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Tolerability and Side-Effect Profile of rhIL-11

Tolerability and Side-Effect Profile of rhIL-11

ABSTRACT: Safety data from two randomized phase II and one abbreviated phase III placebo-controlled, double-blind clinical studies in adult patients with nonmyeloid malignancies indicate that recombinant human interleukin-11 (rhIL-11, also known as oprelvekin [Neumega]) has an acceptable toxicity profile as therapy for the mitigation of chemotherapy-induced thrombocytopenia. Preliminary data also indicate that rhIL-11 is well tolerated by pediatric patients with similar types of cancers. Adverse events associated with rhIL-11 are generally mild or moderate, reversible with drug discontinuation, and easily managed. Many of the common adverse events of rhIL-11—including edema, dyspnea, pleural effusions, conjunctival injection, and in some patients, atrial arrhythmia—occur in association with fluid retention. However, these adverse events can be medically managed and need not limit the use of rhIL-11, particularly if ameliorative measures, such as salt restriction and occasional prophylaxis with a potassium-sparing diuretic to minimize peripheral edema, have been instituted along with close monitoring of fluid and electrolyte status. Such measures are suggested for any patient treated with a diuretic, especially patients with cancer who are receiving multiple medications that complicate overall care. Administration of sequential cycles of rhIL-11 treatment does not appear to result in an increased incidence of adverse events or bone marrow exhaustion. rhIL-11 does not appear to interact adversely with concomitantly administered chemotherapeutic agents or agents commonly used for supportive care, including granulocyte colony-stimulating factor (G-CSF, filgrastim [Neu-pogen]). [ONCOLOGY 14(Suppl 8):41-47, 2000]

Introduction

Recombinant human interleukin-11 (rhIL-11, also known as oprelvekin
[Neumega]) was approved by the US Food and Drug Administration (FDA)
in November 1997 to prevent severe thrombocytopenia and to reduce the
need for platelet transfusions following myelosuppressive
chemotherapy in patients with nonmyeloid malignancies who are at high
risk of severe thrombocytopenia. The approval of a once-daily dose of
50 µg/kg administered subcutaneously was based primarily on
efficacy and safety data from two randomized, placebo-controlled
studies in which a total of 77 patients with solid tumors or
lymphomas were enrolled.[1,2]

The tolerability of rhIL-11 has been evaluated using data from a
total of 355 subjects who had been treated with rhIL-11 (vs 155
subjects treated with placebo) during the clinical development of
this platelet growth factor. This data set includes healthy
volunteers and patients with nonmyeloid cancer who participated in
pharmacodynamic studies of rhIL-11 alone, as well as in
placebo-controlled and open-label rhIL-11 studies in
chemotherapy-induced thrombocytopenia.

The first clinical experience with rhIL-11 was from a phase I study
that characterized the safety (and preliminary efficacy) of rhIL-11
at doses of 10, 25, 50, 75, and 100 µg/kg. Each dose of rhIL-11
was administered once daily for 14 days in 16 women receiving
chemotherapy for breast cancer.[3] The rhIL-11 75-µg/kg/d dose
was not technically considered to be associated with true
dose-limiting toxicity, but subjectively it was not as well tolerated
as doses £ 50 µg/kg/d due to the
higher frequency of reversible, moderate fatigue, myalgia, and
arthralgia.

Dose escalation was stopped at the 100-µg/kg dose after a
patient experienced a minor thrombotic stroke after three doses of
rhIL-11. No adverse sequelae resulted from this stroke and the
patient’s neurologic status returned to baseline levels.
Importantly, this stroke was not associated with thrombocytosis
induced by rhIL-11 or changes in coagulation parameters such as
prothrombin time or partial thromboplastin time. Thus, doses > 50
µg/kg/d were not evaluated in subsequent randomized,
placebo-controlled studies in adults.

A placebo-controlled phase II study established the statistically
significant efficacy of rhIL-11 at the 50-µg/kg/d dose, but not
at the 25-µg/kg/d dose, in achieving[4] the primary efficacy end
point (proportion of patients avoiding platelet transfusions).[1]
Therefore, in a subsequent phase II placebo-controlled study, rhIL-11
was evaluated at only the 50-µg/kg/d dose.[2] The rhIL-11
75-µg/kg/d dose is, however, currently under investigation in
pediatric patients with solid tumors or lymphomas. Pediatric patients
appear to tolerate this dose well and, because of their ability to
clear the drug more rapidly, a dose of 75–100 µg/kg
produces plasma drug concentrations that are comparable to
concentrations achieved in adults with the 50-µg/kg dose.[5]

A phase III study was initiated to further evaluate the safety and
efficacy of rhIL-11 at 50 µg/kg based on the findings of the
phase I and phase II studies. This study had accrued 141 patients,
but was prematurely closed after the FDA granted approval of rhIL-11.

Across the two placebo-controlled, double-blind phase II studies,
patients received subcutaneous daily doses of rhIL-11 50 µg/kg
for 10 to 21 days. In the phase III study, rhIL-11 50 µg/kg/d
was administered for 14 days. In studies that included open-label
cycles, patients received up to eight sequential cycles of rhIL-11.
In these studies, adverse events were assessed and graded for
severity by the investigators according to the World Health
Organization Toxicity Grading Scale or other prespecified
definitions. In general, grades 1, 2, 3, and 4 corresponded to mild,
moderate, severe, and life-threatening severities, respectively.

The results of the two randomized phase II and the one abbreviated
phase III placebo-controlled, double-blind clinical studies support
the acceptable tolerability and safety profile of rhIL-11 in patients
undergoing chemotherapy for nonmyeloid malignancies.[1,2,5,6] Data from these studies indicate that adverse events
associated with rhIL-11 therapy are generally mild, reversible, and
easily managed.

Adverse-Event Profile

Phase II Randomized Placebo-Controlled Studies

Across the two phase II placebo-controlled chemotherapy studies
(study I and study II), only 8 of 72 patients (11%) in the rhIL-11
50-µg/kg group prematurely discontinued the study drug because
of adverse events (most commonly atrial fibrillation or flutter),
compared with 4/67 patients (6%) in the placebo group.[5] A combined
analysis of data from these two studies showed that the adverse
events in the rhIL-11 group were similar in incidence and type to
those seen in the placebo group. There was no difference between the
rhIL-11 and placebo treatment groups in the respective incidence of
fever (36% vs 28%; P = .4), neutropenic fever (48% vs 42%; P
= .5), or flu-like symptoms (eg, chills, 25% vs 25%; P = 1.0).
Thrombotic events, the number of red blood cell transfusions, and the
duration of neutropenia (< 500/µL) were also similar in both groups.

The majority of adverse events reported in these two phase II
studies, regardless of treatment group, were mild (grade 1) in
severity, easily managed, and reversible following discontinuation of
rhIL-11. Eight adverse events occurred with a statistically
significantly (P < .05) higher incidence for rhIL-11 50
µg/kg compared with placebo during the double-blind study cycles (Table
1
). Most of these events were mild or moderate (grade 1 or 2) in
severity.

Across studies I and II, the incidence of severe or life-threatening
adverse events in the rhIL-11 and placebo groups was, in general,
similar. The only adverse event of grade 3 or 4 severity that
occurred with a significantly higher incidence with rhIL-11 50
µg/kg compared with placebo was asthenia (grade 3, 14% [rhIL-11]
vs 3% [placebo]; P = .03, Fisher’s exact test), although
the overall incidence of asthenia was similar between treatment
groups (65% and 64%, respectively; P = 1.0).[5]

Phase III Randomized Placebo-Controlled Double-Blind Study

The design of the phase III study differed from that of the two
previously discussed phase II placebo-controlled studies by the
standardized institution of a masked diuretic (hydrochlorothiazide 25
mg/triamterene 37.5 mg [Maxzide-25MG]) in patients receiving rhIL-11.
This was done in an effort to ameliorate the fluid retention that was
observed in prior studies.[3,5] Its use was based on a randomized
crossover trial of hydrochlorothiazide 25 mg/triamterene 37.5 mg and
rhIL-11 in normal volunteers. However, the systematic use of a
diuretic in this study was subsequently discontinued due to a pattern
of adverse events related to diuretic-induced fluid and electrolyte
imbalance, although the use of a diuretic was still permitted at the
discretion of the investigator.

In this phase III trial, among 88 patients randomized to the rhIL-11
treatment group, 11 (12.5%) discontinued the study drug because of
adverse events (primarily atrial fibrillation or flutter [n = 7;
8%]). These findings are similar to the two phase II controlled
chemotherapy studies. In contrast to the phase II studies, metabolic
adverse events led to the discontinuation of rhIL-11 in four patients
(5%) in the phase III study. The adverse events included dehydration
(n = 1), hypokalemia (n = 1), hypomagnesemia (n = 1), and
hyponatremia (n = 1) and likely occurred secondary to diuretic
therapy. Six of 88 (7%) patients in the rhIL-11 group developed
hypokalemia, compared with 2 of 45 (4%) patients in the placebo
group.

These occurrences, once again, were determined by the investigators
to be associated with diuretic use and were not study-drug related.
The only adverse events that occurred significantly more frequently
in patients in the rhIL-11 group were dizziness, edema, dyspnea,
atrial fibrillation/flutter, and palpitation (P < .05). Two
patients in the rhIL-11 group died unexpectedly. It was concluded
that these deaths were due to hypokalemia (probably related to
diuretic use) and were not directly related to study-drug administration.

The incidence and type of adverse events in the phase III
chemotherapy study (Table 2)
were similar to those seen in the two placebo-controlled phase II
studies (Table 1), with the
exception of dizziness, which was attributed to concomitant diuretic
use.[6] The attribution of dizziness to diuretic therapy is supported
by an observed reduction in the incidence of dehydration from 8%
during systematic once-daily administration of a diuretic to 0% when
the diuretic was discontinued. Additionally, the incidence of
dizziness in the rhIL-11 treatment group was reduced from 44% to 29%
after the study protocol was changed to eliminate mandatory
systematic diuretic use in the rhIL-11 group.[5]

Based on the experience in this phase III study, the routine use of
diuretics during rhIL-11 therapy is not recommended, although their
temporary use to alleviate edema may be indicated in some patients.
If diuretic therapy is indicated, a potassium-sparing diuretic should
be used and serum electrolyte levels and fluid balance should be
monitored closely, as in any patient receiving a diuretic. During the
phase III study, the development of severe hypokalemia (serum
potassium concentrations £ 2.8 mEq/L)
resulted in two fatalities.

Hypokalemia has not been shown to be attributed to treatment with
rhIL-11. In healthy volunteers receiving a dose of 25 µg/kg,
rhIL-11 treatment does not cause potassium depletion,[7] and rhIL-11
has not been associated with hypokalemia in patients with cancer in
studies where diuretic therapy was neither encouraged nor
recommended.[1,3] These findings underscore the importance of close
monitoring of patients with cancer, as they often receive many
therapies that complicate treatment.

As in the phase II controlled trials, the majority of adverse events
in the phase III trial were mild or moderate in severity (grade 1 or
2) and resolved without sequelae after discontinuation of the study
drug. Most adverse events were considered to be due to the
administration of chemotherapy or the patient’s underlying
disease. There were no significant differences between the rhIL-11
and placebo treatment groups in the overall incidence of grade 3 and
4 adverse events (36% [rhIL-11] and 38% [placebo]). However, the
incidence of grade 3 or 4 chills was reported significantly (P
= .04) more frequently in the placebo group (n = 3, 7%) than in the
rhIL-11 group (n = 0). In addition, the only episodes of grade 3 or 4
gastrointestinal hemorrhage (two patients) or pulmonary infarct (one
patient) occurred in the placebo group.

Fluid Retention

The majority of adverse events associated with rhIL-11 (eg, edema,
dyspnea, pleural effusions, and conjunctival injection) are believed
to be the result of fluid retention and increased plasma volume.
Studies in volunteers have shown that treatment with rhIL-11 is
associated with an expansion in plasma volume of approximately 20% as
a result of sodium retention.[8] Edema is the most frequently
reported adverse event; however, it is easily managed and reversible.

Edema and Dyspnea

In the two phase II placebo-controlled chemotherapy studies (studies
I and II), edema and dyspnea associated with rhIL-11 therapy were
most often mild or moderate in severity and were either self-limited
or responded well to diuretic therapy. None of the patients withdrew
from the studies because of edema. In the phase III study, mild or
moderate edema and dyspnea were also two of the most common adverse
events associated with rhIL-11 (Table
2
); however, during the systematic use of masked diuretic, the
incidence of both edema and dyspnea was lowest in patients in the
rhIL-11 group.

Pleural Effusions

All of the seven events of pleural effusion that occurred during the
phase II controlled chemotherapy studies represented in Table
1
occurred in a study of patients with breast cancer (study
II).[2] However, patients in the rhIL-11 group may have been at
higher risk overall for pleural effusions at baseline because more
patients with stage IV metastatic breast cancer were randomized to
the rhIL-11 treatment group (25/40, 63%) than to the placebo group
(18/37; 49%). Therefore, a higher portion of patients in the rhIL-11
group were at risk of developing or having pleural effusions related
to pleural metastases. All of the seven patients who had pleural
effusions had stage IV metastatic breast cancer. In addition, four of
these seven patients had preexisting pleural effusions that worsened
during rhIL-11 treatment. No patients required thoracentesis, and
most pleural effusions responded well to treatment with furosemide.
Thus, patients with a past or current history of pleural effusions
should be monitored closely for increasing fluid accumulation, as
should patients with preexisting ascites.

Dilutional Anemia

Mild, reversible dilutional anemia characterized by moderate
decreases in hemoglobin (15% to 19% reductions from baseline) and
hematocrit levels (approximately 20% reduction from baseline)
secondary to plasma volume expansion has occurred during rhIL-11
therapy in phase I studies in healthy volunteers[5,8] and
nonmyelosuppressed patients with cancer.[3] In the latter population,
anemia developed within 2 to 3 days of initiation of rhIL-11 therapy
and reached a nadir during the second week of dosing.[3,5] However,
hemoglobin levels returned to baseline levels within 2 weeks after
the completion of rhIL-11 therapy.

In the two completed phase II placebo-controlled chemotherapy studies
(studies I and II), rhIL-11–associated increases in plasma
volume were not associated with statistically significant increases
in the incidence of clinically significant anemia or mean
requirements for red blood cell transfusions, compared with
placebo.[1,2] Across these studies, anemia was reported in only 10%
of rhIL-11–treated patients, compared with 6% of placebo-treated
patients.[5] The mean number of red blood cell units transfused per
patient was 1.9 in the rhIL-11 group and 1.7 in the placebo group.

A randomized, double-blind, placebo-controlled phase I study in 12
healthy, salt-restricted volunteers confirmed that the anemia
associated with rhIL-11 therapy is predominantly due to an increase
in plasma volume secondary to sodium retention, rather than a
decrease in red blood cell mass.[8] Together, these data suggest that
reductions in hemoglobin, although common, are not usually clinically significant.

rhIL-11 should be used cautiously in patients with congestive heart
failure in whom fluid retention may precipitate cardiac
decompensation. It may be best to avoid using rhIL-11 in some
patients with severe congestive heart failure. To minimize the risk
of edema and associated sequelae during therapy with rhIL-11,
patients should be instructed to reduce their salt intake, monitor
their weight for gradual changes, and contact their physician if they
notice weight increases or tightening of rings or shoes. In some
patients, edema may be alleviated by the temporary use of a
potassium-sparing diuretic. It should also be noted that the
occurrence of edema with rhIL-11 is reversible upon discontinuation
of therapy.

Atrial Arrhythmias

Among the eight patients (12%) in the two phase II placebo-controlled
chemotherapy studies (studies I and II, Table
1
) who developed atrial arrhythmias during therapy with rhIL-11
50 µg/kg, only three were symptomatic (vs one placebo-treated
patient). None of the patients with atrial arrhythmias developed
clinical sequelae.[1,2] Among the three symptomatic patients, one
patient had preexisting undiagnosed severe aortic stenosis, which was
repaired surgically and maintained with calcium channel blocker
(diltiazem) therapy during the study. The second patient had a prior
history of atrial arrhythmia at study entry. In the third patient,
atrial arrhythmia was controlled with digoxin and verapamil. In the
remaining five patients, the occurrence of atrial arrhythmias was
transient (detected only by Holter monitoring), and reverted to sinus
rhythm without medical intervention or electrical cardioversion. In
most patients, atrial arrhythmias have not recurred during
continuation of rhIL-11 therapy.

Data from all patients who received at least one dose of rhIL-11 have
identified four risk factors as being most likely associated with the
development of atrial arrhythmias. They are patient age, history of
atrial arrhythmias, history of cardiac disorder, and history of
alcohol use. Although these risk factors have been established as
factors associated with the occurrence of atrial arrhythmias in the
general population, treatment with rhIL-11 has been shown to be
significantly associated (P < .05) with the occurrence of
atrial arrhythmias. This suggests that rhIL-11 may provide an
additional risk in patients already at risk for atrial arrhythmias.
Therefore, rhIL-11 should be used with caution in these patients, and
only after consideration of the potential risks in relation to
anticipated benefits.

Because of the association of rhIL-11 with atrial
fibrillation/flutter in previous studies, all patients in the phase
III trial were prospectively monitored with electrocardiograms and
transtelephonic monitoring (TTM), which is more sensitive than Holter
monitoring for detecting transient arrhythmias in symptomatic
patients.[9] Fifteen patients (17%) in the rhIL-11 arm experienced
atrial arrhythmias vs no patients on placebo.

Among the 15 patients who experienced atrial fibrillation/flutter in
the phase III study, 10 patients were symptomatic, although 2
patients had a history of atrial arrhythmia before study entry, and 1
patient had a history of supraventricular tachycardia. Thir-teen of
the 15 cases of rhIL-11–associated atrial fibrillation/flutter
were uncomplicated. Of the two remaining cases, one patient developed
homonymous hemianopsia concurrently with an episode of atrial
fibrillation. This was considered to be due to a cerebral infarction
despite a normal computed tomography scan of the brain. Another
patient had electrocardiographic evidence of myocardial infarction at
the follow-up visit.

The risk of the development of atrial arrhythmias during therapy with
rhIL-11 may be increased in patients with advanced age or a history
of more than moderate alcohol consumption, cardiac disorder,
doxorubicin therapy, diabetes, or hypertension. rhIL-11 should be
used with caution in patients with a history of atrial arrhythmia.
Some cases of atrial arrhythmia may have been the indirect
consequence of increased plasma volume, which has been shown to
induce atrial distention[10] with subsequent decreases in atrial
refractory period.[11]

Analysis of TTM data from the phase III study showed no evidence of
an effect of rhIL-11 on cardiac conduction intervals (PR, QRS, or QTc
intervals), suggesting the absence of direct effects by rhIL-11 on
cardiac function.[5]

Bleeding Complications

Retrospective analysis of the phase II placebo-controlled
chemotherapy studies (studies I and II) showed a significantly (P
< .01, Fisher’s exact test) lower incidence of bleeding
complications—primarily ecchymosis and epistaxis—among
patients in the rhIL-11 group (28%) compared with those in the
placebo group (51%). None of the patients treated with rhIL-11 (n =
69, 0%) developed severe or life-threatening bleeding complications
(grade 3 hemorrhage, hemorrhagic cystitis, or vaginal hemorrhage);
these occurred only among placebo-treated patients (3 of 67, 4.5%).
In the phase III study, bleeding events contributing to
hospitalization occurred in a higher percentage of patients in the
placebo group (5/45, 11.1%) than in the rhIL-11 group (3/88, 3.4%).
These observations reflect the lack of adverse effects of rhIL-11 on
platelet function or blood coagulation (discussed below).

Papilledema

In 6 of 355 patients treated with rhIL-11 during clinical trials,
papilledema was detected following two or more cycles of rhIL-11
treatment. However, in three of these patients, papilledema may have
resulted from central nervous system tumors. During the phase III
study, routine ophthalmologic examinations by ophthalmologists failed
to detect any signs of papilledema in 119 patients for whom safety
data were available.[5]

In preclinical studies in nonhuman primates, papilledema associated
with excessive doses of rhIL-11 (1,000 µg/kg/d for up to 13
weeks) has reversed completely after treatment was discontinued and
has not been associated with histopathologic changes in either the
eye or the central nervous system. These observations suggest that
papilledema occurs rarely and is usually mild, transient, and
reversible upon discontinuation of therapy. However, on the basis of
clinical observations, rhIL-11 should be used cautiously and with
frequent ophthalmologic monitoring in patients with preexisting
papilledema or tumors involving the central nervous system.

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