Impact of Frailty in a Prospective Cohort of Patients with MDS Treated with Hypomethylating Agents

Introduction: Myelodysplastic neoplasms (MDS) are a group of clonal hematopoietic disorders characterized by cytopenias and a risk of progression to Acute Myeloid Leukemia. Frailty is an age-related state of vulnerability that reflects multifactorial loss of physiologic reserve. Up to 25% of patients with MDS are observed to be vulnerable or frail reflecting the advanced age of patients at diagnosis. Frailty has been observed to independently predict survival in patients with myelodysplastic syndromes, even after adjustment for standard risk categories, disease-related factors, and comorbidity indexes. An important determinant affecting survival in higher-risk MDS is the ability to receive an adequate trial of therapy with a hypomethylating agent (HMA). The concern of upfront toxicity in patients with frailty may lead to many not being offered HMA therapy and directly impede their survival. Up to 4-6 cycles of HMA therapy may be needed to derive hematopoietic response and survival benefit and patients with frailty may discontinue HMA prior to deriving benefit. We investigated the independent effect of frailty on overall survival and the likelihood of completion of at least 4-6 cycles of HMA therapy in MDS-CAN, a multi-centre, prospective cohort (NCT02537990) of patients with MDS or chronic myelomonocytic leukemia (CMML). Methods: Consecutive patients with a diagnosis of MDS or CMML who received at least one cycle of HMA (azacytidine, decitabine, decitabine/cedazuridine) were included in the study. Frailty, comorbidity, instrumental activities of daily living, disability, quality of life, fatigue and physical performance measures were evaluated at baseline. Frailty was measured using the Rockwood CSHA 9 point clinical frailty scale (FS) and the MDS-specific 15-item frailty scale (FS-15). Overall Survival (OS) years was defined as the time from HMA start date to death or last follow-up. Cox proportional hazard models were constructed to evaluate the impact of patient- and disease- related variables on OS. Logistic regression models were used to evaluate predictors of completing ≥4 or ≥6 cycles of HMA therapy. Results: A total of 513 patients were included in the study with revised international prognostic scoring system (IPSS-R) risk categories of: very low/low n=22 (4%), intermediate n=103 (20%), high n=145 (28%), and very high n=173 (34%). Median [range] age was 72.7 [66-81] years and 352 (69%) were male. Azacytidine was used in 442 patients while 71 received IV or oral decitabine. The median [interquartile range] number of cycles received was 9 [5-13]. A total of 411 (80%) patients died during the study period, with median [95% confidence interval (CI)] OS for the entire cohort of 1.69 [1.51-1.91] years from HMA start. Frailty was predictive of OS whether measured by the Rockwood FS (P<0.001) or MDS FS-15 (P=0.002). For patients with Rockwood FS categories of 1-2, 3, and ≥4 the actuarial median (95% CI) OS were 2.27 (1.85-2.53) years, 1.38 (1.18-1.71) years, and 1.14 (0.87-1.41) years, respectively. The median [95%CI] OS for MDS FS-15 scores of ≤0.20, 0.21-0.30, and >0.30 were 2.43 (1.07-3.47) years, 1.95 (1.15-2.74) years, and 1.51 (1.32-1.67) years. In multivariable analysis including patient- and disease-specific factors, OS from start of HMA therapy was predicted by older age (Hazard Ratio 1.03 [95%CI 1.01-1.04]), transfusion dependence (HR 1.36 [1.03-1.79], high-risk IPSS-R (HR 2.81 [1.15-6.86]), HMA <4 cycles (HR 3.74 [2.67-5.24]), Rockwood FS (HR 1.14 [1.02-1.27]), and MDS FS-15 score (HR 3.57 [1.25-10.2]). In the study cohort 418 (81%) of patients completed at least 4 cycles of HMA therapy, and 363 (71%) completed ≥6 cycles. In multivariable logistic regression analysis, completion of at least 4- or 6-cycles of HMA therapy were predicted by higher hemoglobin (Odds Ratio 1.03 [95%CI 1.01-1.04] for ≥4 cycles; OR 1.02 [1.001-1.03] for ≥6 cycles), and lower MDS FS-15 scores (OR 0.14 [0.02-0.96] for ≥4 cycles; OR 0.14 [0.03-0.69] for ≥6 cycles). Conclusion: Our study provides further evidence for the importance of frailty evaluation for predicting survival in patients with MDS treated with HMA therapy. The MDS-specific FS-15 measurement of frailty was predictive of patients at risk for not completing 4-6 cycles of HMA therapy and understanding these reasons will be important. Frailty evaluation before HMA may identify patients in need of further supports or alternative therapy strategies.

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