Clinical Cancer Research CR Helping Patients Advances in Breast Cancer
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Bracho, F.
Right arrow Articles by Cairo, M. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Bracho, F.
Right arrow Articles by Cairo, M. S.
Clinical Cancer Research Vol. 7, 58-67, January 2001
© 2001 American Association for Cancer Research

Clinical Trials

A Phase I Clinical, Pharmacological, and Biological Trial of Interleukin 6 Plus Granulocyte-Colony Stimulating Factor after Ifosfamide, Carboplatin, and Etoposide in Children with Recurrent/Refractory Solid Tumors: Enhanced Hematological Responses but a High Incidence of Grade III/IV Constitutional Toxicities1

Francisco Bracho, Mark D. Krailo, Violet Shen, Sharon Bergeron, Virginia Davenport, Wen Liu-Mares, Bruce R. Blazar, Angela Panoskaltsis-Mortari, Carmella van de Ven, Rita Secola, Matthew M. Ames, Joel M. Reid, Gregory H. Reaman and Mitchell S. Cairo2

Lombardi Cancer Center, Georgetown University Hospital, Washington, DC 20007 [F. B.]; University of Southern California School of Medicine, Los Angeles, California 90033 [M. D. K., W. L-M.]; Children’s Hospital of Orange County, Orange, California 92668 [V. S.]; Children’s Hospital of Los Angeles, Los Angeles, California 90027 [S. B., R. S.]; University of Minnesota Cancer Center, Minneapolis, Minnesota 55455 [B. R. B., A. P-M.]; Mayo Clinic, Rochester, Minnesota 55905 [M. M. A., J. M. R.]; Children’s National Medical Center, Washington, DC 20010 [G. H. R.]; and Babies and Children’s Hospital, Columbia University, New York, New York 10032 [V. D., C. v. d. V., M. S. C.]


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
A Phase I trial was conducted to determine the safety, biological activity, and hematopoietic recovery by the combination of interleukin 6 (IL-6) and granulocyte-colony stimulating factor (G-CSF) after myelosuppressive chemotherapy in children. Patients <22 years of age at diagnosis with either recurrent or refractory solid tumors received ifosfamide 1,800 mg/m2/day x 5 days, carboplatin 400 mg/m2/day x 2 days, and etoposide 100 mg/m2/day x 5 days, followed by daily s.c. G-CSF (5 µg/kg/day) and IL-6 (2.5, 3.75, or 5.0 µg/kg/day). Pharmacokinetic, proinflammatory mediator levels, hematopoietic colony assays, and cytokine receptor expression studies were performed during course one. Nineteen patients were evaluable for toxicity and received IL-6 at doses of 2.5 (n = 8), 3.75 (n = 5), or 5.0 (n = 6) µg/kg/day. Dose-limiting constitutional toxicity occurred in two of six patients at 5.0 µg/kg/day, two of five patients at 3.75 µg/kg/day, and two of eight patients at 2.5 µg/kg/day. The maximum tolerated dose (MTD) exceeded the lowest dose tested. Because of lack of drug availability, an MTD was not established. The maximum concentration of IL-6 (2.5 µg/kg/day) was 0.799 ± 1.055 ng/ml (mean ± SD). During the first course, the median time to absolute neutrophil count >=1,000/mm3 and platelets >=100,000 mm3 was estimated at 19 and 23 days, respectively. Peripheral blood progenitor cells expressing receptors to IL-3, IL-6, and G-CSF increased significantly over baseline (P < 0.05). After the first dose of IL-6, IFN-{gamma} levels were abnormal in 13 patients, and IL-1ß levels were abnormal in 10 patients. IL-6 has a high incidence of constitutional toxicity and a lower MTD in children compared with adults. In vivo use of IL-6 in children after chemotherapy remains limited. However, IL-6 may be more optimally investigated in children under ex vivo conditions.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
IL3 -6 is a pleiotropic cytokine originally described as IFN-ß2 (1, 2, 3, 4) with effects on immunoregulation, induction of acute phase protein production, hematopoiesis, and megakaryocytopoiesis (1 , 4) . Specifically, IL-6 acts synergistically with IL-3 to stimulate multilineage hematopoietic blast colony formation (5) and induces megakaryocyte CFUs from murine bone marrow cells (6, 7, 8) . Preclinical in vivo studies have demonstrated that IL-6 increases platelet numbers in healthy rodents and primates (9, 10, 11, 12, 13, 14, 15) . In experimentally irradiated animals, IL-6 accelerated hematopoietic recovery (6 , 10 , 15 , 16) . In animals with chemotherapy-induced myelosuppression, IL-6 enhanced platelet recovery and prevented significant thrombocytopenia (17 , 18) . In several adult human Phase I/II trials (19, 20, 21, 22, 23, 24) , IL-6 at doses of 0.3 to 30 µg/kg/day increased platelet count before and after chemotherapy, accelerated platelet recovery after chemotherapy, and allowed an increase in chemotherapy dose intensity. Toxicities related to IL-6 in these patients included constitutional symptoms such as fever, chills, and myalgia, as well as dose-limiting organ toxicity.

Recently, Bouffet et al. (25) reported the results of a Phase I study of Escherichia coli-derived IL-6 administered s.c. without adjuvant chemotherapy to 12 children with relapsed solid tumors. Platelet counts rose significantly after 1 week of IL-6 therapy. IL-6 was tolerated without major organ toxicity at 10 µg/kg/day; however, side effects included fever, chills, fatigue in most patients, and anemia that required transfusion in 3 patients. They recommended that further Phase II/III trials with IL-6 in children should incorporate doses of 5–10 µg/kg/day to evaluate the efficacy of IL-6 in reducing thrombocytopenia after cytotoxic chemotherapy.

Given the potential of IL-6 to ameliorate chemotherapy-induced thrombocytopenia and the frequent incidence of constitutional symptoms associated with previous human IL-6 clinical trials, the CCG conducted a Phase I trial of IL-6 to determine safety and tolerability after myelosuppressive chemotherapy before conducting a definitive Phase II/III trial. The ICE chemotherapy regimen has been demonstrated to be associated with an excellent response rate in children with recurrent or refractory solid tumors (51%; Ref. 26 ). However, delayed platelet recovery has been the major limiting factor to dose intensification of ICE chemotherapy in children with recurrent or refractory solid tumors, and serious hematopoietic toxicity occurs despite support with double the dose of G-CSF (10 versus 5 µg/kg/day; Ref. 26 ).

Given the pleiotropic effects of IL-6, this CCG study was designed to quantify the frequency and severity of constitutional toxicities related to IL-6 in children, as well as to study the biological correlates of constitutional symptoms and thrombopoiesis. The objectives of the study were to: (a) determine the safe and maximum tolerated dose of IL-6 in children when administered simultaneously with G-CSF after ICE chemotherapy; (b) evaluate the effects of IL-6 and G-CSF on hematopoietic recovery after ICE chemotherapy; (c) determine the pharmacokinetics of IL-6 in children; (d) determine the effects of IL-6 on circulating serum proinflammatory mediators in children; and (e) determine the effects of IL-6 and G-CSF after ICE chemotherapy on circulating subsets of hematopoietic progenitor cells in children.


   PATIENTS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Eligibility.
This protocol (CCG-0931) was opened for patient entry in May 1994 and was closed to patient entry in December 1996 because of lack of drug availability. Patients with refractory or recurrent solid tumors who were <22 years of age at diagnosis were eligible for study entry. All patients were required to have histological verification of malignancy at the time of initial diagnosis and radiological and/or histological evidence of recurrence. Patients with bone marrow involvement by tumor, patients who had received craniospinal irradiation (>=3600 cGy) or radiation therapy to >50% of their bone marrow space, or patients having received previously total body irradiation were ineligible for study entry. Patients with a diagnosis of coagulopathy, thrombotic disorder, autoimmune disease, asthma requiring ongoing therapy, history of HIV, hepatitis B infection, or lymphoma were also excluded. All patients must have recovered from previous CSF therapy and have been off all CSFs for more than 10 days. All patients were required to have adequate bone marrow, liver, renal, and cardiac function at the time of study entry. Adequate bone marrow function at the time of study entry was defined as an ANC >=1000/mm3 and platelet count >=100,000/mm3 . The patient or legal guardian must have signed a documented informed consent approved by the institutional review board indicating awareness of the investigational nature and risks of this study. Patients must have had an adequate performance status of 60 on a Lansky scale (age, 1–16 years) or Karnofsky scale (age, >16 years). Patients were required to be a minimum of 12 months of age at the time of study entry.

Chemotherapy Administration.
Eligible patients received ifosfamide 1,800 mg/m2 on days 0–4, carboplatin 400 mg/m2 on days 0–1, and etoposide 100 mg/m2 on days 0–4. 2-Mercaptoethane sulfonic acid and i.v. hydration were administered during each of the 5 days of ifosfamide. Five doses of 2-mercaptoethane sulfonic acid (360 mg/m2) were given: first dose during ifosfamide, second as a 3-h infusion, and then as a 15- to 30-min infusion every 3 h. Chemotherapy was repeated every 21 days or later when hematological recovery was achieved (ANC >=1,000/mm3 and platelet count >=100,000/mm3 ). IL-6 and G-CSF were discontinued at least 2 days prior to subsequent chemotherapy. After course one, ICE chemotherapy could be reduced by 25% if, in the previous course, hematological recovery failed to occur by day 21. The protocol directed surgical tumor resection was to be considered only after the patient had completed four courses of chemotherapy and response to ICE was assessed. Additionally, no patients received radiotherapy while receiving protocol therapy.

CSF Administration.
Recombinant human E. coliderived IL-6 (SDZ ILS 969), kindly provided by Novartis Pharmaceuticals, was distributed by the NCI. SDZ ILS 969 is supplied as a sterile lyophilizate in vials containing 150 mg of rhIL-6 per vial. The formulated lyophilizate contains >=90% pure rhIL-6 and <0.6 EU/vial of bacterial endotoxin. The biological specific activity was 6.1 x 107 units/mg as determined by hybridoma B13.29 cell line proliferation assay. There were three dose levels used in this study, 2.5, 3.75, and 5.0 µg/kg/day. Recombinant human met G-CSF (r-metHuG-CSF) was also provided by the NCI. The dose of G-CSF was 5 µg/kg/day for all dose levels of IL-6 and for all courses. IL-6 and G-CSF were administered as two separate daily s.c. injections beginning 24 h after the end of chemotherapy. G-CSF was continued until the post nadir ANC was >=1,000/mm3 . IL-6 was administered until the platelet count was >=100,000/mm3 for 2 consecutive days or a maximum of 35 days. In course one only, the first dose of IL-6 preceded the first dose of G-CSF by 12 h to allow for pharmacokinetic sampling. Protocol therapy was terminated for a patient at the time of documented disease progress, regardless of the course during which this progression was noted. Patients failing to achieve the desired ANC and platelet count (i.e., >=1,000/mm3 and >=100,000/mm3 , respectively) by day 35 were considered off protocol therapy and in follow-up.

IL-6 Dose Escalation.
All patients were identified to the CCG registrar within 72 h of starting chemotherapy, and the dose level of IL-6 was assigned at that time. Chemotherapy and IL-6 were continued past course 2 until either disease progression, failure to achieve an ANC >=1,000/mm3 , or platelet count >=100,000/mm3 by day 35, grade IV renal toxicity resulting from ifosfamide, or a maximum of eight courses of therapy.

DLT was defined as either grade IV toxicity or recurrent grade III toxicity related to IL-6 using the NCI Common Toxicity Criteria (version 1) or pain which persisted beyond two doses and was not controlled by narcotic analgesia. Grade III chills were defined as chills occurring with three or more injections; grade IV chills were defined as chills that persisted despite treatment. Grade III chills that recurred on subsequent administration were considered dose-limiting. A minimum of three evaluable patients was entered as a cohort; all patients in the cohort were assigned the same dose. If none of the patients demonstrated DLT, the dose level was escalated in the next cohort. If two or more patients experienced DLT, the MTD had been exceeded, and three more patients were treated at the next lower dose unless six patients had already been treated at that dose. If one of these three patients experienced DLT, then three more patients were accrued at the same level. If none of these three additional patients experienced DLT, then the dose was escalated in subsequent patients. If one or more of these three additional patients experienced DLT, the MTD had been exceeded, and three more patients were treated at the next lower dose (unless six patients had already been treated at that prior dose). If two or more patients of the first three evaluable patients experienced DLT, the MTD had been exceeded, and three more patients were treated at the next lower dose (unless six patients had already been treated at that prior dose).

The MTD is the dose level at which less than one-third of the patients experienced DLT, with at least one-third of patients experiencing DLT at the next higher dose. Intrapatient dose escalation was not done in this study. Only the toxicity evaluation made during the first course of therapy was used in the determination of the MTD.

Hematological Recovery.
CBC, differential, and platelet counts were obtained every other day and daily when either the platelet count was <=20,000/mm3 , ANC <=500/mm3 , ANC >=10,000/mm3 , or platelets >=100,000/mm3 during the first course. In subsequent courses, CBC, differential, and platelet counts were obtained on days 0, 4, 11, 18, and 21.

IL-6 Pharmacokinetics.
Blood specimens for pharmacokinetic analysis were drawn only on the first course of treatment. Prior to treatment on day 0 of the first course prior to chemotherapy, a blood sample was collected when possible for IL-6 baseline concentrations. On day 5 of the first course only, samples were collected at the following times: 0 (pre-IL-6), 1, 2, 4, 6, 8, 10, and 12 h. Blood samples were collected into serum separator tubes and placed immediately on ice until clotted. The samples were then centrifuged, and the separated serum was stored frozen at approximately -70°C prior to shipment to Novartis Pharmaceuticals Corp. for analysis.

Serum concentrations of rhIL-6 were determined by ELISA using a Quantikine rhIL-6 kit (R&D Systems, Minneapolis, MN). Briefly, a monoclonal antibody specific for IL-6 was precoated onto each microtiter plate. Standard, quality control, and unknown samples were pipetted into the wells of the microtiter plate, and any IL-6 present was bound by the immobilized antibody. After washing away the unbound substances, an enzyme-linked polyclonal antibody specific for IL-6 was added to the wells to "sandwich" the IL-6 immobilized during the first incubation. Unbound antibody-enzyme reagent was removed from the wells by washing, followed by addition of substrate solution to the wells. The color that developed was directly proportional to the amount of IL-6 bound in the initial step. After color development was stopped, the intensity of the color was measured at a wavelength of 450 nm.

Each sample (standard, quality control, and unknown) was analyzed in triplicate, and the individual ELISA response values, expressed as absorbance, were used to construct the standard curve. The standard curve was created from the mean absorbance of each triplicate via the SOFTmax 4-parameter program. The concentration estimate was interpolated from the individual standard curves, using the mean response of each triplicate analysis. Samples that had concentration estimates above the upper limit of quantification (200 pg/ml) in the primary analysis were diluted in pooled normal human serum to bring the concentration within the dynamic range of the assay and reanalyzed.

Estimates of the pharmacokinetic parameters were obtained by noncompartmental analysis using GraphPad Prism (GraphPad Software, Inc.; version 2.00). The terminal elimination rate constant (kel) was calculated by linear least squares regression of the linear terminal elimination phase of the graph of natural logarithm of the serum concentration versus time. AUC0–12 was determined by trapezoidal approximation from the time of injection to the last detectable serum concentration (C12 h) with residual area after C12 h, calculated by AUC12 h->{infty} = C12 h/kel. The elimination half-life was calculated by t1/2 = 0.693/kel.

Peripheral Blood Progenitor Cells.
During the first course of IL-6 administration, peripheral blood progenitor cells were measured at the CCG Hematopoiesis Resource Laboratory at Children’s Hospital of Orange County before therapy and when the WBCs recovered to >1,000/mm3 . MNCs were isolated from the blood samples by density gradient separation with Ficoll-Hypaque. An aliquot of this MNC fraction (104 cells/ml) was added to Iscove’s modified Dulbecco’s medium/0.9% methylcellulose (StemCell Technologies, Inc., Vancouver, British Columbia, Canada) supplemented with 2 units/ml of erythropoietin (Epogen; Amgen, Thousand Oaks, CA). Colony formation was induced by stimulation with phytohemagglutinin human leukocyte conditioned medium (StemCell Technologies, Inc.). The cells were plated in 24-well plates (Costar, Cambridge, MA) at 500 cells/well and incubated in a 5% CO2 humidified incubator at 37°C. Colonies were scored after 14–21 days, and clusters of 25+ cells were considered colonies.

Peripheral Progenitor Cell Receptor Expression.
Aliquots of MNCs isolated from peripheral blood, as described above, were stained with fluorochrome conjugated monoclonal antibodies for cytokine receptor, CD41+ and CD34+ expression. CD34+ cell populations were assessed using the human progenitor cell antigen antibody conjugated to PE (Becton Dickinson, Mountain View, CA). Receptor expression was measured using the following antibodies: IL-3/PE (R&D Systems), IL-6/PE (R&D Systems), GM-CSF/PE (R&D Systems), and stem cell factor/PE (R&D Systems). Analysis was performed on a FACStar flow cytometer (Becton Dickinson) with gating on the leukocyte populations of interest using the Simultest Leukogate antibody cocktail. Isotype controls were included for each staining experiment.

Induction of Endogenous Inflammatory Mediators.
Serum was to be analyzed for concentrations of IL-1{alpha}, IL-1ß, TNF-{alpha}, and IFN-{gamma} from samples drawn on day 5 of the first course only, before the first dose of IL-6, and at 1, 2, 4, 6, 8, 10, and 12 h after s.c. administration of IL-6. The G-CSF dose was held until all samples were drawn. When possible, investigators were to submit a serum specimen for analysis of the above-mentioned mediators prior to the start of ICE chemotherapy. Aliquots of patient serum and plasma from different time points were shipped on dry ice overnight to the CCG Cytokine Resource Laboratory at the University of Minnesota Hospital and stored at -70°C. Levels of IL-1{alpha}, IL-1ß, TNF-{alpha}, and IFN-{gamma} were determined by sandwich ELISA using commercially available kits (R&D Systems, Minneapolis, MN) according to manufacturers’ instructions for either the serum or plasma, depending on the optimal matrix empirically determined by the reference lab. The concentrations for each proinflammatory mediator, in pg/ml, were interpolated from standard curves generated for each assay performed. Values were categorized as abnormally elevated if they were above the reference range for 95% of apparently healthy individuals.

Statistical Analysis.
All eligible patients were evaluated for delivery of therapy. Any patient who completed at least 1 week of IL-6 therapy or who was removed from protocol therapy because of DLT was considered in the evaluation of the MTD.

Patients were evaluated for time to hematological recovery for each course of therapy delivered. Any patient who was evaluable for determination of the MTD and had submitted serial peripheral blood counts was considered a candidate for this analysis. The time to ANC recovery was calculated as the number of days from the start of the course to the first CBC where the ANC exceeded 1,000/mm3 . Any CBC done in the interval from the start of chemotherapy to day 9 of the course was not considered in this analysis, because peripheral blood counts dropped precipitously for all patients during this time frame. From among the remaining reported CBCs, the date the patient’s CBC was first >1,000/mm3 ("recovered date") was identified. Next, the date closest to the recovered date at which the patient’s ANC was <1,000/mm3 ("last below date") was identified. Patients removed from therapy because of disease progression prior to recovery of ANC to at least 1,000/mm3 were right censored for recovery of ANC at the time of the last reported CBC. Because of patterns of patient care, the "last below" and "recovered dates" were separated by an average of 2 days (range, 1–7). The survivor function for recovery of ANC to at least 1,000/mm3 , therefore, was estimated using the interval censoring methodology of Turnbull (27) . A similar procedure was followed to estimate the time to recovery of platelets to 100,000/mm3 .

Results of the progenitor and receptor studies are expressed as mean ± SE. The equality of the mean biological measures between baseline and posttherapy time points was assessed using Student’s t test. The fold change was calculated by dividing the mean posttherapy value by the mean pretherapy value.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Characteristics.
Between May 1994 and December 1996, 25 patients, ages 23 months through 21 years (median age, 14 years) with recurrent or refractory solid tumors were enrolled on CCG-0931 (Table 1)Citation . One patient did not receive any protocol therapy, and five additional patients started chemotherapy but did not receive IL-6. These six patients are not considered further. Among the 19 patients considered evaluable for toxicity, two patients were removed from protocol therapy prior to day 21. One was removed on day 14 because of sepsis and multiorgan failure, and one was removed on day 18 because of fever, chills, and bruising at injection sites. Nine patients completed only one course of therapy, four patients completed two courses of therapy, and six completed three or more courses of therapy.


View this table:
[in this window]
[in a new window]

  		Table 1 Patient characteristics

 
Dose Selection and Toxicity Related to IL-6.
Toxicity related to IL-6 was frequent, and constitutional toxicities became dose limiting. There were no noted cardiac, neurological, or hepatic toxicities attributable to IL-6. Table 2Citation summarizes toxicities associated with IL-6. Recurrent or refractory (grade III/IV) chills were particularly frequent, occurring in 10 of 19 evaluable patients including 4 of 6 patients at the highest dose level of 5.0 µg/kg/day.


View this table:
[in this window]
[in a new window]

  		Table 2 Grade III/IV toxicities per dose level for IL-6

 
The initial cohort of 3 patients received IL-6 at 2.5 µg/kg/day, and the next cohort received IL-6 at 5.0 µg/kg/day. Among the 6 patients who received IL-6 at 5.0 µg/kg/day, one child experienced dose-limiting grade III chills, and another experienced dose-limiting grade IV bone pain and myalgia. An intermediate de-escalation dose of 3.75 µg/kg/day was then instituted. Two of 5 patients demonstrated DLT at 3.75 µg/kg/day. One patient experienced dose-limiting grade III chills and the other experienced grade IV chills. Therefore, the dose of IL-6 was de-escalated again to 2.5 µg/kg/day. In this last set of 5 children, one experienced dose-limiting grade IV hypotension and grade III chills; another experienced dose-limiting grade IV hypotension and grade IV bone pain. Dose de-escalation was not continued because of lack of available rhIL-6. Therefore, no MTD could be established, but it is estimated to be <2.5 µg/kg/day.

IL-6 Pharmacokinetics.
The pharmacokinetics of IL-6 were studied in 16 patients who received doses of 2.5, 3.75, or 5.0 µg/kg/day. Pharmacokinetic parameters are summarized in Table 3Citation . A profile of the mean serum IL-6 concentration-time data for patients who received 2.5 µg/kg/day is illustrated in Fig. 1Citation . At 2.5 µg/kg/day, peak serum concentration of IL-6 was observed 2.8 h after administration, and the elimination half-life was 3 h. The equivalent values for all doses combined were 4 and 2.8 h, respectively. Four patients had an apparent plateau concentration of IL-6, and their calculated elimination half-life and AUC0–{infty} could not be determined. The mean AUC0–12 values appeared to increase as the dose was increased, but the substantial interpatient variability found for AUC at each dose level and the limited dose response did not permit evaluation of the linearity of the pharmacokinetics.


View this table:
[in this window]
[in a new window]

  		Table 3 Pharmacokinetic parameters of IL-6 in children

 


View larger version (11K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 1. Pharmacokinetic profile of mean serum IL-6 concentration in children after s.c. administration of 2.5 µg/kg/day. IL-6 was administered s.c. 1 day after ICE chemotherapy, and serum levels were drawn and measured by sandwich ELISA (n = 5).

 
Hematological Recovery, Transfusions, and Infections.
Two patients did not complete the full course of chemotherapy and IL-6/G-CSF therapy, and therefore 17 patients were evaluable for hematological recovery. During course one, the median number of days to ANC recovery >=1,000/mm3 was 19 (Fig. 2)Citation , and the median number of days to platelet recovery >=100,000/mm3 was 23 (Fig. 3)Citation . All patients developed grade IV thrombocytopenia. Evaluation of all courses revealed similar data for ANC recovery (median, 18 days) but delayed platelet recovery (median, 26 days). Patients received a median of five platelet transfusions during course one. During course one, two patients had fulminant infections, two others had infections with chills, rigors, and/or fever, and six had presumed infections with fever. The remaining patients had no evidence of infection.



View larger version (11K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 2. Probability of ANC recovery >=1,000/mm3 in course one of ICE followed by IL-6 + G-CSF by Kaplan-Meier statistics (n = 17).

 


View larger version (12K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 3. Probability of platelet count recovery >=100,000/mm3 in course one of ICE followed by IL-6 + G-CSF by Kaplan Meier statistics (n = 17).

 
Subsets of Peripheral Blood Progenitor Cells.
Specimens were received on 12 children and subsets of PBPCs at baseline and when the WBCs had recovered to >1,000/mm3 after the nadirs were determined. The results are summarized in Fig. 4Citation . Flow cytometric analysis of PBPCs (Fig. 4)Citation demonstrated a significant (P < 0.05) increase above baseline when the WBCs were >1,000/mm3 in the percentage of cells expressing receptors to IL-3 (93 ± 3.51% versus 23.02 ± 10.11%), GM-CSF (93.67 ± 1.3% versus 22.77 ± 22.3%), and IL-6 (97.62 ± 0.12% versus 29.67 ± 13.9%; mean ± SEM). There was >25-fold increase in the subset of cells expressing CD41+ (27.03 ± 15.8% versus 1.03 ± 0.62%, P = 0.055; Fig. 4Citation ) and a 4-fold increase in the CD34+ population (0.63 ± 0.59% versus 0.15 ± 0.08%, P = 0.48). There was no significant change in the percentage of PBPCs expressing c-kit+ (data not shown). Progenitor hematopoietic colony assays demonstrated a 2.8-fold increase in CFU-GM and a 5.8-fold increase in granulocytic erythroid megakaryocytic monocytic colony formation over baseline.



View larger version (14K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 4. Percentage of increase in PBPCs expressing surface markers to CD41+, IL-3 receptor (IL-3 R), GM-CSF receptor (GM-CSF R), and IL-6 receptor (IL-6 R) when the WBCs recovered to >1,000/mm3. *, P < 0.055; **, P < 0.01; ***, P < 0.05 recovery versus day 0. - - -, 100%. Bars, SEM (n = 12).

 
Induction of Proinflammatory Mediators.
Cytokine levels for IL-1{alpha}, IL-1ß, TNF-{alpha}, and IFN-{gamma} were completed on 18 patients. Levels were drawn on day 5 before the first dose of IL-6 and at 1, 2, 4, 6, 8, 10, and 12 h after s.c. administration. The G-CSF dose was held until all samples were drawn. Serum IFN-{gamma} was elevated in 13 of 18 patients after IL-6 administration, and 7 of these patients had elevated levels at hour 0. Serum IL-1ß was elevated in 10 of 18 patients, 1 of whom had an elevated level at hour 0. Serum IL-1{alpha} was elevated in 2 patients, 1 of whom had an elevated level at hour 0. One patient had an elevated TNF-{alpha} level only after IL-6.


   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Thrombocytopenia remains a major DLT of myelosuppressive multiagent chemotherapy. IL-6 has been demonstrated in animal and adult human studies to shorten the duration of thrombocytopenia after myelosuppressive chemotherapy (19 , 23 , 24) . E. coli-derived rhIL-6 also has been demonstrated not to be associated with any significant organ toxicity in children at doses of 5–10 µg/kg/day when given without prior chemotherapy (25) . The CCG conducted a Phase I trial of IL-6 in children with recurrent/refractory tumors to determine a safe and tolerated dose to use in a Phase III randomized trial to determine whether IL-6 could accelerate platelet recovery and reduce the incidence of grade III/IV thrombocytopenia in children receiving ICE chemotherapy. All dose levels tested exceeded the MTD, and DLTs were principally constitutional "flu-like" symptoms. With few exceptions (28) , E. coli-derived IL-6 (10 µg/kg/day) has been tolerated after chemotherapy in adults with only modest constitutional toxicity (19 , 23 , 24 , 29) . At higher doses of IL-6 (20 µg/kg/day), Veldhuis et al. (24) demonstrated DLT characterized by headache, myalgia, fever, chills, and nausea in adult patients with solid tumors. Organ toxicities at doses of IL-6 higher than 20 µg/kg/day have included cardiac arrhythmias, neurological deficits (confusion, hallucinations, and hemiplegia), and severe hepatotoxicity (23 , 24 , 29) .

Bouffet et al. (25) studied the use of E. coli-derived IL-6 given s.c. in children with recurrent/refractory solid tumors. Children were given IL-6 without chemotherapy to determine the toxicity, thrombopoietic, and antitumor effects of IL-6 (25) . In that study, IL-6 was escalated from 1.0 to 10 µg/kg/day in 12 children without organ toxicity. Fever was the only form of grade III/IV toxicity, with most patients having fever and chills requiring prophylactic paracetamol (acetaminophen) therapy. Additionally, fatigue was a universal complaint at doses >2.5 µg/kg/day. These constitutional toxicities were not evaluated as dose-limiting, 10 µg/kg/day was considered tolerable, and the MTD was not reached in that study. The authors further recommended evaluating IL-6 at a dose between 5 and 10 µg/kg/day in children after myelosuppressive chemotherapy. In our study, 2.5 µg/kg/day after ICE chemotherapy was intolerable because of severe constitutional toxicities. However, no prophylactic treatment was given for fevers or chills.

When compared with historical studies with G-CSF alone after ICE chemotherapy, children with recurrent/refractory solid tumors appear to have enhanced platelet recovery during the first course with IL-6 + G-CSF versus G-CSF alone. In a previous CCG study (CCG-0894), 118 children were followed for hematological recovery after ICE chemotherapy at two doses of G-CSF, 5 and 10 µg/kg/day (26) . Median time to platelet recovery in the current study to >=100,000/mm3 was 23 days at dose levels exceeding the MTD of IL-6. In contrast, patients treated on CCG-0894 had a median time to platelet recovery of 27 days (26) . However, the median number of platelet transfusions in course one was five and appears similar to a median of six in the CCG-0894 G-CSF trial (26) .

Several factors may possibly contribute to the decreased MTD in children receiving IL-6 after chemotherapy compared with adults or children who have not received chemotherapy. The addition of prior myelosuppressive chemotherapy in our pediatric trial may have facilitated the development of constitutional side effects of IL-6. In support of this theory, Lazarus et al. (28) noted an excessive amount of toxicity of E. coli-derived IL-6 at 3.0 µg/kg/day in adult patients after high-dose chemotherapy and autologous bone marrow transplantation. They suggested that the increase in dose intensity during preparative regimens prior to transplantation may predispose patients to increased IL-6-related toxicities (28) . Of note, one-third of children in the present study had elevated IFN-{gamma} levels after ICE chemotherapy prior to IL-6 administration. All of these patients had a subsequent rise in IFN-{gamma} levels coincident with or tailing after the peak IL-6 levels.

The pharmacokinetics of s.c. administered IL-6 in children demonstrate high peak serum levels that were reached in 4 h with an elimination half-life of ~2.2 h. Bouffet et al. (25) measured serum IL-6 levels in one child each at three dose levels (1.0, 2.5, and 5.0 µg/kg/day) and found levels within the lower range of our current study. Comparing the same dose of IL-6 (2.5 µg/kg/day) in children and adults, it appears that children in our study have a higher Cmax (0.799 ± 1.055 ng/ml; mean ± SD) than reported previously in adults (highest Cmax, 254 pg/ml; Refs. 29 and 30 ). The more rapid absorption of IL-6 may contribute to the higher incidence of grade III/IV constitutional toxicities at lower doses in children compared with adults.

In our study, IL-6 increased the level of circulating proinflammatory mediators IL-1ß and IFN-{gamma} in many children. These mediators may be partly responsible for the increase in constitutional toxicities secondary to IL-6. Samples were collected after the first dose of IL-6 but before the first dose of G-CSF; therefore, exogenous G-CSF probably did not contribute to the elevation of proinflammatory mediators. Conversely, in several adult studies without chemotherapy, the level of proinflammatory mediators did not increase after administering E. coli or yeast-derived IL-6 (23 , 31) . Some studies have demonstrated an increase after IL-6 in TNF-{alpha} mRNA (32) or IFN-{gamma} mRNA (4) without a correspondent increase in serum levels (32) after IL-6. Only one study (33) demonstrated an increase in serum TNF-{alpha} in two of eight patients. Thus, the difference in tolerance to IL-6 may relate directly to a difference in induction of proinflammatory mediators in children compared with adults. However, it should be noted that there was no statistical correlation with abnormal mediator levels and grade III/IV constitutional toxicity, although the study was not designed to evaluate proinflammatory mediator levels at the time of constitutional toxicities.

The increased severity of constitutional toxicity without organ toxicity at lower doses of IL-6 in children versus adults underlines the need to conduct separate Phase I trials of biological agents and immunomodulators in children. In preclinical animal studies, IL-6 was thought to be safe and without severe constitutional toxicities. Adult IL-6 Phase I studies demonstrated substantial low grade but controllable inflammatory effects of IL-6 (34) . Conversely, agents considered intolerable in adults may be well tolerated in children. Similar doses of PIXY321 are tolerated in children with less frequent constitutional side effects than in adults (35 , 36) . Recently, IL-11 has been shown by Kirov et al. (37) to be well-tolerated in children at 150% the adult MTD (75 µg/kg/day versus 50 µg/kg/day). Furthermore, the pharmacokinetics of IL-11 are different in children versus adults; children eliminate IL-11 more rapidly than adults (37) .

An increase of subsets of cells expressing CD34+ and CD41+ after therapy compared with baseline (day 0) was demonstrated in this study. The number of CFU-GM colonies also increased compared with baseline in this small sample population. IL-6 + G-CSF appears to enhance hematopoietic recovery in vivo by stimulation of both committed and uncommitted subsets of progenitor cells. Chemotherapy alone, G-CSF alone, or the combination thereof have been demonstrated to enhance mobilization of PBPCs (38, 39, 40, 41) . Preclinical studies have demonstrated both additive and synergistic effects of IL-6 and G-CSF in enhancing PBPC mobilization (42 , 43) . In one human study of 27 adults with adenocarcinoma, combined IL-6 and G-CSF were demonstrated to dramatically increase PBPCs 36-fold, whereas IL-6 alone generated an 8-fold rise in PBPCs (44) .

In the present study, we have demonstrated that IL-6 + G-CSF significantly increases the subpopulation of PBMNC expressing receptors to IL-3, IL-6, and GM-CSF and may increase hematopoietic CFUs compared with baseline values. IL-6 + G-CSF could potentiate the hematopoietic effects of each of these endogenous hematopoietic growth factors by increasing growth factor receptor expression. Unfortunately, we do not have data with G-CSF alone to determine the true contribution of the addition of IL-6. Perhaps a short, ostensibly more tolerable course of IL-6 can "prime" the hematopoietic system for the action of other hematopoietic growth factors to enhance hematological recovery after myelosuppression. Sequential administration of IL-6 followed by G-CSF has been shown to increase the platelet count and the number of bone marrow hematopoietic progenitors in neonatal rats over and above that produced by G-CSF alone (45) .

In summary, IL-6 and G-CSF may decrease the time to platelet recovery after myelosuppressive chemotherapy (ICE) and G-CSF alone; however, the excessive toxicity of IL-6 after chemotherapy in children may preclude extensive use of IL-6 in vivo. Unlike Bouffet et al. (25) , this study suggests that the modest potential decrease in time to platelet recovery does not warrant further in vivo Phase II/III studies of IL-6 after myelosuppressive chemotherapy in children. The increase in constitutional toxicities of IL-6 in children as compared with adults may be related to the increased absorption of IL-6 and/or the in vivo increase of circulating proinflammatory mediators. Currently, other thrombopoietic agents may have more clinical applicability with wider therapeutic indices. IL-11 has been approved for chemotherapy-induced severe thrombocytopenia. Other thrombopoietic proteins, including thrombopoietin, are in Phase III clinical trials in adults, and CCG has opened a Phase I/II trial of ICE chemotherapy, followed by recombinant human thrombopoietin and G-CSF (CCG-09717). Future investigations of IL-6 to expand and/or activate stem/immune cells ex vivo may be more promising.


View this table:
[in this window]
[in a new window]

  		Appendix 1. APPENDIX Participating principal investigators—Children’s Cancer Group

 

   ACKNOWLEDGMENTS
 
We thank Linda Rahl, Lisa Bozenhard-Froncek, and Lucia Noll for extraordinary help in preparing the manuscript.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Grant support from the Division of Cancer Treatment, National Cancer Institute, NIH, Department of Health and Human Services. Presented in part at the American Society of Clinical Oncology Meeting, May 1999, Atlanta, GA. Contributing Children’s Cancer Group investigators, institutions, and grant numbers are given in the Appendix . Back

2 To whom requests for reprints should be addressed, at Children’s Cancer Group, P. O. Box 60012, Arcadia, CA 91066-6012. Phone: (626) 447-0064; Fax: (626) 445-4334. Back

3 The abbreviations used are: IL, interleukin; rhIL, recombinant human IL; CFU, colony-forming unit; CCG, Children’s Cancer Group; ICE, ifosfamide, carboplatin, and etoposide; CSF, colony-stimulating factor; G-CSF, granulocyte-CSF; GM-CSF, granulocyte/macrophage-CSF; ANC, absolute neutrophil count; NCI, National Cancer Institute; DLT, dose-limiting toxicity; CBC, complete blood count; AUC, area under the curve; MNC, mononuclear cell; PE, phycoerythrin; MTD, maximum tolerated dose; PBPC, peripheral blood progenitor cell; TNF, tumor necrosis factor. Back

Received 6/22/00; revised 10/23/00; accepted 10/24/00.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Hirano T., Yasukawa K., Harada H., Taga T., Watanabe Y., Matsuda T., Kashiwaramura S., Nakajima K., Koyama K., Iwamatsu A., Tsunasawa S., Sakiyama F., Matsui H., Takahara Y., Taniguchi T., Kishimoto T. Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin. Nature (Lond.)., 324: 73-76, 1986.[CrossRef][Medline]
  2. Le J., Vilcek J. Interleukin 6: a multifunctional cytokine regulating immune reactions and the acute phase protein response. Lab. Investig., 61: 588-602, 1989.[Medline]
  3. Kinashi T., Harada N., Severinson E., Tanabe T., Sideras P., Konishi M., Azuma C., Tominaga A., Bergstedt-Lindqvist S., Takahashi M., Matsuda F., Yaoita Y., Takatsu K., Honjo T. Cloning of complementary DNA encoding T-cell replacing factor and identity with B-cell growth factor II. Nature (Lond.)., 324: 70-73, 1986.[CrossRef][Medline]
  4. Weber J. Interleukin-6: multifunctional cytokine Devita V. T. Hellman S. Rosenberg S. A. eds. . Biologic Therapy of Cancer Updates, 3: 1-9, J. B. Lippincott Company Hagerstown, MD 1993.
  5. Leary A., Ikebuchi K., Hirai Y., Wong G., Yang Y., Clark S., Ogawa M. Synergism between interleukin-6 and interleukin-3 in supporting proliferation of human hematopoietic stem cells: comparison with interleukin-1a. Blood, 71: 1759-1763, 1988.[Abstract/Free Full Text]
  6. Herodin F., Mestries J-C., Janodet D., Martin S., Mathieu J., Gascon M-P., Pernin M-O., Ythier A. Recombinant glycosylated human interleukin-6 accelerates peripheral blood platelet count recovery in radiation-induced bone marrow depression in baboons. Blood, 80: 688-695, 1992.[Abstract/Free Full Text]
  7. Koike K., Nakahata T., Kubo T., Kikuchi T., Takagi M., Ishiguro A., Tsuji K., Naganuma K., Okano A., Akiyama Y., Akabane T. IL-6 enhances murine megakaryocytopoiesis in serum free culture. Blood, 75: 2286-2291, 1990.[Abstract/Free Full Text]
  8. Warren M., Conry L., Rose J. The role of interleukin 6 and interleukin 1 in megakaryocyte development. Exp. Hematol., 17: 1095-1099, 1989.[Medline]
  9. Asano S., Okano A., Ozawa K., Nakahata T., Ishibashi T., Koike K., Kimura H., Tanioka Y., Shibuya A., Hirano T., Kishimoto T., Takaku F., Akiyama Y. In vivo effects of recombinant human interleukin-6 in primates: stimulated production of platelets. Blood, 75: l602-l605, 1990.
  10. Burstein S., Downs T., Friese P., Lyman S., Anderson S., Henthorn J., Epstein R., Savage K. Thrombocytopoiesis in normal and sublethally irradiated dogs: response to human interleukin-6. Blood, 80: 420-428, 1992.[Abstract/Free Full Text]
  11. Ishibashi T., Kimura H., Shikama Y., Uchida T., Kariyone S., Hirano T., Kishimoto T., Takatsuki F., Akiyama Y. Interleukin-6 is a potent thrombopoietic factor in vivo in mice. Blood, 74: 1241-1244, 1989.[Abstract/Free Full Text]
  12. Ishibashi T., Shikama Y., Kimura H., Kawaguchi M., Uchida T., Yamamoto T., Okano A., Akiyama Y., Hirano T., Kishimoto T., Maruyama Y. Thrombopoietic effects of interleukin-6 in long-term administration in mice. Exp. Hematol., 21: 640-646, 1993.[Medline]
  13. Ryffel B., Car B. D., Woerly G., Weber M., DiPadova F., Kammuller M., Klug S., Neubert R., Neubert D. Long-term interleukin-6 administration stimulates sustained thrombopoiesis and acute-phase protein synthesis in a small primate-the marmoset. Blood, 83: 2093-2102, 1994.[Abstract/Free Full Text]
  14. Stahl C., Zucker-Franklin D., Evatt B., Winton E. Effects of human interleukin-6 on megakaryocyte development and thrombocytopoiesis in primates. Blood, 78: 1467-1475, 1991.[Abstract/Free Full Text]
  15. Zeidler C., Kanz L., Hurkuck F., Rittmann K. L., Wildfang I., Kadoya T., Mikayama T., Souza L., Welte K. In vivo effects of interleukin-6 on thrombopoiesis in healthy and irradiated primates. Blood, 80: 2740-2745, 1992.[Abstract/Free Full Text]
  16. Patchen M., MacVittie T., Williams J., Schwartz G., Souza L. Administration of interleukin-6 stimulates multilineage hematopoiesis and accelerates recovery from radiation-induced hematopoietic depression. Blood, 77: 472-480, 1991.[Abstract/Free Full Text]
  17. Takatsuki F., Okano A., Suzuki C., Miyasaka Y., Hirano T., Kishimoto T., Ejima D., Akiyama Y. Interleukin 6 perfusion stimulates reconstitution of the immune and hematopoietic systems after 5-fluorouracil treatment. Cancer Res., 50: 2885-2890, 1990.[Abstract/Free Full Text]
  18. Winton E., Srinivasiah J., Kim B., Hillyer C., Strobert E., Orkin J., Swenson R., McClure H., Myers L., Saral R. Effect of recombinant human interleukin-6 (rhIL-6) and rhIL-3 on hematopoietic regeneration as demonstrated in a nonhuman primate chemotherapy model. Blood, 84: 65-73, 1994.[Abstract/Free Full Text]
  19. D’Hondt V., Humblet Y., Guillaume T., Baatout S., Chatelain C., Berliere M., Longueville J., Feyens A. M., De Greve J., Van Oosterom A., Von Graffenried B., Donnez J., Symann M. Thrombopoietic effects and toxicity of interleukin-6 in patients with ovarian cancer before and after chemotherapy: a multicentric placebocontrolled, randomized Phase Ib study. Blood, 85: 2347-2353, 1995.[Abstract/Free Full Text]
  20. Budd G. T., Pelley R., Samuels B., Gockerman J., Margolin K., Zalupski M., Manfreda S., George M., Bukowski R. Phase II randomized trial of simultaneous rhIL-6 and G-CSF following maid chemotherapy in patients with sarcomas: preliminary results. Proc. Am. Soc. Clin. Oncol., 14: 256 1995.
  21. Aronson F. R., Sznol M., Mier J. W., Oleksowicz L., Fisher R. I., Weiss G. R., Isaacs R. E., Margolin K. A. Interleukin-6: Phase I trials of 1 and 120 hour intravenous infusions. Proc. Am. Soc. Clin. Oncol., 12: 292 1993.
  22. Hamm J., Crawford J., Figlin R., Chang A., Wasserheit C., Lee M., Campion M., Manfreda S., Isaacs R. A Phase I/II study of the simultaneous administration of recombinant human interleukin-6 (rhIL-6; E. coli) and Neuprogen (rhG-CSF; E. coli) following ICE chemotherapy in patients with advanced non-small cell lung carcinoma. Proc. Am. Soc. Clin. Oncol., 13: 332 1994.
  23. van Gameren M., Willemse P., Mulder N., Limburg P., Groen H., Vellenga E., de Vries E. Effects of recombinant human interleukin-6 in cancer patients: a Phase I-II study. Blood, 84: 1434-1441, 1994.[Abstract/Free Full Text]
  24. Veldhuis G. J., Willemse P. H. B., Sleijfer D. T., van der Graaf W. T. A., Groen H. G. M., Limburg P. C., Mulder N. H., de Vries E. G. E. Toxicity and efficacy of escalating dosages of recombinant human interleukin-6 after chemotherapy in patients with breast cancer or non-small-cell lung cancer. J. Clin. Oncol., 13: 2585-2593, 1995.[Abstract]
  25. Bouffet E., Phillip T., Negrier C. I., Ffrench M., Gentilhomme O., Gianella-Borradori A., Brunat-Mentigny M., Blay J. Phase I study of Interleukin-6 in children with solid tumors in relapse. Eur. J. Cancer, 33: 1620-1626, 1997.
  26. Cairo M. S., Shen W-P., Miser J., Krailo M., Blazar B., Reaman G. A randomized trial of two doses of G-CSF (5.0 vs. 10.0 µg/kg/day) following ifosfamide, carboplatin, and etoposide (ICE) chemotherapy in children with recurrent solid tumors (RST): significant clinical activity but no improvement in hematopoietic recovery (HR) with increased dose of G-CSF. Proc. Am. Soc. Clin. Oncol., 14: 255 1995.
  27. Turnbull, B. The empirical distribution function from arbitrarily grouped, censored and truncated data. J. R. Stat. Soc., Ser. B, 290–295, 1976.
  28. Lazarus H. M., Winton E. F., Williams S. F., Grinblatt D., Campion M., Cooper B. W., Gunn H., Manfreda S., Isaacs R. E. Phase I multicenter trial of interleukin 6 therapy after autologous bone marrow transplantation in advanced breast cancer. Bone Marrow Transplant., 15: 935-942, 1995.[Medline]
  29. Weber J., Yang J., Topalian S., Parkinson D., Schwartzentruber D., Ettinghausen S., Gunn H., Mixon A., Kim H., Cole D., Levin R., Rosenberg S. Phase I trial of subcutaneous interleukin-6 in patients with advanced malignancies. J. Clin. Oncol., 11: 499-506, 1993.[Abstract/Free Full Text]
  30. Schrezenmeier H., Marsh J., Stromeyer P., Muller H., Heimpel H., Gordon-Smith E. C., Raghavachar A. A Phase I/II trial of recombinant human interleukin-6 in patients with aplastic anaemia. Br. Haematol., 90: 283-292, 1995.[Medline]
  31. Spaeth-Schwalbe E., Hansen K., Schrezenmeier H., Burger K., Fehm H. L., Born J. Effects of recombinant interleukin-6 (IL-6) in healthy men. Blood, 88: 34b 1996.
  32. Keever-Taylor C. A., Witt P. L., Truitt R. L., Ramanujam S., Borden E. C., Ritch P. S. Hematologic and immunologic evaluation of recombinant human interleukin-6 in patients with advanced malignant disease: evidence for monocyte activation. J. Immunother., 19: 231-243, 1996.[CrossRef]
  33. Banks R., Forbes M., Storr M., Higginson J., Thompson D., Raynes J., Illingworth J., Perren T., Selby P., Whicher J. The acute phase protein response in patients receiving subcutaneous IL-6. Clin. Exp. Immunol., 102: 217-223, 1995.[Medline]
  34. Kammüller M. E. Recombinant human interleukin-6: safety issues of a pleiotropic growth factor. Toxicology, 105: 91-107, 1995.[CrossRef][Medline]
  35. Bishop M. R., Jackson J. D., O’Kane-Murphy B., Schmit-Pokorny K., Vose J. M., Bierman P. J., Warkentin P. I., Armitage J. O., Garrison L., Kessinger A. Phase I trial of recombinant fusion protein PIXY321 for mobilization of peripheral-blood cells. J. Clin. Oncol., 14: 2521-2526, 1996.[Abstract]
  36. Cairo M. S., Weinthal J. A., Garrison L., Krailo M., Kao W. W., Sender L. S., Blazar B., Reaman G. Results of a Phase I trial of PIXY321 following ifosfamide, carboplatin, and etoposide (ICE) chemotherapy in children with recurrent solid tumors: improved multi-lineage hematopoietic reconstitution. Proc. Am. Soc. Clin. Oncol., 14: 255 1995.
  37. Kirov I., Goldman S., Blazar B., van de Ven C., Davenport G., Reaman G., Laver J., Kreissman S., Berg S., Kaye J., Patterson R., Hutabarat R., Dykstra K., Cairo M. Recombinant human interleukin 11 (Neumega) is tolerated at double the adult dose and enhances hematopoietic recovery following ifosfamide, carboplatin, and etoposide (ICE) chemotherapy in children: correlation with rapid clearance, lack of induction of inflammatory cytokines and mobilization of early progenitor cells. Blood., 90: 581a 1997.
  38. Liu K-Y., Akashi K., Harada M., Takamatsu Y., Niho Y. Kinetics of circulating haematopoietic progenitors during chemotherapy-induced mobilization with or without granulocyte colony-stimulating factor. Br. J. Haematol., 84: 31-38, 1993.[Medline]
  39. Dreger P., Haferlach T., Eckstein V., Jacobs S., Suttorp M., Loffler H., Muller-Ruchholtz W., Schmitz N. G-CSF-mobilized peripheral blood progenitor cells for allogeneic transplantation: safety, kinetics of mobilization, and composition of the graft. Br. J. Haematol., 87: 609-613, 1994.[Medline]
  40. Kanold J., Rapatel C., Berger M., Chassagne P., Lutz P., De Lumley L., Plantaz D., Vannier J. P., Malpuech G., Demeocq F. Use of G-CSF alone to mobilize peripheral blood stem cells or collection from children. Br. J. Haematol., 88: 633-635, 1994.[Medline]
  41. Baumann I., Testa N. G., Lange C., De Wynter E., Luft T., Dexter T. M., van Hoef M., Howell A. Haemopoietic cells mobilised into the circulation by lenograstim as alternative to bone marrow for allogeneic transplants. Lancet, 341: 369 1993.[Medline]
  42. Ikebuchi K., Suzuki H., Wada Y., Okano A., Nakamiya M., Akiyama Y., Asano S., Nakahta T. An increase in peripheral blood progenitor cells (PBPC) in non-human primates by co-administration of rhIL-6 and rhG-CSF. Blood, 86: 696a 1995.
  43. Patchen M. L., Fischer R., MacVittie T. J. Effects of combined administration of interleukin-6 and granulocyte colony-stimulating factor on recovery from radiation-induced hemopoietic aplasia. Exp. Hematol., 21: 338-344, 1993.[Medline]
  44. Pettengell R., Luft T., De Wynter E., Coutinho L., Young R., Fitzsimmons L., Scarffe J. H., Testa N. G. Effects of interleukin-6 on mobilization of primitive haemopoietic cells into the circulation. Br. J. Haematol., 89: 237-242, 1994.
  45. Cairo M., Plunkett J., Nguyen A., Clark S., van de Ven C. Sequential administration of interleukin-6 and granulocyte colony-stimulating factor in newborn rats: modulation of newborn granulopoiesis and thrombopoiesis. Pediatr. Res., 30: 554-559, 1991.[Medline]



This article has been cited by other articles:


Home page
 Clin. Cancer Res.Home page
A. L. Angiolillo, V. Davenport, M. A. Bonilla, C. van de Ven, J. Ayello, O. Militano, L. L. Miller, M. Krailo, G. Reaman, and M. S. Cairo
A Phase I Clinical, Pharmacologic, and Biologic Study of Thrombopoietin and Granulocyte Colony-Stimulating Factor in Children Receiving Ifosfamide, Carboplatin, and Etoposide Chemotherapy for Recurrent or Refractory Solid Tumors: A Children's Oncology Group Experience
Clin. Cancer Res., April 1, 2005; 11(7): 2644 - 2650.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
W.-H. Shen, J.-H. Zhou, S. R. Broussard, G. G. Freund, R. Dantzer, and K. W. Kelley
Proinflammatory Cytokines Block Growth of Breast Cancer Cells by Impairing Signals from a Growth Factor Receptor
Cancer Res., August 15, 2002; 62(16): 4746 - 4756.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Bracho, F.
Right arrow Articles by Cairo, M. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Bracho, F.
Right arrow Articles by Cairo, M. S.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online