In a real-world audit of azacitidine (AZA) in higher risk myelodysplasia (MDS) and oligoblastic acute myeloid leukemia (AML) (Mozessohn et al. 2016), 410 of 1101 patients (33%) did not reach the fourth cycle of treatment and had a median overall survival (OS) of 3 months compared to 17 months in those completing ≥ 4 cycles. While early disease progression may account for premature discontinuation, it is plausible that patient related factors including co-morbidities and frailty also contribute. To maximize cost-effectiveness and minimize toxicity, it is necessary to identify patients more likely to complete 4 cycles of AZA. MDS-CAN is a national, prospective registry collecting disease and patient-specific information every 6-12 months. Patient-related factors measured yearly include frailty (Rockwood clinical frailty scale (CFS), comorbidity (Charlson CI and MDS-CI), disability (Lawton-Brody SIADL) and physical performance (4 meter walk test, grip strength, 10 x timed chair-sit test).

OBJECTIVE

Explore patient-related factors predictive of OS and completion of ≥ 4 cycles of azacitidine in MDS patients, and determine if these add prognostic value.

METHODS

All AZA-treated patients in the MDS-CAN registry were included. Number of cycles received and OS were the outcomes of interest. OS was defined as time to death or last follow up after AZA initiation. Cox proportional hazard and logistic regression analyses were used to identify patient-related factors predictive of completing ≥ 4 cycles and OS. Frailty CSF scores were examined dichotomously (1-3 vs. 4+) due to small sample size. Covariates included age, gender, ECOG, IPSS/IPSS-R, time from diagnosis to AZA, transfusion dependence, hemoglobin, platelet, LDH, frailty, disabiliy and physical performance.

RESULTS

Between January 2008 and January 2017, 313 patients were identified with a median follow-up of 15 months. Frailty, comorbidity, disability and physical performance measures were available in 117 of these. Median age was 73 (range 30-97) with a male predominance (71%). Median time from diagnosis to AZA was 3 months (IQR 1-18). Using the IPSS-R, 42% were very high risk, 30% high risk, 21% intermediate risk, and 7% low risk. 50% were transfusion dependent at AZA start. Median frailty CFS score was 3 (range 1-7) with 44% in the higher risk (CFS 4+) category. Median CCI and MDS-CI scores were 1 (range 0-6) and 1 (range 0-4). The median number of AZA cycles was 9 (range 0-83). 63 patients (20%) received < 4 cycles. Patients with higher CFS completed fewer AZA cycles (median 6 vs. 8 for CFS 1-3 vs . CFS 4+ respectively, p=NS). 79% and 60% with a low CFS (1-3) completed ≥ 4 and ≥ 7 cycles respectively, compared with 64% and 43% with CFS of 4+ (p=NS). Median OS (entire cohort) was 20 months (range 1-105). Patients completing ≥ 4 cycles had a median OS of 25 months (95% CI 21-27) compared to 4 months (95% CI 4-8) with < 4 cycles (Figure 1). Frailty independently influenced OS in the IPSS-R higher risk group (19 vs. 10 months for CFS 1-3 vs. 4+; p=0.04) (Figure 2a). Frailty also appeared to impacted OS in the IPSS-R lower risk group (32 vs. 14 months for CFS 1-3 vs. 4+; p=0.3)(Figure 2b), but not with statistical significance possibly due to a small sample size. Factors predictive of OS included time from diagnosis, completing ≥ 4 cycles, age, IPSS, IPSS-R, cytogenetics, marrow blast percentage, Hgb, platelet, LDH, Charlson CI, and ECOG. By multivariate analysis, higher IPSS-R (p= 0.006), age ≥ 65y(HR=1.6; p=0.05) , < 4 cycles (HR=5.1; p <0.0001), and shorter time from diagnosis (HR=0.7; p=0.03) remained predictive of shorter survival. Factors predictive of completing ≥ 4 cycles included age, Hgb, platelet, and MDS-CI score. By multivariate analysis, only MDS-CI remained significant with scores of 2+ being particularly discriminating (HR 8.4 (95% CI 2.3-33), p=0.001). Notably, physical performance tests did not predict OS nor ability to complete 4+ cycles.

CONCLUSION

Patient-related factors provide prognostic information and influence clinical outcomes and length of treatment for azacitidne treated patients. A comorbidity score using MDS-CI of 2 and higher predicts for the inability to tolerate 4+ cycles of AZA, a situation associated with significantly short survival. Better screening of candidates for AZA treatment using patient-related factors may maximize clinical success and minimize the exposure of inappropriate patients to excessive toxicity.

Figure 1
Figure 1.
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Disclosures

Wells: Alexion: 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; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rockwood: Sanofi: Research Funding; Canadian Institute of Health Research: Research Funding; Capital Health Research Fund: Research Funding; Lundbeck: Membership on an entity's Board of Directors or advisory committees; Fountain Family Innovation Fund of the Nova Scotia Health Authority Foundation: Research Funding; Nova Scotia Health Research Foundation: Research Funding; Research Executive Committee of the Canadian Consortium on Neurodegeneration in Aging: Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Alzheimer Society of Canada: Research Funding; Dalhousie Medical Research Foundation: Research Funding. Geddes: Alexion: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Zhu: Celgene: Consultancy, Research Funding; Novartis: Consultancy; Janssen: Consultancy. Sabloff: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Keating: Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Leber: Novartis Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees. Leitch: 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; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Exjade: Speakers Bureau. Yee: Novartis Canada: Honoraria; Celgene Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncoethix: Research Funding; Astex: Research Funding; Karyopharm: Research Funding. St-Hilaire: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Storring: Novartis: Honoraria; Celgene: Honoraria, Research Funding. Shamy: Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Kumar: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Elemary: Celgene: 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; Roche: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Lundbeck: Membership on an entity's Board of Directors or advisory committees. Delage: Pfizer: Research Funding; BMS: Research Funding; AbbVie: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Buckstein: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria.

Topics:
azacitidine, predictor variable, frailty, prostatic hypertrophy risk score, hemoglobin, electrocorticogram, follow-up, toxic effect, transfusion, colony-stimulating factors

Author notes

*

Asterisk with author names denotes non-ASH members.

© 2017 by The American Society of Hematology
2017
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