responders may increase if rHuEpo is used in combination with granulocyte-colony stimulating factor (G-CSF), a result recently confirmed by Balleari and colleagues (2005), and this protocol proved to be effective also in patients with higher endogenous Epo levels (up to 500m U/mL). In the MDS setting, it is particularly important to define correctly the criteria of response to evaluate the efficacy of treatment. A revised version has recently been published by the International Working Group (Cheson et al 2006). In patients with nonmyeloid malignancies, including non-Hodgkin lymphoma and multiple myeloma (MM), response is obtained in 50% to 70 % of patients (Rizzo et al 2002), with the highest response rate in MM. Gabrilove and colleagues (2001) reported that a single weekly dose (QW) of rHuEpo alpha (40 000–60 000U) was as effective as the three times per week protocol, a result confirmed by others (Shasha et al 2003; Chang et al 2005; Witzig et al 2005). Similarly, QW dosing (30 000U) (Cazzola et al 2003) of rHuEpo beta are as effective as 10 000 U x 3 per week. Henry and colleagues (2006) reported that a further extension of the interval between administration of rHuEpo alpha using 80 000 U Q2W was as effective as 40 000 QW with comparable safety. Whether the measurement of endogenous Epo levels is a useful tool to predict the response in patients with solid cancer or lymphoproliferative disorders is questionable (Littlewood et al 2003; Ludwig et al 2004). These are inappropriately low in approximately 25% of all patients with MM, and increase to 50% in patients with stage III disease and 60% in those with renal impairment (Beguin et al 1992). Moreover, in some patients bone marrow infiltration participate to the poor response to rHuEpo (Beguin 1995). In conclusion rHuEpo is convenient and effective treatment capable of reducing transfusion support, increasing hemoglobin level, and improving QoL. Darbepoetin alpha Darbepoetin alpha is a novel hyperglycosilated erythropoietic protein that, in comparison with rHuEpo alpha, contains 5 N-linked carbohydrate chains versus 3 and 22 sialic acid residues versus 14. These characteristics determine a 3 times longer half-life (25.3 h vs 8.45 h), which increases in vivo biological activity in a murine model (Egrie and Browne 2001), and permits less frequent administrations. The roles of carbohydrate and sialic acid residues in deter mining the pharmacokinetics and pharmacodynamics of darbepoetin alpha have been Therapeutics and Clinical Risk Management 2007:3(2) Darbepoetin in anemia of cancer elucidated by Elliot and colleagues (2004). Although less effective than rHuEpo in vitro in inducing colony-forming unit-erythroid proliferation (due to sialic acid residues), the longer half life confers an advantage in vivo, and the reduced aff inity for EpoR fur ther participates to maintain erythropoietic concentrations of darbepoetin over the time. A QW administration of darbepoetin is sufficient for sustained stimulation of erythropoiesis. The percentage of cancer patients with hematopoietic response (hemoglobin >2 g/dL or >12 g/dL in the absence of red blood cell [RBC] transfusion) is dose-related, and time to hemoglobin response reduced compared with three times per week rHuEpo administration (Smith et al 2001; Glaspy et al 2002). Maximum concentration (Cmax) is reached at week 2 after chemotherapy, when the pool of erythroid cells is likely to be reduced as a consequence of chemotherapy (Heatherington et al 2001). This suggests that the clearance of darbepoetin is possibly due to binding to EpoR expressed on erythroid progenitor and precursor cells (Glaspy et al 2005). Finally, there is a trend toward increasing serum concentration of darbepoetin over time, as at cycle 3 concentration was doubled compared with cycle 1. When tested in a randomized study versus placebo in patients with lung cancer (Vasteenkiste et al 2002), QW 150 µ g darbepoetin reduced transfusion support (27% vs 52%) and increased hematopoietic response (66% vs 24%). Similar results were reported by Hedenus and colleagues. (2003) in patients with non-Hodgkin lymphomas, and these authors observed a response to darbepoetin in 69% of patients with basal serum Epo <100 mU/mL versus 44% in those with basal values >100mU/mL. QoL also improved, as shown by a Functional Assessment of Cancer Therapy-Fatigue (FACT-F) score increased in 56% of patients treated with darbepoetin and 44% in the placebo group, although the difference was not significant. Recently Littlewood and colleagues (2006) confirmed the efficacy of darbepoetin in ameliorating fatigue and QoL in patients with lymphoproliferative disorders, in a multicenter randomized trial. Currently in the QW schedule, darbepoetin is administered at the dose of 2.25 µ g/Kg (150 mg fixed dose), to be increased to 4.50 µ g/Kg (300 µ g fixed dose) if response is not observed at week four. Darbepoetin (150 µ g increased to 300 µ g if no response is observed) determines a substantial response also in patients with low-risk MDS (Musto et al 2005; Patton et al 2005) and may offer the advantage of less frequent administrations. In a recent series of 66 patients with low- 271