Inflammatory Waldenström Macroglobulinemia Is Associated with Clonal Hematopoiesis: A Multicentric Cohort

Introduction Waldenström Macroglobulinemia (WM) is a chronic B-cell lymphoma prevalent in elderly patients, characterized by lymphoplasmacytic cells infiltrating the bone marrow and monoclonal immunoglobulin M production. The disease commonly features a gain-of-function mutation in MYD88 (90%) and other genetic anomalies like CXCR4 mutations and chromosome 6 deletions (del6q). Recently, a subset of WM, termed inflammatory WM (iWM), has been identified in approximately one-third of symptomatic patients, marked by elevated C-reactive protein (CRP ≥ 20 mg/L) associated with more del6q and less CXCR4 mutation. This inflammation has been linked to a shorter time to the next treatment with immunochemotherapy and longer response to Bruton tyrosine kinase inhibitors (BTKi, Debureaux et al. Hematologica 2024). Clonal hematopoiesis (CH) involves the clonal expansion of hematopoietic stem cells, typically increasing with age and potentially progressing to myeloid malignancies. CH is also associated with non-malignant inflammatory conditions and increased mortality. To explore the role of CH in iWM, we conducted a multicentric study involving WM patients from seven French centers. Methods Patients with a confirmed diagnosis of WM and with myeloid NGS data on bulk bone marrow (BM) or peripheral blood (PB) samples were included between 2007 and 2024 in seven French centers. CH mutations were detected using NGS of a panel of 62 genes involved in myeloid malignancies, with a cut-off of Variant Allele Frequency (VAF) ≥ 2%. Results Our analysis included 107 patients after excluding those with concurrent myeloid neoplasms, active solid cancers, isolated TP53 mutations, or unconfirmed WM diagnoses. Among these, 46 had iWM, characterized by at least two CRP measurements ≥ 20 mg/L. We identified 63 CH mutations in 42 patients (39%), predominantly in DNMT3A, TET2, and ASXL1 genes (68%). Notably, iWM patients showed a significantly higher prevalence of CH mutations compared to non-iWM patients (67% vs. 28%, p<0.001), particularly in DTA mutations (43% vs. 20%, p=0.01). CRP levels at the time of NGS were higher in patients with CH (median: 25 mg/L) compared to those without CH (median: 10 mg/L, p=0.01). CH was associated with older age but not with other clinical or demographic features. Interestingly, there was no correlation between CH mutation presence and del6q, a chromosomal deletion previously linked to iWM. Investigating the interaction between iWM, del6q, and CH, CRP levels were higher in patients with both del6q and CH compared to patients with only del6q or CH (p=0.005). Discussion This study is the first to associate CH, especially DTA mutations, with iWM, highlighting a novel aspect of the disease's pathophysiology. Our findings also suggest a potential synergistic effect between del6q and CH in contributing to inflammation in WM patients, possibly involving pro-inflammatory cytokines like IL-1b and IL-6. This interaction may influence the effectiveness of BTKi, which are known to inhibit inflammasome activity in myeloid cells and reduce pro-inflammatory cytokine production. Our results underline the need for prospective studies to investigate further the role of CH in WM and its impact on treatment outcomes.