Every 3 weeks dosing with darbepoetin alfa: A new paradigm in anaemia management

The advent of erythropoiesis-stimulating agents (ESAs) such as recombinant human erythropoietin (rHuEPO) and darbepoetin alfa for the treatment of chemotherapy-induced anaemia was associated with decreased requirements for red blood cell (RBC) transfusions and improved quality of life in cancer patients. Dosing of rHuEPO three times per week is the originally approved regimen, although in some countries weekly dosing is approved in some settings. Darbepoetin alfa was the first ESA to be developed with an extended dosing interval, offering the potential for less frequent administration and greater convenience for patients and healthcare professionals. In a placebo-controlled study of once-weekly darbepoetin alfa treatment in anaemic cancer patients undergoing chemotherapy, significantly fewer treated patients required RBC transfusions, regardless of initial haemoglobin levels. A subsequent dose-finding study of once-every-3-week darbepoetin alfa treatment showed that the drug was effective and well-tolerated in anaemic cancer patients and reduced the need for transfusions at all doses compared with placebo. Timing of ESA administration may be crucial to achieve maximum erythropoietic responses, thus synchronous dosing with 3-weekly chemotherapy cycles may improve efficacy and convenience. Recent trials have shown that synchronous dosing is equally effective, with improved convenience, compared with asynchronous dosing, and that fixed-dose (500 microg) treatment achieves similar efficacy and tolerability as administration by weight.     

Darbepoetin alfa administered every 3 weeks alleviates anaemia in patients with solid tumours receiving chemotherapy; results of a double-blind,placebo-controlled,randomised study

This dose-finding, placebo-controlled study evaluated the safety and efficacy of darbepoetin alfa administered every 3 weeks (Q3W) to anaemic patients receiving chemotherapy. In part A, patients (haemoglobin 50% of patients achieving a haematopoietic response. Administration of darbepoetin alfa Q3W has a tolerable safety profile and effectively ameliorates anaemia due to chemotherapy.     

Darbepoetin alfa: potential role in managing anemia in cancer patients

Anemia in cancer patients is frequent but often under-recognized and under-treated. This may be related to misconceptions about the impact of anemia on cancer patients and ill-defined guidelines for treatment, as well as the inadequacies of current therapy. Darbepoetin alfa, a novel erythropoiesis-stimulating protein with a longer serum half-life than epoetin (alpha and beta), is approved to treat anemia in patients with chronic kidney disease. Most recently darbepoetin alfa has received approval by the FDA in USA for the treatment of anemia associated with myelosuppressive chemotherapy and approval in the EU is expected soon. Clinical trials in cancer patients indicate that darbepoetin alfa effectively and safely alleviates anemia in patients receiving chemotherapy. A Phase II trial also indicates that darbepoetin alfa is effective in patients who are not receiving chemotherapy. Thus, darbepoetin alfa has the potential to improve supportive care and thereby, cancer patients' quality of life, and might also impact on treatment outcome.     

Darbepoetin alfa for the treatment of cancer-related anemia: an update

Anemia is a common and potentially debilitating complication of cancer. Darbepoetin alfa (Aranesp, Amgen) has been in routine clinical use for the treatment of chemotherapy-induced anemia since 2002. The extended half-life of darbepoetin alfa permits less frequent and consequently more flexible dosing than other erythropoietic therapies. Data suggest that hemoglobin levels can be effectively and safely increased with darbepoetin alfa in cancer patients who are receiving chemotherapy (patients with treatment-induced anemia), and in those who are not receiving chemotherapy (patients with tumor-induced anemia). This review provides an overview of clinical trial results, particularly those exploring flexible, extended dosing schedules.     

Darbepoetin alfa: potential role in managing anemia in cancer patients

Anemia in cancer patients is frequent but often under-recognized and under-treated. This may be related to misconceptions about the impact of anemia on cancer patients and ill-defined guidelines for treatment, as well as the inadequacies of current therapy. Darbepoetin alfa, a novel erythropoiesis-stimulating protein with a longer serum half-life than epoetin (α and β), is approved to treat anemia in patients with chronic kidney disease. Most recently darbepetin alfa has received approval by the FDA in USA for the treatment of anemia associated with myelosuppressive chemotherapy and approval in the EU is expected soon. Clinical trials in cancer patients indicate that darbepoetin alfa effectively and safely alleviates anemia in patients receiving chemotherapy. A Phase II trial also indicates that darbepoetin alfa is effective in patients who are not receiving chemotherapy. Thus, darbepoetin alfa has the potential to improve supportive care and thereby, cancer patients’ quality of life, and might also impact on treatment outcome.     

Darbepoetin alfa for the treatment of cancer-related anemia: an update

Anemia is a common and potentially debilitating complication of cancer. Darbepoetin alfa (Aranesp^®, Amgen) has been in routine clinical use for the treatment of chemotherapy-induced anemia since 2002. The extended half-life of darbepoetin alfa permits less frequent and consequently more flexible dosing than other erythropoietic therapies. Data suggest that hemoglobin levels can be effectively and safely increased with darbepoetin alfa in cancer patients who are receiving chemotherapy (patients with treatment-induced anemia), and in those who are not receiving chemotherapy (patients with tumor-induced anemia). This review provides an overview of clinical trial results, particularly those exploring flexible, extended dosing schedules.     

Treating anemia of cancer with every-4-week darbepoetin alfa: final efficacy and safety results from a phase II, randomized, double-blind, placebo-controlled study

Darbepoetin alfa is an erythropoiesis-stimulating agent (ESA) approved for treating chemotherapy-induced anemia. This phase II, double-blind, placebo-controlled study examined the efficacy of darbepoetin alfa for treating anemia of cancer (AoC) in patients not receiving chemotherapy or radiotherapy. Patients were randomized 3:1 to receive darbepoetin alfa (6.75 microg/kg) or placebo every 4 weeks; the end of the study was at week 17. The primary endpoint was the percentage of patients with a hematopoietic response. Secondary endpoints included transfusion incidence and safety parameters. Efficacy analyses were performed on 162 patients in the darbepoetin alfa group and 56 patients in the placebo group. The Kaplan-Meier percentages of patients who achieved a hematopoietic response (darbepoetin alfa, 69%; placebo, 24%) or achieved the target hemoglobin (darbepoetin alfa, 85%; placebo, 50%) differed significantly between treatment groups. The transfusion incidence did not differ between treatment groups probably because of the low baseline transfusion rates in AoC patients. The incidence of adverse events (including on-study deaths) was similar in both groups. In conclusion, darbepoetin alfa appeared to be well tolerated and significantly increased hemoglobin levels in these AoC study patients.     

A Randomized,Double-Blind,Placebo-Controlled,Phase III Noninferiority Study of the Long-Term Safety and Efficacy of Darbepoetin Alfa for Chemotherapy-Induced Anemia in Patients With Advanced NSCLC

IntroductionThis study evaluated noninferiority of darbepoetin alfa versus placebo for overall survival (OS) and progression-free survival (PFS) in anemic patients with NSCLC treated to a 12.0-g/dL hemoglobin (Hb) ceiling.MethodsAdults with stage IV NSCLC expected to receive two or more cycles of myelosuppressive chemotherapy and Hb less than or equal to 11.0 g/dL were randomized 2:1 to blinded 500 μg darbepoetin alfa or placebo every 3 weeks. The primary endpoint was OS; a stratified Cox proportional hazards model was used to evaluate noninferiority (upper confidence limit for hazard ratio [HR] < 1.15). Secondary endpoints were PFS and incidence of transfusions or Hb less than or equal to 8.0 g/dL from week 5 to end of the efficacy treatment period.ResultsThe primary analysis set included 2516 patients: 1680 were randomized to darbepoetin alfa; 836 to placebo. The study was stopped early per independent Data Monitoring Committee recommendation after the primary endpoint was met with no new safety concerns. Darbepoetin alfa was noninferior to placebo for OS (stratified HR = 0.92; 95% confidence interval [CI]: 0.83‒1.01) and PFS (stratified HR = 0.95; 95% CI: 0.87‒1.04). Darbepoetin alfa was superior to placebo for transfusion or Hb less than or equal to 8.0 g/dL from week 5 to end of the efficacy treatment period (stratified odds ratio = 0.70; 95% CI: 0.57‒0.86; p < 0.001). Objective tumor response was similar between the groups (darbepoetin alfa, 36.4%; placebo, 32.6%). Incidence of serious adverse events was 31.1% in both groups. No unexpected adverse events were observed.ConclusionsDarbepoetin alfa dosed to a 12.0-g/dL Hb ceiling was noninferior to placebo for OS and PFS and significantly reduced odds of transfusion or Hb less than or equal to 8.0 g/dL in anemic patients with NSCLC receiving myelosuppressive chemotherapy.     

Effectiveness of darbepoetin alfa versus epoetin alfa in patients with chemotherapy-induced anemia treated in clinical practice

PRIMARY PURPOSE: The objective of this retrospective observational cohort study was to compare the effectiveness of darbepoetin alfa with that of epoetin alfa in patients with chemotherapy-induced anemia using data from noncontemporaneous chart audits conducted at a community-based oncology practice. MATERIALS AND METHODS: For the first chart audit, data were collected from consecutive patients with nonmyeloid malignancies with diagnoses of chemotherapy-induced anemia and hemoglobin levels < or = 10.5 g/dl who were receiving concurrent chemotherapy and had at least 5 weeks of visits from July-September 2000. After therapeutic substitution of darbepoetin alfa for epoetin alfa for all patients with chemotherapy-induced anemia, data were collected from consecutive darbepoetin alfa-treated patients with diagnoses of chemotherapy-induced anemia and at least 8 weeks of visits from June-October 2002 (darbepoetin alfa was approved in July 2002). RESULTS: Most (86%) of the 212 epoetin alfa-treated patients had received an initial dose of 40,000 U once weekly, and most (85%) of the 196 darbepoetin alfa-treated patients had received a fixed dose of either 100 microg once weekly (49%) or 200 microg every 2 weeks (36%). At 8 weeks, the mean change in hemoglobin level was 1.1 g/dl for the darbepoetin alfa patient group and 1.0 g/dl for the epoetin alfa patient group. DISCUSSION: Utilization, dose escalation rates, and clinical outcomes were considered comparable for the darbepoetin alfa and epoetin alfa patient groups. CONCLUSIONS: Darbepoetin alfa, 100 microg once weekly or 200 microg every 2 weeks, appears to be as effective as epoetin alfa, 40,000 U once weekly, for the treatment of chemotherapy-induced anemia in the clinical practice setting.     

Double-blind,placebo-controlled,randomized phase III trial of darbepoetin alfa in lung cancer patients receiving chemotherapy

BACKGROUND: Patients receiving chemotherapy often develop anemia. Darbepoetin alfa (Aranesp(TM)) is an erythropoiesis-stimulating glycoprotein that has been shown, in dose-finding studies, to be safe and clinically active when administered to patients with cancer every 1, 2, or 3 weeks. This phase III study compared the safety and efficacy of darbepoetin alfa with placebo in patients with lung cancer receiving chemotherapy. METHODS: In this multicenter, double-blind, placebo-controlled study, 320 anemic patients (hemoglobin or=25% improvement; mean difference = 13%; 95% CI = 2% to 23%, P =.019) than patients receiving placebo. Patients receiving darbepoetin alfa did not appear to have any untoward effect in disease outcome and did not develop antibodies to the drug. Adverse events were similar between the groups. CONCLUSIONS: Patients with chemotherapy-associated anemia can safely and effectively be treated with weekly darbepoetin alfa therapy. Darbepoetin alfa decreased blood transfusion requirements, increased hemoglobin concentration, and decreased fatigue. Although no conclusions can be drawn about survival from this study, the potential salutary effect on disease outcome warrants further investigation in a prospectively designed study.     

Addition of darbepoetin alfa to dose-dense chemotherapy: results from a randomized phase II trial in small-cell lung cancer patients receiving carboplatin plus etoposide

Darbepoetin alfa, an erythropoiesis-stimulating agent (ESA), is used in cancer patients as a supportive care for anemia. For small-cell lung cancer (SCLC), several studies have shown that the administration of ESAs does not affect survival but decreases the need for blood transfusions and improves the quality of life (QOL) of patients receiving chemotherapy. The present randomized phase II study assessed the feasibility, efficacy, and safety of the administration of darbepoetin alfa to patients with SCLC receiving dose-dense (every 2 weeks) standard chemotherapy consisting of carboplatin plus etoposide, pegfilgrastim prophylactically. Seventy-four chemotherapy-naive patients with limited or extensive SCLC received combination chemotherapy for 6 cycles, and half of the patients additionally received darbepoetin to achieve a target hemoglobin concentration of 12-13 g/dL. The primary study outcome, progression-free survival, showed no difference between the 2 arms of the study. Among the secondary endpoints, objective response was similar in the presence and absence of darbepoetin (best response rates = 75.0% vs. 77.8%). Likewise, 1-year survival rates were not different between the 2 treatment arms (40.1% vs. 45.9%). There were no significant differences in grade 3/4 toxicities. As expected, the need for blood transfusions differed significantly: 19.4% of patients in the darbepoetin arm received transfusions versus 38.9% in the control arm. Analysis of European Organization for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ-C30) scales at different time points showed that the darbepoetin group's QOL was significantly better for certain readouts and never significantly worse than that of the control group. Thus, the combination of darbepoetin alfa with dose-dense carboplatin plus etoposide was feasible and well tolerated. Addition of darbepoetin alfa to chemotherapy lowered the need for blood transfusions and did not affect measures of survival and objective response.     

Darbepoetin alfa administered every three weeks is effective for the treatment of chemotherapy-induced anemia

Patients with cancer receiving chemotherapy often have chemotherapy-induced anemia (CIA) and reduced quality of life. Darbepoetin alfa can effectively treat CIA when administered at an extended dosing interval of once every 3 weeks (Q3W). Darbepoetin alfa administered Q3W may allow synchronization of darbepoetin alfa therapy with chemotherapy administered Q3W. This multicenter, open-label, 16-week study evaluated the effectiveness and safety of darbepoetin alfa administered as a fixed dose (300 mug) Q3W in patients with CIA. Eligible patients (> or =18 years) were anemic (hemoglobin <11g/dl), had a nonmyeloid malignancy, and were receiving multicycle chemotherapy. This analysis includes 1,493 patients who received at least one dose of darbepoetin alfa. The effect of baseline hemoglobin (<10 or > or =10 g/dl) on clinical outcomes was evaluated. Patients in the > or =10-g/dl stratum achieved the hemoglobin target range (11-13 g/dl)in less time than patients in the <10-g/dlstratum (3 weeks vs. 9 weeks). More patients in the > or =10-g/dl stratum achieved the hemoglobin target range (87% vs. 66%); however, similar proportions of patients in both strata maintained hemoglobin within the target range (73% vs. 71%). Fewer patients in the > or =10-g/dl stratum received RBC transfusions from week 5 to the end of the study (12% vs. 28%). Over 50% of patients in both strata reported clinically significant improvements (> or =3-point increase) in Functional Assessment of Cancer Therapy-Fatigue score. Twenty-eight percent of patients reported serious adverse events; 3% of all patients had a venous or arterial thrombotic event. This study demonstrates that darbepoetin alfa Q3W is well tolerated and effective for treating CIA.     

Efficacy and safety of every-2-week darbepoetin alfa in patients with anemia of cancer: a controlled, randomized, open-label phase II trial

This randomized, controlled trial evaluated the effect of darbepoetin alfa on hospitalization days, transfusion requirements, hemoglobin levels, and fatigue in patients with anemia of cancer (AOC). Eligible patients were anemic (hemoglobin or=18 years old, and had not received chemotherapy or radiotherapy within 4 weeks of study screening. Patients were randomized 4:1 to receive darbepoetin alfa, 3.0 microg/kg every 2 weeks (Q2W) (n = 226), or observation only for 12 weeks (n = 59), followed by an optional 9 weeks of darbepoetin alfa, 3.0 microg/kg Q2W. Endpoints were compared between the two treatment arms at week 13. A planned interim analysis indicated that assumptions regarding hospitalization in the study design were incorrect, so the study was terminated early. Therefore, results for the primary endpoint should be interpreted cautiously. The hospitalization rate was similar (0.5 days) for both the darbepoetin alfa and observation groups (p = .73). Transfusion incidence (weeks 5-12) was significantly lower for darbepoetin alfa patients (8%) than for observation patients (22%) (p = .0092). By week 13, hemoglobin increased by 2.1 g/dl in patients receiving darbepoetin alfa, compared with 0.1 g/dl in the observation group p < .0001. Hemoglobin improvements were paralleled by an increase in Functional Assessment of Cancer Therapy-Fatigue score (mean change in score at week 13: darbepoetin alfa, 6.0; observation, 2.2; p < .05). Darbepoetin alfa Q2W can significantly improve hemoglobin levels and reduce transfusion requirements in patients with AOC, resulting in significant improvements in health-related quality of life.     

Darbepoetin alfa for chemotherapy-induced anemia: evolution to extended dosing intervals

Anemia is a frequent problem in cancer patients, especially in those treated with chemotherapy, and has an important negative impact on quality of life. Red blood cell transfusions provide clear but rather temporary comfort. The development of erythropoietic stimulating agents (ESAs) led to a more durable anemia treatment. Darbepoetin alfa is a unique ESA with a long plasma half life, thereby suitable for administration with different dosing intervals. Apart from administration every week, darbepoetin alfa also proved to be efficient in reducing red blood cell transfusion rates and in improving health-related quality of life when administered at a dose of 500 µg once every 3 weeks. This is a convenient therapy schedule because it can be synchronized with the chemotherapy cycle in many patients. Recently, concerns have been raised about the long-term safety of ESAs, more specifically about their effect on survival. Available data must be interpreted with caution, but at present there is no clear evidence to support a negative effect on outcome with darbepoetin alfa therapy when used according to the guidelines for treatment of chemotherapy-induced anemia. Further studies focusing on survival as the primary end point are ongoing.     

Evaluating erythropoietic agents for the treatment of anaemia in the oncology setting

Anaemia is a common complication of cancer and its treatment. It is also associated with substantial impairment of patient quality of life (QOL). Erythropoietic agents are primary treatment options for cancer-related anaemia (CRA). This review summarises evidence supporting clinical use of the approved erythropoietic agents (epoetin alfa, epoetin beta, darbepoetin alfa). A MEDLINE((R)) search from January 2000 to September 2004 using the search terms "epoetin alfa," "epoetin beta," "darbepoetin alfa," "erythropoietin," and "anaemia" was conducted to identify studies evaluating erythropoietic agents in the treatment of CRA. Recent presentations at professional meetings were also included. Erythropoietic agents increase haemoglobin levels, decrease transfusion requirements, and improve QOL in patients with CRA. However, variations in study design, patient populations, dose titration schedules, and outcome measures among available studies make data comparisons between clinical trials difficult. Head-to-head trials are comparing erythropoietic agents in a randomised setting; other trials are evaluating optimal dosage schedules. Clinically relevant differences among approved erythropoietic agents have not been determined in direct comparative trials; however, epoetin alfa appears to be at least as effective as darbepoetin alfa in treatment of CRA.     

Effects of chemotherapy on endogenous erythropoietin levels and the pharmacokinetics and erythropoietic response of darbepoetin alfa: a randomised clinical trial of synchronous versus asynchronous dosing of darbepoetin alfa

The introduction of longer-acting erythropoietic agents into the practice of oncology has demanded an understanding of the interaction of chemotherapy with the pharmacokinetics and haematological effects of these erythropoietins. We report results of a randomised trial comparing the haematological effects of darbepoetin alfa, 6.75 mug/kg, administered once every 3 weeks to anaemic cancer chemotherapy patients on either an asynchronous (day 15) or synchronous (day 1) schedule relative to their every-3-week chemotherapy. A total of 81 patients were randomised and received the study drug (43 asynchronous; 38 synchronous). No difference was observed between groups in the primary endpoint of mean haemoglobin change after 6 weeks of therapy (P=0.45) and change scores were similar to those observed with standard weekly darbepoetin alfa therapy. In a subset of patients evaluated with intensive pharmacokinetic sampling, an increase in endogenous erythropoietin concentration (up to 4-fold) lasting approximately 1 week following chemotherapy administration was observed in both groups. Synchronous administration of darbepoetin alfa was associated with a 1.3-fold increase in the area under the darbepoetin alfa concentration-time curve compared with asynchronous administration. Our data suggest that darbepoetin alfa is effective administered every 3 weeks regardless of timing of administration with respect to chemotherapy and that receptor-mediated uptake by the erythron may be an important clearance mechanism for erythropoietic proteins.     

Efficacy of pegfilgrastim and darbepoetin alfa as hematopoietic support for dose-dense every-2-week adjuvant breast cancer chemotherapy.

PURPOSE: Dose-dense, every-2-week adjuvant chemotherapy using doxorubicin/cyclophosphamide (AC; 60/600 mg/m2 every 2 weeks x four cycles) followed by paclitaxel (175 mg/m2 every 2 weeks x four cycles), requiring filgrastim on days 3 through 10 of each cycle has been shown to improve survival compared with every-3-week treatment schedules but is associated with greater risk of RBC transfusion (13%). The role of long-acting hematopoietic growth factors in facilitating every-2-week chemotherapy and minimizing hematologic toxicity has not been established. PATIENTS AND METHODS: Women with stage I to III breast cancer received dose-dense AC --> paclitaxel as neoadjuvant or adjuvant chemotherapy. Patients received pegfilgrastim 6 mg subcutaneous (SQ) on day 2 of each cycle. Darbepoetin alfa was initiated at 200 microg SQ every 2 weeks for hemoglobin < or = 12 g/dL, and administered thereafter, according to a preplanned algorithm. The primary end points were to evaluate the percentage of patients with febrile neutropenia and the percentage of patients requiring RBC transfusion. RESULTS: Among 135 women treated on this single arm study, there were two cases of febrile neutropenia (incidence 1.5%). No patients received RBC transfusion. Darbepoetin alfa therapy was initiated in 92% of patients. The modest leukocytosis seen during paclitaxel cycles was attributable, in part, to corticosteroid premedication. Other toxicity and dose-delivery were similar to dose-dense AC --> paclitaxel in Cancer and Leukemia Group B 9741. CONCLUSION: Pegfilgrastim and darbepoetin alfa are effective and safe in facilitating every-2-week AC --> paclitaxel, minimizing rates of febrile neutropenia and RBC transfusion.     

Cost-effectiveness of darbepoetin alpha in an every-3-weeks schedule

Darbepoetin alfa is an erythropoeisis-stimulating agent that can be given in an every week (QW) or every-3-weeks (Q3W) schedule for the treatment of chemotherapy-induced anemia. We assessed the cost-effectiveness of Q3W darbepoetin alfa compared to QW darbepoetin alfa, from both a health-care and societal perspective in France. Based on a clinical trial design, a decision-tree model with a 16-week time horizon was developed in Excel(R). A probabilistic sensitivity analysis was carried out. The Q3W regimen resulted in lower total costs per patient from the health-care (-180 euro [95 % CI = -461.2;74]) and societal (-243 euro [95 % CI = -588;62]) perspective. Probabilistic sensitivity analysis showed an incremental cost-effectiveness ratio in favor of Q3W treatment from both perspectives. The Q3W schedule is cost saving compare to the QW schedule. It also reduces the burden of the frequent visits for the patients.