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.

Sasaki:Pfizer: Consultancy; Chugai: Other: Lecture fees; Enliven: Research Funding; Novartis: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy; Otsuka: Other: Lecture fees. Kantarjian:AbbVie, Amgen, Ascentage, Ipsen Biopharmaceuticals, KAHR Medical, Novartis, Pfizer, Shenzhen Target Rx, Stemline,Takeda: Consultancy, Honoraria. Montalban-Bravo:Takeda: Research Funding; Rigel: Research Funding. McCloskey:Bristol-Myers Squibb/Pfizer: Consultancy; BluePrint Health: Speakers Bureau; Incyte: Speakers Bureau; Novartis: Consultancy; Blueprint Medicines: Consultancy; Stemline Therapeutics: Speakers Bureau; Amgen: Speakers Bureau; Jazz Pharmaceuticals: Speakers Bureau; Takeda: Speakers Bureau; BluPrint Oncology: Honoraria. Griffiths:MDS International Foundation: Honoraria; Physicians Educational Resource: Honoraria; Abbvie: Consultancy; Apellis Pharmaceuticals: Consultancy, Research Funding; CTI Biopharma: Consultancy; Novartis: Consultancy, Research Funding; Partner Therapeutics: Consultancy; Picnic Health: Consultancy; Servier: Consultancy; Blueprint Medicines: Research Funding; ASH: Honoraria; MJH Health: Honoraria; MediCom Worldwide: Honoraria; Alexion Pharmaceuticals/ AstraZeneca Rare Disease: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Celldex Pharmaceuticals: Research Funding; AAMDS: Honoraria; MedscapeLive: Honoraria; Takeda Oncology: Consultancy; Astex Pharmaceuticals/Taiho Oncology/Otsuka: Consultancy, Research Funding; Celgene/Bristol-Myers Squibb: Consultancy, Research Funding; NextCure: Research Funding. Yee:Astex: Other: research support; Forma Therapeutics: Other: research support; F. Hoffmann-La Roche: Other: research support; Genentech: Other: research support; Geron: Other: research support; Gilead Sciences: Other: research support; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: research support; Bristol Myers Squibb/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Taiho Pharma: Membership on an entity's Board of Directors or advisory committees; Taiho Pharma: Honoraria. Zeidan:Pfizer: Consultancy, Honoraria; Glycomimetics: Consultancy, Honoraria; Schroedinger: Consultancy, Honoraria; Faron: Consultancy, Honoraria; Geron: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria; Regeneron: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Zentalis: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Sumitomo: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Kura: Consultancy, Honoraria, Research Funding; Kyowa Kirin: Consultancy, Honoraria; Medus: Consultancy, Honoraria; Orum: Consultancy, Honoraria; Rigel: Consultancy, Honoraria; Astex: Research Funding; Notable: Consultancy, Honoraria; Vinerx: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Lava Therapeutics: Consultancy, Honoraria; Boehringer-Ingelheim: Consultancy, Honoraria; Agios: Consultancy, Honoraria; BioCryst: Consultancy, Honoraria; ALX Oncology: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Chiesi: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Research Funding; Treadwell: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Shattuck Labs: Research Funding; Karyopharm: Consultancy, Honoraria; Syros: Consultancy, Honoraria, Research Funding; Servier: Consultancy, Honoraria; Hikma: Consultancy, Honoraria; Keros: Consultancy, Honoraria; Taiho: Consultancy, Honoraria; Syndax: Consultancy, Honoraria; Akeso Pharma: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Savona:Astex Pharmaceuticals for travel grant.: Other: Financial or Material Support; ALX Oncology Inc.; Astex Pharmaceuticals; Incyte Corporation; and Takeda Pharmaceutical Company Limited.: Research Funding; Empath Biosciences; Karyopharm and Ryvu Therapeutics: Current holder of stock options in a privately-held company; AbbVie; Bristol Myers Squibb; CTI BioPharma Corp.; Geron; Karyopharm; Novartis Pharmaceuticals Corporation; Ryvu Therapeutics; and Sierra Oncology, Inc.: Consultancy. Oganesian:Taiho Oncology: Current Employment. Sano:Taiho Oncology: Current Employment. Keer:Taiho Oncology Inc: Current Employment. Garcia-Manero:Forty Seven: Research Funding; Merck: Research Funding; Helsinn: Other: Personal fees; Novartis: Research Funding; H3 Biomedicine: Research Funding; Janssen: Research Funding; Genentech: Research Funding; Bristol Myers Squibb: Other: Personal fees, Research Funding; AbbVie: Research Funding; Onconova: Research Funding; Aprea: Research Funding; Astex: Research Funding; Amphivena: Research Funding; Helsinn: Research Funding; Astex: Other: Personal fees; Curis: Research Funding; Genentech: Other: Personal fees.