Diagnosis and Management of Waldenstrom's Macroglobulinemia

Abstract

Waldenström macroglobulinemia (WM) is an IgM secreting lymphoplasmacytic lymphoma. Mutations in MYD88 (95%–97%) and CXCR4 (30%–40%) are common in patients with WM. TP53 is also altered in up to 30% of WM patients, particularly those previously treated. Mutated MYD88 triggers the expression and activation of HCK that drives multiple pro-survival signaling cascades, including BTK. There are over 40 CXCR4 mutation types in WM. WM patients bearing nonsense CXCR4 variants can present with symptomatic hyperviscosity and show greater resistance to covalent BTK inhibitors (cBTK-i). The cBTK-i zanubrutinib shows greater response activity and/or improved progression-free survival in WM patients with wild-type MYD88, mutated CXCR4, or altered TP53. New or emerging options for patients progressing on c-BTKi include pirtobrutinib, BGB-16673, venetoclax, and sonrotoclax. Combinations of BTK inhibitors with chemoimmunotherapy and BCL2 antagonists have advanced. Algorithms for patients with treatment-naïve and previously treated WM based on genomics, disease characteristics, and co-morbidities are discussed.