Granulocyte colony-stimulating factor in established febrile neutropenia: a randomized study of pediatric patients. Granulocyte colony-stimulating factor in the treatment of high-risk febrile neutropenia: a multicenter randomized trial. Prophylactic human granulocyte colony-stimulating factor after induction therapy in pediatric acute myeloid leukemia. Granulocyte colony-stimulating factor ameliorates toxicity of intensification chemotherapy for acute lymphoblastic leukemia. Recombinant human granulocyte-macrophage colony-stimulating factor in the treatment of febrile neutropenia: a double blind placebo-controlled study in children. Improving treatment of chemotherapy-induced neutropenic fever by administration of colony-stimulating factors. [Granulocyte colony-stimulating factor in the treatment of febrile neutropenia]. Human granulocyte colony-stimulating factor after induction chemotherapy in children with acute lymphoblastic leukemia. A randomized phase-III study of the efficacy of granulocyte colony-stimulating factor in children with high-risk acute lymphoblastic leukemia. Berlin-Frankfurt-Münster Study Group.
Infection in neutropenic patients is potentially life-threatening and carries important implications for hospital resource use. Prophylactic administration of cytokines may reduce the severity of neutropenia, but involves the treatment of all patients for the possible benefit of a minority. This study evaluates whether treatment with cytokines in the setting of established febrile neutropenia will influence outcome and be potentially more cost-effective.
                In a double-blind study, pediatric patients with fever and severe neutropenia were randomized to receive granulocyte colony-stimulating factor ([G-CSF] filgrastim; 5 microg/kg/d) or placebo, in addition to antibiotics. The study protocol required a resolution of fever and a neutrophil count > or = 0.2 x 10(9)/L for hospital discharge. Patients could be randomized for up to four independent febrile episodes. A total of 186 episodes of febrile neutropenia were investigated.
                Patients randomized to G-CSF had a shorter hospital stay (median, 5 v 7 days; P = .04) and fewer days of antibiotic use (median, 5 v 6 days; P = .02). G-CSF-treated patients also had more rapid neutrophil recovery and higher neutrophil levels at discharge. The 2-day reduction in hospital stay reduced the median bed cost by 29% per patient admission (P = .04).
                Under the clinical guidelines of our institution, the use of G-CSF in the treatment of established febrile neutropenia produced a small but significant reduction in the time that children required antibiotics and hospital admission, with possible cost savings. Granulocyte colony-stimulating factors (G-CSFs) have been shown to help prevent febrile neutropenia in certain subgroups of cancer patients undergoing chemotherapy, but their role in treating febrile neutropenia is controversial. The purpose of our study was to evaluate-in a prospective multicenter randomized clinical trial-the efficacy of adding G-CSF to broad-spectrum antibiotic treatment of patients with solid tumors and high-risk febrile neutropenia.
                A total of 210 patients with solid tumors treated with conventional-dose chemotherapy who presented with fever and grade IV neutropenia were considered to be eligible for the trial. They met at least one of the following high-risk criteria: profound neutropenia (absolute neutrophil count <100/mm(3)), short latency from previous chemotherapy cycle (<10 days), sepsis or clinically documented infection at presentation, severe comorbidity, performance status of 3-4 (Eastern Cooperative Oncology Group scale), or prior inpatient status. Eligible patients were randomly assigned to receive the antibiotics ceftazidime and amikacin, with or without G-CSF (5 microg/kg per day). The primary study end point was the duration of hospitalization. All P values were two-sided.
                Patients randomly assigned to receive G-CSF had a significantly shorter duration of grade IV neutropenia (median, 2 days versus 3 days; P = 0.0004), antibiotic therapy (median, 5 days versus 6 days; P = 0.013), and hospital stay (median, 5 days versus 7 days; P = 0.015) than patients in the control arm. The incidence of serious medical complications not present at the initial clinical evaluation was 10% in the G-CSF group and 17% in the control group (P = 0.12), including five deaths in each study arm. The median cost of hospital stay and the median overall cost per patient admission were reduced by 17% (P = 0.01) and by 11% (P = 0.07), respectively, in the G-CSF arm compared with the control arm.
                Adding G-CSF to antibiotic therapy shortens the duration of neutropenia, reduces the duration of antibiotic therapy and hospitalization, and decreases hospital costs in patients with high-risk febrile neutropenia. Children with acute myelogenous leukemia (AML) have a high risk of infectious complications that might be reduced by prophylactic granulocyte colony-stimulating factor (G-CSF). However, G-CSF could induce AML blast proliferation. The prospective randomized trial AML-BFM 98 investigated the impact of G-CSF on hematopoetic recovery and infectious complications (primary endpoints) and on outcome (secondary endpoint) in children (aged 0-18 years) with de novo AML. Patients with more than 5% blasts in day-15 bone marrow or with FAB M3 were not included. Between 1998 and 2003, 161 children with AML were randomized to receive G-CSF after inductions 1 and 2, whereas 156 patients were assigned to the control group. Time of neutropenia after inductions 1 and 2 was significantly shorter in the G-CSF group (23 vs 18 days and 16 vs 11 days; P=.02 and=.001, respectively). G-CSF did not decrease the incidence of febrile neutropenia (72 and 36 patients vs 78 and 37 patients, respectively), microbiologically documented infections (27 and 25 patients vs 36 and 19 patients, respectively) and infection-associated mortality (5 vs 2 patients). Both groups had similar 5-year event-free survival (EFS; 59%+/-4% vs 58%+/-4%). Since G-CSF does not influence the risk of infectious complications or outcome in children undergoing therapy for AML, one cannot advocate the routine use of G-CSF in this patient group. Intensification chemotherapy improves the prognosis for children with acute lymphoblastic leukemia (ALL), but results in considerable morbidity, primarily due to myelosuppression with resultant neutropenia. Recombinant granulocyte colony-stimulating factor (G-CSF) shortens neutropenia following intensive chemotherapy, but potential benefits in the therapy of ALL remain inadequately explored. Accordingly, a randomized, crossover study was undertaken to clarify this issue.
                Seventeen children with acute lymphoblastic leukemia or T-cell non-Hodgkin lymphoma and treated on standard protocols were randomized to receive G-CSF following either the first or second intensification blocks of chemotherapy. G-CSF was administered as a single daily subcutaneous injection of 5 mcg/kg from day 9 following the start of intensification therapy, and continued until the neutrophil count exceeded 0.5 x 10(9)/l for 3 days. Study endpoints were days of neutropenia (neutrophils < 1 x 10(9)/l) and severe neutropenia (neutrophils < 0.5 x 10(9)/l), days in hospital, days of fever, and days on antibiotics.
                There were significant reductions in the duration of neutropenia (95% confidence interval 3.8-8 days, P = 0.0001), severe neutropenia (95% confidence interval 1.8-7.4 days, P = 0.002), and days in hospital (95% confidence interval 0.9-6.3 days, P = 0.01) for children receiving G-CSF. Overall, the duration of neutropenia was longer following the second block (95% confidence interval 2.2-6.4 days, P = 0.0003), but this difference was abolished by G-CSF, and children, receiving G-CSF after the second intensification were more likely to restart maintenance chemotherapy on schedule (P = 0.05).
                G-CSF reduces the hematological toxicity of intensification chemotherapy and may allow improved compliance with treatment scheduling. In a double blind study of 58 episodes of fever and profound neutropenia, children with cancer received either recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) or placebo, combined with identical antimicrobial therapy, i.e. imipenem, on admission. The criteria for discontinuation of therapy were identical. A difference was demonstrated both in the number of hospital days, totaling 252 days in the rhGM-CSF group and 354 in the placebo group, days receiving antibiotics (220 vs. 322), and in the resolution of neutropenia (4.5 days vs. 6.0 days; P < 0.05). The number of episodes requiring antimicrobial therapy for longer than 10 days was 5 of 28 (12%) in the rhGM-CSF group as opposed to 15 of 30 (50%) in the placebo group (P = 0.01). rhGM-CSF was well-tolerated. We conclude that rhGM-CSF was efficacious in accelerating myeloid recovery and reducing the length of hospitalization in febrile neutropenia. Several randomized trials have tested the use of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in relieving chemotherapy-induced bone marrow suppression. However, the use of CSFs in the treatment of neutropenic fever remains virtually unexplored.
                This study evaluated the benefits of adding CSF therapy to the standard antibiotic treatments given to cancer patients for chemotherapy-induced neutropenic fever. The usefulness of CSFs was quantified in terms of reducing the following: (a) the duration of neutropenia, (b) the length of hospitalization, and (c) the overall cost of the treatment.
                A randomized trial was conducted to test whether the administration of either G-CSF or GM-CSF improved the outcome of standard antibiotic therapy (ceftazidime plus amikacin) in nonleukemic cancer patients with fever (> 38 degrees C) and grade IV neutropenia (absolute neutrophil count [ANC] < 500/mm3) induced by standard-dose chemotherapy. Of 121 patients who entered the trial, 39 received G-CSF (5 micrograms/kg body weight per day), 39 received GM-CSF (5 micrograms/kg body weight per day), and 43 received a placebo beginning just after the first dose of antibiotics. Treatments were continued for at least 5 days (7 days with clinically or microbiologically documented infections) or until 2 days after fever subsided and ANCs rose above 1000/mm3.
                The median duration of grade IV neutropenia (ANC of < 500/mm3) was 2 days in both CSF arms and 3 days in the placebo arm (P < .001). The median duration of neutropenia with an ANC of less than 1000/mm3 was also significantly shorter in patients receiving G-CSF or GM-CSF (P < .001). The median duration of fever was similar in the three arms. The median hospital stay was 5 days (range, 5-14 days) in the G-CSF arm, 5 days (range, 5-10 days) in the GM-CSF arm, and 7 days (range, 5-34 days) in the placebo arm (P < .001). The median time on CSF was 4 days in both treatment arms. The mean cost of overall treatment was reduced by $1300-$1400 in the CSF arms compared with the placebo arm (P = .11 for G-CSF versus placebo; P = .06 for GM-CSF versus placebo; P = .7 for G-CSF versus GM-CSF).
                Adding G-CSF or GM-CSF therapy to antibiotic treatment shortens the duration of neutropenia and the duration of hospitalization in patients with neutropenic fever. A statistically nonsignificant trend toward lower cost was observed in the CSF arms as compared with the placebo arm.
                The benefits of CSFs to cancer patients with chemotherapy-induced neutropenic fever merit further evaluation in large randomized trials. To determine whether granulocyte colony-stimulating factor (G-CSF) used in addition to antibiotic therapy, in patients with chemotherapy-induced febrile neutropenia shortens the period of fever, neutropenia and hospitalization.
                The study was prospective. Patients with lymphoblastic acute leukemia (LAL) were included. They received intensive chemotherapy of induction, intensification, or consolidation. At random, a group received amikacin-ceftriaxone; if no had response after 3 days, we added vancomicin and, after 7 days, amphotericin. The other group received in addition these antibiotics, granulocyte colony-stimulating factor.
                The groups were comparable in the magnitude of the initial neutropenia (< 0.5 x 10(9)/L), site of the infection, chemotherapy received germs isolated, age, and sex. The patients of the group that received FEC-G were cured in the course of 3.1 days; in the group without FEC-G, this occurred in 7.2 days (p = 0.0001). At the end of the infectious episode, the number of neutrophils, in the group with FEC-G, was of 1.9 x 10(9)/L versus 0.7 x 10(9)/L (p = 0.0009). The mortality was of one and two cases (p = 0.46). The global mortality was 7.5%.
                The addition of FEC-G to the treatment with antibiotics, in febrile neutropenia, decreases duration of days with fever, hospitalization and neutropenia. However, the frequency of cure is not augmented. Recombinant human granulocyte colony-stimulating factor PO1 CA-20180ilgrastim) hastens the recovery from neutropenia after P30 CA-21765emotherapy, but its role in the management of childhood leukemia is unclear.
                We randomly assigned 164 patients with acute lymphoblastic leukemia (age range, 2 months to 17 years) to receive placebo or G-CSF (10 microg per kilogram of body weight per day subcutaneously), beginning one day after the completion of remission-induction therapy and continuing until the neutrophil count was greater than or equal to 1000 per cubic millimeter for two days. The clinical and laboratory effects of this therapy were documented for 21 days. The area under the plasma G-CSF concentration-time curve was measured on days 1 and 7 in both groups.
                Responses to the growth factor could be assessed in 148 patients (73 in the G-CSF group and 75 in the placebo group). G-CSF treatment did not significantly lower the rate of hospitalization for febrile neutropenia (58 percent in the G-CSF group vs. 68 percent in the placebo group; relative risk, 0.85; 95 percent confidence interval, 0.59 to 1.16), increase the likelihood of event-free survival at three years (83 percent in both groups), or decrease the number of severe infections (five in the G-CSF group vs. six in the placebo group). Patients treated with G-CSF had shorter median hospital stays (6 days vs. 10 days, P=0.011) and fewer documented infections (12 vs. 27, P=0.009). The median total costs of supportive care were similar in the G-CSF and placebo groups ($8,768 and $8,616, respectively). Among patients who did not have febrile neutropenia during the first week of G-CSF or placebo injections, higher systemic exposure to the growth factor on day 7 was significantly related to a lower probability of subsequent hospitalization (P=0.049).
                G-CSF treatment had some clinical benefit in children who received induction chemotherapy for acute lymphoblastic leukemia, but it did not reduce the rate of hospitalization for febrile neutropenia, prolong survival, or reduce the cost of supportive care. Overall chemotherapeutic treatment results in pediatric acute lymphoblastic leukemia (ALL) are good, with event-free survival (EFS) rates over 70%. However, for a subset of patients characterized by high-risk (HR) features the outcome is less favorable, with EFS rates below 50%. Intensification of chemotherapy may improve the outcome for those patients, but increased toxicity, particularly myelosuppression, limits the escalation of dose intensity. Recombinant methionyl human granulocyte colony-stimulating factor (r-metHuG-CSF) is known to reduce myelosuppression after cancer chemotherapy in adults. The objective of this study was to examine the effect of r-metHuG-CSF on myelosuppression in HR pediatric ALL patients and on the overall response rate to chemotherapy. Patients with HR pediatric ALL were randomized to receive nine alternating cycles of chemotherapy according to the German ALL-Berlin-Frankfurt-Münster 90 protocol either alone or followed by r-metHuG-CSF administered prophylactically at a dose of 5 microg/kg/d subcutaneously. In both groups, the planned interval between chemotherapy courses was a minimum of 21 days. We report here interim results of 34 patients. The incidence of febrile neutropenia (absolute neutrophil count <0.5 x 10(9)/L and oral temperature > or = 38.5 degrees C) was 17% in children receiving r-metHuG-CSF, as compared with 40% in the control group (P = .007). In addition, the median total duration of febrile neutropenia was reduced from 20.3 to 6.2 days per patient (P = .02). Culture-confirmed infections occurred less frequently in the r-metHuG-CSF group (8% v 15%; P = .04), and the total duration of intravenous antibiotic use was significantly reduced from 32.2 days to 18.2 days per patient (P = .02). A tighter adherence to the planned treatment schedule was also facilitated by r-metHuG-CSF (P = .007). With a median follow-up of 3.3 years, the estimated EFS of 4 years is 41% +/- 12%. In conclusion, r-metHuG-CSF administered prophylactically in the interval between chemotherapy courses significantly reduced febrile neutropenia, culture-confirmed infections, and duration of intravenous antibiotic administration and allowed for tighter adherence to the treatment schedule.
Children with ALL treated with CSF benefit from shorter hospitalisation and fewer infections. However, there was no evidence of shortened duration of neutropenia nor fewer treatment delays. There was also no useful information about survival.
The role of CSF in the context of febrile neutropenia episodes is still uncertain. Although current data show statistical benefit with CSF use, substantial heterogeneity between included trials does not allow this conclusion.