Type: Oral
Session: 637. Myelodysplastic Syndromes – Clinical and Epidemiological I
Hematology Disease Topics & Pathways:
Research, clinical trials, MDS, adult, Clinical Research, Chronic Myeloid Malignancies, CMML, Diseases, Myeloid Malignancies, Study Population, Human
Methods: 133 subjects with MDS/CMML were enrolled to ASCERTAIN and were randomly assigned either IV decitabine for cycle 1 and oral decitabine/cedazuridine for cycle 2 or the opposite treatment sequence. All subjects continuing beyond cycle 2 received oral decitabine/cedazuridine for all subsequent cycles until treatment discontinuation for disease progression, toxicity, patient’s decision, or hematopoietic stem cell transplantation. Whole blood collected prior to treatment was used for DNA isolation and molecular abnormalities identified using next generation sequencing (NGS) hematologic malignancy panel of 179 genes including 30 genes from the NCCN MDS panel.
Results: Of the 133 treated subjects, NGS analysis was available for 125 subjects. The percentage of subjects with mutations in the following genes were: TET2 (36.8%), TP53 (35.2%), ASXL1 (28%), DNMT3A (25.6%), SRSF2_MFSD11 (17.6%), SF3B1 (15.2%), STAG2 (12.8%), EZH2 (11.2%), RUNX1 (11.2%), U2AF1 (10.4%), BCOR (10.4%), CBL (8.8%). TP53, EZH2, RUNX1, CBL, DNMT3A, SF3B1, and ASXL1 were selected for further analysis based on their reported negative impact on OS and leukemia-free survival (LFS). TP53 and CBL mutations were closely associated with a worse OS (Hazard Ratio[HR] and 95% CI: 1.70 (1.00, 2.87) and 2.54 (1.19, 5.43), respectively) and LFS (HR and 95% CI: 1.63 (0.98, 2.72) and 2.01 (0.95, 4.26), respectively) compared with WT gene status, while subjects with DNMT3A mutation showed a trending advantageous relationship with OS and LFS over WT gene status. The TP53mut population (N=44) was characterized by median age 70.5 years, 63.6% M: 36.4% F, 91% MDS: 9% CMML, IPSS categories: 20% HR, 30% Int-2, 39% Int-1, 2% LR, 9% N/A, Cytogenetics: 27% Better-risk, 18% Intermediate risk, 48% Poor risk, 5% N/A, ECOG 0: 39%, 1: 61%, MA 68%, BA/multi-hit 32%. The median OS and LFS of the TP53mut population were 25.5 and 22.1 mo., respectively, compared to the TP53 WT group with mOS and LFS estimates 33.7 and 31.7 months, respectively (Figure 1). The TP53mut population was further characterized by allelic status and found to have 14 subjects with BA mutations and 30 subjects with MA TP53 mutations without other chromosomal deletions. The respective estimated mOS and 95% CI in the BA vs MA were 13.0 (5.3, 29.1) months vs. 29.2 (19.8, NE) mo. (Figure 2).
Conclusion: The NGS mutational profile of MDS and CMML subjects in the ASCERTAIN trial included 35% with TP53mut and this group had a worse survival than those with WT TP53 apparently driven by the poor outcome of those with BA TP53mut. Further LOH studies will help refine this analysis, but in this conservative estimate, treatment with oral decitabine/cedazuridine in the ASCERTAIN study resulted in an estimated survival of 13 months for BA TP53mut which compares favorably with historical results.
Disclosures: Savona: Taiho Pharmaceutical: Consultancy; Geron: Consultancy; ALX Oncology: Research Funding; Takeda: Consultancy; Sierra Oncology: Consultancy, Other: travel expenses; Novartis: Consultancy; Astex Pharmaceuticals: Research Funding; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: travel expenses; AbbVie: Consultancy, Other: travel expenses; Incyte Corporation: Research Funding; Ryvu Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Other: Travel expenses, Research Funding; Forma: Consultancy; Karyopharm Therapeutics: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. McCloskey: Pfizer: Consultancy; Blueprint Medicine: Speakers Bureau; COtA: Current equity holder in publicly-traded company; Takeda: Consultancy, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Novartis: Consultancy; Jazz: Consultancy, Speakers Bureau; Incyte: Speakers Bureau. Griffiths: Astex Pharmaceuticals: Research Funding; BMS/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Blueprint Medicines: Research Funding; Celldex Therapeutics: Research Funding; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Medicom Worldwide: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Physician Educational Resource: Honoraria; Picnic Health: Honoraria; Takeda Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Apellis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; AAMDSIF: Honoraria. Yee: Janssen: Research Funding; Astex: Research Funding; Forma Therapeutics: Research Funding; Karyopharm: Research Funding; Treadwell: Research Funding; Gilead: Research Funding; Geron: Research Funding; TaiHo: Consultancy; Shattuck Labs: Consultancy; Abbvie: Honoraria; Pfizer: Consultancy; Jazz: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Takeda: Consultancy; GlaxoSmithKline: Consultancy; F. Hoffmann La Roche: Consultancy, Research Funding; Bristol-Myers Squibb/Celgene: Consultancy; Astellas: Consultancy. Zeidan: BMS, AbbVie, Takeda, Novartis, Aprea, Amgen, Otsuka, Gilead, Kura, Loxo Oncology, Geron, Mendus, Tyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Al-Kali: Astex: Other: research support to institution. Patel: Agios: Membership on an entity's Board of Directors or advisory committees. Sabloff: Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Actinium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Taiho Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees. Dao: Astex Pharmaceuticals, Inc.: Current Employment. Odenike: Abbvie; Impact Biomedicines; Celgene; Novartis; BMS; Taiho Pharmaceutical; CTI; Threadwell therapeutics; Bristol-Myers Squibb/Celgene (Inst): Consultancy; Celgene (Inst); Incyte (Inst); Astex Pharmaceuticals (Inst); NS Pharma (Inst); Abbvie (Inst); Janssen Oncology (Inst); OncoTherapy Science (Inst); Agios (Inst); AstraZeneca (Inst); CTI BioPharma Corp (Inst); Kartos Therapeutics (Inst); Aprea AB (Inst): Research Funding. Kantarjian: Pfizer: Honoraria, Research Funding; Takeda: Honoraria; Novartis: Honoraria, Research Funding; NOVA Research: Honoraria; Jazz Pharmaceuticals: Research Funding; KAHR Medical Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ipsen Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; ImmunoGen: Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Astellas Health: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ascentage: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding. DeZern: Novartis: Consultancy, Honoraria; GERON: Other: DSMB; CTI BioPharma: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Syntrix Pharmaceuticals: Research Funding. Roboz: Clovis Oncology: Other: Travel and accommodation expenses; Amgen: Consultancy, Other: travel; Daiichi Sankyo: Consultancy; Takeda: Consultancy; Genentech/Roche: Consultancy, Other: Travel and accommodation expenses; Karyopharm Therapeutics: Research Funding; Bayer: Consultancy, Other: Travel and accommodation expenses; Sunesis Pharmaceuticals: Other: Travel and accommodation expenses, Research Funding; Astex Pharmaceuticals: Consultancy, Other: Travel and Accommodation expenses, Research Funding; Novartis: Consultancy, Other: Travel and accommodation expenses, Research Funding; Jazz: Consultancy, Other: travel; Sandoz: Consultancy, Other: Travel and accommodation expenses; Mesoblast: Consultancy; Celltrion: Consultancy, Other: Travel and accommodation expenses; Otsuka: Consultancy; Eisai: Other: Travel and accommodation expenses; Jasper Therapeutics: Consultancy; CTI: Research Funding; Amphivena Therapeutics: Other: Travel and accommodation expenses, Research Funding; Helsinn Therapeutics: Consultancy; Roche: Consultancy; MEI Pharma: Consultancy, Research Funding; MedImmune: Consultancy, Research Funding; Mofitt Cancer Center: Research Funding; Bristol Myers Squibb: Consultancy; Array BioPharma: Other: Travel and accommodation expenses; Pfizer: Consultancy, Honoraria, Other: Travel and accommodation expenses; Janssen: Consultancy, Other: travel and accommodation expenses, Research Funding; GlaxoSmithKline: Consultancy; Celgene: Consultancy, Other: travel and accommodation expenses, Research Funding; Bristol Myers Squibb: Consultancy; Astellas: Consultancy; Amgen: Consultancy; Agios: Consultancy, Research Funding; AbbVie: Consultancy, Other: travel and accommodations, Research Funding; Actinium: Consultancy; Agios: Other: travel, Research Funding; Onconova Therapeutics: Research Funding; Tensha Therapeutics: Research Funding. Busque: Novartis: Consultancy. Buckstein: Taiho: Honoraria, Research Funding; Takeda: Research Funding; BMS: Honoraria, Research Funding. Leber: Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AMGEN: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Oganesian: Astex Pharmaceuticals, Inc.: Current Employment. Chan: Astex Pharmaceuticals, Inc.: Current Employment. Hao: Astex Pharmaceuticals, Inc.: Consultancy, Ended employment in the past 24 months. Azab: Astex Pharmaceuticals, Inc.: Consultancy, Ended employment in the past 24 months. Garcia-Manero: Curis: Honoraria, Research Funding; Gilead Sciences: Research Funding; Acceleron Pharma: Consultancy; Aprea: Honoraria; Genentech: Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Astex: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.
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