The Prognostic Value for Survival of Self-Reported Fatigue in Patients with Newly Diagnosed Myelodysplastic Syndromes: An International Prospective Observational Study By the Gimema
Authors: Efficace Fabio , Al Essa Wael , Platzbecker Uwe , Niscola Pasquale , Palumbo Giuseppe A , Caocci Giovanni , Puglia Serena , Sparano Francesco , Breccia Massimo , Luppi Mario , Stauder Reinhard , Ricco Alessandra , Petranovic Duska , Baron Frederic , Voso Maria Teresa , Frairia Chiara , Capodanno Isabella , Sarlo Chiara , Invernizzi Rosangela , Fozza Claudio , Doro Maribel , Vignetti Marco 
Published: December 2024

BACKGROUND
The ability to accurately predict survival in patients with myelodysplastic syndromes (MDS) is critical to guide treatment decisions. Although well-established prognostic indices are available, very limited data exists on the potential prognostic value for survival of patient-reported outcomes (PRO) in the MDS setting.
OBJECTIVE
We performed a prospective observational study to investigate whether the assessment of self-reported fatigue severity during the diagnostic workup could predict overall survival (OS) beyond baseline key factors, including the Revised International Prognostic Scoring System (IPSS-R).
METHODS: Adult patients with newly diagnosed MDS were consecutively enrolled in a large international prospective observational study involving 53 centers across 11 countries. Overall survival was defined from the date of MDS diagnosis to death from any cause. At study entry patients were classified according to the IPSS-R and also completed a PRO assessment, including the EORTC QLQ-C30. The prognostic value of the EORTC QLQ-C30 self-reported fatigue scale (i.e., 3 items) and the IPSS-R categories were analyzed using univariate and multivariate Cox proportional hazards models, checking the proportionality assumption. The following key variables were included in the starting univariate model: time since diagnosis, sex, living arrangements, transfusion dependency, ECOG performance status, HCT comorbidity index and white blood cell count. We also explored how to integrate self-reported fatigue into the scoring algorithm of the IPSS-R to increase its predictive accuracy. To this end, two thresholds for fatigue were identified, one for the higher-risk group and one for the lower-risk group by the IPSS-R. This resulted in a new risk-score classification, i.e. the FA-IPSS-R. Differences among Kaplan-Meier OS estimation of the newly developed risk group categories (by combining self-reported fatigue plus the IPSS-R risk group classification) were assessed by log-rank test. Statistical significance for all tests was set as α=0.05.
RESULTS: Overall, 927 patients with MDS were enrolled between November 2008 and December 2018. The IPSS-R was available for 902 patients, who had a median age of 73 years (IQR 66-79). Of these, 521 (58%) were classified as higher-risk and 381 (42%) as lower-risk by the IPSS-R. At baseline, 142 (16%) patients were transfusion-dependent and 488 (54%) had ≥ 1 comorbidities. We observed 457 deaths, and the median OS was 30 months (95% confidence interval [CI], 26-35). The median OS was 68 months (95% CI, 56-82) and 19 months (95% CI, 17-21) for patients with IPSS-R lower and higher-risk disease, respectively. In multivariate analysis, baseline factors independently associated with reduced OS were ECOG performance status ≥ 2 (hazard ratio [HR] 1.733, 95% CI 1.347-2.230; p&lt;0.001), transfusion dependency (HR 1.267, 95% CI 1.001-1.604; p=0.049), higher-risk IPSS-R score (HR 2.938, 95% CI 2.336-3.695; p&lt;0.001) and a higher score for self-reported fatigue (HR 1.080, 95% CI 1.040-1.120; p&lt;0.001). The latter translates into an 8% increase in the hazard of death for every 10-point increase (i.e., higher severity) in the fatigue scale (ranging from 0 to 100) of the EORTC QLQ-C30. We then aimed to incorporate fatigue into the IPSS-R scoring system to investigate whether it could enhance its predictive accuracy. Integration of fatigue severity into the two broad IPSS-R risk categories (i.e. lower- and higher-risk) yielded four risk group categories, with statistically significant different OS (p&lt;0.001). Two-year OS for patients with the lowest FA-IPSS-R risk was 80.8% (95% CI, 75.5-86.6) and only 31.6% (95% CI, 25.1-39.7) for those with the highest FA-IPSS-R risk. By integrating the EORTC QLQ-C30 fatigue severity into the standard IPSS-R (i.e., five risk groups), the FA-IPSS-R scoring algorithm generated six group categories with distinct survival outcomes (p&lt;0.001).
CONCLUSION
Our findings suggest that self-reported fatigue severity provides independent prognostic information for OS in patients with lower and higher risk MDS disease. Integration of a brief self-assessment of fatigue during the diagnostic workup of MDS may also enhance the predictive accuracy of the IPSS-R. Further analyses are needed to finalize the development of a patient-centric prognostic index combining fatigue and the IPSS-R.