Effects of Dose Adjustment Rules on Safety during Erythropoietic Therapy: A Retrospective Analysis of Darbepoetin alfa Administered Either Every 3 Weeks or Weekly.
Authors: Hedenus Michael , Canon Jean-Luc , Kotasek Dusan , Lillie Tom , Hendricks Lisa , Yao Bin , Vansteenkiste Johan 
Published: April 2020

Abstract
Background: Rapid increases in hemoglobin (Hb) concentrations or achievement of high Hb levels during erythropoiesis-stimulating protein (ESP) therapy may put anemic patients undergoing chemotherapy at increased risk for cardiovascular/thromboembolic adverse events (AEs). A potential safety concern of less frequent ESP administration (eg, every 3 weeks [Q3W] vs weekly [QW]) is that higher single doses may cause rapid increases in Hb levels. Dose adjustment rules may provide physicians with guidance on how to minimize these risks; however, defining appropriate rules can be challenging.
Methods: To evaluate the ability of dose reduction rules to discriminate between natural Hb variability and inappropriate Hb increases, we performed a pooled analysis of 5 randomized, double-blind studies involving Q3W and QW darbepoetin alfa (Aranesp®; DA) vs placebo. In these studies, 2335 eligible patients (pts) had cancer and anemia, were undergoing chemotherapy, and had received ≥1 dose of study drug. AE categories of interest in this analysis were hypertension, seizure, ischemic myocardial infarction, and embolism/thrombosis (arterial and venous). Three definitions for excessive rate-of-rise in Hb were compared as triggers for dose reduction: ≥1-g/dL increase in 14 days; ≥1.5-g/dL in 21 days; or ≥2-g/dL in 28 days.
Results: Of the 3 definitions evaluated for excess rate-of-rise in Hb concentration, the 2-g/dL increase in 28 days best discriminated pts receiving DA treatment from placebo pts (see Table). The 1-g/dL increase in 14 days rule did not discriminate well between inappropriate Hb increases related to ESP therapy and natural Hb variability (ie, placebo). These results suggest that a 2-g/dL increase in 28 days may be associated with an increased risk of thrombotic events in pts receiving DA therapy compared with pts receiving placebo, after adjusting for thrombotic event history and ECOG performance status; the 1-g/dL increase in 14 days rule was not associated with an increased risk of thrombotic events in a similar analysis. No significant differences in the exposure-adjusted incidence rate of embolism/thrombosis events were observed between the DA extended-dose and 2.25-μg/kg QW groups, regardless of the definitions used.
Conclusions: The 2-g/dL increase in 28 days definition discriminates natural Hb variability and excess rate-of-rise that may be associated with cardiovascular/thromboembolic AEs. The 1-g/dL increase in 14 days rule resulted in an excessive rate of “false positives,” even in the absence of ESP therapy.
Placebo DA QW 2.25 μg/kg All DA Q3W extended dosing All DA N = No. of pts evaluable for safety; E = Total 16 person-week exposure period; n = Pts who experienced event; R = Exposure-adjusted incidence rate based on the no. of pts with event in a 16-week time period (R=n/E). No. of pts (N) 379 1049 907 1956 Exposure adjusted time (E) 321.1 979.1 928.8 1908 Hb threshold, n (R)     ≥ 13 g/dL at any time 23 (0.07) 344 (0.35) 233 (0.25) 577 (0.30) Excess rise in Hb, n (R)     ≥ 1 g/dL in 14 days 212 (0.66) 796 (0.81) 690 (0.74) 1486 (0.78)     ≥ 1.5 g/dL in 21 days 138 (0.43) 654 (0.67) 560 (0.60) 1214 (0.64)     ≥ 2 g/dL in 28 days 83 (0.26) 487 (0.50) 390 (0.42) 877 (0.46)