Phase II Trial of Darbepoetin Alfa in Myelodysplastic Syndrome (MDS): Preliminary Efficacy, Safety, and In Vitro Results.

Recombinant human erythropoietin (EPO) has been evaluated in MDS using a spectrum of doses and schedules, usually daily or thrice weekly, with an average erythroid response rate of 20% in published trials. Darbepoetin alfa (DA) is a hyperglycosylated analog of EPO with a longer serum half-life and greater in vivo potency. We evaluated the efficacy and safety profile of weekly subcutaneous DA dosing in MDS patients (pts) who had not received prior EPO treatment, with a hemoglobin (Hb) ≤ 10g/dL and/or red blood cell transfusion-dependence. During the induction phase, DA was begun at 4.5 mcg/kg/week (wk). For pts who did not achieve a major erythroid response by 6 wks (International Working Group response criteria), the DA dose was doubled to 9 mcg/kg/wk for 6 wks. In patients without a major erythroid response, G-CSF 2.5 mcg/kg twice weekly was added to DA 9 mcg/kg/wk for an additional 6 wks. Patients achieving an erythroid response underwent a ≥ 3-month maintenance phase. Dose reduction occurred for ≥ grade 3 non-hematologic toxicity or excess Hb response (Hb ≥ 13 g/dL). To date, 12 pts have been enrolled. FAB diagnoses were: RA (n=3), RARS (n=5), CMML (n=1), RAEB (n=3); divided into IPSS Low (n=6), Intermediate-1 (n=4) and Intermediate-2 (n=2). Of the 10 pts evaluable for erythroid responses (2 were too early), 7 responded: 5 major (3 RA, 2 RARS), 2 minor (RARS, RAEB), with 3 non-responders (2 RAEB, 1 RARS). The median durability of the major erythroid responses was 12.5 months. Doses for the 5 major erythroid responders were: DA 4.5 mcg/kg/wk (1), DA 9 mcg/kg/wk (1), and DA 9 mcg/kg/wk + G-CSF (3). DA was dose-reduced in 2 patients for excess Hb response. DA was generally well tolerated with no unexpected non-hematologic toxicity. One pt with baseline diabetic chronic renal insufficiency developed grade 2 proteinuria and increased creatinine levels, and grade 3 hypertension. Of 3 patients hospitalized for pneumonia, 1 (RAEB) expired. Progressive thrombocytopenia (grade 2 to 3 or worsening grade 3) occurred in 3 pts (2 RAEB, 1 RARS). Evaluation of the stimulatory effects of DA and EPO on in vitro marrow erythroid colony formation indicated that for those MDS pts with BFU-E growth (4 of 7 pts), similar BFU-E efficacy occurred compared with normal marrow (n=7), with DA being less stimulatory than EPO. These findings are consistent with known differences between in vitro responses (a function of receptor binding affinities) and in vivo efficacy (related to the extended serum half life of DA compared with EPO). Plateau (peak)/2 stimulatory concentrations were: DA 1nM (37ng/ml), EPO 0.2nM (0.78U/ml). In vivo/in vitro correlations are being assessed. These initial data indicate good tolerability and encouraging erythroid responses with once weekly DA dosing with or without G-CSF in MDS pts. Updated results of ongoing accrual will be presented.