Recombinant human interleukin-11 (rhIL-11, also known as oprelvekin
[Neumega]), is the only platelet growth factor currently available in
the United States for the prevention of chemotherapy-associated
severe thrombocytopenia in patients with nonmyeloid malignancies who
are at high risk for the development of this condition. The
recommended treatment regimen in adults is 50 µg/kg administered
subcutaneously, once daily, beginning 6 to 24 hours after completion
of the chemotherapy cycle and continuing until the platelet count is ³
50,000/µL. Individual treatment courses longer than 21 days are
not recommended, and the drug should be discontinued at least 2 days
before the start of the next chemotherapy cycle.
The results of several clinical trials have established the role of
rhIL-11 as a thrombopoietic growth factor. Dose-ranging and
placebo-controlled[2,3] clinical trials of rhIL-11 in adults and open
clinical trials of rhIL-11 in children[4,5] undergoing chemotherapy
for solid tumors or lymphoma have provided clinical evidence of
attenuation of platelet nadir and stimulation of platelet production.
These trials have shown that rhIL-11 accelerates the recovery of
platelet counts, facilitating the administration of the planned
chemotherapy without dose modification. This article presents
background pharmacologic information and a discussion of data from
clinical trials supporting the efficacy of rhIL-11, through its
thrombopoietic effects, for the prevention of chemotherapy-induced
severe thrombocytopenia in high-risk patients with nonmyeloid
rhIL-11 is well absorbed subcutaneously with a bioavailability of
more than 80%; repeated doses do not accumulate in plasma. The
pharmacodynamic properties of rhIL-11 were determined in a phase I
dose-ranging study in nonmyelosuppressed patients (age range: 26 to
67 years) with locally advanced (stage IIIB, n = 3) or metastatic
(stage IV, n = 13) breast cancer. rhIL-11 was administered both
before (cycle 0) and after up to four monthly cycles of
After a 14-day washout period following the prechemotherapy dosing of
rhIL-11, patients received two to four cycles of chemotherapy with
cyclophosphamide (Cytoxan, Neosar) at a dose of 1,500 mg/m² and
doxorubicin at 60 mg/m² administered on the first day of each
cycle. Chemotherapy was repeated every 28 days. Cohorts of at least
three patients received rhIL-11 alone at doses of 10, 25, 50, 75, or
100 µg/kg/d subcutaneously for 12 days (days 3 through 14 of
each treatment cycle). The use of granulocyte colony-stimulating
factor (G-CSF, filgrastim [Neupogen]) (5 µg/kg/d) was permitted
during the third and fourth chemotherapy cycles if patients
experienced a febrile neutropenic event or an absolute neutrophil
count (ANC) of £ 500/µL for more
than 5 days during the first two cycles.
In nonmyelosuppressed patients (ie, cycle 0, prior to chemotherapy),
daily dosing with rhIL-11 over the dose range of 10 to 75 µg/kg
produced a dose-dependent rise in platelet count that was apparent
between 5 and 9 days after the start of dosing (Figure
1). Platelet counts reached peak levels after a median of 14 to
19 days. Figure 1 shows the
platelet-response profile at doses of 10, 25, and 50 mg/kg per
day.[1,7] These doses produced increases in platelet counts of 76%,
93%, and 108%, respectively, from baseline values. At the
50-µg/kg/d dose, peak platelet counts occurred at a median of 16
days after the initiation of therapy. As seen in Figure
1, increases in platelet counts were sustained for approximately
1 week after rhIL-11 was discontinued. At the 75-µg/kg/d dose,
an increase of 185% over the baseline value was observed.
Across two chemotherapy cycles (myelosuppressed state), rhIL-11 doses ³
25 µg/kg/d produced higher median nadir platelet counts (>
100,000/µL) than the 10-mg/kg/d dose (< 70,000/µL). Only
doses that were ³ 25 µg/kg/d
prevented severe thrombocytopenia (defined as a platelet count <
20,000/µL, the level often used as a threshold for platelet
Effects on Platelet Function and Coagulation Factors
Treatment with rhIL-11 had no apparent effect on platelet function.
There were no changes in either adenosine diphosphate
(ADP)induced platelet activation or platelet aggregation
induced by various agents (ADP, epinephrine, collagen, ristocetin, or
arachidonic acid), indicating a lack of effect of rhIL-11 on platelet
reactivity or platelet aggregating behavior, respectively. At all
doses studied, treatment with rhIL-11 was not associated with
significant changes in prothrombin time or partial thromboplastin
At the 50-µg/kg/d dose, a statistically significant increase
from baseline in mean fibrinogen level was seen by day 12 of
treatment. These findings are in accordance with those of an earlier
study in healthy adult volunteers in which treatment with rhIL-11 (25
µg/kg/d subcutaneously for 7 days), resulted in statistically
significant increases in mean plasma fibrinogen concentration and
mean von Willebrand factor, compared with both baseline and placebo
(fibrinogen: P < .001 vs baseline, P < .01 vs
placebo; von Willebrand: P < .001 vs baseline, P =
.02 vs placebo).
In this study, rhIL-11 alone (without G-CSF) did not ameliorate
chemotherapy-associated leukopenia or neutropenia, suggesting that
the predominant biological activity of rhIL-11 is on the
megakaryocytic cell lineage, contrasting with the stimulation of
other hematopoietic lineages observed in vitro. There was no
evidence of interference by rhIL-11 on the efficacy of G-CSF in
ameliorating neutropenia when these cytokines were administered
concurrently. This is an important finding because the simultaneous
use of these two cytokines addresses the two major dose-limiting
toxicities of myelotoxic chemotherapy.
Treatment with rhIL-1l was associated with dose-related increases in
acute-phase proteins during both pre- and postchemotherapy cycles. At
all doses studied, maximal increases in C-reactive protein occurred
within the first week of therapy and remained at statistically
significantly (P < .05) elevated levels from day 5 through
day 15, compared with baseline pretreatment levels. Levels of
C-reactive protein rapidly returned to baseline levels following
discontinuation of rhIL-11.
Treatment with rhIL-11 was associated with an expansion in plasma
volume of approximately 20%, which is believed to occur secondary to
rhIL-11 stimulation of renal sodium reabsorption. The reversible
expansion in plasma volume led to the development of dependent
peripheral edema and dilutional anemia as two of the most commonly
reported side effects. Edema and constitutional symptoms (myalgia,
arthralgia, headache, and fatigue) were primarily considered to be
mild or moderate in severity at rhIL-11 doses of £
Edema was also a common occurrence during subsequent controlled
clinical evaluations of rhIL-11 at 50 µg/kg, but it was usually
mild to moderate, easily managed, and either resolved spontaneously
or relieved by temporary use of a diuretic.[2,3] In these studies,
plasma volume expansion was also the most likely underlying cause of
other observed side effects, such as palpitations, dyspnea, headache,
and transient atrial arrhythmias. Increased plasma volume may have
contributed to the development of atrial arrhythmias in a subset of
patients by causing atrial distention (which has been demonstrated in
dogs treated with rhIL-11) and a subsequent decrease in the
atrial refractory period.
In patients with cancer, transtelephonic monitor data showed no
evidence of any effects of rhIL-11 treatment on cardiac conduction
intervals, specifically PR, QRS, QT, or QTc intervals, indicating
that rhIL-11 has no direct effect on cardiac function.
rhIL-11 did not cause clinically significant fevers or capillary leak
syndrome. The 75-µg/kg/d dose was not associated with true
dose-limiting toxicity but was subjectively less well tolerated than
lower doses. Thus, evaluation of this dose was not pursued in
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