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
Recombinant human interleukin-11 (IL-11 [Neumega]) stimulates plateletproduction and inhibits inflammation in clinical studies in cancer patients,according to research presented at a symposium held last summer in NewYork City. The potential benefits of the cytokine in preserving epithelialcell integrity and preventing mucus membrane injury also are under study.
Thrombocytopenia is a potentially serious side effect of chemotherapyestimated to occur in about 25% of patients. To date, chemotherapy-inducedthrombocytopenia has been managed by reducing chemotherapy dosages, delayingsubsequent 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 moreaggressive with chemotherapy...and that starts causing problems as faras the platelets because we don't have...an effective approved growth factor,until now," said Dr. Muhammad Hussein, director of Multiple MyelomaPrograms 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% to30% of patients. From 20% to 30% of patients develop antibodies to transfusedplatelets, 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 hasfocused on identifying substances that can stimulate platelet growth, thusallowing for optimal chemotherapy and minimizing the need for platelettransfusions.
Research has shown that endogenous IL-11 stimulates platelet growth,among other effects, and a recombinant form of this growth factor, producedby Genetics Institute, Inc, has shown promise in preclinical and clinicalstudies, said Dr. Steven Clark, co-chair of the symposium. Interleukin-11stimulates the growth and development of platelet-producing cells calledmegakaryocytes, said Dr. Clark, senior vice president of Discovery Researchat Genetics Institute. It also inhibits the production of monocytes andmacrophages. These effects are at least part of the mechanism by whichrecombinant human IL-11 stimulates platelet production and inhibits inflammationin preclinical and clinical studies.
Dr. Hussein described the results of a multicenter, randomized, placebo-controlledtrial of recombinant human IL-11 in patients with various types of cancerwho had previously been transfused with platelets for severe chemotherapy-inducedthrombocytopenia. Of 27 evaluable patients treated with 50 mcg/d of recombinanthuman IL-11, 8 (30%) did not require platelet transfusions, as comparedwith 1 (4%) of 27 patients in the placebo group.
"IL-11 at this dose seems to be effective in decreasing the frequencyof platelet transfusion as well as enhancing platelet recovery, and thetoxicity 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-controlledstudy of recombinant human IL-11 (50 mcg/d) in the treatment of 77 womenwith breast cancer who were receiving moderately high-dose chemotherapywith cyclophosphamide (Cytoxan, Neosar) and doxorubicin. The study furtherassessed the safety of IL-11 during up to six cycles of this chemotherapy.
"There was a very significant difference between the numbers ofpatients who required platelet transfusion in the placebo group, as comparedto the patients who required it in [the] IL-11 [group]," said Dr.Claudine Isaacs, assistant professor of medicine, Georgetown UniversityMedical Center, Washington, DC.
Overall, 68% of the patients who received IL-11 during two cycles ofthis high-dose chemotherapy did not require platelet transfusion, as opposedto 41% of those who received placebo. Among patients who completed thetwo cycles of chemotherapy without any major protocol violation, 79% ofthe IL-11-treated patients avoided a platelet transfusion vs only 48% ofthe placebo-treated patients.
"...There were more significant differences following the secondcycle of chemotherapy," said Dr. Isaacs. Platelet transfusions werenot required in 79% of the patients who received IL-1 during cycle 2, ascompared with 52% of those given placebo.
Although the number of patients who had received prior chemotherapywas very small, the difference between the IL-2 and placebo groups wasstill striking, according to Dr. Isaacs. Only 1 of 8 such patients in theplacebo arm who completed the two cycles of chemotherapy got away withoutneeding a platelet transfusion, whereas 7 (63%) of 11 patients in the IL-11arm were able to avoid a transfusion.
The number of platelet transfusions required also differed significantlybetween 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 patientsafter 19 days, whereas this was not the case for the placebo recipients.
Interleukin-11 was very well tolerated. The vast majority of adverseevents were grade 1 or 2, noted Dr. Isaacs. About 10% of patients in bothgroups had grade 3 or 4 adverse events.
"IL-11 allowed the continuation of the chemotherapy on time andwithout dose reduction. And it's the first therapy that's been proven toprevent the need for platelet transfusions and to accelerate platelet recoveryduring multiple cycles of chemotherapy in patients who have severe chemotherapy-inducedthrombocytopenia," Dr. Isaacs concluded.
Second Breast Cancer Trial Shows Positive Trends
Dr. James Vretenberg, associate professor of medicine, Duke UniversityMedical Center in Durham, North Carolina, also studied recombinant humanIL-11 in 75 patients with metastatic or high-risk primary breast cancerwho were being treated with high-dose chemotherapy and hematopoietic support.After being reinfused with their own peripheral blood progenitor cellsor an autologous bone marrow graft, patients received 25 or 50 mcg/d ofIL-11 or placebo.
"There...was a trend in decreased platelet transfusion requirementsin the interleukin-11 groups as compared with placebo," said Dr. Vretenberg."There was a suggestion of a decrease in the number of patients whorequired more than 10 units of platelets, and also the number of patientswho failed to engraft their platelets by day 30."
Interleukin-11 was well tolerated in this study. No significant differencesemerged 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 potentiallyuseful physiologic activities. One of the more "striking" effects,said Dr. Steven Opal, "is its ability to promote and maintain epithelialcell integrity and to prevent mucus membrane injury following radiationand chemotherapeutic agents in murine models."
"And also in a hamster model of radiation or chemotherapy-inducedmucus membrane injury, not only can one show preservation of the gastrointestinalmucosa but also reduction in lethality from these injurious effects ofthese agents on the gastrointestinal tract," added Dr. Opal, associateprofessor of medicine, Brown University School of Medicine, Providence,Rhode Island.
In a rat model designed to simulate the sepsis seen in patients withlow white blood cell counts, recombinant human IL-11 provided significantprotection from the invasive bacteria. The animals treated with IL-11 hada 40% survival rate compared to the control group. Also, said Dr. Opal,the control animals exhibited very impressive necrosis and thinning ofthe gastrointestinal mucosa, whereas the IL-11 treated animals had remarkablepreservation of their gastrointestinal histology.
To simulate clinical situations even more closely, Dr. Opal and colleaguescombined recombinant human IL-11 with antimicrobial agents. Animals thatreceived ciprofloxacin (Cipro) had a 60% survival rate, but those receivingIL-11 and the antimicrobial had a 100% survival rate.
"...This strategy might prove to be beneficial if given in combinationwith a conventional therapy in the febrile neutropenic patient who hasgram-negative sepsis," said Dr. Opal.