Epidemiology of Waldenström Macroglobulinemia

Abstract

Waldenström macroglobulinemia(WM) is a non-Hodgkin lymphoma characterized bythe presence of a CD20+ lymphoplasmacytic infiltratein the bone marrow and an elevated serum immunoglobulin M monoclonal protein.1 The lymphoplasmacytic cells present in WM commonly display highlevels of surface CD19, CD20, and immunoglobulinlight chain expression, but the malignant B-lymphocytes typically lack CD10 expression. The plasmacyticcomponent expresses the same immunoglobulin lightchain as the lymphocytic component, is positive forCD138, and shows diminished expression of B-cell-associated antigens such as CD19, CD20, and PAX5.Conventional cytogenetic analyses initially determineddeletions of chromosome 6q to be the most commonrecurrent abnormality in WM, and this abnormalitywas identified in approximately half of the patientsstudied.2 Although the deletion of 6q is present inaround 50% of WM patients, its presence cannot beused for diagnosis of the disease as the deletion iswidely observed in other B-cell malignancies, such asmarginal zone lymphoma, multiple myeloma andchronic lymphocytic leukemia. Recent data obtainedfrom whole genome sequencing of WM patientsreported a mutation in MYD88 in 90% of cases,which leads to a leucine to proline substitution incodon 265 (L265P).3 This MYD88 mutation hasbecome a biomarker for differentiating WM fromother related entities such as marginal zone lymphoma, where MYD88 L265P was detected in lessthan 10% of cases. Furthermore, a low prevalence ofMYD88 mutations in IgM-MGUS suggests that themutation is associated with disease progression orthat there is more than one type of IgM-MGUS,with only certain types of IgM-MGUS progressingto WM. The second most common somatic alterationsidentified in WM are the C-X-C chemokine receptortype 4 (CXCR4) mutations.4,5 Somatic CXCR4 mutations in WM are similar to the germlineCXCR4WHIM mutations described in the rareWHIM (warts, hypogammaglobulinemia, infections,myelokathexis) syndrome. A WHIM mutation inCXCR4 results in the permanent activation by itsligand, stromal derived factor 1 alpha (SDF-1a/CXCL-12), leading to activation of AKT andmitogen-activated protein kinase (MAPK) and promoting survival. Currently, three subpopulations ofWM have been genomically defined and thesegroups respond differently to BTK inhibition. WMpatients with mutated MYD88 and CXCR4WTbenefit the most from ibrutinib exhibiting an overallresponse rate (ORR) of 100%, followed by thosewith mutated MYD88 and CXCR4WHIM (ORR86%) and MYD88WT and CXCR4WT (ORR 60%).Gene expression profile (GEP) analysis of WM hasalso provided useful information about the transcriptional signature of the disease. A significant findinghas been the high level of IL-6 transcript expressionin WM when compared to multiple myeloma, CLL,and normal B cells.6 The increase in IL-6 expressionin WM is suggestive of a functional relationshipbetween IL-6, RANTES (CCL5), and IgM secretionthat appears to be mediated through the JAK/STATand PI3K pathways.7,8 Although the specific mechanisms of increased immunoglobulin secretion in WMare still not entirely understood, the pathogenic roleof IL-6 and the JAK/STAT pathway in WM meritsfurther study. A multitude of potentially effectivetherapies targeting cell-survival pathways are in development and offer a more precise approach for WMpatients. One such agent, ibrutinib, a Bruton's tyrosinekinase inhibitor, was recently granted approval inWM.9 A clearer understanding of WM biology willallow for optimal development and selection of therapies in the future.