Impact of the 15-Item Frailty Scale in IPSS-R/IPSS-M Subgroup of Patients (Pts) with Myelodysplastic Syndromes (MDS)
Authors: Wang Xin , Qin Tiejun , Xu Zefeng , Qu Shiqiang , Li Bing , Pan Li Juan , Gao Qingyan , Jiao Meng , Zhao Jinying , Xie Wenjun , Gale Robert Peter , Xiao Zhijian 
Published: December 2024

Introduction Prognostic models such as the Revised International Prognostic Scoring System (IPSS-R) and the Molecular IPSS (IPSS-M) have been widely used in MDS pts. However, frailty, which is essential for clinical outcomes, is not considered in these prognostic tools. A 15-item frailty score (FS-15) specific to MDS pts was developed, including laboratory indicators, self-care, physical status, fatigue assessment, tumor history, and BMI. We aim to validate the FS-15 and further explore its potential to improve the predictive ability of IPSS-R and IPSS-M.
Methods In total, 812 consecutive subjects with newly diagnosed de novo MDS from 08/2016 to 06/2023 were enrolled. Frailty index (FI) was calculted according to the FS-15; all pts miss &lt;20% of the 15 elements. To determine the significant FI cut-off score related to the overall survival (OS), we constructed a receiver-operating characteristic (ROC) curve. We identified the point with the highest Youden index as the cut-off score (0.44). Pts were stratified into risk categories according to the IPSS-R and IPSS-M separately. Survival analysis was then performed to evaluate the impact of reclassification by FS-15 within each IPSS-M and IPSS-R risk group, and the C-index was calculated for each model to compare their predictive accuracy.
Results The median age was 55 (IQR: 42-64) years, and 65% were male. The median follow-up time was 22.5 (20.2-24.9) months (mo), and the median OS was 43.3 (95%CI: 36.8-49.8) mo. The mean FI score was 0.43 (SD = 0.13), and the median was 0.42 (IQR: 0.35-0.54), with a range of 0.08-0.81. FI score differed significantly by gender (p = 0.006), age (p = 0.014), IPSS-R (p = 0.001), and IPSS-M (p = 0.014). Using the FS-15, pts were divided into two groups based on the identified cut-off value 0.44 (FS-15 score ≤0.44 was 452 pts, and &gt;0.44, 360 pts). Subjects with cut-off values higher than 0.44 had lower hemoglobin (P = 0.005) and higher IPSS-M categories (P = 0.010). Kaplan-Meier OS curves using the cut-off value of 0.44 showed a highly significant difference (p &lt; 0.0001) with a median survival of 54.7 mo (95%CI: 47.5-NA) and 31.5 mo (95%CI: 22.9-41.0), respectively.
Using the IPSS-M model, 20 subjects (2.5%) were classified as very low-risk, 122 (15.0%) as low-risk, 107 (13.2%) as moderate low-risk, 99 (12.2%) as moderate high-risk, 185 (22.8%) as high-risk and 200 (24.6%) as very high-risk, 3-year overall survivals were 88.4%, 80.5%, 68.0%, 62.7%, 40.0% and 32.2% respectively(P &lt; 0.0001). We further stratified different IPSS-M risk groups by FS-15 frailty score (≤0.44 vs. &gt;0.44 ). The frailty index cut point further refined the projected survivals of the IPSS-M risk groups. Subjects with FS-15 scores ≤0.44 had significantly higher 3-year survival rates compared to those &gt;0.44 in the IPSS-M low-risk group (88.7% vs. 68.2%, P = 0.026) and very high-risk group (40.3% vs. 26.4%, P = 0.036). In other IPSS-M risk groups, the 3-year survival rates of the FS ≤0.44 group were lower than that of the FS &gt;0.44 group, but the differences were not statistically significant. The same method was used for analysis in each risk group of IPSS-R, and the differences in the very low-risk group(100.0% vs. 66.7%, P = 0.008) and the high-risk group(50.7% vs. 27.8%, P = 0.019) were statistically significant. So, a patient classified as having a higher risk disease according to the IPSS-M/IPSS-R but exhibiting a low degree of frailty as measured by the FS-15 might have a longer-than-expected lifespan.
The C-index for the IPSS-M model was 0.682 (95% CI: 0.649-0.716); after incorporating FS-15, the C-index increased to 0.699 (95% CI: 0.663-0.733). Moreover, the integrated model of FS-15 and IPSS-R also had a higher C-index than IPSS-R (0.691 [95% CI: 0.657-0.727] vs. 0.666 [95% CI: 0.626-0.733]). The addition of FS-15 significantly improved the predictive performance of the IPSS-M and IPSS-R models.
Conclusion This study firstly validated the feasibility of FS-15 evaluation and its potential use in prognostic assessment and providing clearer clinical guidance for newly diagnosed de novo MDS pts. In addition, we demonstrated that FS-15 could refine the risk stratification of IPSS-R and IPSS-M. The incorporation of the frailty score significantly enhances the predictive accuracy of the IPSS-R and IPSS-M models, suggesting that in addition to clinical, pathological, and cytogenetic data, frailty factors also need to be taken into account in outcome prediction for pts with MDS.