A Hgb Exceeding 120g/L Does Not Increase Risk of Vascular Complications or Disease Progression in Patients with MDS Treated with Erythropoietic Stimulating Agents, a Single-Institution Retrospective Study of the MDS-CAN Registry

Background

Erythropoiesis stimulating agents (ESAs) are recommended for management of anemia in lower-risk MDS to ameliorate anemia related symptoms and prevent blood transfusions. However, drug cessation/reduction once hemoglobin (Hgb) levels exceed 115-120g/L is mandated based on evidence extrapolated from ESA studies in chronic renal disease and non-hematologic malignancies that suggests elevated risks of cardiovascular and thrombotic complications and inferior disease free survival at higher Hgb levels. These recommendations exist despite a lack of evidence supporting similar relationships with ESA use in MDS, and compelling data supporting improvements in patient-reported quality of life at higher Hgb levels.

Objectives

Our study objectives were to 1) compare the incidence, and risk factors associated with, arterial and venous thrombotic events experienced by MDS patients while treated with ESAs, who either achieved Hgb levels >120g/L or did not; 2) compare overall survival (OS) and leukemia-free survival (LFS) in these patient groups.

Methods

We retrospectively evaluated single-center data extracted from the prospective MDS-CAN registry. Patients with MDS who were treated with ESAs and achieved a Hgb level of >120g/L at any time were included. Baseline demographic, ESA, and laboratory information were collected. The vascular complication rates of those achieving a Hgb of >120 were calculated. Logistic regression analysis was used to compare the characteristics of the patients that did or did not have these complications. Kaplan-Meier OS and LFS curves were also compared by log-rank test in patients who achieved or did not achieve a Hgb of >120 g/L at any time.

Results

A total of 291 patients received ESAs for whom serial Hgbs were available. Of these, 87 (29.9%) patients achieved Hgb levels >120g/L at one or more times while on ESA treatment and were included for analysis of vascular events. 65 (74.7%) patients were treated with Epoietin, 14 (16.1%) with Darbepoetin, and 8 (9.2%) received both. Median maximum doses of Epoietin and Darbepoietin were 40,000 (IQR 40,000 - 60,000) and 500 (IQR 500 - 500) units respectively.

57 (65.2%) patients were male and the median age at start of ESA treatment was 76.3 years (IQR 66.3 - 81.5). The IPSS-R categories at ESA start were very low (17.7%), low (45.2%), intermediate (30.6%), high (4.9%), and very high (1.6%). The median time to ESA start from MDS diagnosis was 5.1 months (IQR 1.45 - 20.21), and median length of time on ESA was 37.0 months (IQR 14.88 - 78.16). The median Hgb while on ESA was 110g/L with 16 (18.4%) patients maintaining a median Hgb >120g/L during ESA treatment.

Among these 87 patients, 11 (12.6%) developed a new vascular event on therapy at a median time of 54.8 months (IQR 23.6 - 74.1) from ESA start, of which 8 (9.2%) were arterial and 3 (3.5%) were venous events. The median closest Hgb immediately preceding the event was 95g/L (IQR 88.0 - 107.0). In univariate logistic regression analysis, only a previous history of vascular events was significantly related to the development of a new vascular complication (p=0.006, OR 6.7, 95% CI 1.9-29.4). On study median Hgb and other baseline clinical/laboratory characteristics were not predictive.

The actuarial OS since ESA treatment start for these 87 patients was 70.5 months (95% CI 51.9 - 94.2) and did not differ between patients with a median Hgb >120g/L or <120g/L (70.5 vs. 75.5 months, p=0.93). The actuarial LFS was 69.5 months (95% CI 51.9 - 82.7) and did not differ between the patients with a median Hgb >120g/L or <120g/L (75.5 vs. 66.9 months, p = 0.83).

Finally, in comparison to 204 MDS patients on ESA treatment who did not ever achieve a Hgb >120g/L, the 87 patients who achieved a Hgb >120g/L had a statistically significant improvement in actuarial median OS (35.7 vs. 70.5 months, p=0.002) and LFS (31.5 vs. 69.5 months, p = 0.0006).

Conclusion

Out of 87 MDS patients treated with ESAs who achieved a Hgb >120g/L, 11 developed a new vascular event, but the Hgb preceding the event was <100g/L. A previous history of vascular events was the only significant predictive risk factor suggesting Hgb levels do not correlate with new vascular complications. Notably, patients who achieved a Hgb >120g/L on ESA had improved OS compared to those with a Hgb <120g/L without any increase in leukemia. A propensity matched analysis comparing vascular event incidence, OS, and LFS in patients with Hgb levels >120g/L or <120g/L will be completed.

Mozessohn:Abbvie: Honoraria. Chow:Sobi: Consultancy, Honoraria, Other: supported travel. Tsui:Apobiologix: 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; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Industry supported grants and Industry sponsored travel; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Precision Dx: 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. Buckstein:Abbvie: Honoraria; BMS: Honoraria, Research Funding; Taiho: Honoraria, Research Funding; Keros: Other: Advisory Board.