Oral Decitabine/Cedazuridine in Patients with MDS and TP53 Mutations: A Propensity Score Matching Analysis from the Phase II and III Trials

Patients with myelodysplastic syndrome harboring TP53 mutations have poor outcomes. Decitabine/cedazuridine has been suggested to have activity in TP53^mut MDS. This study evaluates decitabine/cedazuridine in TP53^mut MDS treated in the phase 2 and 3 studies that led to the FDA approval of these drugs. Using the WHO 2022 classification, we divided patients into three groups: TP53^wt, TP53^single-hit, and TP53^multi-hit. A total of 180 patients were analyzed of which 73 (40.5%) had TP53 mutations, 23 with TP53^multi-hit. Patients with TP53^multi-hit were enriched for complex cytogenetics (69.5%), and had fewer median number of co-mutations (2.5, IQR 2-3) compared to TP53^single-hit (3, IQR 1-5), or TP53^wt (4, IQR 3-6) (p=0.002). Complete response rates were similar between these groups, but patients with TP53^multi-hit had a relatively higher likelihood of lack of response with 39.1% vs 28%, and 27.1% for TP53^single-hit, and TP53^wt, respectively (p = 0.2). Patients with TP53^multi-hit also received fewer courses of therapy due to progression, 5 vs 7.5 for TP53^single-hit, and 9 for TP53^wt (p =0.016). Patients with TP53^mult-hit lost response earlier with 8.2 months, vs 13.2 months for TP53^single-hit, and 15.1 months for TP53^wt (p=0.1). Median overall survival (mOS) was 11.5 months (95% CI: 8.6 - 19.1) for TP53^mult-hit, 22.1 months (95% CI: 14.6 - 35.9) for TP53^single-hit, and 31.7 months (95% CI: 19.5 - 51.1) for TP53^wt MDS (log-rank, p < 0.005). With a median follow-up time of 21.5 months, at a landmark analysis of 4 months, hematopoietic stem cell transplantation (HSCT) did not result in improved survival. A propensity score matched 47 patients treated with decitabine/cedazuridine and TP53^mut were matched to 47 with MDS and TP53^mut treated with single agent IV hypomethylating agent (HMA) using age, ECOG performance status, IPSS-R scores, and TP53 VAF as matching features. Median overall survival was 13.1 months (95% CI: 8.4 - 21.3) for decitabine/cedazuridine vs 8.0 months (95% CI: 5.2 - 13.0) for single agent IV HMA (log-rank, p=0.047). In patients with MDS harboring TP53^mut, decitabine/cedazuridine may improve survival compared to conventional single-agent IV HMA.