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Darbepoetin Alfa: Impact on Treatment for Chemotherapy-Induced Anemia and Considerations in Special Populations

Darbepoetin Alfa: Impact on Treatment for Chemotherapy-Induced Anemia and Considerations in Special Populations

ABSTRACT: Our objective was to evaluate the effects of darbepoetin alfa (Aranesp) on hemoglobin and transfusions in anemic patients with cancer undergoing chemotherapy, and the impact of age, sex, baseline hemoglobin, chemotherapy type, and tumor type. Patients were randomized to one of three darbepoetin alfa groups based on average weekly dose (< 1.5 µg/kg, 1.5 to 2.25 µg/kg, and > 2.25 µg/kg) or to placebo. Dose response was evaluated for change in hemoglobin, hemoglobin and hematopoietic responses, and red blood cell transfusion rates. Hazard ratios for the incidence of hemoglobin response and transfusions were calculated. Adverse events and antibody formation were assessed. Treatment effects were observed for all hemoglobin end points and incidence of transfusion. The incidence of hematopoietic response among the darbepoetin alfa dose groups ranged from 46% (95% confidence interval [CI] = 33%-60%) to 74% (95% CI = 66%-81%) and increased with higher darbepoetin alfa dose. Patients receiving darbepoetin alfa were more likely to exhibit a hemoglobin response and less likely to require a transfusion, compared with placebo, irrespective of the patient characteristics examined. No increased risk of adverse events and no development of neutralizing antibodies were observed with darbepoetin alfa use. Darbepoetin alfa increased the likelihood of a hemoglobin response and decreased the need for transfusions in cancer patients with chemotherapy-induced anemia. [ONCOLOGY 16(Suppl 11):37-44, 2002]

Cancer patients commonly
exhibit anemia that has a multi-factorial etiology and involves a variety of symptoms, including fatigue,
dizziness, dyspnea, headache, and lethargy.[1-5] This anemia can have an adverse
impact on these patients, potentially resulting in increased morbidity and
decreased quality of life.[2,5] The frequency and severity of anemia are
dependent upon many factors, including the type, duration, and extent of the
malignancy, as well as the type and intensity of the chemotherapy.[5] Severe
anemia or symptomatic mild-to-moderate anemia requires medical management,
possibly through the use of red blood cell (RBC) transfusions, which involves
potential risks including acute transfusion reactions or transmission of
infectious agents.[6,7] Such risks may prove to be unacceptable, as frequent RBC
transfusions with allogeneic blood may adversely affect the immune system of
these patients, thereby increasing the likelihood of infections, decreasing
times to relapse, or shortening survival times.[7] Even mild (10 to 12 g/dL) and
moderate (8 to 10 g/dL) anemia may be poorly tolerated by some patients because
of the resultant increased fatigue and decreased quality of life; however, RBC
transfusions are no longer considered routine medical management in these
patients because of the associated risks.[5,8,9]

The availability of recombinant human erythropoietin (rHuEPO)
for the safe and effective treatment of chemotherapy-induced anemia in cancer
patients has provided an alternative, or supplement, to blood transfusions in
this population.[10] Furthermore, some studies have shown rHuEPO to be
associated with improvements in health-related quality of life.[8,9] Many
studies have demonstrated generally similar effects of rHuEPO on the reduction
of the requirement for RBC transfusions and the ability to increase hemoglobin
concentration in patients across a broad range of nonmyeloid malignancies and
chemotherapy agents, although a range of response rates has been
observed.[8,9,11-15]

As observed by Seidenfeld et al,[16] comparisons between studies
are difficult because different studies used varying definitions of response,
different analysis populations (eg, intent-to-treat vs efficacy evaluable
subsets), and an assortment of treatment period durations. Abels and
colleagues[11] reported 48% and 58% response rates (³ 6 hematocrit points) for
patients treated with cisplatin and noncisplatin chemotherapy, respectively,
during a 12-week treatment period in which rHuEPO dose increases were permitted,
while Glaspy et al[8] reported a 53% hemoglobin response rate (³ 2.0-g/dL
increase in hemoglobin) after a 16-week treatment period.

Recently, in a report of a meta-analysis of the use of rHuEPO to
treat chemotherapy-induced anemia, Seidenfeld et al indicated that evaluation of
a treatment effect for rHuEPO was impeded because there were a limited number of
studies with large populations, and few studies with consistent designs.[16]
However, based on this analysis, Seidenfeld et al[16] concluded that there was
no evidence that earlier initiation of rHuEPO therapy spared more patients from
transfusions or resulted in greater quality-of-life improvements than waiting
for hemoglobin concentrations to decline to nearly 10 g/dL.

Darbepoetin alfa (Aranesp) is a next-generation erythropoietic
protein that has been shown to be safe and effective in treating
chemotherapy-induced anemia in cancer patients.[17-22] Compared with epoetin
alfa, darbepoetin alfa has an increased sialic acid content, which contributes
to its extended serum half-life (approximately threefold longer) and increased
biologic activity.[23,24] Darbepoetin alfa and rHuEPO appear to act by similar
mechanisms, essentially by binding to the erythropoietin receptor and
stimulating erythropoiesis, thus causing RBC precursors to proliferate and
enhancing their survival. Darbepoetin alfa, however, exhibits an early and
sustained erythropoietic effect, allowing darbepoetin alfa to be administered
less frequently than rHuEPO while maintaining efficacy.

At the time of initial licensure of a new agent, many questions
regarding its clinical utility are still not yet fully reported in the
literature. There exists a need to elaborate the various characteristics of the
new agents to permit effective clinical use. These characteristics include the
dose response, the impact of important covariates (ie, age or sex) on the
treatment effect, the nature of any specific recommendations that may be needed
if a differential treatment effect is observed in specific subpopulations, and
any specific safety precautions that should be undertaken with regard to
high-risk groups, eg, those with cardiovascular comorbidity. Frequently, a
single study cannot provide the answers to all these questions, and a
comprehensive evaluation of all the experience gained in clinical studies is
required to draw meaningful conclusions. While the answers to these questions
are unlikely to differ significantly between darbepoetin alfa and rHuEPO due to
the identical mechanism of action, comprehensive reviews addressing these
important data are limited even for rHuEPO, despite 10 years of clinical use.

We pooled data from four completed, similarly designed studies
of darbepoetin alfa[17-19] to perform an integrated analysis of the relationship
of darbepoetin alfa dose to a number of efficacy variables. Additionally,
results are presented that evaluate the treatment effect of darbepoetin alfa
among a number of subgroups based on important patient characteristics,
including age, sex, baseline hemoglobin, tumor type, and chemotherapy type.

Methods

Study Population

The main differences between the eligibility criteria in the
four studies included in this analysis were tumor type (lung cancer vs solid
tumors vs lymphoproliferative malignancies) and chemotherapy restriction
(platinum-containing only vs no restrictions). Common eligibility criteria
included the following: Eligible patients had to be of legal age with a
diagnosis of cancer (solid tumors or lymphoproliferative malignancies) and
anemia (hemoglobin concentration £ 11.0 g/dL) primarily due to cytotoxic
chemotherapy or cancer, and had to be receiving concomitant chemotherapy for the
duration of the study treatment period (12 weeks). Patients also were required
to have adequate renal function (serum creatinine level of ≤ 2.0 mg/dL) and an
Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 2
(three studies) or 0 to 3 (one study).

Patients who were anemic for reasons other than cancer or its
treatment and patients who had received RBC transfusions immediately before
study entry (two RBC transfusions within 4 weeks or any RBC transfusions within
2 weeks) were excluded. To ensure that patients were not anemic due to nutrition
or iron deficiency, patients were required to have a vitamin B12 level of
³ 200
pg/mL, a folate level of ³ 2.0 ng/mL, and ferritin and transferrin saturation
levels of at least 10 mg/dL and 15%, respectively. Patients with primary or
metastatic cancer involving the central nervous system, and patients with
seizures, unstable angina, or uncontrolled hypertension, were also excluded from
all studies.

The institutional review boards or ethics committees of the
participating centers approved the protocol. Informed consent was obtained from
all patients before any study-related procedure was performed.

Study Design and Conduct

Four multicenter, randomized studies were conducted in the
United States, Europe, Australia, and Canada. One study was open-label in design
and used rHuEPO as an active control. The remaining three studies were
double-blind and placebo-controlled.

The studies included doses of darbepoetin alfa from 0.5 to 8.0
µg/kg once weekly and 3.0 to 9.0 µg/kg every 2 weeks. In addition to similar
eligibility criteria, all of the studies had identical, planned treatment
lengths (12 weeks), identical dose adjustment rules upon reaching
predefined hemoglobin thresholds, and identical recommendations regarding
transfusions. Two studies allowed dose increases of darbepoetin alfa if the
patient’s hemoglobin had not increased by at least 1 g/dL after approximately
1 month of therapy (week 5 or 6).

Rationale for Pooling Data

The information from each of the selected studies was integrated
to obtain a larger patient sample in which to evaluate the dose-response
relationship for a nonmyeloid malignancy population as a whole, as well as to
evaluate the impact of important covariates such as age, sex, baseline
hemoglobin, chemotherapy type, and tumor type on the treatment effect of
darbepoetin alfa. As the individual studies included in this analysis involved
specific tumor types, pooling of the data from these studies resulted in a
patient population with a broader spectrum of tumor types and chemotherapy
regimens consistent with the previously published data on rHuEPO.

The criteria for pooling were mainly clinical—the studies had
been designed with common characteristics in terms of treatment length,
intervention strategies, and assessments, as well as patient eligibility
criteria. Importantly, both the hemoglobin- and transfusion-based results from
the four studies were similar where common average weekly doses existed for such
a comparison. For example, in the average weekly dose range 1.5 to 2.25 µg/kg,
the difference between darbepoetin alfa and placebo with respect to change in
hemoglobin over a 12-week treatment phase was between 1.3 and 1.6 g/dL for the
three placebo-controlled studies. In the active controlled study, similar
changes from baseline were observed.

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