Oral decitabine-cedazuridine versus parenteral hypomethylating agents in treatment-Naïve TP53-mutated Myelodysplastic Syndromes

Abstract Introduction TP53-mutated myelodysplastic syndrome (mTP53-MDS) is characterized by genomic instability, resistance to standard therapies, and poor overall survival (OS). Decitabine-cedazuridine (Dec-C), an oral fixed-dose combination of a hypomethylating agent (HMA) and a cytidine deaminase inhibitor, offers greater convenience for patients (pts) over parenteral HMA (pHMA). Recent analyses from clinical trials (Savona et al., ASH 2022; Urrutia et al., ASH 2024) suggest improved OS with Dec-C in mTP53-MDS compared to historical cohorts treated with pHMA. We conducted a real-world study comparing clinical outcomes of Dec-C vs. pHMA in pts with mTP53-MDS. Methods Adults with mTP53-MDS treated at Vanderbilt University Medical Center were evaluated. Pts were grouped by initial therapy: Dec-C or pHMA (azacitidine or decitabine). Clinical, pathologic, cytogenetic, and molecular data were extracted from electronic medical records. Responses were assessed according to IWG 2023 criteria. Overall response rate (ORR) included complete remission (CR), CR with partial hematologic recovery (CRh), CR with limited count recovery (CRL), partial remission (PR), and hematologic improvement (HI). Results Seventy-six pts were included (Dec-C, n=25; pHMA, n=51). Overall, median age was 68 years (range, 27–90); 55% were male, 95% White, and 29% had ECOG performance status ≥2. Venetoclax was used with HMA in 22 pts (Dec-C, n=4; pHMA, n=18), and those pts were excluded from further analyses. In the HMA monotherapy cohort (n=54; Dec-C, n=21), baseline clinical characteristics were generally comparable between Dec-C and pHMA groups. Median time from diagnosis to treatment was 38 days for Dec-C vs. 24 days for pHMA (p=0.05). MDS with biallelic TP53 inactivation (biTP53) was the most common WHO 2022 subtype (Dec-C vs. pHMA: 67% vs. 55%; p=0.37). Median baseline bone marrow blast counts were comparable between cohorts (Dec-C vs. pHMA: 3% vs. 5%; p=0.19). No significant differences were observed in TP53 mutation number, frequency of complex karyotype, or IPSS-R/M risk distribution between treatment groups. Dec-C pts had a significantly higher median TP53 variant allele frequency at baseline (45% vs. 23.5%, p=0.013). Median number of HMA cycles received was 4 (1-26) in the Dec-C group vs. 3 (1-14) in the pHMA group (p=0.05). Among response-evaluable pts (n=34), ORR and composite CR (CR + CRh+ CRL) rates were comparable between Dec-C and pHMA groups (60% vs. 53%, p=0.42; and 33% vs. 42%, p=0.97, respectively). Pts achieved best response after a median of 3 cycles of HMA therapy, with no significant difference between groups. However, fewer Dec-C pts achieved RBC transfusion independence at best response (13% vs. 65%, p=0.003). The Dec-C group experienced significantly fewer febrile neutropenia events during the first two cycles compared to pHMA (17% vs. 55%, p=0.009). Transformation to acute myeloid leukemia occurred in 16 pts (33%), including 7 pts in the Dec-C group. In our cohort, 15 pts (Dec-C, n=5) underwent allogeneic stem cell transplant (allo-SCT). Overall, we observed a trend toward improved median OS (mOS) with Dec-C vs. pHMA (13.7 vs. 10.5 months, p=0.05). Among non-transplanted pts (n=39), mOS was significantly longer with Dec-C (12.9 vs. 7.8 months, p=0.01). Among allo-SCT recipients, mOS was not reached with Dec-C vs. 16.8 months with pHMA (p=0.16). Finally, mOS trended longer with Dec-C in both biTP53 (n=32; 12.9 vs. 9.4 months, p=0.31) and monoallelic TP53 mutation cohorts (not reached vs. 10.7 months; p=0.10), though differences were not statistically significant. In a multivariable Cox regression model (including ECOG-PS, blast count category, composite CR status, allo-SCT, and Dec-C use), allo-SCT was the only independent predictor of improved OS (HR = 0.23, 95% CI: 0.08–0.63; p = 0.004), whereas frontline Dec-C use showed a trend toward improved OS (HR = 0.49, 95% CI: 0.23–1.03; p = 0.06). Conclusions In this single-center study of patients with mTP53-MDS, Dec-C demonstrated comparable response rates and an acceptable safety profile compared to pHMA, with a trend toward improved OS across different clinical and molecular subgroups. The lower incidence of febrile neutropenia with Dec-C may reflect variability in initial dosing schedules. Although limited by small sample size and retrospective design, these real-world findings can inform clinical use of Dec-C as a potentially effective frontline option for patients with mTP53-MDS.