Risk of Adverse Events Is Similar in Patients (Pts) Who Did or Did Not Achieve Hemoglobin (Hb) Above 12g/dL in a Phase 3 Clinical Trial of Darbepoetin alfa (DA) Administered Weekly (QW) or Every 3 Weeks (Q3W) in Anemic Cancer Pts Receiving Chemotherapy.
Authors: Ludwig Heinz , Canon Jean-Luc , Vansteenkiste Johan , Hamilton Lisa , Suto Tamás 
Published: October 2019

Abstract
Until now data on the frequency of adverse events (AEs) at different Hb levels have been lacking; these could help to define the impact of using different therapeutic Hb thresholds for erythropoiesis-stimulating agents. To evaluate the impact of when Hb >12g/dL, we evaluated data from a double-blind, randomized, active-controlled clinical trial of DA in anemic cancer pts (Hb <11g/dL) receiving chemotherapy (Canon, JNCI2006;98:373), the most recently conducted trial reflecting approved DA doses (2.25mcg/kg QW and 500mcg Q3W) and current treatment practices in Europe.
Methods: This posthoc analysis evaluates transfusion (TFN) and AE data in pts who did or did not achieve Hb >12g/dL during the study. Dose withholding occurred when Hb >13g/dL, and DA was restarted at 60% of previous dose once Hb ≤12g/dL. AEs of interest (hypertension, seizure, ischemic myocardial infarction, and embolism/thrombosis [arterial and venous]) were evaluated.
Results: Over 700 pts (50% women) were enrolled. Previously it was reported that the QW and Q3W groups in this study had comparable efficacy (TFN rates from wk 5 to end of treatment, 30% and 23%, respectively), and 23.9% and 21.5%, respectively, reached Hb >13g/dL during the study. In this posthoc analysis, within each dose group and between each group, pts had similar rates of each AE of interest regardless of the maximum Hb achieved on study (Table). 43% in both groups reached Hb >12g/dL; mean (SD) number of QW visits Hb remained above 12g/dL was 5.2 (3.56) and 5.1 (3.89) visits, respectively. Pts with Hb ≤12g/dL had higher rates of death and TFN than those with Hb>12g/dL.
Conclusions: Both DA regimens (2.25mcg/kg QW and 500mcg Q3W) were equally effective at preventing the need for TFN. Furthermore, control of Hb in both dose groups was similar as evidenced by the proportion of pts reaching a Hb >12 or 13g/dL. Finally, in this trial, regardless of DA regimen, pts with Hb >12g/dL did not exhibit greater rates of any AE of interest compared to those with Hb ≤12g/dL.
Table. Outcomes by Maximum Hb on Study Outcomes Maximum Hb N = Number of pts evaluable; E = Total 16 person week exposure period; n = Number of pts experiencing event; r = Exposure adjusted pt incidence rate based on the number of pts with AEs in a 16-week time period (r=n/E). DA Dose Group ≤ 12g/dL >12g/dL Subjects / Exposure Time [N/E] 2.25μg/kg QW 202 / 177.5 150 / 154.5 500μg Q3W 200 / 177.7 153 / 159.3 Deaths [n(r)] 2.25μg/kg QW 43(0.24) 9(0.06) 500μg Q3W 31(0.17) 7(0.04) Transfusions [n(r)] 2.25μg/kg QW 96(0.54) 26(0.17) 500μg Q3W 85(0.48) 15(0.09) Hypertension [n(r)] 2.25 μg/kg QW 7(3.47) 6(4.00) 500μg Q3W 4(2.00) 4(2.61) Seizure [n(r)] 2.25μg/kg QW 0(0.00) 1(0.67) 500μg Q3W 1(0.50) 0(0.00) Ischemic myocardial infarction [n (r)] 2.25μg/kg QW 2(0.99) 1(0.67) 500μg Q3W 4(2.00) 1(0.65) Embolism/thrombosis (Arterial and Venous) [n (r)] 2.25μg/kg QW 17(8.42) 11(7.33) 500μg Q3W 16(8.00) 14(9.15)