Background: The prognosis of patients (pts) with myelodysplastic syndrome (MDS) varies based on risk stratification and response to therapy. However, no validated surrogate endpoint has been used to predict outcomes in this population. This study aims to analyze the impact of complete cytogenetic response (CCyR) on leukemia-free survival (LFS) and overall survival (OS) in MDS pts.

Methods: We conducted a retrospective study including pts with MDS and abnormal cytogenetic abnormalities who were treated at our institution between 2002 and 2023. Pts with isolated minus Y were excluded. Pts were treated at front-line hypomethylating agents (HMAs) with or without a second drug. The response was assessed using the revised IWG criteria (Blood, 2023), and CCyR was defined as a diploid karyotype in at least 10 metaphases by conventional cytogenetics without any other cytogenetic abnormalities before allogenic stem cell transplant (allo-SCT). Pts were categorized into four groups based on their response and cytogenetic analysis: CCyR (with a complete or incomplete count recovery), complete response without CCyR (CR), CR with limited count recovery/CR with partial hematologic recovery (CRL/CRh), and non-CR.

Results: A total of 1153 MDS pts were included with a median follow-up of 59 months (range, 0.03-240.7). The median age at the time of evaluation was 69 years (range, 18-94), 45% pts were classified as RAEB-1 or RAEB-2, and 68% had either high or very-high risk MDS. 203 pts (18%) achieved a CCyR in a median time of 4.3 months (range, 0.16-111.9) with 33% experiencing the suboptimal hematologic recovery. 124 pts (11%) achieved CR, 207 (18%) achieved CRL/CRh and 619 (54%) achieved non-CR. 261 pts (23%) underwent allo-SCT. Older age (odds ratio [OR] 0.979, 95% confidence interval [CI], 0.968-0.991, p=0.001) was associated with lower CCyR rates, while MDS-biTP53 subtype was associated with higher CCyR rates (OR 1.920, 95% CI, 1.201-3.069, p=0.006).

With censoring at the time of allo-SCT, the 5-year LFS was 12%, 10%, 18%, and 24% in the non-CR, CRL/CRh, CR, and CCyR group, respectively (p<0.001), and the 5-year crude survival rates were 13%, 10%, 21%, and 27% in the non-CR, CRL/CRh, CR, and CCyR group, respectively (p<0.001). Using a 4-month landmark multivariate analysis for OS, higher hemoglobin (HR 0.812, 95% CI, 0.775-0.851, p<0.001), higher platelet count (HR 0.998, 95% CI, 0.997-0.998, p<0.001), response (CR: HR 0.755, 95% CI, 0.591-0.966, p=0.025; CCyR: HR 0.482, 95% CI, 0.393-0.590, p<0.001), and allo-SCT (HR 0.738, 95% CI, 0.592-0.921, p=0.007) were associated with favorable OS. On the other hand, older age (HR 1.016, 95% CI, 1.009-1.023, p<0.001), therapy-related status (HR 1.265, 95% CI, 1.069-1.498, p=0.006), higher percentage of blasts in peripheral blood (HR 1.039, 95% CI, 1.008-1.071, p=0.013), MDS subtype (MDS-EB1: HR 1.483, 95% CI, 1.158-1.785, p=0.001; MDS-EB2: HR 1.658, 95% CI, 1.300-2.114, p<0.001; CMML and MDS/MNP: HR 1.433, 95% CI, 1.048-1.960, p=0.024), and cytogenetic risk by the revised International Prognostic Scoring System (IPSS-R) (poor: HR 1.385, 95% CI, 1.006-1.907, p=0.046; and very poor: HR 1.825, 95% CI, 1.379-2.415, p<0.001) were associated with worse OS.

In a subgroup analysis based on IPSS-R risk stratification, the 5-year OS with censoring allo-SCT was 41%, 27%, 44%, and 69% in the non-CR, CRL/CRh, CR, and CCyR groups, respectively (p=0.033) among lower-risk MDS pts. Among higher-risk MDS pts, the 5-year OS was 7%, 4%, 17%, and 18% in the non-CR, CRL/CRh, CR, and CCyR groups, respectively (p<0.001).

Conclusion: The achievement ofCCyR in pts with MDS and abnormal karyotype improves LFS and OS. CCyR can be used as a valid surrogate endpoint for long-term outcomes in MDS and abnormal cytogenetic abnormalities.

Disclosures

Kantarjian:AbbVie, Amgen, Ascentage, Ipsen Biopharmaceuticals, KAHR Medical, Novartis, Pfizer, Shenzhen Target Rx, Stemline,Takeda: Consultancy, Honoraria. Jabbour:AbbVie, Adaptive Biotechnologies, Amgen, Astellas Pharma, BMS, Genentech, Incyte, Pfizer, Takeda: Consultancy; AbbVie, Adaptive Biotechnologies, Amgen, Ascentage Pharma Group, Pfizer, Takeda: Research Funding. Chien:AbbVie: Consultancy; Rigel Pharmaceuticals: Consultancy. Montalban-Bravo:Takeda: Research Funding; Rigel: Research Funding. Short:Novartis: Honoraria; Amgen: Honoraria; Adaptive Biotechnologies: Honoraria; Xencor: Research Funding; Autolus: Honoraria; BeiGene: Honoraria; Sanofi: Honoraria; Stemline Therapeutics: Research Funding; GSK: Consultancy, Research Funding; Takeda Oncology: Honoraria, Research Funding; Astellas Pharma, Inc.: Honoraria, Research Funding; Pfizer Inc.: Honoraria; NextCure: Research Funding. Daver:FATE Therapeutics: Other: Consulting Fees, Research Funding; Celgene: Consultancy; Genentech: Consultancy, Research Funding; Jazz: Consultancy; Astellas: Consultancy, Research Funding; Servier: Consultancy, Research Funding; Novartis: Consultancy; Pfizer: Consultancy, Research Funding; Agios: Consultancy; Hanmi: Research Funding; Novimmune: Research Funding; Syndax: Consultancy; Gilead: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Arog: Consultancy; Trovagene: Research Funding; Menarini Group: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Shattuck Labs: Consultancy; KITE: Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Glycomimetics: Research Funding. Borthakur:Catamaran Bio, AbbVie, PPD Development, Protagonist Therapeutics, Janssen: Consultancy; Pacylex, Novartis, Cytomx, Bio Ascend: Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals, Ryvu, PTC Therapeutics: Research Funding. Kadia:Genentech: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Sellas: Consultancy, Research Funding; JAZZ: Research Funding; Novartis: Honoraria; Abbvie: Consultancy, Research Funding; AstraZeneca: Research Funding; ASTEX: Research Funding; Ascentage: Research Funding; Cellenkos: Research Funding; Incyte: Research Funding; Rigel: Honoraria; Amgen: Research Funding; Regeneron: Research Funding; DrenBio: Consultancy, Research Funding; Pfizer: Research Funding; Servier: Consultancy. Wierda:Numab Therapeutics: Research Funding; Novartis: Research Funding; Oncternal Therapeutics: Research Funding; GSK: Research Funding; Kite: Research Funding; Oncternal Therapeutics: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Acerta Pharma: Research Funding; F. Hoffmann-La Roche Ltd.: Research Funding; Juno Therapeutics: Research Funding; Loxo Oncology: Research Funding; Gilead Sciences: Research Funding; Cyclacel Pharmaceuticals Inc: Research Funding; Janssen: Research Funding; Nurix Therapeutics: Research Funding; BMS: Research Funding; Eli Lilly: Research Funding; AstraZeneca: Research Funding; Genentech, Inc.: Research Funding; AbbVie: Research Funding; Accutar Biotechnology: Research Funding; National Comprehensive Care Center (NCCN): Other: Financial relationship (Chair, CLL). Garcia-Manero:Novartis: Research Funding; Helsinn: Research Funding; Janssen: Research Funding; Merck: Research Funding; Genentech: Other: Personal fees; Astex: Other: Personal fees; Forty Seven: Research Funding; Helsinn: Other: Personal fees; Genentech: Research Funding; Bristol Myers Squibb: Other: Personal fees, Research Funding; Aprea: Research Funding; Curis: Research Funding; AbbVie: Research Funding; H3 Biomedicine: Research Funding; Onconova: Research Funding; Amphivena: Research Funding; Astex: Research Funding. Sasaki:Novartis: Consultancy, Research Funding; Enliven: Research Funding; Daiichi-Sankyo: Consultancy; Chugai: Other: Lecture fees; Pfizer: Consultancy; Otsuka: Other: Lecture fees.

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2024
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