Colony-stimulating factor-1 receptor inhibition attenuates microgliosis and myelin loss but exacerbates neurodegeneration in the chronic cuprizone model.

Multiple sclerosis (MS), especially in its progressive phase, involves early axonal and neuronal damage resulting from a combination of inflammatory mediators, demyelination, and loss of trophic support. During progressive disease stages, a microenvironment is created within the central nervous system (CNS) favoring the arrival and retention of inflammatory cells. Active demyelination and neurodegeneration have also been linked to microglia (MG) and astrocyte (AST)-activation in early lesions. While reactive MG can damage tissue, exacerbate deleterious effects, and contribute to neurodegeneration, it should be noted that activated MG possess neuroprotective functions as well, including debris phagocytosis and growth factor secretion. The progressive form of MS can be modeled by the prolonged administration to cuprizone (CPZ) in adult mice, as CPZ induces highly reproducible demyelination of different brain regions through oligodendrocyte (OLG) apoptosis, accompanied by MG and AST activation and axonal damage. Therefore, our goal was to evaluate the effects of a reduction in microglial activation through orally administered brain-penetrant colony-stimulating factor-1 receptor (CSF-1R) inhibitor BLZ945 (BLZ) on neurodegeneration and its correlation with demyelination, astroglial activation, and behavior in a chronic CPZ-induced demyelination model. Our results show that BLZ treatment successfully reduced the microglial population and myelin loss. However, no correlation was found between myelin preservation and neurodegeneration, as axonal degeneration was more prominent upon BLZ treatment. Concomitantly, BLZ failed to significantly offset CPZ-induced astroglial activation and behavioral alterations. These results should be taken into account when proposing the modulation of microglial activation in the design of therapies relevant for demyelinating diseases. Cover Image for this issue: https://doi.org/10.1111/jnc.15394.

Should we screen patients with hematologic malignancies for COVID-19?

The coronavirus disease (COVID-19) pandemic has posed several challenges to the hematology community to re-organize the medical care of patients with hematologic malignancies. Whereas the oncology societies favored a more or less conservative approach which considered the possibility of delaying treatment administration on a case-by-case basis, the hematology community guidelines were less stringent and recommended adequate individualized regimens. As countries are de-escalating the lockdown and the medical community is unable to foresee the end of the current outbreak will and whether the pandemic would eventually come back as a seasonal infection, there is interest in screening of patients with hematology malignancies with COVID-19 instead of limiting access to curative treatments. The rapidly accumulating knowledge about COVID-19 allows a better understanding of the diagnostic tools that may be potentially used in screening. Herein, we briefly review the pathophysiology of COVID-19, the rationale of screening of patients with hematologic malignancies, tools for screening, and available guidelines.

Associations between hematopoietic growth factors and risks of venous thromboembolism, stroke, ischemic heart disease and myelodysplastic syndrome: findings from a large population-based cohort of women with breast cancer.

PURPOSE: To determine the risk of venous thromboembolism (VTE), stroke, ischemic heart disease, and myelodysplastic syndrome (MDS) in association with the receipt of colony-stimulating factors (CSFs) and/or erythropoiesis-stimulating agents (ESAs) in women with breast cancer. METHODS: We studied 77,233 women with breast cancer aged ≥65 in 1992-2009 from the Surveillance, Epidemiology, and End Results-Medicare linked data with up to 19 years of follow-up. RESULTS: Incidence of VTE increased from 9 cases in women receiving no chemotherapy and no CSFs/ESAs to 22.79 cases per 1,000 person-years in those receiving chemotherapy with CSFs and ESAs. Women with chemotherapy who received both CSFs and ESAs (adjusted hazard ratio and 95 % confidence interval 2.01, 1.80-2.25) or received ESAs without CSFs (2.03, 1.74-2.36) were twice as likely to develop VTE than those receiving no chemotherapy and no CSFs/ESAs, whereas those receiving CSF alone without ESA were 64 % more likely to have VTE (1.64, 1.45-1.85). Risk of MDS was significantly increased by fivefold in patients receiving ESA following chemotherapy. CONCLUSIONS: Receipts of CSFs and ESAs were significantly associated with an increased risk of VTE in women with breast cancer. Use of ESAs was significantly associated with substantially increased risks of MDS. These findings support those of previous studies.

Myeloid growth factors.

Febrile neutropenia, a common side effect of myelosuppressive chemotherapy in patients with cancer, can result in prolonged hospitalization and broad-spectrum antibiotic use, often prompting treatment delays or dose reductions of drug regimens. Prophylactic use of myeloid growth factors (mainly the colony-stimulating factors filgrastim and pegfilgrastim) in patients of heightened risk can reduce the severity and duration of febrile neutropenia. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Myeloid Growth Factors provide recommendations on the use of these agents mainly in the oncology setting based on clinical evidence and expert consensus. This version includes revisions surrounding the issue of timing of pegfilgrastim administration. It also includes new sections on tbo-filgrastim, a recently approved agent that is biologically similar to filgrastim, and the role of myeloid growth factors in the hematopoietic cell transplant setting.

Colony stimulating factors (including erythropoietin, granulocyte colony stimulating factor and analogues) for stroke.

BACKGROUND: Colony stimulating factors (CSFs), also called haematopoietic growth factors, regulate bone marrow production of circulating red and white cells, and platelets. Some CSFs also mobilise the release of bone marrow stem cells into the circulation. CSFs have been shown to be neuroprotective in experimental stroke. OBJECTIVES: To assess (1) the safety and efficacy of CSFs in people with acute or subacute ischaemic or haemorrhagic stroke, and (2) the effect of CSFs on circulating stem and blood cell counts. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (last searched September 2012), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 4), MEDLINE (1985 to September 2012), EMBASE (1985 to September 2012) and Science Citation Index (1985 to September 2012). In an attempt to identify further published, unpublished and ongoing trials we contacted manufacturers and principal investigators of trials (last contacted April 2012). We also searched reference lists of relevant articles and reviews. SELECTION CRITERIA: We included randomised controlled trials recruiting people with acute or subacute ischaemic or haemorrhagic stroke. CSFs included stem cell factor (SCF), erythropoietin (EPO), granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), macrophage-colony stimulating factor (M-CSF, CSF-1), thrombopoietin (TPO), or analogues of these. The primary outcome was functional outcome at the end of the trial. Secondary outcomes included safety at the end of treatment, death at the end of follow-up, infarct volume and haematology measures. DATA COLLECTION AND ANALYSIS: Two review authors (TE and NS) independently extracted data and assessed trial quality. We contacted study authors for additional information. MAIN RESULTS: We included a total of 11 studies involving 1275 participants. In three trials (n = 782), EPO therapy was associated with a significant increase in death by the end of the trial (odds ratio (OR) 1.98, 95% confidence interval (CI) 1.19 to 3.3, P = 0.009) and a non-significant increase in serious adverse events. EPO significantly increased the red cell count with no effect on platelet or white cell count, or infarct volume. Two small trials of carbamylated EPO have been completed but have yet to be reported. We included eight small trials (n = 548) of G-CSF. G-CSF was associated with a non-significant reduction in early impairment (mean difference (MD) -0.4, 95% CI -1.82 to 1.01, P = 0.58) but had no effect on functional outcome at the end of the trial. G-CSF significantly elevated the white cell count and the CD34+ cell count, but had no effect on infarct volume. Further trials of G-CSF are ongoing. AUTHORS' CONCLUSIONS: There are significant safety concerns regarding EPO therapy for stroke. It is too early to know whether other CSFs improve functional outcome.

Mirtazapine-induced neutropenic sepsis in an older person: a case report.

BACKGROUND: Mirtazapine is a frequently prescribed psychotropic drug for depression in older age. It is considered safe and has a side-effect profile uniquely favorable to an older person affected by reduced appetite, difficulty maintaining body weight, or insomnia. However, it is largely unknown that mirtazapine can cause a dangerous decline in neutrophil count. CASE PRESENTATION: We present a case of mirtazapine-induced severe neutropenia in a 91-year-old white British woman requiring drug withdrawal and granulocyte-colony stimulating factor administration. CONCLUSION: This case is of significance because mirtazapine is regarded as a safe, and often preferable, antidepressant in older age. However, this case demonstrates a rare, life-threatening side effect of mirtazapine and calls for greater pharmacovigilance when prescribing it. There is no previous report of mirtazapine-induced neutropenia requiring drug withdrawal and granulocyte-colony stimulating factor administration in an older person.

The effect of concomitant use of Colony-Stimulating factors on bleomycin pulmonary toxicity - A systematic review and meta-analysis.

BACKGROUND: Changes in the incidence of bleomycin pulmonary toxicity (BPT) as a result of adding colony-stimulating factors (CSF) to bleomycin regimens has been investigated in numerous studies. We performed a systematic review and meta-analysis to assess the outcomes of these studies. METHODS: A systematic search was performed using Pubmed, Scopus, Web of Science, and Embase on April 2021. Studies evaluating the incidence of BPT in patients receiving bleomycin with and without CSF were included. In addition, meta-analysis was performed by pooling odds ratios using R. RESULTS: Out of 340 obtained records, our qualitative and quantitative analysis included 3234 and 1956 patients from 22 and 14 studies, respectively. The quantitative synthesis showed that addition of CSF significantly increased the risk of BPT incidence (OR = 1.82, 95 % CI: 1.37-2.40, p < 0.0001; I2 = 10.7 %). Subgroup analysis did not show any association between continent, bleomycin dose, cancer type, type of study, and pulmonary function test with BPT incidence. CONCLUSION: This systematic review and meta-analysis showed that co-administration of CSF with bleomycin increases the incidence of BPT. The physicians need to consider this finding while deciding the best strategy for this cohort of patients.

Colony stimulating factors for prophylaxis of chemotherapy-induced neutropenia in children.

INTRODUCTION: Febrile neutropenia (FN) is one of the complications of chemotherapy that can increase the risk of infection and mortality. Granulocyte colony-stimulating factors (G-CSFs) are used in practice to prevent and treat episodes of neutropenia. The use of G-CSFs in children with cancer has not been studied much for primary prophylaxis of FN. AREAS COVERED: Current data suggest that G-CSFs have a similar pharmacokinetic profile in children and adults. Clinical trials published from 2002 to 2021 using G-CSFs in pediatric cancer patients were reviewed. All evaluated clinical trials used a dosage of 5 mcg/kg of filgrastim daily until neutrophil recovery or a single dose of 100 mcg/kg pegfilgrastim. Filgrastim demonstrated the benefit in decreasing the duration of fever, hospital stay, and antibiotic use in high-risk neuroblastoma patients. Pegfilgrastim showed similar efficacy in reducing the occurrence of FN and infections, with bone pain as an adverse effect. EXPERT OPINION: Filgrastim 5 mcg/kg/day or pegfilgrastim 100 mcg/kg single dose is appropriate when given at least 24 hours or after the chemotherapy in pediatric patients who weigh 45 kg or more. More prospective randomized trials are necessary to further investigate the efficacy and safety of G-CSFs in children with different types of cancer.

Biosimilars: are they ready for primetime in the United States?

The introduction of alternative versions of biologic products, also known as biosimilars, into the United States market has been gaining increasing visibility as patents for many agents are nearing expiration. Unlike generics, which are regulated under the Hatch-Waxman legislation passed in 1984, the approval process for biosimilars in the United States has not been defined. In 2004, the European Union established a regulatory pathway for these agents, and the FDA is now following suit. The economic implications are large, with $66.9 billion spent on the top 20 biologics in 2009. Of the top 10 biologics, 6 are routinely used in oncology. As the regulatory requirements are debated, several critical issues must be resolved. The most obvious is that the agents must be shown to be comparable to the original biologic they intend to replace. Knowledge of pharmacokinetic parameters alone will not be adequate, but the amount of clinical data required by the FDA remains unclear. The regulations will define the ease with which a biosimilar can be brought to market, and the associated costs of trials will influence the ultimate price of the medications. Balancing the needs of the relevant stakeholders is critical to ensure patient safety while controlling costs, improving access, and encouraging innovation. This is not an easy balance to strike.

Nested Case-Control Study Utilizing MID-NET® on Thrombocytopenia Associated With Pegfilgrastim in Patients Treated With Antineoplastic Agents.

Although several spontaneous case reports on the occurrence of thrombocytopenia in patients treated with human granulocyte colony-stimulating factor (G-CSF) preparations have been accumulated, its actual causality is still unclear. To investigate the association between G-CSF preparations (filgrastim, nartograstim, lenograstim, and pegfilgrastim) available in Japan and thrombocytopenia in patients treated with antineoplastic agents, a nested case-control study was conducted using the Medical Information Database NETwork (MID-NET®) with the cohort of the Japanese population taking antineoplastic agents between 2009 and 2018. A case of thrombocytopenia was defined as a patient who had decreased platelet counts (< 50,000/mm3 ). We identified a maximum of 10 controls for each case matched on the index date. Adjusted odds ratios (aORs) and their 95% confidence intervals (CIs) of thrombocytopenia for the use of G-CSF preparations compared with nonuse were estimated using conditional logistic regression. From the cohort in which 33,124 patients were included, 733 cases and 5,592 controls were identified. Compared with the nonuse of G-CSF preparations, the use of any G-CSF preparations increased the risk of thrombocytopenia (aOR: 5.7, 95% CI: 4.3-7.5). More detailed analysis showed that a distinctive increased risk was observed when pegfilgrastim was prescribed at 2-7 days before the index date (aOR: 7.4 95% CI: 2.0-28.1). Associations of the other G-CSF preparations with thrombocytopenia were unclear due to the inconsistent results among different analyses. A significantly increased risk of thrombocytopenia associated with pegfilgrastim was identified, leading to a revision of precautions in the package inserts of pegfilgrastim as a regulatory safety action.

Clinical practice guidelines for the use of colony-stimulating factors in cancer treatment: Implications for oncology nurses.

Chemotherapy-induced neutropenia (CIN) is a common and serious toxicity of cancer chemotherapy. It can lead to febrile neutropenia (FN), which often requires patients to be hospitalised for intravenous antibiotic therapy. Chemotherapy dose reductions or delays, which can compromise clinical outcomes, may also result from CIN and FN. Prophylactic use of colony-stimulating factors (CSFs) reduces the incidence, duration, and severity of FN, and there is evidence that it helps maintain scheduled chemotherapy dose delivery. In 2006, three organisations published new or updated guidelines for the use of CSFs in cancer treatment. Each recommends that FN risk be determined individually for each patient, taking into account patient- and disease-specific risk factors, the chemotherapy regimen, and treatment intent. Particular consideration should be given to patients who are > or =65 years old, receiving chemotherapy regimens associated with > or =20% risk of FN, receiving dose-dense chemotherapy, and receiving treatment that is adjuvant, potentially curative, or intended to prolong survival. Accordingly, oncology nurses can play an important role in assessing and identifying patients at risk for FN before every chemotherapy cycle. There is evidence that, regardless of practice type or size, implementing guidelines for CSF use within a multidisciplinary team improves patient outcomes.

Use of colony-stimulating factors for chemotherapy-associated neutropenia: review of current guidelines.

Chemotherapy-associated neutropenia is often dose-limiting and may compromise treatment efficacy. Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage-colony-stimulating factor (GM-CSF) are increasingly used to prevent febrile neutropenia (FN) or to increase dose-density. This review discusses recent changes in treatment guidelines for chemotherapy-associated neutropenia. Primary prophylactic use of CSFs is now recommended as a treatment option at an overall risk of FN of 20%, not taking into account cost-effectiveness. To estimate the risk of FN, patient-, disease-, and treatment-related factors predicting an adverse outcome of FN have been determined. Dose-dense chemotherapy has become feasible with the use of CSFs. However, clinical benefit has been shown only for specific chemotherapy regimens in breast cancer, small cell lung cancer (SCLC), and non-Hodgkin's lymphoma (NHL), for the latter particularly for patients above 60 years of age. Strategies are being developed to tailor the use of CSFs to patients with a high risk of adverse outcome of FN.

Role of colony stimulating factors (CSFs) in solid tumours: results of an expert panel.

Febrile neutropenia is a relatively frequent event in cancer patients treated with chemotherapy. A relevant body of scientific evidence has been produced in the last 2 decades, through clinical trials addressing the efficacy of colony stimulating factors (CSFs) in the prevention and treatment of febrile neutropenia. The correct use of CSFs needs to be optimized, and several guidelines have been produced and periodically updated, in order to uniform and guide clinical practice. The aim of this review is to synthesize the most relevant clinical trials and the most important existing guidelines about the role of CSFs in solid tumours. Role of CSFs as primary prophylaxis, secondary prophylaxis and treatment of afebrile and febrile neutropenia is discussed. A special focus is dedicated to neutropenia and the use of CSFs in the treatment of the three "big killers" among the solid tumours: breast cancer, lung cancer and colorectal cancer.

Recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) shortens the period of neutropenia after autologous bone marrow transplantation in a primate model.

The effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) on hematopoietic reconstitution after autologous bone marrow transplantation was evaluated in a primate model. Animals were given a continuous intravenous infusion of recombinant human GM-CSF for several days both before and after transplantation or only after the transplant procedure. Marrow ablation was accomplished by total body irradiation. In both groups of animals, the neutrophil count reached 1,000/mm3 by 8-9 d posttransplant compared with an interval of 17 and 24 d for two concurrent controls. After withdrawal of GM-CSF, neutrophil counts fell to values comparable to those observed in untreated controls. Accelerated recovery of platelet production was also observed in four of the five animals. Two additional animals were initially given GM-CSF several weeks posttransplantation because of inadequate engraftment. Prompt and sustained increases in neutrophil and platelet counts were observed. We conclude that GM-CSF may be useful in accelerating bone marrow reconstitution.

Phase I study of granulocyte colony-stimulating factor in patients with transitional cell carcinoma of the urothelium.

Recombinant human granulocyte colony-stimulating factor (rhG-CSF) was administered at a dose of 1-60 micrograms/kg of body weight to 22 patients with transitional cell carcinoma before chemotherapy as part of a Phase I/II study. In all patients, a specific dose-dependent increase in the absolute neutrophil count (ANC) of 1.8-12 fold was seen. In addition, this augmentation in the ANC was accompanied by an increase in leukocyte alkaline phosphatase, a marker of secondary granule formation. In six of eight patients analyzed, an increase in bone marrow myeloid to erythroid cell ratio was seen. Day 14 peripheral blood cell derived colony forming unit granulocyte macrophage were also increased by day 6 of rhG-CSF treatment. Circulating levels of eosinophils and basophils were unchanged; however, a 10-fold increase in monocytes was observed in patients treated at the highest doses. There was also a small increase in CD3+ lymphocytes that was not dose dependent. Hemoglobin, hematocrit, and platelet count remained near baseline throughout the period of rhG-CSF administration. These findings demonstrate that rhG-CSF is a potent stimulus for normal neutrophil proliferation and maturation.

Hematopoietic colony stimulating factors in cardiovascular and pulmonary remodeling: promoters or inhibitors?

Hemopoietic colony stimulating factors (HCSFs) are naturally occurred substances that are released in response to infection or inflammation and regulate the proliferation and differentiation of hemopoietic progenitor cells. Some representative members of this peptide family induce atherogenesis through the mediation of monocyte-endothelial cell adhesive interaction and promotion of angiogenesis within the atherosclerotic plaques. HCSFs, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), also promote post-infarction cardiac remodeling though the enhanced activation and infiltration of monocytes into injured myocardial tissue and through altered equilibrium of collagen deposition/degradation. On the other hand, exogenous administration of granulocyte colony-stimulating factor (G-CSF) or eythropoietin (EPO) in patients with chronic ischemic disease or recent myocardial infarction have lead to beneficial arteriogenesis or myocardial cell regeneration, thus preventing adverse cardiac remodeling. While GM-CSF may hold therapeutic potential as an inhibitor of lung fibrogenesis, G-CSF appears to promote fibrosis in the lungs. The pathophysiological role of HCSFs also depends on the timing of their action on cardiovascular remodeling, as well as on the target progenitor hematopoietic cell. This article summarizes current knowledge about the clinical and therapeutic implications of these factors in chronic artery disease, post-infarction cardiac remodeling, chronic heart failure and in pulmonary fibrosis.

Recombinant human granulocyte-macrophage colony-stimulating factor in patients with advanced malignancy: a phase Ib trial.

We evaluated the toxic, hematopoietic, and immunomodulatory effects of recombinant human granulocyte-macrophage colony-stimulating factor (rHuGM-CSF). The rHuGM-CSF was administered at doses up to 50 micrograms/kg by daily 2-hour intravenous infusions to 11 patients with advanced malignancy. It induced dose-related increases in cells of the myeloid series, but it had no significant effect on reticulocyte or platelet counts. Bone marrow cellularity increased with higher doses of rHuGM-CSF, but there was a dose-related decrease in the number of colony-forming units--granulocyte-monocyte--and colony-forming units--granulocyte-erythrocyte-monocyte-megakaryocyte--per 10(5) bone marrow cells. The rHuGM-CSF caused transient increased expression of CD11b and CD16 on granulocytes but increased expression of HLA-DR and decreased expression of the high-affinity Fc receptor on monocytes and no change in monocyte production of H2O2. Thus, rHuGM-CSF has potent effects on granulocyte, eosinophil, and monocyte numbers in the peripheral blood and bone marrow. In addition, it enhances the expression of monocyte and granulocyte activation-associated surface markers.

Trends in the use of colony-stimulating factors.

Colony-stimulating factors are potent manipulators of the hematopoietic and immune systems. An increasing number of colony-stimulating factors with expanded indications and uses are available. To provide safe and efficacious therapy, clinicians must understand how colony-stimulating factors and other biologic response modifiers work and know about product use, patient education, and patient monitoring. This article provides an overview of the current colony-stimulating factor products, uses, indications, administration, management, and patient education.