Levels of recombinant human granulocyte colony-stimulating factor in serum are inversely correlated with circulating neutrophil counts.

Recombinant human granulocyte colony-stimulating factor (rhG-CSF) is effective in countering chemotherapy-induced neutropenia. However, serum rhG-CSF levels cannot be maintained throughout the course of rhG-CSF therapy. The drop in serum rhG-CSF levels may vary with the duration of rhG-CSF administration or with the circulating neutrophil counts. We investigated the relationship between serum G-CSF levels and circulating neutrophil counts and the pharmacokinetics of rhG-CSF for patients with lung cancer who had been treated with myelosuppressive chemotherapy and then with subcutaneous rhG-CSF (lenograstim, 2 micrograms per kg of body weight per day). Twelve patients were randomly assigned to four groups with different rhG-CSF therapy schedules. Serum G-CSF levels were measured by an enzyme immunoassay method. Serum G-CSF levels during the rhG-CSF therapy greatly exceeded endogenous G-CSF levels and were mainly due to the presence of exogenous rhG-CSF rather than increased levels of endogenous G-CSF. Despite the duration of rhG-CSF administration, serum G-CSF levels during rhG-CSF therapy were inversely correlated with circulating neutrophil counts (r2 = 0.73, P < 0.0001). The value for the area under the concentration-time curve of rhG-CSF on the day of neutrophilia was lower than that on the day of neutropenia (P < 0.05). Our results suggest that the fall in serum G-CSF levels during rhG-CSF therapy may result from increased clearance and/or decreased absorption of rhG-CSF, two processes related to circulating neutrophil counts.     

Use of G-CSF for granulocyte transfusion therapy

Patients with neutropenia, especially neutropenia following aggressive myeloablative therapy, are at high risk for developing infectious complications caused by bacteria and opportunistic fungi. Infections remain one of the leading causes of treatment failure in patients with cancer. Thus, new and innovative therapeutic strategies are needed for management of neutropenic patients with infection. Because neutrophils represent the first line of host defense, granulocyte transfusion therapy should be a logical therapeutic approach. Although such therapy has been employed sporadically for several decades, clinical benefit has been compromised by technical problems and low granulocyte yields resulting from inadequate donor stimulation. The discovery of granulocyte colony-stimulating factor (G-CSF) as a means to elevate blood neutrophil counts when administered to normal donors has rekindled interest in granulocyte transfusion therapy. Extensive experience has been gained worldwide with G-CSF in clinical practice, and adverse events have been minimal when G-CSF has been administered to patients or healthy persons in human trials. This review focuses on the use of G-CSF in granulocyte transfusion therapy, including technical considerations of granulocyte leukapheresis and storage, donor selection and stimulation, as well as treatment results and associated risks.     

A case report of familial cyclic neutropenia.

A 34-year-old female with cyclic neutropenia is reported. Family studies showed that her three sons and her mother were also involved. Oscillations in the blood neutrophil counts were almost regular, with a periodicity of 21 days. Numbers of colony-forming unit--granulocyte macrophage (CFU-GM) formed from the bone marrow cells of normal volunteers co-cultured with the patient's serum or mononuclear cell-conditioned medium (MNC-CM) were examined. Her serum prepared during the neutropenic phase inhibited the growth of CFU-GM, while her MNC-CM stimulated it. Human granulocyte colony-stimulating factor (hG-CSF) level in her serum was persistently high, with the peak occurring during the neutropenic phase. These results suggest that some inhibitory factors in the serum may be pathophysiologically important for cyclic neutropenia. To control infections, a pharmacological dose of hG-CSF was administered for 7 days around the early neutropenic phase. Her peripheral neutrophil counts oscillated from 1,200/mm3 to 17,000/mm3 with G-CSF, and from 150/mm3 to 1,800/mm3 without G-CSF.     

Chronic neutropenia. A new canine model induced by human granulocyte colony-stimulating factor.

Normal dogs were treated with recombinant human granulocyte colony-stimulating factor (rhG-CSF) at 10 micrograms/kg/day for 30 d, which caused an initial neutrophilia, followed by a prolonged period of chronic neutropenia. A control dog treated with recombinant canine G-CSF (rcG-CSF) showed persistent neutrophilia over 3 mo. Serum from dogs during neutropenia contained an antibody to rhG-CSF, which neutralized the stimulatory effects of both rhG-CSF and rcG-CSF on dog marrow neutrophilic progenitor cell growth and on NFS-60 cell proliferation. 4 mo after discontinuation of rhG-CSF, the dogs' neutrophil counts returned to the normal range. Rechallenge with the rhG-CSF re-induced severe neutropenia in 1 wk. Neutropenia was transferred by plasma infusion from a neutropenic dog to a previously normal dog. These data suggest that human rhG-CSF immunizes normal dogs and thereby induces neutralization of endogenous canine G-CSF and neutropenia. This model system should allow more precise definition of the in vivo role of G-CSF.     

Persistent, therapeutically relevant levels of human granulocyte colony-stimulating factor in mice after systemic delivery of adeno-associated virus vectors.

Adeno-associated virus (AAV) vectors have been shown to preferentially transduce hepatocytes after systemic administration in adult mice and to provide long-term expression of introduced genes. One application of this technology would be for the production of granulocyte colony-stimulating factor (G-CSF), which increases mature neutrophil numbers in humans and in animals, and has therapeutic effects in disorders featuring chronic neutropenia, including cyclic, severe congenital, and idiopathic neutropenia, and glycogen storage disease type Ib. We have treated mice by tail vein injection of AAV vectors encoding human G-CSF, and have detected high G-CSF levels and marked elevation of neutrophil counts for at least 5 months. A therapeutically relevant amount of G-CSF production was obtained when the liver-specific mouse albumin promoter-enhancer was used to drive G-CSF expression. In mice receiving higher amounts of vector, plasma levels of human G-CSF gradually increased over 3 weeks to high concentrations, whereas for lower amounts human G-CSF remained at initial, low levels. The previously observed effect of gamma irradiation, to increase AAV transduction rates, was diminished when large amounts of vector were used. Absolute neutrophil counts increased 10- to 50-fold for the period of observation to levels that would be therapeutic in the treatment of cyclic neutropenia. In conclusion, gene therapy with AAV vectors synthesizing G-CSF shows promise for the treatment of disorders featuring neutropenia.     

Neutropenia Associated with Long-Term Ceftaroline Use

Ceftaroline is a fifth-generation cephalosporin with potent antimicrobial activity against Gram-positive and Gram-negative pathogens. Neutropenia is a rare serious adverse event for the class of cephalosporins; however, we observed several cases of severe neutropenia in our outpatient infectious disease practice believed to be associated with ceftaroline use. The aim of this study was to determine the incidence of neutropenia among patients receiving ceftaroline therapy for more than 7 days. We conducted a retrospective cohort analysis of patients admitted to an 800-bed regional medical center between June 2012 and December 2014 who received ceftaroline for more than 7 days to assess the incidence of developing clinically significant neutropenia. Demographic and patient care data points as well as underlying admitting and chronic diagnoses were retrospectively collected from the medical record. Clinically significant neutropenia was defined as an absolute neutrophil count (ANC) less than 1,500 cells/mm³. Analysis was performed to determine the incidence, severity, and outcome of neutropenia following ceftaroline administration. A total of 39 patients were included in the cohort. The median duration of therapy was 27 days. Seven patients (18%) developed neutropenia while on ceftaroline therapy. Four (10%) of the neutropenic patients had an ANC of <500 cells/mm³. The median first neutropenic day was day 17, with the median ANC nadir of 432 cells/mm³ on day 24. We determined that extended ceftaroline infusion is associated with the development of neutropenia. We recommend obtaining a complete blood count (CBC) with differential at the onset of therapy and weekly thereafter. Should the ANC fall below 2,500 cells/mm³, then twice-weekly CBCs should be monitored for the duration of ceftaroline therapy, and therapy should be discontinued if the ANC falls to 1,500 cells/mm³ or less.     

Granulocyte transfusion therapy in abdominal organ transplant recipients

Background: Patients with neutropenia are at increased risk for infections. Granulocyte transfusions (GT) have had mixed success in treatment of neutropenic infections in adult patients with hematologic malignancy. This study examined the outcomes of GT therapy in neutropenic solid organ transplant recipients, a novel population for this therapy. Methods: We performed a retrospective examination of the transfusion and medical records of all 14 solid organ‐transplant recipients without hematologic malignancy who experienced neutropenia and received GT therapy from 2004 to 2006. Results: Twelve patients received GT therapy for an active infection and two patients for infection prophylaxis. The mean absolute neutrophil count (ANC) one day increment per GT in these patients was 526/μl (median 215/μl). The mean ANC one day increment per dose of 10¹⁰ granulocytes was 246/μl (median 86/μl). Of the 12 infected patients, four patients (33%) showed a clinical response to GT with improvement or resolution of the infection, 7 (58%) patients had no clinical response and one additional patient had a clinical response to a course of GT but died during a second GT course. Neither patient receiving GT for prophylaxis developed an infection. Conclusions: We observed temporal increases in ANC to levels above 1,000/μl in 15/18 (83.3%) courses of GT. We observed a clinical response to infection in 5/12 (42%) patients, the remaining infected patients had no clinical response. Our results suggest that GT therapy in neutropenic solid organ transplant recipients can boost peripheral blood neutrophil counts. Additional studies areneeded to document an independent clinical benefit for GT in this patient population. J. Clin. Apheresis, 2009. © 2009 Wiley‐Liss, Inc.     

Filgrastim therapy in acute nonlymphoblastic leukemia

AIM: To specify effects of the granulocytic colony-stimulating factor (G-CSF) in the treatment of acute nonlymphoblastic leukemia. MATERIAL AND METHODS: Thirteen patients with acute myeloid leukemia (AML) were treated in the Hematological Clinic of the Higher Medical Institute in Plovdiv in 1996-1998. All of them received a standard induction therapy with cytosin arabinoside + daunorubicin (7 + 3 days). During the first neutropenic phase (neutrophils < 0.5 x 10(9)/l) G-CSF filgrastim was applied (5 microg/kg/day, s.c.) until a recovery of the neutrophil count reached > 1.0 x 10(9)/l and was maintained for 3 successive days. The control group consisting of patients matched by age, gender, an AML cytomorphologic variant was given the same therapy but filgrastim. RESULTS: The study group showed quicker recovery of the neutrophil count (12.6 vs 16.8 days), reduced febrile period (9.8 vs 12.4 days) and shorter duration of parenteral antibiotic treatment (9.8 vs 12.4 days) compared to controls. No statistically significant difference between both groups was found in the duration of the antimycotic treatment (p > 0.05). No cytological signs of aggravation of basic disease were absent in patients who received filgrastim. CONCLUSION: Administration of G-CSF in AML is useful as it promotes rapid overcoming of neutropenia and its complications.     

Treatment with granulocyte colony-stimulating factor increases interleukin-1 receptor antagonist levels during engraftment following allogeneic stem-cell transplantation

BACKGROUND: The effect of treatment with granulocyte colony-stimulating factor (G-CSF) on interleukin-1 receptor antagonist (IL-1ra) plasma concentrations as well as the role of IL-1ra on leucocyte recovery and parameters of infection within the first 30 days after haematopietic stem-cell transplantation (HSCT) are not well known. MATERIAL AND METHODS: Twenty-seven patients undergoing myeloablative therapy followed by allogeneic SCT for various haematological disorders were either treated with (n = 18) or without (n = 9) G-CSF. IL-1ra plasma levels were serially determined by ELISA starting at day - 1 and continued until patients were engrafted. RESULTS: Patients receiving G-CSF had significantly shorter neutropenic periods and significantly lower mean C-reactive protein serum levels during the first 3 weeks succeeding bone marrow transplantation (BMT). Importantly, starting at day + 11 and paralleling the rise of peripheral blood leucocytes, increasing IL-1ra plasma concentrations were observed in both treatment groups. However, the magnitude of the IL-1ra surge was far greater in the G-CSF treatment group. Peak IL-1ra plasma level observed on day + 19 was 882.3 +/- 879.2 pg mL(-1) (mean +/- SD) in patients receiving G-CSF compared with 285.8 +/- 175.2 pg mL(-1) (mean +/- SD) in patients not receiving G-CSF (P = 0.0130). Furthermore, a direct correlation of IL-1ra with peripheral blood leucocytes was verified by the Spearman rank test (P = 0.0025). CONCLUSION: Granulocyte colony-stimulating factor-mediated acceleration of neutrophil recovery following myeloablative therapy correlated with increased IL-1ra plasma concentrations. Our data suggest that IL-1ra constitutes an intrinsic component of the anti-inflammatory and neutrophil differentiating efficacy of G-CSF and, thus, IL-1ra may be required for the in vivo activity of G-CSF.     

Probable vancomycin-induced neutropenia

OBJECTIVE: To report a case of vancomycin-induced neutropenia and provide a review of the literature. CASE SUMMARY: A 64-year-old white man was treated with intravenous vancomycin 1.5 g/day for finger osteomyelitis. He developed neutropenia after 21 days of vancomycin therapy. The absolute neutrophil count reached a nadir of 418 cells/mm(3) during vancomycin use and returned to normal 7 days after its discontinuation. The eosinophil count was also elevated during the neutropenic episode and probably related to vancomycin. Based on the Naranjo probability scale, the reaction was probably related to vancomycin use. DISCUSSION: Articles describing cases of vancomycin-induced neutropenia were identified. All patients developed neutropenia as a result of vancomycin therapy >/=12 days. Neutrophil counts generally increased following discontinuation of vancomycin. One article reported successful resolution of neutropenia and infection by switching the patient's therapy to the structurally related antibiotic agent teicoplanin. Other patients were continued on vancomycin therapy, and neutropenia was treated with moderate to good success with filgrastim. Rechallenge was not generally attempted. The mechanism of neutropenia caused by vancomycin is unclear, but appears to be immune-mediated. CONCLUSIONS: Vancomycin therapy should not be prolonged unless absolutely necessary, and therapy should be reserved for patients with clear indications for the drug, such as infections due to gram-positive organisms resistant to other therapies. Patients should have periodic assessment of white blood cell and neutrophil counts with consideration to discontinue vancomycin if neutropenia develops.     

An adult dog with cyclic neutropenia treated by lentivirus- mediated delivery of granulocyte colony-stimulating factor

Cyclic neutropenia occurs in humans and gray collie dogs, is characterized by recurrent neutropenia, and is treated by daily injections of recombinant granulocyte colony-stimulating factor (G-CSF). After showing that canine recombinant G-CSF increased neutrophil counts in an affected dog, we administered intramuscularly 2 x 10(9) infectious units (IU) of a lentiviral vector encoding canine G-CSF cDNA. Elevated, therapeutic neutrophil production was obtained for nearly 18 months. Lentiviral vector treatment provided a mean neutrophil count of 29,230 +/- 12,930 cells/microl, which was significantly increased over both the pretreatment value (5,240 +/- 4,800 cells/microl; p < 0.0001) and the neutrophil count during G-CSF administration (17,820 +/- 11,100 cells/microl; p < 0.0001). By systemic infusion of recombinant G-CSF to normal dogs we estimated that 2 x 10(9) IU of lentivirus delivered 3.5 microg of G-CSF per kilogram per day. After lentiviral vector treatment the gray collie gained weight, showed no clinical signs of infection and fever, and no longer needed housing in a pathogen-free environment. Genomic DNA harvested from muscle at the injection sites was positive for provirus, whereas gonad, lung, spleen, heart, liver, kidney, and noninjected muscle samples were negative. These studies show that an adult animal is responsive long-term to lentivirus-mediated G-CSF delivery, suggesting this approach may be applied for treatment of adult patients with cyclic and other neutropenias.     

Granulocyte transfusions from G-CSF-stimulated donors for the treatment of severe infections in neutropenic pediatric patients with onco-hematological diseases

From March 1994 to January 2001, 15 courses of granulocyte transfusion (GTX) were administered to 13 neutropenic patients (6 male and 7 female patients; median age 7 years, range 3 months to 14 years) affected by: acute lymphoblastic leukemia (ALL) in 6 cases, acute myeloid leukemia (AML) in 5, very severe aplastic anemia in 1, and familial erythrophagocytic lymphohistiocytosis (FEL) in 1. Infections were classified as microbiologically defined and clinically defined infections in 8 and 7 episodes, respectively. Before the GTX transfusions, broad-spectrum antibacterial and antifungal therapy had been administered for a median of 12 (range 5-28) and 8 days (range 2-50), respectively, with no improvement. G-CSF was administered prior to GTX in 9 episodes of infection, with a median of 9 days of treatment (range 4-30). Leukapheresis was obtained from 15 related donors (father, 10; mother, 3; sister, 1; aunt, 1) after s.c. stimulation with G-CSF, 300 micro g daily, starting from day -3 (where day 0 was the day of the first granulocyte collection) and continuing throughout the period of GTX treatment. The donors' median white blood cell (WBC) count at leukapheresis was 31.6 x 10(9)/l (range 12-56), and the median yield was 31.39 x 10(9) WBC (range 2.96-64.73 x 10(9)), with a proportion of PMN of 90-95%. Overall, 70 GTX were administered, with a median of 4 GTX per episode of infection (range 2-11). The combination of GTX with antimicrobial therapy led to complete or partial recovery in 6 and in 3 of 15 episodes (60%), respectively. Priming of the donor with G-CSF was well tolerated, the most common side-effects being bone pain, malaise and paresthesia. All donors are alive and well after a median of 4.5 years (range 0.8-7.7) from donation. We conclude that GTX is potentially useful when the severity of the infection and the host's immunodeficiency make any other antimicrobial treatment ineffectual. Long-term safety data on the stimulation of donors with G-CSF have been reassuring to date. Further controlled studies are needed to assess the exact role of GTX in the outcome of neutropenic patients with severe infection and any criteria for patient selection and the timing of GTX administration.     

Treatment of carbimazole-induced agranulocytosis and sepsis with granulocyte colony stimulating factor

We present the management of agranulocytosis and neutropenic sepsis secondary to carbimazole with recombinant human granulocyte colony stimulating factor (G-CSF). A 72-year-old woman with a history of thyrotoxicosis presented with sore throat and fever two weeks after starting carbimazole. Investigations confirmed a leucopenia and neutropenia. G-CSF was used as an adjunctive therapy with discontinuation of carbimazole, barrier nursing and a broad-spectrum antibiotic regimen to treat her neutropenic sepsis. Total white cell count and neutrophil count returned to normal and she made an uneventful recovery. She was subsequently rendered euthyroid with radioiodine treatment.     

Close Association between Clearance of Recombinant Human Granulocyte Colony-Stimulating Factor (G-CSF) and G-CSF Receptor on Neutrophils in Cancer Patients

Recombinant human granulocyte colony-stimulating factor (rhG-CSF) is used to counter chemotherapy-induced neutropenia. Our previous study showed an inverse correlation between serum rhG-CSF levels and the number of circulating neutrophils in cancer patients (H. Takatani, H. Soda, M. Fukuda, M. Watanabe, A. Kinoshita, T. Nakamura, and M. Oka, Antimicrob. Agents Chemother. 40:988–991, 1996). The aim of this study was to clarify the relationship between rhG-CSF clearance and G-CSF receptors on circulating neutrophils. In five cancer patients receiving chemotherapy, a bolus dose of rhG-CSF (5 μg/kg) was injected intravenously during defined phases of posttreatment neutropenia and neutrophilia. Serum rhG-CSF levels were measured by a chemiluminescence enzyme immunoassay and analyzed by moment analysis. G-CSF receptors on neutrophils were detected by flow cytometry with biotinylated rhG-CSF. rhG-CSF clearance was significantly higher at neutrophilia than at neutropenia (1,497 ± 132 versus 995 ± 266 ml/h; P < 0.01). The percentage of G-CSF receptor-positive neutrophils, reflecting the number of G-CSF receptors per cell, was low at neutropenia without rhG-CSF therapy (44.5% ± 22.1%) and high at neutrophilia with rhG-CSF therapy (73.0% ± 11.4%; P < 0.01). rhG-CSF clearance closely correlated with the percentage of G-CSF receptor-positive neutrophils (r² = 0.91; P < 0.0001) and neutrophil count (r² = 0.72; P < 0.005). Our results indicate that, in cancer patients receiving chemotherapy, rhG-CSF increases the number of G-CSF receptors per cell as well as circulating neutrophil counts, resulting in modulation of its own clearance.     

Imipenem/cilastatin as initial therapy for febrile neutropenic patients

Imipenem 2 g daily was administered intravenously to 40 evaluable patients with neutropenia and fever. Twenty-three patients had acute leukaemia and 17 malignant lymphoma. The overall response rate was 70.0%. Of the 14 patients with documented infection, 9 (64.3%) responded. Poorer responses were observed in patients with pneumonia (40%) or pseudomonal infection (50%). The response rate was significantly higher among patients with increasing neutrophil counts during therapy (P less than 0.02). Fungal infection was a common cause of treatment failure. Gastrointestinal side effects and skin rashes were occasionally seen. No patient developed central nervous system toxicity. Imipenem is a practical alternative to antibiotic combinations for management of neutropenic infection. However, careful monitoring is essential in the subgroups of patients with pneumonia or pseudomonal infections, who may require modifications of therapy.     

Clinical efficacy of adjunctive G-CSF on solid tumor and lymphoma patients with established febrile neutropenia

Background

The use of granulocyte colony-stimulating factor (G-CSF) as a prophylaxis against febrile neutropenia (FN) is well documented in the literature; however, the therapeutic use of G-CSF in the treatment of FN remains controversial. This study assessed the efficacy of adjunctive G-CSF in the treatment of FN by evaluating clinical outcomes.

Methods

This was a single-center, prospective cohort study conducted at the National Cancer Center in Singapore. Adult patients who had received chemotherapy and developed FN between January 2009 and January 2012 were included in the analysis. The clinical efficacy of adjunctive G-CSF was evaluated by investigating the duration of hospitalization, duration to absolute neutrophil count (ANC) recovery, duration of grade IV neutropenia, duration to fever resolution, duration of antibiotic therapy, and incidence of documented infections. A multivariate analysis was performed to identify patients who could potentially benefit from adjunctive G-CSF.

Results

Four hundred and thirty patients were analyzed. Majority manifested low-risk FN (81.2 %) based on the Multinational Association of Supportive Care in Cancer (MASCC) scoring. Compared to patients who did not receive adjunctive G-CSF, patients receiving adjunctive G-CSF had a nonsignificant reduction in the duration of hospitalization (3.5 vs. 3.7 days, p?=?0.41) and in ANC recovery time (3.4 vs. 3.5 days, p?=?0.76). Neutropenia-related mortality was lower among those who have received adjunctive G-CSF (2.4 vs. 8.4 %, p?=?0.006). Patients of Indian ethnicity and those who underwent gemcitabine-containing chemotherapy were less likely to receive adjunctive G-CSF treatment.

Conclusions

This observational study suggested that adjunctive G-CSF may confer clinical benefits among solid tumor and lymphoma patients with established febrile neutropenia. Further research should be conducted to validate the findings.     

Suboptimal Duration of Granulocyte Colony–stimulating Factor Use and Chemotherapy-induced Neutropenia in Women Diagnosed With Breast Cancer

Purpose

Prophylactic use of granulocyte colony–stimulating factor (G-CSF) is recommended for cancer patients who are at high risk of neutropenic events. However, whether the clinical effectiveness of G-CSF from randomized controlled trials translates into “real-world” clinical practice is questionable. The goal of this retrospective cohort study was to examine the impact of G-CSF prophylaxis and other potential risk factors of severe neutropenia in women with breast cancer.

Methods

Our study subjects were women who were diagnosed with breast cancer and who received a new course of chemotherapy between January 1, 2010, and December 31, 2010, at a cancer center in Taiwan. Generalized estimating equations were applied to examine the association between G-CSF prophylaxis and neutropenic events.

Findings

We identified 353 women with breast cancer who received a total of 2776 cycles of chemotherapy. G-CSF was used as primary prophylaxis in 7% (n = 202) of cycles and as secondary prophylaxis in 11% (n = 319) of cycles. The mean duration of G-CSF for primary and secondary prophylaxis was 4.9 and 3.7 days, respectively. A chemotherapy regimen with high risk of febrile neutropenia was found to be a risk factor for severe neutropenic events (odds ratio, 3.22 [95% CI, 1.97–5.27]). Prophylactic use of G-CSF was not statistically significantly associated with febrile neutropenia.

Implications

The major determinants of neutropenic events among patients with breast cancer were the content and intensity of chemotherapy regimens. Suboptimal use of G-CSF may not be effective in preventing neutropenic events among women with breast cancer.     

Effects of Renal Function on Pharmacokinetics of Recombinant Human Granulocyte Colony-Stimulating Factor in Lung Cancer Patients

Animal studies suggest that the kidney is involved in the elimination of recombinant human granulocyte colony-stimulating factor (rhG-CSF), which is used for patients with neutropenia during cancer chemotherapy. Since anticancer drugs induce nephrotoxicity, it is important to clarify the role of the kidney in the pharmacokinetics of rhG-CSF in cancer patients. Our study was designed to evaluate the relationship between the pharmacokinetics of rhG-CSF and renal function in lung cancer patients compared to the absolute neutrophil count (ANC). The pharmacokinetic studies were conducted with 25 lung cancer patients. Following chemotherapy using platinum-based compounds, a bolus 5 microg of rhG-CSF/kg of body weight was intravenously injected from the first day of leukopenia or neutropenia. Pharmacokinetic parameters were estimated by fitting the concentration in serum-time data to a two-compartment model according to the population pharmacokinetics and the Bayesian method. Creatinine clearance (CL(CR)) was predicted by the Cockcroft-Gault formula. rhG-CSF clearance (CL(G-CSF)) correlated significantly with the ANC (r = 0.613; P < 0.001) and CL(CR) (r = 0.632; P < 0.001). Multiple linear regression analysis showed that the combination of the ANC and CL(CR) accounted for 57.4% of the variation of CL(G-CSF). In patients with an ANC of <1,000/microl, CL(CR) accounted for 72.9% of the variation of CL(G-CSF) (P < 0.001). Our findings suggest that renal function and neutrophil counts correlate with CL(G-CSF) and that the role of renal function in eliminating rhG-CSF is important in lung cancer patients with neutropenia.     

Prophylactic antibiotics eliminate bacteremia and allow safe outpatient management following high-dose chemotherapy and autologous stem cell rescue

This study examines the effectiveness of prophylactic ciprofloxacin and rifampin following high-dose chemotherapy and autologous stem cell rescue (HDC/ASCR). Specific endpoints included the incidence of fever, clinically documented infection, bacteremia, and readmission rates from an outpatient bone marrow transplant setting following infection or fever. A group of 97 patients receiving 134 cycles of HDC/ASCR were studied. Patients were given ciprofloxacin 750 mg p.o. twice daily and rifampin 300 mg p.o. twice daily beginning on the day of stem cell reinfusion (24-48 h after completion of high-dose chemotherapy). Most patients were either discharged to an outpatient setting following completion of their chemotherapy or received all of their chemotherapy in an outpatient setting. Febrile neutropenia was treated with empirical antibiotics in an outpatient setting unless it was complicated by hypotension, renal failure, severe mucositis or other problems. The median duration of neutropenia (absolute neutrophil count below 500/mm³) was 7 days. Neutropenic fever occurred in 62% of patients but clinically documented bacterial infection occurred in only 2 (1.5%) patients during their neutropenic period. No bacteremia was noted. Readmission to the hospital following fever or infection occurred in 26% of patients maintained in the outpatient setting. There were no deaths from a bacterial infection in this study although 1 patient (0.7%) died from aspergillosis. Prophylactic ciprofloxacin and rifampin is a well-tolerated and highly effective combination that effectively decreases the risk of both gram-positive and gram-negative bacterial infection following HDC/ASCR. It facilitates outpatient management of myelosuppressed patients receiving autologous stem cell rescue.Presented in part as an invited lecture at the 7th International Symposium: Supportive Care in Cancer, Luxembourg, 20–23 September 1995     

Granulocyte colony-stimulating factor use in cancer patients

OBJECTIVE: To conduct a retrospective drug utilization evaluation comparing the use of granulocyte colony-stimulating factor (G-CSF) at a university medical center with the American Society of Clinical Oncology (ASCO) CSFs Practice Guidelines. METHODS: Patients who received G-CSF from June 1, 1996, to December 31, 1996, were identified through the pharmacy computer system and the medical records were reviewed for a randomly selected sample of 26% of the 289 patients identified. Outpatient, inpatient, and electronic medical records were reviewed for the indication, dosage, day of initiation, day of discontinuation, and absolute neutrophil count (ANC) monitoring plan for each course of G-CSF; these records were subsequently compared with the ASCO guidelines. RESULTS: The use of G-CSF after chemotherapy was evaluated in 51 patients who received a total of 182 courses of G-CSF. The goal of chemotherapy was curative in 61% of courses. Sixty-five percent of G-CSF courses were prescribed for primary prophylaxis. Of these, 74% followed chemotherapy in patients with an expected incidence of febrile neutropenia > or =40% or followed chemotherapy in patients with compromised marrow reserve secondary to extensive prior therapy or in patients older than 60 years. Most of the G-CSF courses (75%) were rounded to the nearest vial size. The areas of greatest departure from the ASCO guidelines included aspects of initiation and discontinuation of G-CSF courses and inadequate documentation of ANC recovery. CONCLUSIONS: These results demonstrate a number of specific opportunities for oncology pharmacists to improve the use of G-CSF in patients receiving chemotherapy. Recommendations were made to the pharmacy and therapeutics committee and medical oncologists to improve compliance with the ASCO guidelines.