Recombinant human interleukin-11 (IL-11 [Neumega]) stimulates platelet
production and inhibits inflammation in clinical studies in cancer patients,
according to research presented at a symposium held last summer in New
York City. The potential benefits of the cytokine in preserving epithelial
cell integrity and preventing mucus membrane injury also are under study.
Thrombocytopenia is a potentially serious side effect of chemotherapy
estimated to occur in about 25% of patients. To date, chemotherapy-induced
thrombocytopenia has been managed by reducing chemotherapy dosages, delaying
subsequent cycles of chemotherapy, or transfusing platelets.
"The number of platelet transfusions, in the United States at least,
has appeared to have tripled over the past decade. We are getting more
aggressive with chemotherapy...and that starts causing problems as far
as the platelets because we don't have...an effective approved growth factor,
until now," said Dr. Muhammad Hussein, director of Multiple Myeloma
Programs at the Cleveland Clinic Cancer Center.
Platelet transfusions are associated with a number of problems, Dr.
Hussein noted. Fever, the most frequent complication, occurs in 18% to
30% of patients. From 20% to 30% of patients develop antibodies to transfused
platelets, which makes future platelet transfusions ineffective. Also,
the risk of bacterial infections has probably been underestimated. Finally,
although relatively rare, viral infections, such as hepatitis and HIV,
are still a problem despite safety procedures now in place.
Search for Platelet Growth Factors
As a result of all these potential risks, considerable research has
focused on identifying substances that can stimulate platelet growth, thus
allowing for optimal chemotherapy and minimizing the need for platelet
Research has shown that endogenous IL-11 stimulates platelet growth,
among other effects, and a recombinant form of this growth factor, produced
by Genetics Institute, Inc, has shown promise in preclinical and clinical
studies, said Dr. Steven Clark, co-chair of the symposium. Interleukin-11
stimulates the growth and development of platelet-producing cells called
megakaryocytes, said Dr. Clark, senior vice president of Discovery Research
at Genetics Institute. It also inhibits the production of monocytes and
macrophages. These effects are at least part of the mechanism by which
recombinant human IL-11 stimulates platelet production and inhibits inflammation
in preclinical and clinical studies.
Dr. Hussein described the results of a multicenter, randomized, placebo-controlled
trial of recombinant human IL-11 in patients with various types of cancer
who had previously been transfused with platelets for severe chemotherapy-induced
thrombocytopenia. Of 27 evaluable patients treated with 50 mcg/d of recombinant
human IL-11, 8 (30%) did not require platelet transfusions, as compared
with 1 (4%) of 27 patients in the placebo group.
"IL-11 at this dose seems to be effective in decreasing the frequency
of platelet transfusion as well as enhancing platelet recovery, and the
toxicity profile is relatively mild," said Dr. Hussein.
Trial in Breast Cancer Patients Receiving High-Dose Chemotherapy
Also presented at the symposium were findings from a double-blind, placebo-controlled
study of recombinant human IL-11 (50 mcg/d) in the treatment of 77 women
with breast cancer who were receiving moderately high-dose chemotherapy
with cyclophosphamide (Cytoxan, Neosar) and doxorubicin. The study further
assessed the safety of IL-11 during up to six cycles of this chemotherapy.
"There was a very significant difference between the numbers of
patients who required platelet transfusion in the placebo group, as compared
to the patients who required it in [the] IL-11 [group]," said Dr.
Claudine Isaacs, assistant professor of medicine, Georgetown University
Medical Center, Washington, DC.
Overall, 68% of the patients who received IL-11 during two cycles of
this high-dose chemotherapy did not require platelet transfusion, as opposed
to 41% of those who received placebo. Among patients who completed the
two cycles of chemotherapy without any major protocol violation, 79% of
the IL-11-treated patients avoided a platelet transfusion vs only 48% of
the placebo-treated patients.
"...There were more significant differences following the second
cycle of chemotherapy," said Dr. Isaacs. Platelet transfusions were
not required in 79% of the patients who received IL-1 during cycle 2, as
compared with 52% of those given placebo.
Although the number of patients who had received prior chemotherapy
was very small, the difference between the IL-2 and placebo groups was
still striking, according to Dr. Isaacs. Only 1 of 8 such patients in the
placebo arm who completed the two cycles of chemotherapy got away without
needing a platelet transfusion, whereas 7 (63%) of 11 patients in the IL-11
arm were able to avoid a transfusion.
The number of platelet transfusions required also differed significantly
between the IL-11 and placebo groups (.8 vs 2.2 transfusions). Furthermore,
platelet counts recovered to more than 50,000 in all the IL-2-treated patients
after 19 days, whereas this was not the case for the placebo recipients.
Interleukin-11 was very well tolerated. The vast majority of adverse
events were grade 1 or 2, noted Dr. Isaacs. About 10% of patients in both
groups had grade 3 or 4 adverse events.
"IL-11 allowed the continuation of the chemotherapy on time and
without dose reduction. And it's the first therapy that's been proven to
prevent the need for platelet transfusions and to accelerate platelet recovery
during multiple cycles of chemotherapy in patients who have severe chemotherapy-induced
thrombocytopenia," Dr. Isaacs concluded.
Second Breast Cancer Trial Shows Positive Trends
Dr. James Vretenberg, associate professor of medicine, Duke University
Medical Center in Durham, North Carolina, also studied recombinant human
IL-11 in 75 patients with metastatic or high-risk primary breast cancer
who were being treated with high-dose chemotherapy and hematopoietic support.
After being reinfused with their own peripheral blood progenitor cells
or an autologous bone marrow graft, patients received 25 or 50 mcg/d of
IL-11 or placebo.
"There...was a trend in decreased platelet transfusion requirements
in the interleukin-11 groups as compared with placebo," said Dr. Vretenberg.
"There was a suggestion of a decrease in the number of patients who
required more than 10 units of platelets, and also the number of patients
who failed to engraft their platelets by day 30."
Interleukin-11 was well tolerated in this study. No significant differences
emerged between the two groups with regard to the incidence of atrial arrhythmias.
Other Potentially Useful Actions
In addition to its effects on hematopoiesis, IL-11 has other potentially
useful physiologic activities. One of the more "striking" effects,
said Dr. Steven Opal, "is its ability to promote and maintain epithelial
cell integrity and to prevent mucus membrane injury following radiation
and chemotherapeutic agents in murine models."
"And also in a hamster model of radiation or chemotherapy-induced
mucus membrane injury, not only can one show preservation of the gastrointestinal
mucosa but also reduction in lethality from these injurious effects of
these agents on the gastrointestinal tract," added Dr. Opal, associate
professor of medicine, Brown University School of Medicine, Providence,
In a rat model designed to simulate the sepsis seen in patients with
low white blood cell counts, recombinant human IL-11 provided significant
protection from the invasive bacteria. The animals treated with IL-11 had
a 40% survival rate compared to the control group. Also, said Dr. Opal,
the control animals exhibited very impressive necrosis and thinning of
the gastrointestinal mucosa, whereas the IL-11 treated animals had remarkable
preservation of their gastrointestinal histology.
To simulate clinical situations even more closely, Dr. Opal and colleagues
combined recombinant human IL-11 with antimicrobial agents. Animals that
received ciprofloxacin (Cipro) had a 60% survival rate, but those receiving
IL-11 and the antimicrobial had a 100% survival rate.
"...This strategy might prove to be beneficial if given in combination
with a conventional therapy in the febrile neutropenic patient who has
gram-negative sepsis," said Dr. Opal.