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Every-2-Week Darbepoetin Alfa Is Comparable to rHuEPO in Treating Chemotherapy-Induced Anemia

Every-2-Week Darbepoetin Alfa Is Comparable to rHuEPO in Treating Chemotherapy-Induced Anemia

ABSTRACT: The safety and efficacy of darbepoetin alfa (Aranesp) at 3.0 µg/kg administered every 2 weeks and recombinant human erythropoietin (rHuEPO) given as 40,000 U weekly or 150 U/kg three times weekly were evaluated by pooling data from three darbepoetin alfa clinical studies. All studies enrolled anemic (hemoglobin ≤ 11.0 g/dL) patients receiving multicycle chemotherapy. Open-label study drug was administered by subcutaneous injection. Hemoglobin concentrations, red blood cell transfusion requirements, and standard safety parameters were evaluated. Of 260 patients who received darbepoetin alfa at 3.0 µg/kg every 2 weeks and 115 patients who received rHuEPO three times weekly or once weekly, hematopoietic response (change in hemoglobin from baseline of ³ 2 g/dL or hemoglobin concentration of ³ 12 g/dL) was achieved in 71% (95% confidence interval [CI] = 65%-78%) of patients who received darbepoetin alfa every 2 weeks, comparable to the response in patients who received rHuEPO (71%; 95% CI = 61%-81%). The mean increase in hemoglobin concentration over 13 weeks was also similar: 1.48 g/dL (95% CI = 1.28-1.68 g/dL) for darbepoetin alfa and 1.31 g/dL (95% CI = 0.97-1.64 g/dL) for rHuEPO. The proportion of patients in the darbepoetin alfa group requiring transfusions was lower (7%; 95% CI = 4%-11%) than that in the rHuEPO group (14%; 95% CI = 8%-22%). Darbepoetin alfa every 2 weeks was well tolerated with a safety profile comparable to that of rHuEPO. In conclusion, darbepoetin alfa at a dose of 3.0 µg/kg given every 2 weeks safely increases hemoglobin concentration to the same extent as rHuEPO. [ONCOLOGY 16(Suppl 11):31-36, 2002]

It is increasingly recognized that
fatigue in cancer patients—primarily caused by anemia resulting from chemotherapy or other aspects of the
disease process—is associated with debilitating effects on quality of life and
functioning.[1,2] Surveys performed by the multidisciplinary Fatigue Coalition
indicated that fatigue was the primary complaint in one-quarter of patients
after chemotherapy (ahead of nausea at 13%), and that 61% of cancer patients
felt their lives were affected more by fatigue than by pain associated with
their disease.[3] Cancer-related anemia has traditionally been treated with red
blood cell transfusions; however, concerns over the safety of the blood supply
and potential adverse effects of transfusions in cancer patients have led to the
development of erythropoietic agents as a safer alternative for increasing
hemoglobin levels in these patients.

Improved understanding of the deleterious effects of anemia and the
availability of recombinant human erythropoietin (rHuEPO) have led to a great
deal of active investigation of the benefits of erythropoietic therapy in
patients with chemotherapy-induced anemia. Most recently, with the development
of darbepoetin alfa (Aranesp) and research into once-weekly therapy for rHuEPO (rHuEPO
is licensed for this indication at a dose of 150 U/kg three times weekly),
considerable efforts have been focused on reducing the need for frequent
injections. For patients with cancer (and their caregivers), each injection can
be a reminder of their disease; for those for whom self-injection is not an
option, each clinic visit is an interruption of normal life and may create
significant logistic challenges relating to transportation, child care, or work.
For clinic staff, administrative work and time are increased. A recent study of
patients with chronic renal insufficiency reported that, on average, these
patients spent 90 minutes traveling to/from the clinic and waiting to be seen,
and 49% relied on someone else for transportation.[4] It is likely that these
findings would also be true for cancer patients. Thus, reducing the dosing
frequency of erythropoietic agents given to patients with chemotherapy-induced
anemia would be beneficial.

Weekly administration was shown to be effective in patients with
chemotherapy-induced anemia in a large, open-label, uncontrolled study using a
single subcutaneous injection of 40,000 U of rHuEPO (this dose could be
increased to 60,000 U if a 1.0-g/dL hemoglobin increase had not been observed
after 4 weeks).[5] With this regimen, 68% of patients achieved a hematopoietic
response (a hemoglobin concentration ³ 12.0 g/dL and/or an increase
of ³ 2.0 g/dL without preceding transfusions) by the end of the 16-week
treatment period, which is comparable to the response observed with
three-times-weekly dosing.[5,6] However, this dose represents an increase of
approximately 33% over the more routinely studied dose and schedule of 150 U/kg
three times weekly[7-9] or the dosing regimen of 10,000 U of rHuEPO three times
weekly, which has also been reported.[6] Based on these results, weekly dosing
is now accepted in clinical practice in the United States, although not in other
regions.

Darbepoetin alfa, a unique recombinant protein produced by modifying the gene
for erythropoietin, is a more potent erythropoietic agent. Darbepoetin alfa
stimulates erythropoiesis through the same mechanism as endogenous
erythropoietin and rHuEPO.[10] However, darbepoetin alfa was engineered to have
additional carbohydrate side chains (five total N-linked glycosylation side
chains with up to 22 sialic acid residues) compared with rHuEPO (three total
N-linked glycosylation side chains with up to 14 sialic acid residues).
Sialic acid content is directly correlated with in vivo activity, possibly due
to the degree of clearance by the asialoglycoprotein receptor in the liver[11];
the increased sialic acid content of darbepoetin alfa reduces its clearance and
results in an extended serum residence time.[12]

Darbepoetin alfa was initially approved for use in patients with renal
failure. Pharmacokinetic studies in this indication showed that darbepoetin alfa
had an approximately threefold longer terminal half-life than rHuEPO (25.3 vs
8.5 hours).[13] An extensive clinical development program has evaluated the
pharmacokinetics, efficacy, and safety of various dose and schedule combinations
of darbepoetin alfa during cancer chemotherapy. Phase I and II studies explored
dosing intervals ranging from weekly to every-4-week administration.[14-21]
These included an every-2-week dosing schedule, which appeared to be effective
in alleviating anemia in patients with solid tumors receiving
chemotherapy.[14,19]

Comparisons between rHuEPO studies (or between rHuEPO studies and darbepoetin
alfa studies) may be confounded due to differences in factors such as study
design, populations, treatment duration, analytical methodologies, response
definitions, or the use of analysis sets other than the intent-to-treat set. To
obtain a more precise estimate of the effect of darbepoetin alfa administered at
3.0 µg/kg every 2 weeks, and to evaluate the relative effect of this dose
and schedule compared with rHuEPO, data from three clinical studies of similar
design have been pooled.[14-17,19,20] Unlike comparisons with historical
literature, this approach eliminates differences in analytical methodologies,
treatment duration, and other potentially confounding factors. This report
describes the results of this combined analysis.

Patients and Methods

Study Population

The population evaluated and the design of each of the three studies included
in these analyses were similar. All study centers were in the United States.
Eligible patients were men or women ³ 18 years of age who were
receiving multicycle chemotherapy and had anemia (hemoglobin concentration
£
 11.0 g/dL). Patients were required to have adequate renal and hepatic
function and could not be iron deficient (defined as both transferrin saturation
< 15% and ferritin < 10 ng/mL). Patients with known cardiac
disease or hematologic disorders that could cause anemia were not eligible. Each
center’s independent ethics committee or central ethics committee approved the
protocol, and patients provided written informed consent before any
study-specific procedures were done.

The principal difference between the eligibilty criteria in the three studies
was tumor type (solid tumors were specified in two studies and nonmyeloid
malignancies in the third). However, as most patients in both groups had solid
tumors, and no difference has been noted between the effect of erythropoietic
agents on patients with hematologic malignancies and those with solid
tumors,[5,6] this is not thought to have an impact on the validity of the
conclusions from this pooled analysis.

Study Design

All three studies were multicenter and open-label in design. The dose of
rHuEPO could be increased in both studies contributing rHuEPO data (at week 8 or
week 6), and the dose of darbepoetin alfa could be increased in one of the two
studies contributing darbepoetin alfa data (at week 7). The requirement for
withholding drug due to reaching specified maximum hemoglobin concentrations
(14 g/dL for women, 15 g/dL for men) was the same in all studies. Red
blood cell transfusions were recommended if hemoglobin decreased to £ 8.0
g/dL or patients had symptoms

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