Association between Targeted Therapy and Survival in Patients with MDS
Authors: Russo Pierantonio , Nathan Ramaa , Pfeffer Daniel , Moore Alex 
Published: December 2024

Introduction
Traditional therapies have shown limited effectiveness, in high risk patients with Myelodysplastic Syndromes (MDS). However, targeted therapy, even without achieving complete remission (CR), prolongs survival in high-risk MDS patients. This real-world study examines survival in MDS patients with targetable mutations on targeted and non-targeted therapies.
Methods
We analyzed genomic test data (July 2018 to December 2023), sourced from a leading genomics data provider and linked with Symphony administrative claims data. We identified the patients undergoing genetic biomarker tests, (panel vs. single gene), turnaround time (TAT) from test order to result, and test results.
A cohort of 3,617 MDS patients with at least 6 months of pre-diagnosis claims history and positive test results for IDH1, IDH2, SF3B1, or TP53 mutations were identified. Targeted therapy was recorded if patients had claims for ivosidenib (IDH1), enasidenib (IDH2), luspatercept (SF3B1), or cedaxuridine (TP53) in the Symphony administrative claims data. Confounding factors included age at diagnosis, sex, baseline Elixhauser Comorbidity Index (ECI), TAT, and multiple positive mutation results. Mortality was tracked from MDS diagnosis over a 12-month period, with patients censored if they left the database or if no event occurred within 12 months. Cox proportional hazards models were used to determine the impact of targeted and non-targeted therapies on overall survival (OS).
Results
The cohort included 3,617 MDS patients with a median age of 75 years (22-79) (58% males and 42% females) with medium to severe baseline ECI (score &gt;5) in 40.5%. Targeted therapy for was recorded only in 324 (9%). A multivariate Cox proportional hazard model demonstrated a decreasing risk of death over time for those on targeted therapy. Across all mutations, the hazard model showed a reduced risk of death with use of target therapy by 46.5% (HR=0.535; p&lt;0.01).
For individual mutations, the multivariate models showed that targeted therapy reduced risk of death within 12 months by 68.4% for IDH1 (HR=0.316), 99.5% for IDH2(HR=0.0005; p&lt;0.01), 45.8% (HR=0.542) for SF3B1, and 17.8% (HR=0.822) for TP53. Of these, the HRs for IDH1, SF3B1, and TP53 were not statistically significant (p&gt;0.05) at 95% CI, indicating the need for larger sample sizes as measured using a power of 0.8.
Additional multivariate analyses were conducted across all mutations, separately for patients aged 65 years or older (N=3,126; 86%) and for patients aged less than 65 years (N=491; 14%). For patients 65 years or older, the hazard models showed use of targeted therapy reduced risk of death within 12 months by 48% (HR=0.518; p&lt;0.01). For patients less than 65 years, the hazard models showed use of targeted therapy reduced risk of death within 12 months by 21% (HR=0.794; p&gt;0.05), but was not statistically significant, indicating the need for a larger sample size.
Conclusion
These findings suggest a potential benefit of targeted therapies in reducing mortality risk among MDS patients with specific mutations, even if further studies with a larger sample size would be needed to achieve robust statistical significance for patients exhibiting specific mutations. In addition, our study confirms that a significant number of biomarker-positive MDS patients do not receive targeted therapies, highlighting challenges such as disparities in access to care and provider awareness. Addressing these issues is essential to ensure all eligible patients benefit from advancements in targeted therapies, ultimately improving survival and quality of life.