Genomic Landscape of Waldenström Macroglobulinemia and Its Impact on Treatment Strategies.

Abstract

Next-generation sequencing has revealed recurring somatic mutations in Waldenström macroglobulinemia (WM), including <i>MYD88</i> (95%-97%), <i>CXCR4</i> (30%-40%), <i>ARID1A</i> (17%), and <i>CD79B</i> (8%-15%). Deletions involving chromosome 6q are common in patients with mutated <i>MYD88</i> and include genes that modulate NFKB, BCL2, Bruton tyrosine kinase (BTK), and apoptosis. Patients with wild-type <i>MYD88</i> WM show an increased risk of transformation and death and exhibit many mutations found in diffuse large B-cell lymphoma. The discovery of <i>MYD88</i> and <i>CXCR4</i> mutations in WM has facilitated rational drug development, including the development of BTK and CXCR4 inhibitors. Responses to many agents commonly used to treat WM, including the BTK inhibitor ibrutinib, are affected by <i>MYD88</i> and/or <i>CXCR4</i> mutation status. The mutation status of both <i>MYD88</i> and <i>CXCR4</i> can be used for a precision-guided treatment approach to WM.