Clinical Studies of IL-11, New Platelet Growth Factor, Presented
Clinical Studies of IL-11, New Platelet Growth Factor, Presented
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 transfusions.
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, Rhode Island.
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.