Real-world clinical characteristics and outcomes of patients with myelodysplastic syndrome with TP53 mutation

Abstract Introduction: TP53 mutations (TP53m) are observed in ~10% of patients (pts) with myelodysplastic syndromes (MDS) and constitute a high-risk prognostic indicator. Pts with TP53m have poor outcomes and increased risk of acute myeloid leukemia (AML). Additional research is needed to better understand this patient population and define optimal treatment pathways. This study sought to provide critical evidence on the clinical characteristics and outcomes of a large population of pts with TP53m MDS treated in the real-world setting. Methods: This retrospective, observational study utilized the COTA real-world database derived from the electronic health records of partnered healthcare centers in the US. Eligible pts were diagnosed with MDS between 1/1/2015 to 12/31/2023 and tested for TP53m. Pts were excluded if they were missing key study dates. Index date was defined as the initiation of first line (1L) antineoplastic therapy (or date of diagnosis if comparing untreated pts). Patient characteristics and treatment patterns were summarized descriptively by TP53m status (TP53m vs. TP53 wild type (TP53wt)). The window used to identify TP53m was defined as any time prior to diagnosis until 30 days following index date. Time-to-event outcomes were evaluated using the Kaplan-Meier method, including real-world progression-free survival (rwPFS), real-world leukemia-free survival (rwLFS), and real-world overall survival (rwOS). Real-world overall response rate (rwORR) to 1L therapy and rate of progression to AML were calculated as the proportion of pts experiencing the event. Results: A total of 1,192 MDS pts were identified to meet the study criteria including test results for TP53m at study initiation. Of these, 193 (16.2%) were TP53m, and 999 (83.8%) were TP53wt. Among TP53m MDS, median age at diagnosis was 73 years, and pts were predominantly male (63.7%), White (72.0%), and treated in the community setting (51.3%). Median follow up time (reverse KM) from diagnosis was 57.7 months (mos) (95% CI: 43.5, 82.6). Demographic characteristics were generally similar between TP53m and TP53wt. Pts with TP53m were more likely to have documented complex karyotype (40.9% vs. 1.7%) and del(7q) (31.6% vs. 4.1%), as well as high (26.9% vs. 14.8%) or very high (37.8% vs. 6.1%) IPSS-R score. The most common co-occurring mutations included TET2 (11.4%), U2AF1 (7.8%), and ASXL1 (6.2%). Compared to TP53wt, a greater proportion of pts with TP53m initiated 1L (79.3% vs. 46.4%) and 2L (28.0% vs. 14.8%) treatment with antineoplastic therapy. Additionally, pts with TP53m had a shorter time to 1L therapy initiation (0.9 mos (IQR: 0.6, 1.8)) compared to TP53wt (2.0 mos (IQR: 0.9, 7.8)). Among the pts treated with 1L therapy, pts with TP53m were more likely to receive 1L therapy containing venetoclax (13.1% vs. 3.2%) or 1L allogeneic stem cell transplant (SCT) (9.8% vs. 5.0%). rwORR to 1L therapy was similar between TP53m (29.4% (95% CI: 22.2%, 36.6%)) and TP53wt (29.5% (95% CI: 25.4%, 33.7%)). However, long-term outcomes were significantly worse for treated pts with TP53m as compared to TP53wt (median (95% CI)): rwPFS: 6.9 mos (5.9, 8.7) vs. 14.3 mos (12.8, 16.0); rwLFS: 9.9 mos (7.8, 12.1) vs. 23.4 mos (20.3, 27.4); rwOS: 11.8 mos (9.8, 13.9) vs. 28.2 (25.0, 31.9). Within treated TP53m MDS, 1L SCT conferred a survival benefit (14.2 mos (95% CI: 8.0, not reached) vs. 11.8 mos (95% CI: 9.5, 13.4)), but treatment with 1L venetoclax was associated with shorter median rwOS (5.7 mos (95% CI: 3.8, not reached) vs. 12.3 mos (95% CI: 9.8, 14.7)). Within TP53m MDS regardless of treatment, median rwOS was 13.8 mos (95% CI: 11.2, 15.2). Co-occurring mutations associated with better rwOS in TP53m MDS regardless of treatment included ASXL1 (31.6 vs. 14.2 mos), SF3B1 (24.9 vs. 13.8 mos), and U2AF1 (17.3 vs. 13.8 mos). Contrarily, documented co-occurring complex karyotype was associated with worse rwOS as compared to normal karyotype (9.6 vs 31.9 mos). Additionally, pts with TP53m were nearly twice as likely to progress to AML (22.3% vs. 11.9%). Conclusions: To our knowledge, this is one of the largest US-based real-world studies investigating pts with MDS harboring TP53m. Our study found that pts with TP53m had significantly inferior long-term outcomes as compared to pts with TP53wt. 1L SCT was the only treatment associated with improved rwOS. Future research is needed to further investigate optimal treatment approaches to address the high unmet need.