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Cytokine Dec 2000Recombinant human interleukin 11 (rhIL-11) is a multifunctional cytokine with immunomodulatory activity on both T cells and macrophages. The effects of rhIL-11 in a...
Recombinant human interleukin 11 (rhIL-11) is a multifunctional cytokine with immunomodulatory activity on both T cells and macrophages. The effects of rhIL-11 in a murine model of contact hypersensitivity (CHS) response have been studied. The CHS response is a T cell-mediated response directed against chemically modified self-proteins following epidermal exposure to haptens. CHS is generated in two phases. The sensitization phase involves dermal dendritic cell recognition of haptenized proteins and antigen presentation. The effector phase involves T cell recognition and activation. In mice sensitized with oxazolone, CHS was induced by secondary challenge to the right ear and measured by ear swelling 24 h later. rhIL-11 significantly suppressed CHS as measured by ear swelling and tissue myeloperoxidase activity when injected subcutaneously for 5 days from the day of sensitization or when administered only on the day before and the day of challenge, but was not effective when administered prior to or on the day of sensitization. These results indicate that subcutaneously administered rhIL-11 may modulate the effector phase of CHS. Administration of rhIL-11 as an oral gavage prior to sensitization also reduced CHS. However oral administration of rhIL-11 after sensitization had no effect. These results suggest that orally and subcutaneously administered rhIL-11 may act through different mechanisms to affect CHS.
Topics: Administration, Oral; Animals; Antineoplastic Agents; Biopsy; Dendritic Cells; Dermatitis, Contact; Dose-Response Relationship, Drug; Edema; Epidermis; Female; Humans; Hyperplasia; Injections, Subcutaneous; Interleukin-11; Interleukin-2; Mice; Mice, Inbred BALB C; Peroxidase; RNA, Messenger; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; T-Lymphocytes; Time Factors
PubMed: 11097746
DOI: 10.1006/cyto.2000.0792 -
Blood May 1996We performed a phase I trial of recombinant human interleukin-11 (rhIL-11) in women with breast cancer. Cohorts of three to five women were accrued to five dosage levels... (Clinical Trial)
Clinical Trial
We performed a phase I trial of recombinant human interleukin-11 (rhIL-11) in women with breast cancer. Cohorts of three to five women were accrued to five dosage levels of rhIL-11 (10, 25, 50, 75, and 100 micrograms/kg/d). rhIL-11 alone was administered by a daily subcutaneous injection for 14 days during a 28-day prechemotherapy "cycle 0." Patients (pts) subsequently received up to four 28-day cycles of cyclophosphamide (1,500 mg/m2) and doxorubicin (60 mg/m2) chemotherapy followed by rhIL-11 at their assigned dose (days 3 through 14). Sixteen pts (13 stage IV, 3 stage IIIB) were accrued to this study. Median age was 53 years and median Eastern Cooperative Oncology Group Performance Status was 0. A grade 3 neurologic event was seen in 1 pt at 100 micrograms/kg. Because of the degree of grade 2 constitutional symptoms (myalgias/arthralgias and fatigue) at 75 micrograms/kg, dose escalation was stopped and 75 micrograms/kg was the maximally tolerated dose. No other grade 3 or 4 adverse events related to rhIL-11 were seen. The administration of rhIL-11 was not associated with fever. Reversible grade 2 fatigue and myalgias/arthralgias were seen in all pts at 75 micrograms/kg. Weight gain of 3% to 5% associated with edema was seen at doses > 10 micrograms/kg but a capillary leak syndrome was not seen. rhIL-11 alone was associated with a mean 76%, 93%, 108%, and 185% increase in platelet counts at doses of 10, 25, 50, and 75 micrograms/kg, respectively. No significant changes in leukocytes were seen. A mean 19% decrease in hematocrit was observed. Acute-phase proteins increased with treatment at all doses. Compared with patients at the 10 micrograms/kg dose, patients receiving doses > or = 25 micrograms/kg experienced less thrombocytopenia in the first two cycles of chemotherapy. We conclude that rhIL-11 has thrombopoietic activity at all doses studied, is well tolerated at doses of 10, 25, and 50 micrograms/kg, and at doses > or = 25 micrograms/kg has the potential to reduce chemotherapy-induced thrombocytopenia in this model.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cohort Studies; Female; Humans; Injections, Subcutaneous; Interleukin-11; Middle Aged; Recombinant Proteins; Thrombocytopenia
PubMed: 8611685
DOI: No ID Found -
Gan To Kagaku Ryoho. Cancer &... Apr 2005YM 294 was administered for chemotherapy-induced thrombocytopenia in patients with gynecologic cancer at a dose of 50 microg/kg in order to examine the efficacy and... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
YM 294 was administered for chemotherapy-induced thrombocytopenia in patients with gynecologic cancer at a dose of 50 microg/kg in order to examine the efficacy and safety by a randomized trial, using the non-treatment observation group as a control. Increase in the nadir platelet counts as well as shortening of the days to return the platelet number to>100,000/ microl were significantly higher in the 50 microg/kg groups, in comparison with the non-treatment observation group. The major adverse drug reactions observed in the 50 microg/kg groups were edema, erythema of injection site, and fever. All of these adverse reactions were either mild or moderate (not serious), and they resolved. Abnormal changes in laboratory value for which a casual relationship with the study drug could not be excluded were reversible and manageable. The efficacy and safety of 50 microg/kg groups for chemotherapy-induced thrombocytopenia in patients with gynecological cancer was confirmed by the results of this study.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Cisplatin; Doxorubicin; Drug Administration Schedule; Edema; Erythema; Female; Humans; Interleukin-11; Middle Aged; Ovarian Neoplasms; Paclitaxel; Platelet Count; Recombinant Proteins; Thrombocytopenia; Uterine Cervical Neoplasms
PubMed: 15853214
DOI: No ID Found -
Journal of Clinical Oncology : Official... Nov 1997Thrombocytopenia may compromise cancer treatment, causing chemotherapy dose reductions, schedule alterations, or the need for platelet transfusions. We evaluated the... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
Randomized placebo-controlled study of recombinant human interleukin-11 to prevent chemotherapy-induced thrombocytopenia in patients with breast cancer receiving dose-intensive cyclophosphamide and doxorubicin.
PURPOSE
Thrombocytopenia may compromise cancer treatment, causing chemotherapy dose reductions, schedule alterations, or the need for platelet transfusions. We evaluated the efficacy and safety of recombinant human interleukin-11 (rhIL-11; Neumega, Genetics Institute, Inc, Cambridge, MA), a novel thrombopoietic growth factor, in reducing the need for platelet transfusions in patients who undergo dose-intensive chemotherapy.
PATIENTS AND METHODS
Women with advanced breast cancer received cyclophosphamide (3,200 mg/m2) and doxorubicin (75 mg/m2) plus granulocyte colony-stimulating factor (G-CSF; 5 microg/kg/d). Patients were randomized to blinded treatment with placebo or 50 microg/kg/d rhIL-11 subcutaneously for 10 or 17 days after the first two chemotherapy cycles.
RESULTS
Seventy-seven patients were randomized and constitute the intent-to-treat (ITT) population. Sixty-seven patients (the assessable subgroup) either completed both cycles without a major protocol violation (n = 62) or received a platelet transfusion before treatment was discontinued after the first cycle. In the ITT population, rhIL-11 significantly decreased the requirement for platelet transfusions; 27 of 40 (68%) patients who received rhIL-11 did not require transfusions, compared with 15 of 37 (41%) in the placebo group (P = .04). Treatment with rhIL-11 significantly reduced the total number of platelet transfusions required in the assessable subgroup (P = .03) and the time to platelet recovery to more than 50,000/microL in the second cycle (P = .01). Most adverse events associated with rhIL-11 were reversible, mild to moderate in severity, and likely related to fluid retention.
CONCLUSION
rhIL-11 is safe and effective in reducing treatment-associated thrombocytopenia and the need for platelet transfusions in patients who undergo dose-intensive chemotherapy, and thus may permit chemotherapy to be administered as planned at intended doses and thereby maximize the potential for a successful outcome.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cyclophosphamide; Doxorubicin; Female; Humans; Interleukin-11; Middle Aged; Platelet Transfusion; Recombinant Proteins; Thrombocytopenia
PubMed: 9363868
DOI: 10.1200/JCO.1997.15.11.3368 -
Lancet (London, England) Jan 2003Bacteraemia in patients with haematological malignant disease causes substantial morbidity. Recombinant human interleukin 11 (rhIL-11) prevents gastrointestinal... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
Recombinant human interleukin 11 and bacterial infection in patients with [correction of] haematological malignant disease undergoing chemotherapy: a double-blind placebo-controlled randomised trial.
BACKGROUND
Bacteraemia in patients with haematological malignant disease causes substantial morbidity. Recombinant human interleukin 11 (rhIL-11) prevents gastrointestinal epithelial disintegrity and has immunomodulatory actions. Our aim was to ascertain whether or not treatment with rhIL-11 can prevent gut-associated infections.
METHODS
We did a double-blind placebo-controlled randomised trial, to which we enrolled 40 patients with haematological malignant disease who were undergoing chemotherapy. Patients received either rhIL-11 50 microg/kg (n=20) or placebo (n=20) daily by subcutaneous injection from the day before the start of chemotherapy until resolution of neutropenia or for 21 days, whichever was longer. Our primary outcome measure was a reduction in bacteraemia. Analysis was by intention to treat.
FINDINGS
Significantly fewer patients who received rhIL-11 rather than placebo developed bacteraemia, particularly of gastrointestinal origin: the proportion of patients with at least one positive blood culture was 0.65 and 0.25, respectively (p=0.02). The numbers of patients (placebo vs rhIL-11) for each number of distinct isolates were: no organism isolated seven versus 15, one organism nine versus four, two organisms two versus one, three organisms one versus none, and four organisms one versus none (p=0.01), suggesting a lower bacterial load in the rhIL-11 than in the placebo group. Time to first bacteraemic event was longer in patients who received rhIL-11 (p=0.03) than in those who received placebo.
INTERPRETATION
rhIL-11 reduces the frequency and load of bacteraemia in patients with haematological malignant disease undergoing chemotherapy, possibly by gastrointestinal cytoprotective or immunological mechanisms [corrected].
Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bacteremia; Double-Blind Method; Female; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Interleukin-11; Leukemia, Myeloid; Male; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recombinant Proteins
PubMed: 12559860
DOI: 10.1016/s0140-6736(03)12322-7 -
Leukemia Research Jun 2004During therapy with imatinib (Gleevec), 20-30% of patients with CML in chronic phase develop grade > or =3 thrombocytopenia. This leads to treatment interruptions and...
During therapy with imatinib (Gleevec), 20-30% of patients with CML in chronic phase develop grade > or =3 thrombocytopenia. This leads to treatment interruptions and dose reductions that result in a decreased probability of achieving a cytogenetic response. Interleukin-11 (oprelvekin) is a megakaryopoietic cytokine that reduces the incidence and severity of thrombocytopenia associated with chemotherapy. We report on the use of interleukin-11 in three CML patients with grade > or =3, imatinib-induced thrombocytopenia. In all three patients, interleukin-11 led to improved platelets, uninterrupted administration of imatinib and improved cytogenetic response. This observation suggests that interleukin-11 may be beneficial for patients with imatinib-induced thrombocytoepnia.
Topics: Adult; Antineoplastic Agents; Benzamides; Cytogenetic Analysis; Female; Humans; Imatinib Mesylate; Interleukin-11; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged; Piperazines; Platelet Count; Protein-Tyrosine Kinases; Pyrimidines; Thrombocytopenia; Time Factors
PubMed: 15120938
DOI: 10.1016/j.leukres.2003.11.003 -
The American Journal of Gastroenterology Dec 2004To evaluate the effects of recombinant human interleukin (rhIL)-11 on liver histology in patients with chronic hepatitis C virus (HCV) infection and advanced liver...
OBJECTIVES
To evaluate the effects of recombinant human interleukin (rhIL)-11 on liver histology in patients with chronic hepatitis C virus (HCV) infection and advanced liver disease who had failed antiviral therapy.
METHODS
This was an open-label study of rhIL-11 (Neumega), Wyeth Laboratories, Collegeville, PA) at a dose of 5 microg/kg administered by subcutaneous injection daily for 12 wk. The primary efficacy endpoint was the change in the Knodell Histology Activity Index (HAI) between pre- and posttreatment liver biopsies. Secondary efficacy endpoints included changes in plasma alanine transaminase (ALT) concentrations and in the number of platelets.
RESULTS
The Knodell HAI improved in 11 (55%) of the 20 subjects enrolled, with the mean score improving from 7.3 to 5.9 (p= 0.006). Eight subjects (40%) experienced significant improvement as defined by a decrease of at least two points in the HAI. IL-11 treatment was also associated with a decrease in ALT levels from a mean level of 113 IU/L at baseline to 65 IU/L at week 12 (p < 0.001). Platelet levels increased from a mean of 143 x 10(3)/microl at baseline to 198 x 10(3)/mul at week 12 of treatment (p < 0.001). Overall, rhIL-11 was well tolerated and no serious adverse events (AEs) were reported. The most common AE was edema of the lower extremities, which occurred in all subjects.
CONCLUSIONS
The findings from this pilot study suggest that rhIL-11 may be beneficial for patients with hepatic inflammation and advanced liver disease associated with chronic HCV infection. Larger clinical trials are warranted to further evaluate the long-term antiinflammatory and antifibrotic effects of rhIL-11.
Topics: Adult; Aged; Female; Hepatitis C, Chronic; Humans; Injections, Subcutaneous; Interleukin-11; Liver Function Tests; Male; Middle Aged; Pilot Projects; Platelet Count; Polymerase Chain Reaction; Recombinant Proteins; Statistics, Nonparametric; Treatment Outcome
PubMed: 15571583
DOI: 10.1111/j.1572-0241.2004.40047.x -
Arthritis Research 2001Interleukin-11 (IL-11) is a pleiotropic cytokine that regulates the growth and development of hematopoietic stem cells and decreases the proinflammatory mediators of... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
Results of a phase-I/II randomized, masked, placebo-controlled trial of recombinant human interleukin-11 (rhIL-11) in the treatment of subjects with active rheumatoid arthritis.
Interleukin-11 (IL-11) is a pleiotropic cytokine that regulates the growth and development of hematopoietic stem cells and decreases the proinflammatory mediators of cytokine and nitric oxide production. In animal models of arthritis, treatment with recombinant human IL-11 (rhIL-11) reduces both the level of synovitis and the histologic lesion scores in the joints. The goal of this phase-I/II study in adults with rheumatoid arthritis (RA) was to evaluate the safety and clinical activity of different doses and schedules of rhIL-11 in patients with active RA for whom treatment with at least one disease-modifying antirheumatic drug had failed. This was a multicenter, randomized, placebo-controlled trial that evaluated the safety and tolerability of rhIL-11 in 91 patients with active RA. rhIL-11 was administered subcutaneously; patients were randomized into one of five treatment groups (ratio of rhIL-11 to placebo, 4:1). Patients were treated for 12 weeks with either 2.5 or 7.5 microg/kg of rhIL-11 or placebo twice per week or 5 or 15 microg/kg of rhIL-11 or placebo once per week. The status of each subject's disease activity in accordance with the American College of Rheumatology (ACR) criteria was assessed before, during, and after completion of administration of the study drug. Administration of rhIL-11 was well tolerated at all doses and schedules. The most frequent adverse event was a reaction at the injection site. The data suggest a statistically significant reduction in the number of tender joints (P < 0.008) at the 15 microg/kg once-weekly dose schedule but showed no overall significant benefit at the ACR criterion of a 20% response. The trial showed rhIL-11 to be safe and well tolerated at a variety of doses and schedules over a 12-week treatment period in patients with active RA. The only adverse event clearly associated with rhIL-11 administration was reaction at the injection site.
Topics: Adult; Aged; Aged, 80 and over; Arthritis, Rheumatoid; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Injections, Subcutaneous; Interleukin-11; Joints; Male; Middle Aged; Recombinant Proteins; Treatment Outcome
PubMed: 11438043
DOI: 10.1186/ar309 -
Experimental Hematology Sep 1996We examined the effects of recombinant human interleukin 11 (rhIL-11) on in vivo human hematopoiesis. Twelve women with advanced breast cancer and no evidence of bone... (Clinical Trial)
Clinical Trial
We examined the effects of recombinant human interleukin 11 (rhIL-11) on in vivo human hematopoiesis. Twelve women with advanced breast cancer and no evidence of bone marrow (BM) involvement were treated with 10, 25, 50, or 75 micrograms/kg/day of rhIL-11 administered subcutaneously for 14 consecutive days. Examination of bone marrow trephine biopsies obtained before and after rhIL-11 treatment revealed unchanged BM cellularity at all doses, and a statistically significant increase in megakaryocyte (MK) frequencies (from 0.5 +/- 0.1% to 1.0 +/- 0.3%) following administration of the two highest doses (p < 0.001). The BM biopsies also showed an increased proportion of immature myeloid and erythroid precursors following 14 days of treatment in all cases. The mean proportion of marrow cells stained with PC10, a monoclonal antibody (mAb) that recognizes the proliferating cell nuclear antigen (PCNA), increased from 16.3 +/- 5.7% to 45.8 +/- 17.1% (p < 0.001) following the two highest treatment doses. Most of the PC10+ cells were promyelocytes and proerythroblasts. In this same group, the proportion of PC10+ MKs increased from 28.3 +/- 11.5% to 56.8 +/- 24.3% (p < 0.01) after treatment, while megakaryocyte ploidy analysis revealed a greater number of higher ploidy (64N) megakaryocytes following rhIL-11 treatment (p < 0.012). Numbers of BM and peripheral blood (PB) CD34+, CD34+DR+, and CD34+DR- cells did not change following rhIL-11 treatment. Following rhIL-11 therapy at the highest dose studied, a 3- and 10-fold increase in the number of committed BM MK progenitor cells (CFU-MK) was observed in two of three patients, while no change was seen in the number of the other BM or PB progenitor cells examined. rhIL-11 administration was also associated with an increase in BM reticulin content (fibrosis grade 1-2) in 7 patients. These results indicate that the administration of rhIL-11 to patients with normal hematopoiesis stimulates MK endoreduplication, PCNA expression, and, at high doses, increases MK and CFU-MK progenitor cell numbers. In addition, rhIL-11 was able to stimulate precursor cells of different marrow lineages without affecting the number of assayable progenitor cells.
Topics: Administration, Cutaneous; Breast Neoplasms; Cell Count; Female; Hematopoiesis; Humans; Interleukin-11; Megakaryocytes; Ploidies; Recombinant Proteins
PubMed: 8862439
DOI: No ID Found -
Gan To Kagaku Ryoho. Cancer &... Apr 2005An early phase II study was conducted to examine the efficacy and safety of YM 294 on chemotherapy-induced thrombocytopenia in patients with solid tumors and malignant... (Clinical Trial)
Clinical Trial
An early phase II study was conducted to examine the efficacy and safety of YM 294 on chemotherapy-induced thrombocytopenia in patients with solid tumors and malignant lymphoma. The response rates which were judged as having good or excellent efficacy by the investigators were 66.7% in all groups with 25 microg/kg or more, and the increase in nadir platelet counts and decrease in platelet transfusions were observed. Adverse reactions were fever, edema, abnormal electrocardiogram and weight gain. All adverse reactions as well as abnormal changes in laboratory values for which the casual relationship with the study drug could not be excluded were resolved and proved to be not serious. The results of this study suggest the efficacy of YM 294 at 25 microg/kg or more for chemotherapy-induced thrombocytopenia in patients with solid tumors and malignant lymphoma. It was considered that a study should be performed to assess the efficacy and safety of YM 294 using a dose of 25 microg/kg or more in the future.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Cisplatin; Drug Administration Schedule; Edema; Etoposide; Female; Fever; Humans; Interleukin-11; Lung Neoplasms; Lymphoma; Male; Middle Aged; Neoplasms; Ovarian Neoplasms; Platelet Count; Recombinant Proteins; Thrombocytopenia
PubMed: 15853215
DOI: No ID Found