Background:

High-risk myelodysplastic syndromes (HR-MDS) carry a poor prognosis, with median overall survival under three years and post-hypomethylating agent (HMA) failure survival as low as 4 to 6 months. HMAs have been the standard of care but yield only ~50% initial response and limited long-term benefit. Oral decitabine/cedazuridine (DEC-C) was FDA-approved in 2020 as the first oral HMA for MDS and CMML and offer a similar safety and efficacy to IV/SC decitabine with trends toward improved treatment persistence and acute myeloid leukemia (AML)-free survival in real-world datasets. Meanwhile, venetoclax combined with HMAs in HR-MDS has shown promising response rates with improved potential for transplantation in responders, although substantial myelosuppression is common with the dual agent therapy. We conducted a retrospective cohort study to determine survival outcomes and progression to acute myeloid leukemia in HR-MDS patients treated upfront with oral DEC-C compared to use of intravenous HMA with venetoclax (VEN/HMA) in HR-MDS patients.

Methods: We utilized the TriNetXtmglobal federated health research network which included 149 different healthcare organizations. By utilizing ICD-10 and ICD oncology codes, patients with HR-MDS were identified and separated into two cohorts based on time to initiation of either oral DEC-C, or azacitidine or decitabine in combination with venetoclax within 4 weeks of the index diagnosis event. Propensity score matching (PSM) was conducted, matching cohorts based on age, gender, race and prior exposure to antineoplastic agents. Primary outcome measure of interest was overall survival (OS), and Kaplan-Meier survival analysis was conducted excluding patients with primary outcome prior to the index diagnosis event. Progression to AML was a secondary outcomes measure, and Pearson's chi-squared test was additionally employed to analyze measures of association. An analysis using Cox-proportional hazards model for progression to AML was performed with covariates including age, sex, race, and Charlson comorbidity index including acute myocardial infarction, heart failure, personal history of malignant neoplasm, cerebral infarction, dementia, chronic pulmonary disease, liver disease, diabetes and chronic kidney disease.

Results:

A total of 125 patients with HR-MDS who were treated upfront with DEC-C and 351 such patients who received VEN/HMA were identified. 116 patients in each cohort were matched 1:1 based on PSM. Baseline characteristics including age, gender and race were well balanced in the matched cohorts. Kaplan-Meier estimates of survival at 5-years predicted a median OS of 695 days in the upfront DEC-C treated HR-MDS cohort compared to 421 days in the upfront VEN/HMA treated HR-MDS cohort, corresponding to OS probability at 5-years of 37.2% and 16% respectively (log-rank test p=0.0323). Kaplan-Meier estimates of risk of progression to AML at 5-years predicted a risk of progression of 614 days in the DEC-C group versus 214 days in the VEN/HMA group, with overall risk of progression at 5-years of 44.9% and 9% respectively (log-rank test p=0.032). In addition, overall risk of progression at 5-years estimated by hazards ratio (HR)was 0.57 with 95% CI 0.4 – 0.82 (p=0.0038) in favor of DEC-C treatment group. Risk of progression to AML by Cox-proportional hazards model showed statistically significant benefit associated with younger age and upfront treatment with DEC-C, HR of 0.98 (95% CI 0.96 – 0.99, p = 0.031) and 0.38 (95% CI 0.17 – 0.87, p = 0.021) respectively.

Conclusion:

Our matched cohort analysis of front-line use of DEC-C was associated with better OS and lower risk of progression to AML compared to VEN/HMA in HR-MDS patients. Further prospective studies are warranted to confirm such benefits associated with this new oral agent in the treatment of HR-MDS patients.

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2025
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