Trends in overall survival in MDS from 2000–2022: Have therapeutic advances made a difference?

Abstract Introduction Myelodysplastic Syndrome (MDS) is a neoplastic clonal disorder of the hematopoietic stem cells, leading to dysplasia and ineffective hematopoiesis, with a high risk of transformation to acute myeloid leukemia. It has a variety of phenotypes and genotypes and clinically manifests as cytopenias such as anemia, leukopenia, or thrombocytopenia. Over time, treatment for MDS has evolved from supportive care to hypomethylators (azacitidine, decitabine, decitabine/cedazuridine), followed by newer agents such as luspatercept. Hypomethylators have been the first-line treatment since 2004, until 2019, when newer erythroid maturation agents such as luspatercept were added to the treatment regimen. We conducted a retrospective population-based observational study to assess temporal trends in overall survival of MDS over the last 22 years and also evaluated the impact of race and chemotherapy on outcomes. Methods We extracted 50,602 cases of MDS from the SEER Plus Research Database (ICD-O-3 code 9989/3), November 2024 Submission (2000-2022). Patients were grouped by diagnosis year into three eras: pre-HMA (2000-2004), HMA era (2005-2018), and post-HMA/luspatercept era (2019-2022). They were also grouped by race and by whether they received chemotherapy. Survival analysis was performed using Kaplan-Meier methods, and differences between groups were assessed using the log-rank test (GraphPad Prism). Median overall survival (MoS) was calculated in months. Results A total of 50,602 patients with MDS were identified in the SEER database between 2000 and 2022, with 6,158 diagnosed in 2000-2004 (pre-HMA era), 35,451 in 2005-2018 (HMA era), and 8,993 in 2019-2022 (luspatercept/oral HMA era). Median overall survival for 2000-2004 group was 30, for 2005-2018 was 28 and 2019-2022 was 25 (p<0.0001).Comparing survival amongst different races during these time periods, during 2000-2004, survival for whites was 29, black 38, hispanic 31, asian 31, alaskan 39(p<0.0001), in 2005- 2018 survival for whites was 27, black 39, hispanics 30, asian 30, alaskan 36(p<0.0001), between 2019-2022 survival for whites was 24, black 31, hispanics 23, asian 24, alaskan 34(p<0.0001).While comparing patients with chemo vs no chemo, survival in the 2000-2004 group was 26 vs 30 (p<0.009), survival in the 2005-2018 group was 20 vs 31(p<0.0001), survival in the 2019-2022 group was 19 vs 28 (p<0.0001). Conclusion Despite the introduction of hypomethylating agents and more recent therapies such as luspatercept and oral HMAs, median overall survival in MDS has steadily declined over the past two decades, from 30 months (2000-2004) to 28 months (2005-2018) and 25 months (2019-2022) (p<0.0001). This trend reflects a more aggressive disease over the years from worsening (high grade) mutations, greater recognition of high risk MDS/ therapy related MDS or declining lead time bias leading to more accurate survival. Notably, patients receiving chemotherapy consistently had worsening survival compared to not receiving chemo, likely due to patients with advanced disease receiving chemotherapy (leading to a possible lower overall survival in that cohort of patients). Racial disparities in survival persisted across all eras, with Black patients demonstrating the longest median survival, and White patients the shortest. However, all racial groups experienced a decline in survival over time.The decline in survival despite therapeutic evolution identifies an urgent need to revisit our current treatment approaches in MDS. The effectiveness of hypomethylating agents and newer agents like luspatercept appears limited, particularly among higher-risk patients. Future efforts should focus on refining risk stratification, identifying gender specific risk factors and clinical approach, expanding access to clinical trials, and exploring treatment options such as novel targets for antibodies or T cell modulation therapies to ensure improved survival in near future.