Impact of <i>TP53</i> mutation status on cancer-specific survival after first-line treatment in lymphoplasmacytic lymphoma.

Abstract

e19573 Background: Lymphoplasmacytic lymphoma (LPL) is an indolent B-cell neoplasm encompassing Waldenström macroglobulinemia (WM) and non-IgM LPL. Testing for MYD88 and CXCR4 mutations is part of routine clinical workup of LPL; these mutations have relevance for therapy selection since patients (pts) with MYD88 mut / CXCR4 wt LPL/WM have superior BTK inhibitor (BTKi) response rates compared to those with other mutation profiles. Previous work by our group and others has found TP53 mutations to be associated with decreased overall survival in LPL, but the impact of TP53 mutations on treatment-related outcomes is not well characterized. Methods: This retrospective single-institution study included all pts (n = 107) at our institution with a diagnosis of LPL who had next-generation sequencing (NGS) data available from bone marrow samples obtained prior to initiation of first-line treatment. The NGS panels used for this study had &gt;250x coverage of all 10 coding exons of TP53 . Overall survival (OS) was calculated from the start date of first-line therapy; inter-group differences in OS were evaluated by log rank test. Results: The median age at diagnosis was 66 years (range 36 – 91); 56 (52%) were male and 97 (91%) were White. Median time from diagnosis to treatment initiation was 7 months and median length of follow-up from treatment initiation was 28 months (95% confidence interval (CI): 20-37 months). TP53 mutations (TP53 mut ) were found in 11/107 (10%) pts. Median TP53 variant allele frequency was 19% (&lt;5-28%). No significant difference was found in sex, race, MYD88/CXCR4 mutation statuses or median age at treatment initiation between pts with TP53 wild-type (TP53 wt ) vs. TP53 mut LPL. The 3-year OS rate was 77% (95% CI: 64-93%) in TP53 wt vs. 52% (95% CI: 22-100%) in TP53 mut LPL (p = 0.08); the incidence of LPL-related deaths was 2/96 (TP53 wt ) and 2/11 (TP53 mut ). First-line chemo-immunotherapy (CIT) was used in 83 (78%) of pts, and BTKi-based regimens were used in 24 (22%) pts. The proportion of pts receiving first-line CIT or BTKi did not differ significantly between the TP53 wt and TP53 mut patient cohorts. When evaluating OS in pts grouped by TP53 mutation status and type of first-line treatment, pts with TP53 mut LPL who received first-line CIT trended towards having the worst outcomes (p = 0.087); those who received first-line BTKi had similar outcomes regardless of TP53 mutation status. Conclusions: We performed a systematic analysis of the impact of TP53 mutation status on survival outcomes after first-line treatment in LPL. Pts with TP53 mut had a trend towards worse survival outcomes. The worst survival outcomes were seen in those with TP53 mut who received first-line CIT. Our findings highlight the prognostic value of TP53 mutation testing in LPL and suggest preferential first-line use of BTKi over CIT in those with such mutations. These results require validation in larger cohorts with longer follow-up times.