Introduction: Myelodysplastic syndrome (MDS) is a complex and heterogeneous malignancy characterized by bone marrow failure, cytopenia and risk of acute myeloid leukemia (AML). The current standard of care for patients requiring disease-modifying therapy is limited to hypomethylating agents (HMAs), lenalidomide or allogeneic stem cell transplant (SCT). There is limited evidence regarding the real-world treatment patterns and resulting outcomes for patients who experience disease progression and require later lines of therapy (LOTs). Our study sought to characterize a large population of patients with MDS treated in the real-world setting.

Methods: This retrospective, observational study utilized the COTA real-world database, derived from electronic health records (EHR) of partnered healthcare centers in the US. Eligible patients were diagnosed with MDS between 1/1/2015 to 12/31/2023 and received first-line (1L) treatment. Patients were excluded if they were missing key study dates. Index date was defined as initiation of 1L antineoplastic therapy. Patient characteristics and treatment patterns were summarized descriptively by LOT. Revised International Prognostic Scoring System (IPSS-R) score was abstracted from the clinical documentation and, if unavailable, derived using relevant data. Real-world progression-free survival (rwPFS) and overall survival (rwOS) were evaluated using the Kaplan-Meier method. COTA's mortality variable includes dates of death from the EHR and is supplemented with third-party data. The resulting composite variable has been validated in prior publications. Real-world overall response rate (rwORR) and rate of progression to AML were calculated as the proportion of patients experiencing the event.

Results: A total of 1,429 patients were identified to meet the study criteria. Median age at diagnosis was 73 years, and patients were predominantly male (61.0%), White (74.4%), and treated in the community setting (69.1%). Median follow up time (reverse KM) from diagnosis was 54.1 months (mos) (95% CI: 49.5, 59.1). About one quarter (23.2%) of patients had an IPSS-R score of low or very low at diagnosis, and 21.9% and 36.8% had intermediate and high/very high scores, respectively. The most common cytogenetic abnormalities were del5q (23.2%), trisomy 8 (13.2%), and del20q (9.2%). The most common molecular abnormalities were TP53 (10.7%), TET2 (10.0%), and ASXL1 (9.7%).

Of the 1,429 patients who received 1L, 446 (31.2%) went on to receive 2L, of which 107 (24.0%) went on to receive 3L, and 21 (19.6%) received 4L+. HMA therapy was the most common 1L treatment (79% of patients), and 54 (3.8%) patients received an allogeneic stem cell transplant in 1L. Use of 1L venetoclax increased in accordance with increasing IPSS-R scores (very low: 0%, very high: 10.1%). Patients with lower IPSS-R scores experienced longer time to 1L initiation compared to patients with higher IPSS-R scores (very low: 6.2 mos, very high: 0.9 mos). The proportion of patients receiving 2 or more LOTs was similar across IPSS-R categories (very low: 30.4%, very high: 30.8%).

rwORR to 1L therapy was 31.1% (95% CI: 28.7%, 33.5%) and was similar for 2L treatment (30.9% (95% CI: 26.7%, 35.2%); however, rwORR dropped substantially for 3L (19.6% (95% CI: 12.1%, 27.2%)) and 4L+ treatment (14.3% (95% CI: 0%, 29.3%). Patients with higher IPSS-R score and those who received later LOTs experienced worse outcomes: rwPFS (IPPS-R very low: 21.0 vs. very high: 6.8 mos, 1L: 12.5 vs. 4L+: 7.2 mos), rwOS (IPPS-R very low: 54.9 vs. very high: 11.1 mos, 1L: 22.9 vs. 4L+: 10.8 mos). Among patients who initiated 1L treatment, the rate of progression to AML was 21.5% (95% CI: 19.4%, 23.6%). The rate of progression to AML was similar in patients requiring later LOTs (20.9% for 2L, 24.3% for 3L, and 23.8% for 4L). The rate of progression to AML increased with increasing IPSS-R score (very low: 8.9%, very high 29.3%).

Conclusions: In a large population of patients with MDS treated in the real-world setting, our study provides critical insights on the treatment patterns and outcomes of patients with MDS. These findings underscore poor outcomes for patients who are high risk at diagnosis and those who exhaust early treatment approaches. More importantly, our findings demonstrate the need for new therapeutic approaches for this group of patients.

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2025
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