, 77 with IgM-MGUS, 84 with splenic marginal zone lymphoma (SMZL) and 52 with B-cell chronic lymphoproliferative disorders (B-CLPD). DNA was obtained from bone marrow cells (n=204) and peripheral blood (n=67). The aims of this study were: i) to assess the prevalence of the mutation in WM, IgM-MGUS, SMZL, and B-CLPD; ii) to analyze the relationship between MYD88 (L265P) mutation and clinical phenotype; iii) to evaluate the impact of the mutation on the risk of progression from IgM-MGUS WM or other lymphoproliferative disorders.
The MYD88 (L265P) mutation was detected in 58/58 (100%) patients with WM, either asymptomatic (n=39) or symptomatic (n=18), and in 36/77 (47%) patients with IgM-MGUS. In addition, it was detected in 5/84 (6%) patients with SMZL and in 3/52 (6%) with B-CLPD; of these MYD88 (L265P)-positive subjects, 4 SMZL and 2 B-CLPD patients carried a serum IgM monoclonal component, while the remaining B-CLPD patient carried a double (IgM and IgG) monoclonal component.
Compared with IgM-MGUS patients with wild-type MYD88, those carrying MYD88 (L265P) had significantly higher levels of IgM (P<.0001), lower levels of IgG (P=.04) and IgA (P=.04), and higher incidence of Bence-Jones proteinuria at diagnosis (P=.002). During the follow-up, 9 patients with IgM-MGUS progressed to WM (7 cases) or to marginal zone lymphoma (2 cases). Using a case-control approach, the risk of evolution of patients with MYD88 (L265P) was significantly higher as compared to that of patients with wild-type MYD88 sequence (OR 4.7, 95% confidence interval 0.8–48.7, P=.047).
In conclusion, the findings of this study indicate that: i) the allele-specific PCR we developed is able to detect the MYD88 (L265P) mutation in all patients with WM and in nearly half the patients with IgM-MGUS, and therefore represents a useful diagnostic tool; ii) MYD88 (L265P) is an uncommon molecular lesion in SMZL and in B-CLPD, but is associated with an IgM monoclonal component in the few positive patients, suggesting that some cases of B-CLPD might be included in the spectrum of WM; iii) in IgM-MGUS, the mutation is associated with greater disease burden and higher risk of disease progression, and therefore represents a useful prognostic marker.

Disclosures:
No relevant conflicts of interest to declare.