Understanding Waldenström's macroglobulinemia A multimodal approach

Waldenström’s Macroglobulinemia (WM) is a rare B-cell non-Hodgkin lymphoma (NHL) with heterogeneous clinical presentation due to possible involvement of nearly every organ system. The identification of MYD88 and CXCR4 mutations in this disease have accelerated the understanding of WM pathophysiology and the development of effective therapeutic targets, thereby expanding the treatment repertoire. Despite these treatment advances, WM remains incurable. Also, diagnosis is challenging in certain cases, especially when distinguishing it from other IgM secreting B-cell NHL. The research described in this thesis enhances the understanding of WM's pathogenesis, diagnosis, and treatment, aiming for improved patient outcomes. Chapters 2 and 3 explore the efficacy of the ixazomib, rituximab, and dexamethasone (IRd) regimen in relapsed WM, highlighting reduced neurotoxicity and high overall response rate. Chapter 4 presents a diagnostic model for differentiating WM from 'gray zone' cases of overlapping marginal zone lymphoma, based on clinicopathological characteristics. Chapters 5 and 6 offer an extensive analysis of 30-year trends in primary therapy, relative survival, and conditional relative survival of Dutch WM patients. Chapter 7 reveals the intact T-cell subset composition in the PB and bone marrow of WM patients, comparable to healthy donors, even in relapsed. Chapter 8 evaluates potential biomarkers in anti-MAG peripheral neuropathy (PN), including serum neurofilament light chain (NfL), contactin-1 (CNTN1), and complement activation products C3b/c and C4b/c. Chapter 9 examines WM patients' treatment preferences through a discrete choice experiment, and Chapter 10 assesses Dutch hematologists' knowledge and perspectives on WM diagnosis and treatment, showing improved consistency and adherence to guidelines post the national guideline publication.