Fatigue, However Measured, Continues to Refine Prognosis in Higher Risk MDS: An MDS-CAN Study
Authors: Amitai Irina , Geddes Michelle , Zhu Nancy , Keating Mary-Margaret , Sabloff Mitchell , Christou Grace , Leber Brian , Khalaf Dina , Leitch Heather A. , St-Hilaire Eve , Finn Nicholas , Shamy April , Yee Karen W.L. , Storring John M. , Nevill Thomas J. , Delage Robert , Elemary Mohamed , Banerji Versha , Chodirker Lisa , Mozessohn Lee , Parmentier Anne , Siddiqui Mohammed , Mamedov Alexandre , Zhang Liying , Buckstein Rena J. 
Published: November 2020

Background:
The incorporation of patient-reported outcomes with traditional disease risk classification, was found to strengthen survival prediction in patients with myelodysplastic syndromes (MDS). A recently reported model, FA-IPSS(h), found that patients' reported fatigue, assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life-Core 30 (QLQ-C30), among higher-risk IPSS population, further stratifies them into distinct sub-groups with different survival outcomes (Efficace et al, 2018). Compared to the IPSS, the revised IPSS (IPSS-R) is more refined in prognostic assessment and an IPSS-R score of &gt; 3.5 may identify higher risk disease (Pfeilstocker et al, 2016). The Edmonton Symptom Self Assessment Scale (ESAS) Global Fatigue Scale (GFS), is a single-item fatigue rating scale (0-10, with 10 being the highest degree), which has been previously recommended by the National Comprehensive Cancer Network to screen for fatigue in all cancer populations.
Aims:
(1) to validate the FA-IPSS(h), among the Canadian MDS registry (2) investigate whether a modified index, integrating higher risk by IPSS-R with patient reported fatigue according to the GFS, is able to identify individual subgroups with divergent overall survival (OS).
Methods:
All adult patients diagnosed with MDS with an IPSS-R score &gt;3.5 within 6 months before the date of registration were eligible for this analysis. Fatigue was assessed both by the QLQ-C30 questionnaire and the GFS. Frailty was assessed by the Canadian Study of Health and Aging (CSHA) 9 point Rockwood clinical frailty scale. Survival was calculated using standard Kaplan-Meier analysis.
Results:
This analysis included 331 patients. Median age was 73 years (range, 30-98 years), 65.7% were male, median blast % was 6% (range, 0-30), median IPSS-R score was 5.2 (range, 3.5-10) and 55% had high and intermediate-2 (Int-2) IPSS risk, 68% had high and very high IPSS-R risk disease, 66% were exposed to a hypomethylating agent. Median fatigue scores increased with Rockwood frailty scores. The median QLQ-C30 fatigue score was 33 (interquartile range (IQR), 22-55.6) and 4 (IQR, 2-6) by the GFS with 59% recording high fatigue (&gt;4). At a median follow-up of 17 months (IQR, 9-30 months), 233 deaths were observed. The actuarial median OS was 19.3 months (95% CI, 16.5-21.7). We applied the FA-IPSS(h) using QLQ-C30 fatigue cutoffs of 45 (figure 1a) and found a significant difference in OS (p&lt;0.0001) (table 1). We then divided the cohort into 2 groups: A) IPSS-R score &gt;3.5 + Low Fatigue (&lt;45) (n=226) and B) IPSS-R score &gt;3.5 + High Fatigue (≥45) (n=96). We found a significant difference in OS between these 2 groups, median OS 19.5 months (95% CI, 17.2-24.3) in group A versus 15.2 months (95% CI, 11.9-22.0) in group B (p=0.02) (figure 1b). We found similar results with these refinements, using the QLQ-C30 cutoff of 33 (the median in our patient population) (p&lt;0.0001). Similarly, high fatigue defined by ESAS GFS (&gt;4), was able to distinguish OS using the IPSS (p&lt;0.0001) (figure 1c) and IPSS-R &gt;3.5 (p=0.005) (figure 1d).
Conclusions:
We were able to externally validate the FA-IPSS (h) using a threshold QLQ-C30 fatigue score of 45, as originally described and 33 (Canadian median), using both the IPSS and IPSS-R (score &gt;3.5) classifications to define higher risk MDS. The easier to deploy ESAS GFS score of &gt;4 further discriminates survival using the IPSS and IPSS-R. This emphasizes the power of self-reported fatigue at refining OS predictions in higher risk MDS and further bolsters the importance of considering patient related outcomes in global assessments.

Disclosures
Geddes: Taiho: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding. Keating:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Hoffman La Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy; Servier: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Taiho: Membership on an entity's Board of Directors or advisory committees. Leber:Lundbeck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda/Palladin: Honoraria, Membership on an entity's Board of Directors or advisory committees; Treadwell: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Leitch:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Taiho: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Exjade: Speakers Bureau. Shamy:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Storring:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Nevill:Jazz Pharmaceuticals: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Delage:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Elemary:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chodirker:Hoffman Laroche: Honoraria. Buckstein:Novartis: Honoraria; Celgene: Research Funding; Takeda: Research Funding; Celgene: Honoraria; Astex: Honoraria.