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4598 Impact of Frailty in a Prospective Cohort of Patients with MDS Treated with Hypomethylating Agents

Program: Oral and Poster Abstracts
Session: 637. Myelodysplastic Syndromes: Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
Research, MDS, Adult, Elderly, Clinical Research, Health outcomes research, Chronic Myeloid Malignancies, Diseases, Real-world evidence, Registries, Myeloid Malignancies, Human, Study Population
Monday, December 9, 2024, 6:00 PM-8:00 PM

James T England, MD, MSc, FRCPC1, Liying Zhang, PhD2*, Karen Yee, MD, FRCPC3*, Michelle Geddes, MD4, Nancy Zhu, MD, FRCPC5*, April Shamy, MD6, Heather A Leitch, MD, PhD7, Mitchell Sabloff, MSc, MD, FRCPC8, Grace Christou, MD, MSc, FRCPC9*, Brett L. Houston, MD, PhD10,11, Brian Leber, MD12, Dina Khalaf, MSc, MBBS13, Eve St-Hilaire, MD, FRCP14*, Nicholas Finn, BSc, MD15*, Thomas J. Nevill, MD, FRCPC16, Amy Trottier, MD, MSc, FRCPC17, John M. Storring, MDCM, FRCPC18, Mohamed Elemary, MD, MSc, PhD19*, Robert Delage, MD, MSc20 and Rena Buckstein, MD, FRCPC1

1Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
2Sunnybrook Health Sciences Centre, Toronto, ON, Canada
3Princess Margaret Cancer Centre / University Health Network, Toronto, ON, Canada
4Tom Baker Cancer Centre, University of Calgary, Calgary, AB, Canada
5Clinical Assistant Professor Division of Hematology, Department of Medicine, University of Alberta, Edmonton, AB, Canada
6Jewish General Hospital, McGill University, Montreal, QC, CAN
7Hematology, St. Paul's Hospital, University of British Columbia, Vancouver, BC, Canada
8Ottawa Hospital Research Institute, Ottawa, ON, Canada
9Division of Hematology, The Ottawa Hospital, Ottawa, ON, Canada
10Cancercare Manitoba, Winnipeg, MB, CAN
11University of Manitoba, Winnipeg, MB, CAN
12Division of Hematology, Juravinski Cancer Center, Hamilton, ON, Canada
13Juravinski Cancer Centre, McMaster University, Hamilton, ON, Canada
14Hematology/Oncology, Dr. Georges-L-Dumont University Centre, Moncton, NB, CAN
15Hematology/oncology, Dr. Georges-L-Dumont University Centre, Moncton, CAN
16Department of Medicine, Division of Hematology, University of British Columbia, Leukemia Bone Marrow Transplant Program of British Columbia and Vancouver General Hospital, Vancouver, BC, Canada, Vancouver, BC, CAN
17Hematology, Queen Elizabeth II Health Sciences Centre, Halifax, NS, Canada
18McGill University Health Centre, Montreal, QC, Canada
19Provincial Hematology and Blood and Marrow Transplant Program, Saskatchewan Cancer Agency, University of Saskatchewan, Saskatoon, SK, Canada
20Integrated Cancer Center, CHU de Québec, Laval University, Quebec, QC, Canada

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.

Disclosures: England: GSK: Honoraria; Novartis: Honoraria. Yee: Astex: Other: research support; Forma Therapeutics: Other: research support; F. Hoffmann-La Roche: Other: research support; Genentech: Other: research support; Geron: Other: research support; Gilead Sciences: Other: research support; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: research support; Bristol Myers Squibb/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Taiho Pharma: Membership on an entity's Board of Directors or advisory committees; Taiho Pharma: Honoraria. Geddes: GSK: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Taiho: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Syros: Research Funding. Zhu: Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals,: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees. Shamy: BMS: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria. Leitch: Janssen: Honoraria; BeiGene: Honoraria; AstraZeneca: Honoraria. Sabloff: Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Christou: AbbVie Corporation: Honoraria; TAIHO pharma: Honoraria; Bristol Myers Squibb: Honoraria. Leber: BMS: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Otsuka: Research Funding, Speakers Bureau; Abbvie: Consultancy, Research Funding, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Amgen: Research Funding, Speakers Bureau; Astellas: Research Funding, Speakers Bureau; Jazz: Research Funding, Speakers Bureau; Treadwell: Research Funding, Speakers Bureau; SOBI: Research Funding, Speakers Bureau; Alexion/GSK: Research Funding, Speakers Bureau; Astex: Research Funding, Speakers Bureau; Paladin: Research Funding, Speakers Bureau; Roche: Research Funding, Speakers Bureau; Servier: Research Funding, Speakers Bureau; Janssen: Research Funding, Speakers Bureau. Khalaf: Pfizer: Honoraria; Paladin: Honoraria; Novartis: Honoraria. St-Hilaire: Taiho: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Finn: BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Storring: Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trails, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trails, Speakers Bureau; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trails, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trails, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Taiho: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Syndax: Other: Clinical Trails. Buckstein: BMS: Honoraria, Research Funding; Abbvie: Honoraria; Keros: Other: Advisory Board; Taiho: Honoraria, Research Funding.

*signifies non-member of ASH