Background:

Oral decitabine/cedazuridine (ASTX727) is a fixed dose combination of decitabine (35 mg) and the cytidine deaminase inhibitor cedazuridine (100 mg) given once daily X 5 days on a 28-day cycle producing pharmacokinetic (PK) exposure equivalent to the standard intravenous (IV) decitabine regimen of 20 mg/m 2 daily X 5 days on a 28-day cycle. This was demonstrated in the pivotal ASCERTAIN study (Garcia-Manero, et al, ASH 2019) as it provided a PK bridge to existing decitabine data and demonstrated median OS was 31.7 mo. (Savona,et al. Intl. MDSF International Congress on MDS, 2021). Subjects were initially classified by the International Prognosis Scoring System (IPSS) for historical reasons, however IPSS-R and IPSS-M are enhancements to IPSS that provide dynamic risk assessment for predicting clinical outcomes in MDS. Here, the objective was to re-classify the MDS subjects enrolled on the ASCERTAIN study by IPSS-R and IPSS-M and measure the impact of informing patient outcomes based on re-calculated risk assessment.

Methods:

One hundred thirty-three subjects with MDS/CMML (chronic myelomonocytic leukemia) were enrolled in 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 HSCT. 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 all genes commonly mutated in MDS. In the initial analysis of clinical outcomes, subjects were classified by IPSS with response assessment by IWG 2006 IPSS low and Int-1 risk levels were categorized as lower-risk MDS (LR-MDS), whereas IPSS Int-2 and high-risk categories were categorized as higher-risk MDS (HR-MDS). Subjects with sufficient data based on (e.g., available heme parameters, cytogenetics, NGS etc.) were reclassified by IPSS-R and IPSS-M. Subjects with IPSS-R score of ≤3.5 or IPSS-M of either very low, low, or moderate low were categorized as LR-MDS. Similarly subjects with IPSS-R score of >3.5 or an IPSS-M categorization of either moderate high, high, or very high were categorized as HR-MDS. Reclassified subjects were reassessed for CR (Complete Response), OS, and LFS and Harrell's concordance index (c-index) was used to describe the level of agreement between each scale and outcomes.

Results:

Based on the available data, the number of MDS subjects in the different risk classifications were the following: IPSS: 117, IPSS-R: 104, and IPSS-M: 105. Thirteen and 12 subjects on the IPSS could not be reclassified in the IPSS-R and IPSS-M, respectively, including 5 Int-1 and 2 low-risk MDS cases. CMML subjects were excluded from these analyses. Re-classification generally resulted in the upgrade of the subjects from LR-MDS to HR-MDS (Fig. 1). Thirty-one (26.5%) subjects from IPSS were reallocated in the IPSS-R to different risk categories; 3 (9.7%) were downgraded and 28 (90.3%) were upgraded. Similarly on reclassification with IPSS-M 34 (32.4%) of the patients reclassified; 5 (14.8%) were downgraded and 29 (85.3%) were upgraded. For IPSS LR-MDS, 23.2% of patients achieved CR, and 22.9% in the IPSS HR-MDS. Similarly, 21.6% patients achieved CR in the IPSS-R LR-MDS, and 23.9% in the IPSS-R HR-MDS; 26.3% patients achieved CR in the IPSS-M LR-MDS, and 20.9% in the IPSS-M HR-MDS. The c-index for the IPSS was .64 (OS) and .67 (LFS), IPSS-R was .70 (OS) and .71 (LFS), and .75 (OS) and .78 (LFS) for the IPSS-M (Table1).

Conclusion:

Reclassification from IPSS to IPSS-R or IPSS-M upgraded multiple subjects from a LR to a HR category, describing the ASCERTAIN patient population as a majority higher risk population with worse prognosis than previously assumed based on the IPSS. The efficacy as measured by the CR rates did not change when the LR and HR categories were defined by the different risk stratification systems. In contrast, the c-index improves with migration from IPSS to IPSS-R to IPSS-M, indicating an increased discriminatory ability of IPSS-M score in comparison to IPSS and IPSS-R, to predict patient outcomes.

Garcia-Manero:Genentech: Research Funding; Bristol Myers Squibb: Other: Medical writing support, Research Funding; AbbVie: Research Funding. McCloskey:BluPrint Oncology: Honoraria; Bristol-Myers Squibb/Pfizer: Consultancy, Honoraria, Speakers Bureau; Blueprint Medicines: Consultancy; Novartis: Consultancy; Amgen: Speakers Bureau; BluePrint Health: Speakers Bureau; Incyte: Speakers Bureau; Jazz Pharmaceuticals: Speakers Bureau; Stemline Therapeutics: Speakers Bureau; Takeda: Speakers Bureau. Griffiths:Bristol Myers Squibb: Consultancy, Research Funding; Abbvie: Consultancy; MDS International Foundation: Honoraria; Physicians Educational Resource: Honoraria; Apellis Pharmaceuticals: Consultancy, Research Funding; Blueprint Medicines, Inc: Research Funding; Taiho Oncology: Consultancy; Alexion Pharmaceuticals: Consultancy, Research Funding; S. Karger Publishing: Honoraria; Picnic Health: Membership on an entity's Board of Directors or advisory committees; AstraZeneca Rare Disease: Consultancy, Research Funding; Medscape: Honoraria; Vera and Joseph Dresner Foundation: Membership on an entity's Board of Directors or advisory committees; Takeda Oncology: Consultancy; AAMDSIF: Honoraria; CTI Biopharma: Consultancy; Celldex Therapeutics: Research Funding; MediCom Worldwide, Inc.: Honoraria; NextCure, Inc: Research Funding; Artis Ventures: Membership on an entity's Board of Directors or advisory committees; Partner Therapeutics: Consultancy; Genentech, Inc.: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Astex Pharmaceuticals: Research Funding; American Society of Hematology: Honoraria. Zeidan:Gilead: Consultancy, Honoraria; Kura: Consultancy, Honoraria; Chiesi: Consultancy, Honoraria; ALX Oncology: Consultancy, Honoraria; BioCryst: Consultancy, Honoraria; Notable: Consultancy, Honoraria; Orum: Consultancy, Honoraria; Mendus: Consultancy, Honoraria; Zentalis: Consultancy, Honoraria; Schrödinger: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Syndax: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Ionis: Consultancy, Honoraria; Regeneron: Consultancy, Honoraria; Tyme: Consultancy, Honoraria; Astex: Research Funding; Shattuck Labs: Research Funding; Foran: Consultancy, Research Funding; Syros: Consultancy, Honoraria; Lox Oncology: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; BeyondSpring: Consultancy, Honoraria; Otsuka: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Taiho: Consultancy, Honoraria; Geron: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Boehringer-Ingelheim: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Celgene/BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Yee:Astex Pharmaceuticals, Inc.: Research Funding; Taiho: Consultancy; Forma Therapeutics: Research Funding; Geron: Research Funding; Gilead: Research Funding; Janssen: Research Funding; Karyopharm: Research Funding; Treadwell: Research Funding; Astellas: Consultancy; Bristol-Myers Squibb/Celgene: Consultancy; F. HOffmann La Roche: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Jazz: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; Shattuck Labs: Consultancy; Takeda: Consultancy; AbbVie: Honoraria. Deeg:CSL Behring: Research Funding. Patel:Servier LLC: Current Employment. Sabloff: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; 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; 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. Zhu:Taiho Oncology: Consultancy; MDS Foundation: Consultancy. Odenike:BMS/Celgene, Novartis, Rigel, Servier, Taiho ; DSMB-Kymera therapeutics: Membership on an entity's Board of Directors or advisory committees; ABBVIE, Astrazeneca, Agios, Aprea, Astex, BMS/Celgene, CTI, Daiichi, Incyte, Janssen, Kartos, Novartis, NS-Pharma and Oncotherapy Sciences: Research Funding. DeZern:Novartis: Membership on an entity's Board of Directors or advisory committees; Geron: Membership on an entity's Board of Directors or advisory committees; Caribou: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; Appellis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sobi: Consultancy. O'Connell:Genentech: Other: Prior research support. Provision of drug for the study ; Astex Pharmaceuticals, Inc: Other: Prior research support. Provision of drug for the study . Roboz:Actinium: Consultancy; AbbVie: Consultancy; Agios: Consultancy; Amgen: Consultancy; Astellas: Consultancy; AZ: Consultancy; BMS: Consultancy; Blueprint: Consultancy; Bluebird bio: Consultancy; GSK: Consultancy; Janssen: Consultancy, Research Funding; Jasper: Consultancy; Jazz: Consultancy; MEI: Consultancy; Mesoblast: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Syndax: Consultancy; Takeda: Consultancy. Busque:Novartis: Honoraria; BMS: Honoraria; Taiho: Honoraria; Paladin: Honoraria. Buckstein:Abbvie: Honoraria; Taiho: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Leber:Gilead/KITE: Honoraria, Speakers Bureau; Roche: Honoraria, Speakers Bureau; Treadwell: Honoraria, Speakers Bureau; Otsuka: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Astex: Honoraria, Speakers Bureau; Astellas: Honoraria, Speakers Bureau; AMGEN: Honoraria, Speakers Bureau; Palladin Canada: Honoraria, Speakers Bureau; Jazz Canada: Honoraria, Speakers Bureau; Taiho Canada: Honoraria; Novartis Canada: Consultancy, Honoraria, Speakers Bureau; Janssen Canada: Honoraria, Speakers Bureau; Pfizer Canada: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb Canada: Honoraria, Speakers Bureau; Alexion Canada: Honoraria, Speakers Bureau; AbbVie Canada: Consultancy, Honoraria, Speakers Bureau. Lee:Astex Pharmaceuticals, Inc.: Current Employment. Chan:Astex Pharmaceuticals, Inc.: Current Employment. Souza:Astex Pharmaceuticals, Inc.: Current Employment. Sano:Astex Pharmaceuticals, Inc.: Current Employment. Keer:Astex Pharmaceuticals, Inc.: Current Employment. Savona:CTI BioPharma Corp.: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; AbbVie Inc.: Membership on an entity's Board of Directors or advisory committees; Forma Therapeutics Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Geron Corporation: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics Inc.: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Ryvu Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology, Inc.: Membership on an entity's Board of Directors or advisory committees; Taiho: Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceutical Company: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Patents & Royalties; ALX Oncology: Research Funding; Astex Pharmaceuticals: Research Funding; Incyte Corporation: Research Funding.

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2023
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