Abstract
Myelodysplastic neoplasms (MDS) are a group of clonal malignancies of hematopoietic stem cells where progressive cytopenias and potential progression to secondary Acute Myeloid Leukemia (AML) lead to significant morbidity/mortality, impaired quality-of-life (QoL), and healthcare resource burden. Patients with higher-risk MDS are considered for therapy with hypomethylating agents (HMAs), to help restore hematopoiesis, delay progression to AML, and improve overall-survival (OS). Azacytidine (AZA) and decitabine (DEC) have commonly been used without direct clinical trial comparison between these agents. Prior have observed no difference in OS; but these analyses are limited by the lack of patient-level and disease risk factors that may influence efficacy and tolerability.
In Canada access to DEC remains inconsistent across jurisdictions due to the lack of direct comparison between available HMAs or in randomized clinical trial against best available therapy. The current study aims to retrospectively evaluate the differences in clinical outcomes for patients treated with AZA or DEC adjusted for disease risk-category and patient-specific factors.
The Canadian MDS Registry (MDS-CAN; NCT02537990)) is national cohort of prospectively evaluated patients with MDS which includes data on treatments in addition to baseline disease-risk and patient-specific factors. Patients with a diagnosis of MDS, CMML, or AML with 20-30% blasts, enrolled in the MDS-CAN registry from 2006 to 2025 were included. Baseline data included age, sex, performance status, comorbidity data, frailty score, IPSS-R, and prior MDS treatments. Baseline characteristics were compared using Wilcoxon rank-sum test for continuous variables, and Chi-square or Fisher exact test for categorical variables as appropriate
The primary outcome was OS and was compared with log-rank test; evaluated for the whole cohort and then stratified by IPSS-R disease risk. Secondary outcomes included Leukemia-Free Survival (LFS), change in transfusion dependence (TD)/independence (TI) status, and differences in QoL measurements.
We also conducted a propensity-score matched analysis of OS and LFS matching patients based on IPSS-R, Rockwood frailty score, and TD status.
In total 529 patients with MDS were included, of whom 442 were treated with AZA and 87 received DEC. Patients who received DEC had fewer blasts and lower IPSS-R score; Otherwise, there were no observed differences in demographic or clinical features. Patients treated with AZA received more cycles of therapy compared to patients treated with DEC (median [range] 10 [1-111] cycles AZA vs. 5 [1-72] cycles DEC, p<0.0001).
With median follow-up of 18.5 (range 0-148) months 401(76%) patients died during the study period. Median OS was longer in the DEC-treated patients (34.4 vs. 21.1 months, p=0.002). When stratified by IPSS-R score there remained a statistically significant difference favouring DEC in patients with IPSS-R score >3.5 (34.4 vs. 20.0 months, P=0.02). No significant difference in LFS was between patients treated with DEC or AZA (90.8 vs. 89.8 months, p=0.08).
For the propensity score analysis patients were matched with an a priori model including baseline IPSS-R, Rockwood frailty score, and TD at baseline. In total 76 patients who received DEC were matched to 76 AZA patients. The matched cohorts demonstrated no observed difference in OS (37.0 vs. 31.1 months, p=0.28), or LFS (90.8 vs. 89.8 months, p=0.15) between the treatment groups.
Measures of QoL demonstrated remarkable stability over the course of the study for global score, physical functioning, and social functioning, with no significant difference between AZA and DEC treated patients. There was an observed increase in dyspnea (p=0.04) and fatigue (p=0.04) scores over time in DEC-treated patients, while these values improved slightly in patients who received AZA.
There was no significant difference in survival or global, physical, and social QoL metrics between patients with MDS treated with either DEC or AZA. There may be a survival benefit for DEC in patients with higher-risk MDS (IPSS-R >3.5). Patients who received DEC were treated with fewer cycles of therapy compared to AZA and may have greater increase in fatigue and dyspnea scores.
