Prognostic Significance of <i>TP53</i> Mutations in Lymphoplasmacytic Lymphoma

Background: Lymphoplasmacytic lymphoma (LPL) is an indolent B-cell neoplasm, of which the most common subtype is Waldenström macroglobulinemia (WM). Somatic mutations affecting MYD88 and CXCR4 are found in over 90% and 40% of patients with WM respectively, and these 2 genes are part of routine clinical testing. While the negative prognostic effect of TP53 mutations is well-established in diseases such as multiple myeloma and CLL, their impact in WM is less well-characterized. Moreover, the clinical presentation of patients with TP53 mutations has not previously been described. We conducted a retrospective single-institution analysis to evaluate the impact of TP53 mutations in patients with LPL/WM and IgM monoclonal gammopathy of undetermined significance (MGUS). Methods: All patients (n=255) with a diagnosis of either WM, non-IgM LPL or IgM MGUS, who had undergone next generation sequencing (NGS) gene panel testing on a bone marrow sample performed at our institution, were included in this analysis. For patients who had NGS testing on more than one date, the earliest NGS panel test results were used. Between 6/2016-9/2020, the 29-gene EndCancer panel was used (n=116), and between 10/2020-4/2024, the 162-gene EndLymphoma panel was used (n=139). While some genes, including TP53, MYD88 and CXCR4, were captured by both NGS panels, others including IGLL5 and ARID1A, were only tested as part of the EndLymphoma panel. Both panels had &amp;gt;250x coverage of the 10 coding exons of TP53 (total 394 codons) except for a short stretch of 7 codons from exon 3 missing in both panels, and 5 codons from exon 4 missing only in the EndCancer panel. Overall survival (OS) was calculated from time of first NGS panel for all patients; survival metrics were compared using log rank tests. Results: The median age of the study population (n=255) at LPL/WM or IgM MGUS diagnosis was 71 years (range 32-97); 145 were male (57%), and 228 (89%) self-identified race as White or Caucasian. At the time of NGS panel testing, 155 (61%) had symptomatic WM, 73 (29%) had smoldering WM, 14 (5%) had symptomatic non-IgM LPL, 10 (4%) had smoldering non-IgM LPL and 3 (1%) had IgM MGUS. Median time from initial diagnosis to NGS testing was 18 months (range: 0-283.5 months), and median length of follow-up after NGS testing was 31.5 months (95% CI: 26.0 - 39.3 months). Genes with the highest percentage of mutations were MYD88 (187/255; 73%), CXCR4 (79/255; 31%), IGLL5 (36/139; 26%), ARID1A (16/139; 11.5%) and TP53 (28/255; 11%). TP53 mutations were most common in patients with symptomatic WM (26/155), followed by those with symptomatic non-IgM LPL (1/14), and smoldering WM (1/73); no patients with smoldering non-IgM LPL (0/10) or IgM MGUS (0/3) exhibited these mutations. TP53 mutations were associated with shorter median overall survival (OS) (50.4 vs. not reached, p &amp;lt;0.0001), and a significantly higher risk of death (hazard ratio (HR) 5.5; 95% CI: 2.6-11.6). On univariate analyses of MYD88, CXCR4, IGLL5 and ARID1A, none were predictive of OS. However, by multivariate analysis of TP53, MYD88 and CXCR4 mutations, TP53 mutations were an independent predictor of overall survival (p &amp;lt;0.0001; HR 5.3; 95% CI: 2.4-11.8). Sub-group analysis of patients with MYD88 mutations (n=187) further revealed that those with TP53 mutations (n=23) had a significantly worse prognosis (p&amp;lt;0.0001; HR 7.2; 95% CI:2.9-17.8) regardless of CXCR4 mutation status. On review of disease features, no statistically significant differences were noted in the incidences of neuropathy (43 vs 40%), hyperviscosity (21 vs 17%), Bing Neel syndrome (7 vs 2%), bone lesions (7 vs 6%), acquired von Willebrand disease (0 vs 3%) and cold agglutinin hemolytic anemia (4 vs 3%) between those with and without TP53 mutations. Conclusions: In our analysis of patients with WM, non-IgM LPL, and IgM MGUS, the most frequently mutated genes were MYD88, CXCR4, IGLL5, ARID1A and TP53. Despite having similar clinical features, patients with TP53 mutations had a significantly reduced overall survival and increased risk of death compared to those without these mutations. The prognostic significance of TP53 suggests that TP53 mutation testing should be a part of routine clinical testing for LPL/WM patients. Novel therapeutic strategies are needed to improve the outcomes of LPL/WM patients with TP53 mutations.