Treatment of Anemia of Myelodysplastic Syndromes and Improvements in Cardiac Geometry.

Introduction: Anemia is a common complication of myelodysplastic syndromes (MDS). Recently, it has been associated with cardiac changes (remodeling) which, in turn, may lead to cardiovascular morbidity and mortality (Oliva et al., Leuk Res, 2005). Hemodynamic factors may lead to gradual cardiac enlargement and left ventricular hypertrophy (LVH) to be expected in such patients at Hb < 10.7 g/dL. Epoetins induce erythroid responses in about 40% of cases so from a pharmoeconomic viewpoint an accurate selection of patients more likely to be responders is recommended. Though increases in Hb levels are correlated with improvements in quality of life (QoL), the effects on cardiac geometry have not been explored. We report preliminary results of a Phase II study in 20 patients with low and intermediate-1 risk MDS and Hb < 11 g/d treated with darbepoetin alfa (DPO)for at least 24 weeks.

Patients and Methods: The primary endpoint is the change in cardiac geometry in treated patients. The secondary endpoint is the change in QoL. Patients receive DPO 150 mcg s.c weekly to be increased to 300 mcg weekly in non-responders. Treatment target is Hb=12.0 g/dL. Cardiac geometry is evaluated at baseline, at 24 weeks and at one year by echocardiographic measurements carried out according to the recommendations of the American Society of Echocardiography by an external investigator who is blind to the biochemical results. Left ventricular mass index (LVMI) is calculated according to the Devereux equation and adjusted for body surface area. LVH is defined by a LVMI > 100 g/sqm in women or > 131 g/sqm in men. QoL changes are measured using the QOL-E questionnaire.

Results: Patients included in the study are 12M/8F of median age 76 (range 49–84) years. Baseline Hb level was median 9.0 (range 7.5–10.8) g/dL. Five patients were transfusion-dependent. In the 3 patients with baseline Hb > 10.5 g/dL, cardiac geometry was normal in one patient and 2 patients had initial remodelling while, below this cut-off, 10 (59%) had LVH (p=0.038). Fourteen patients received at least 24 weeks of DPO and were evaluated for changes in cardiac geometry. One out of 3 transfusion-dependent patients responded with a decrease in transfusion requirement and 9 out of 11 patients had an erythroid response with at least 1.0 g/dL increase in Hb. Median change in LVMI was −3.5 (range −53.37 to 51.43). Responders had improvements in cardiac geometry (p=0.033): remarkably, of the 4 patients with baseline eccentric hypertrophy, one improved and one completely normalized. At univariate ANOVA analysis, response to treatment was associated with improvements in QOL-E treatment outcome index (p=0.021), specific (p=0.001), fatigue (p=0.02), physical (p=0.028), functional (p=0.022), and general (p=0.048) scores.

Conclusions: Our preliminary data suggest that erythroid responses in anemic MDS patients are associated with improvements in cardiac geometry and QoL. The improvement in cardiac remodeling may reduce the risk of cardiac morbidity and mortality. Larger studies are necessary to confirm these results and to evaluate the cost-effectiveness of the treatment strategies for anemia considering the potentials for decreasing cardiovascular risk.