Granulocyte Colony-stimulating Factor Treatment Research Articles

Therapeutic use of granulocyte colony-stimulating factor (G-CSF) in patients with febrile neutropenia: a comprehensive systematic review for clinical practice guidelines for the use of G-CSF 2022 from the Japan Society of Clinical Oncology.

Febrile neutropenia represents a critical oncologic emergency, and its management is pivotal in cancer therapy. In several guidelines, the use of granulocyte colony-stimulating factor (G-CSF) in patients with chemotherapy-induced febrile neutropenia is not routinely recommended except in high-risk cases. The Japan Society of Clinical Oncology has updated its clinical practice guidelines for the use of G-CSF, incorporating a systematic review to address this clinical question. The systematic review was conducted by performing a comprehensive literature search across PubMed, the Cochrane Library, and Ichushi-Web, focusing on publications from January 1990 to December 2019. Selected studies included randomized controlled trials (RCTs), non-RCTs, and cohort and case-control studies. Evaluated outcomes included overall survival, infection-related mortality, hospitalization duration, quality of life, and pain. The initial search yielded 332 records. Following two rounds of screening, two records were selected for both qualitative and quantitative synthesis including meta-analysis. Regarding infection-related mortality, the event to case ratio was 5:134 (3.73%) in the G-CSF group versus 6:129 (4.65%) in the non-G-CSF group, resulting in a relative risk of 0.83 (95% confidence interval, 0.27-2.58; p = 0.54), which was not statistically significant. Only median values for hospitalization duration were available from the two RCTs, precluding a meta-analysis. For overall survival, quality of life, and pain, no suitable studies were found for analysis, rendering their assessment unfeasible. A weak recommendation is made that G-CSF treatment not be administered to patients with febrile neutropenia during cancer chemotherapy. G-CSF treatment can be considered for patients at high risk.

Vascular damage and excessive proliferation compromise liver function after extended hepatectomy in mice.

Surgical resection remains the gold standard for liver tumor treatment, yet the emergence of post-operative liver failure, known as the small for size syndrome (SFSS), poses a significant challenge. The activation of hypoxia sensors in a SFSS liver remnant initiated early angiogenesis, improving vascular architecture, safeguarding against liver failure and reducing mortality. The study aimed to elucidate vascular remodeling mechanisms in SFSS, its impact on hepatocyte function and subsequent liver failure. Mice underwent extended partial hepatectomy to induce SFSS, with a subset exposed to hypoxia immediately after surgery. Hypoxia bolstered post-hepatectomy survival rates. Early proliferation of liver sinusoidal cells, coupled with recruitment of putative endothelial progenitor cells (EPC), increased vascular density, improved lobular perfusion, and limited hemorrhagic events in the regenerating liver under hypoxia. Administration of granulocyte colony stimulating factor (G-CSF) in hepatectomized mice mimicked the effects of hypoxia on vascular remodeling and EPC recruitment, but failed to rescue survival. Compared to normoxia, hypoxia favored hepatocyte function over proliferation, promoting functional preservation in the regenerating remnant. Injection of AAV8-TBG-HNF4α virus for hepatocyte-specific overexpression of HNF4α, the master regulator of hepatocyte function, enforced functionality in proliferating hepatocytes but did not rescue survival. The combination of HNF4α overexpression and G-CSF treatment rescued survival after SFSS-setting hepatectomy. In summary, SFSS arises from an imbalance and desynchronized interplay between functional regeneration and vascular restructuring. To improve survival following SFSS-hepatectomy, it is essential to adopt a two-pronged strategy aimed at preserving the function of proliferating parenchymal cells and simultaneously attenuating vascular damage.

Resilient anatomy and local plasticity of naive and stress haematopoiesis

The bone marrow adjusts blood cell production to meet physiological demands in response to insults. The spatial organization of normal and stress responses are unknown owing to the lack of methods to visualize most steps of blood production. Here we develop strategies to image multipotent haematopoiesis, erythropoiesis and lymphopoiesis in mice. We combine these with imaging of myelopoiesis1 to define the anatomy of normal and stress haematopoiesis. In the steady state, across the skeleton, single stem cells and multipotent progenitors distribute through the marrow enriched near megakaryocytes. Lineage-committed progenitors are recruited to blood vessels, where they contribute to lineage-specific microanatomical structures composed of progenitors and immature cells, which function as the production sites for each major blood lineage. This overall anatomy is resilient to insults, as it was maintained after haemorrhage, systemic bacterial infection and granulocyte colony-stimulating factor (G-CSF) treatment, and during ageing. Production sites enable haematopoietic plasticity as they differentially and selectively modulate their numbers and output in response to insults. We found that stress responses are variable across the skeleton: the tibia and the sternum respond in opposite ways to G-CSF, and the skull does not increase erythropoiesis after haemorrhage. Our studies enable in situ analyses of haematopoiesis, define the anatomy of normal and stress responses, identify discrete microanatomical production sites that confer plasticity to haematopoiesis, and uncover unprecedented heterogeneity of stress responses across the skeleton.

G-CSF increases calprotectin expression, liver damage and neuroinflammation in a murine model of alcohol-induced ACLF.

Background and aims: Granulocyte colony-stimulating factor (G-CSF) has been proposed as a therapeutic option for patients with ACLF, however clinical outcomes are controversial. We aimed at dissecting the role of G-CSF in an alcohol-induced murine model of ACLF. Methods: ACLF was triggered by a single alcohol binge (5g/kg) in a bile duct ligation (BDL) liver fibrosis model. A subgroup of mice received two G-CSF (200μg/kg) or vehicle injections prior to acute decompensation with alcohol. Liver, blood and brain tissues were assessed. Results: Alcohol binge administered to BDL-fibrotic mice resulted in features of ACLF indicated by a significant increase in liver damage and systemic inflammation compared to BDL alone. G-CSF treatment in ACLF mice induced an increase in liver regeneration and neutrophil infiltration in the liver compared to vehicle-treated ACLF mice. Moreover, liver-infiltrating neutrophils in G-CSF-treated mice exhibited an activated phenotype indicated by increased expression of CXC motif chemokine receptor 2, leukotriene B4 receptor 1, and calprotectin. In the liver, G-CSF triggered increased oxidative stress, type I interferon response, extracellular matrix remodeling and inflammasome activation. Circulating IL-1β was also increased after G-CSF treatment. In the cerebellum, G-CSF increased neutrophil infiltration and S100a8/9 expression, induced microglia proliferation and reactive astrocytes, which was accompanied by oxidative stress, and inflammasome activation compared to vehicle-treated ACLF mice. Conclusion: In our novel ACLF model triggered by alcohol binge that mimics ACLF pathophysiology, neutrophil infiltration and S100a8/9 expression in the liver and brain indicate increased tissue damage, accompanied by oxidative stress and inflammasome activation after G-CSF treatment.

Impact of different genetic mutations on granulocyte development and G-CSF responsiveness in congenital neutropenia

AbstractCongenital neutropenia (CN) is a genetic disorder characterized by persistent or intermittent low peripheral neutrophil counts, thus increasing susceptibility to bacterial and fungal infections. Various forms of CN, caused by distinct genetic mutations, exhibit differential responses to granulocyte colony–stimulating factor (G-CSF) therapy, with the underlying mechanisms not fully understood. This study presents an in-depth comparative analysis of clinical and immunological features in 5 CN patient groups (severe congenital neutropenia [SCN]1, SCN3, cyclic neutropenia [CyN], warts, hypogammaglobulinaemia, infections and myelokathexis [WHIM], and Shwachman-Bodian-Diamond Syndrome [SBDS]) associated with mutations in ELANE, HAX1, CXCR4, and SBDS genes. Our analysis led to the identification of 11 novel mutations in ELANE and 1 each in HAX1, CXCR4, and G6PC3 genes. Investigating bone marrow (BM) granulopoiesis and blood absolute neutrophil count after G-CSF treatment, we found that SCN1 and SCN3 presented with severe early-stage disruption between the promyelocyte and myelocyte, leading to a poor response to G-CSF. In contrast, CyN, affected at the late polymorphonuclear stage of neutrophil development, showed a strong G-CSF response. WHIM, displaying normal neutrophil development, responded robustly to G-CSF, whereas SBDS, with moderate disruption from the early myeloblast stage, exhibited a moderate response. Notably, SCN1 uniquely impeded neutrophil development, whereas SCN3, CyN, WHIM, and SBDS also affected eosinophils and basophils. In addition, SCN1, SCN3, and CyN presented with elevated serum immunoglobulins, increased BM plasma cells, and higher A Proliferation-Inducing Ligand levels. Our study reveals a strong correlation between the stage and severity of granulocyte development disruption and the efficacy of G-CSF therapy.

A nitrous oxide/oxygen fixed mixture to reduce pain induced by the hypodermic injection: study protocol for a randomized, controlled trial

BackgroundPatients with hematological malignancies received multiple hypodermic injections of recombinant human granulocyte colony-stimulating factor. Procedural pain is one of the most common iatrogenic causes of pain in patients with hematological malignancies. It is also identified as the most commonly occurring problem in clinical care in the Department of Hematology and Oncology at Shenzhen University General Hospital. However, providing immediate relief from pain induced by hypodermic injection of recombinant human granulocyte colony-stimulating factor remains a major challenge. This trial aims to evaluate the safety and analgesic efficacy of a fixed nitrous oxide/oxygen mixture for patients with hematological malignancies and experiencing procedural pain caused by hypodermic injection of recombinant human granulocyte colony-stimulating factor in the department.MethodsThe nitrous oxide/oxygen study is a single-center, randomized, double-blind, placebo-controlled trial involving patients with hematological malignancies who require hypodermic injections of recombinant human granulocyte colony-stimulating factor for treatment. This trial was conducted in the Hematology and Oncology Department of Shenzhen University General Hospital. A total of 54 eligible patients were randomly allocated to either the fixed nitrous oxide/oxygen mixture group (n = 36) or the oxygen group (n = 18). Neither the investigators nor the patients known about the randomization list and the nature of the gas mixture in each cylinder. Outcomes were monitored at the baseline (T0), immediately after hypodermic injection of recombinant human granulocyte colony-stimulating factor (T1), and 5 min after hypodermic injection of recombinant human granulocyte colony-stimulating factor (T2) for each group. The primary outcome measure was the score in the numerical rating scale corresponding to the highest level of pain experienced during hypodermic injection of recombinant human granulocyte colony-stimulating factor. Secondary outcomes included the fear of pain, anxiety score, four physiological parameters, adverse effects, total time of gas administration, satisfaction from both patients and nurses, and the acceptance of the patients.DiscussionThis study focused on the safety and analgesic efficacy during hypodermic injection of recombinant human granulocyte colony-stimulating factor procedure. Data on the feasibility and safety of nitrous oxide/oxygen therapy was provided if proven beneficial to patients with hematological malignancies during hypodermic injection of recombinant human granulocyte colony-stimulating factor and widely administered to patients with procedural pain in the department.Trial registrationChinese Clinical Trial Register, ChiCTR2200061507. Registered on June 27, 2022. http://www.chictr.org.cn/edit.aspx?pid=170573&htm=4

Safety and efficacy of peripheral blood stem cells collection in healthy children and pediatric patients with thalassemia major weighing 20 kg or less.

Peripheral blood stem cell (PBSC) collection in children poses challenges due to their small size, low body weight (BW), and unique pediatric physiology, especially among children weighing 20 kg (kg) or less. PBSC collection data of both healthy children and patients with thalassemia major (TM) weighing 20 kg or less between January 2013 and December 2020 were reviewed. Moreover, PBSCs characteristics along with various aspects of efficiency and safety between healthy donors and patients with TM were compared. A total of 262 PBSC procedures were performed on 255 children. Of these, 91 procedures were carried out on 85 allogeneic healthy donors, and 171 auto-backup collections were performed on 170 patients with TM to ensure PBSC availability and prevent transplantation failure. A minimum pre-apheresis hemoglobin (HGB) level of 60 g/L was discovered to be safe and feasible in patients with TM. The median CD34+ cell dose in the PBSC product during the initial apheresis procedure was higher in healthy donors compared to patients with TM (7.29 ± 5.28 × 106 cells/kg vs5.88 ± 4.23 × 106 cells/kg, P = .043). The total CD34+ cells/kg recipient weight exhibited a positive correlation with pre-apheresis monocyte counts, but a negative correlation with donor weight. Apheresis significantly reduced hematocrit and platelet counts in the allogeneic group compared to the autologous group. Patients with TM experienced a higher occurrence of bone pain related to granulocyte colony-stimulating factor treatment. Notably, no serious complications related to PBSCs mobilization, central venous catheter placement, or the apheresis procedure were observed in either group. PBSCs collection was both safe and effective in healthy children and pediatric patients with TM weighing 20 kg or less.

Impact of Recombinant Granulocyte Colony-Stimulating Factor During Neoadjuvant Therapy on Outcomes of Resected Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease characterized by chronic inflammation and a tolerogenic immune response. The granulocyte colony-stimulating factor (G-CSF)-neutrophil axis promotes oncogenesis and progression of PDAC. Despite frequent use of recombinant G-CSF in the management and prevention of chemotherapy-induced neutropenia, its impact on oncologic outcomes of patients with resected PDAC is unclear. This cohort study assessing the impact of G-CSF administration was conducted on 351 patients with PDAC treated with neoadjuvant therapy (NAT) and pancreatic resection at a high-volume tertiary care academic center from 2014 to 2019. Participants were identified from a prospectively maintained database and had a median follow-up of 45.8 months. Patients receiving G-CSF (n=138; 39.3%) were younger (64.0 vs 66.7 years; P=.008), had lower body mass index (26.5 vs 27.9; P=.021), and were more likely to receive 5-FU-based chemotherapy (42.0% vs 28.2%; P<.0001). No differences were observed in baseline or clinical tumor staging. Patients receiving G-CSF were more likely to have an elevated (>5.53) post-NAT neutrophil-to-lymphocyte ratio (45.0% vs 29.6%; P=.004). G-CSF recipients also demonstrated higher circulating levels of neutrophil extracellular traps (+709 vs -619 pg/mL; P=.006). On multivariate analysis, G-CSF treatment was associated with perineural invasion (hazard ratio [HR], 2.65; 95% CI, 1.16-6.03; P=.021) and margin-positive resection (HR, 1.67; 95% CI, 1.01-2.77; P=.046). Patients receiving G-CSF had decreased overall survival (OS) compared with nonrecipients (median OS, 29.2 vs 38.7 months; P=.001). G-CSF administration was a negative independent predictor of OS (HR, 2.02; 95% CI, 1.45-2.79; P<.0001). In the inverse probability weighted analysis of 301 matched patients, neoadjuvant G-CSF administration was associated with reduced OS. In patients with localized PDAC receiving NAT prior to surgical extirpation, G-CSF administration may be associated with worse oncologic outcomes and should be further evaluated.

Whole-Brain Radiotherapy Alone vs Preceded by Bevacizumab, Etoposide, and Cisplatin for Untreated Brain Metastases From Breast Cancer

The incidence of brain metastasis is increasing in patients with metastatic breast cancer. Treatments to extend the control of brain metastasis are urgently required. To investigate whether the addition of an induction treatment of bevacizumab, etoposide, and cisplatin (BEEP) improves brain-specific progression-free survival (PFS) after whole-brain radiotherapy (WBRT). This open-label, randomized, multicenter clinical trial assessed patients with brain metastases from breast cancer (BMBC) in Taiwan from September 9, 2014, to December 24, 2018, with survival follow-up until December 31, 2021. Key inclusion criteria included metastatic brain tumors not suitable for focal treatment, WBRT naivety, age 20 to 75 years, and at least 1 measurable brain metastatic lesion. The primary end point was brain-specific PFS, with an expected hazard ratio of 0.60, a 2-sided α ≤ .20, and power of 0.8. Eligible patients were randomly assigned at a ratio of 2:1 to the experimental arm, which involved 3 cycles of BEEP followed by WBRT, or the control arm, which involved WBRT alone. The primary end point was the determination of brain-specific PFS by local investigators according to the Response Evaluation Criteria in Solid Tumors, version 1.1, the initiation of other brain-directed treatment after WBRT, or death. Other key end points included brain-specific objective response rate after 8 weeks of BEEP treatment or WBRT and 8-month brain-specific PFS rate, PFS, and overall survival. A total of 118 patients with BMBC were randomized, with the intention-to-treat cohort comprising 112 patients. The median age was 56 years (range, 34-71 years), and 61 patients (54.5%) had ERBB2 (formerly HER2 or HER2/neu)-positive disease. The median (range) brain-specific PFS was 8.1 (0.3-29.5) vs 6.5 (0.9-25.5) months in the experimental and control arms, respectively (hazard ratio, 0.71; 95% CI, 0.44-1.13; P = .15; significant at predefined α ≤ .20). The brain-specific objective response rate at 2 months was not significantly different (BEEP treatment vs WBRT, 41.9% vs 52.6%), but the 8-month brain-specific PFS rate was significantly higher in the experimental group (48.7% vs 26.3%; P = .03). Adverse events were generally manageable with prophylactic granulocyte colony-stimulating factor treatment. The findings show that induction BEEP before WBRT may improve the control of BMBC compared with using upfront WBRT, which could address an unmet need for an effective systemic treatment for intractable brain and extracranial metastases from metastatic breast cancer. ClinicalTrials.gov Identifier: NCT02185352.

Efficacy and safety of recombinant human granulocyte colony-stimulating factor in patients with poor ovarian response: protocol for a multicentre, randomised, controlled trial

IntroductionApproximately 17.5% of couples of reproductive age have experienced infertility. Women with a poor ovarian response (POR) must undergo in vitro fertilisation (IVF) and embryo transfer to achieve pregnancy. However,...

G-CSF Induces MAIT Cells to Exert Anti-Intestinal Gvhd Effects Dependent on CXCR6 Mediated Chemotaxis

Background: Graft-versus-host disease (GVHD) is a major complication leading to transplantation failure and affecting overall survival after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Granulocyte colony-stimulating factor (G-CSF) can induce T-cell tolerance and altering graft cell components to enhance GVHD prevention in HSCT. MAIT cells are a group of innate immune T cells. It has unique biological properties, including mucosal tissue enrichment, activation of microbial riboflavin derivatives and tissue repair properties, which determine MAIT cells play an important role in mucosal immunity. Previous studies found that a high MAIT cell counts in G-CSF-induced grafts (G-grafts) is associated with a low incidence of gut acute GVHD (aGVHD). However, the effect of G-CSF mobilization on the phenotype, function and its regulatory mechanism in GVHD of MAIT cells has not been elucidated. Methods: MAIT cells in PB samples from four healthy donors before and after G-CSF treatment were isolated for Single-cell RNA sequencing (Figure A). Flow cytometry, In vitro experiment and NOD-SCID-IL-2Rg−/− mice (NSG mice) were performed to observe the phenotypic, functional changes and the dynamic distribution of G-CSF induced donor-derived MAIT cells in recipients. Results: A total of 80709 MAIT cells were divided into 14 clusters. Based on key type-associated marker genes and gene sets, MAIT0 (clusters 5 and 9), MAIT1 (cluster 7), MAIT2 (clusters 4 , 11), Cycling MAIT (clusters 12, 13), Activation (clusters 0, 8), ISG (cluster 10) and MAIT17 (clusters 1,2,3,6) cells were identified (Figure B,C). The subset frequencies and expression signatures of immunosuppression (MAIT2 and Cycling cells from cluster 12) and tissue repair (Activation and MAIT17) were both increased at both transcriptome (Figure D) and protein levels, suggesting that G-CSF enhanced the immune tolerance and tissue repair of MAIT cells. In vitro further confirmed that G-CSF-induced MAIT cells showed a stronger inhibition for T cell proliferation (Figure E). Besides, overexpressed genes related to immune regulation in G-CSF induced MAIT cells were strongly enriched in cluster 12 with high CSF3R (G-CSF receptor) expression (Figure F). The cluster 12 also showed the enrichment of IL-17 and TNF signaling pathway favoring tissue repair function, while downregulation of Graft-versus-host disease pathway upon G-CSF mobilization, indicating that G-CSF-CSF3R interaction is the potential mechanism by which G-CSF mediates the immune regulation of MAIT cells. Based on whether recipients develop gut aGVHD or not after allo-HSCT, the matched donor grafts after G-CSF mobilization were divided into two groups termed as post-G-CSF-no gut aGVHD (n=3) and post-G-CSF-gut aGVHD group (n=1), respectively. MAIT cells in post-G-CSF-no gut aGVHD group overexpressed CSF3R and its related target genes, immunosuppression and tissue repair signatures compared with post-G-CSF-gut aGVHD. Besides, MAIT cells from G-PB of recipients without gut aGVHD had a higher CD114 expression (encoded by CSF3R) compared with gut aGVHD (Figure G). These results suggest that the enhanced immunosuppression and tissue repair function of MAIT cells induced by G-CSF may exert anti-gut aGVHD effects. The NSG mice confirmed MAIT cells in G-PB to tissue chemotaxis especially gut tissues in the recipient. A higher frequency of MAIT cells was detected in gut tissues in the low GVHD score group (GVHD Score＜3) compared with the high GVHD score group on post-transplant day 14 (Figure H), suggesting recruited MAIT cells in gut tissues favor anti-gut aGVHD effect. Moreover, CXCR6 was the most differentially expressed chemotactic receptor gene between post-G-CSF-no gut aGVHD and post-G-CSF-gut aGVHD group (Figure I). At the protein level, the expression of CXCR6 were significantly upregulated upon G-CSF administration (Figure I), while that of CCR6 and CXCR6 was non-significant. These results suggest that CXCR6 is necessary for G-CSF induced MAIT cell recruitment to the gut tissue. Conclusions G-CSF-CSF3R interactions enhance immunosuppression and tissue repair functions of MAIT cells, while CXCR6 recruits these functional MAIT cells from PB to gut tissues to exert anti-gut aGVHD effect. Hence, CSF3R and CXCR6 expression in G-CSF mobilized MAIT cells is crucial to exert anti-gut aGVHD effect, and has the potential to become predictive markers of gut aGVHD.

Noncoding GATA2 Genetic Variation As a Determinant of Hematopoietic Stem/Progenitor Cell Activity and Mobilization Efficiency

Germlinecoding and enhancer variants within the hematopoietic regulator GATA2 create a bone marrow failure and leukemia predisposition (Soukup and Bresnick, 2020). We generated a mouse model of GATA2 deficiency syndrome by engineering mice with a single-nucleotide variant in an intronic enhancer (+9.5) from GATA2 deficiency patients combined with deletion of the enhancer from the second allele (compound heterozygous; CH). This system models patients harboring a germline pathogenic allele accompanied by epigenetic silencing of the normal allele. Unlike homozygous Gata2 coding or regulatory deletions that are embryonic lethal, CH represents a unique system to analyze postnatal GATA2 function. We demonstrated that adult germline Gata2 variation alters steady-state HSPCs, blocks HSPC expansion and differentiation upon chemotherapy, attenuates long-term repopulating activity following bone marrow transplantation, leads to bone marrow failure following chronic inflammation by the viral mimetic polyI:C, alters HSPC response to the bacterial cell wall component LPS and attenuates HSPC mobilization in response to granulocyte colony stimulating factor (G-CSF) (Soukup et al., 2019, Soukup et al., 2021). As short-term G-CSF treatment induces HSPC metabolic gene signatures (Fast et al., 2021) and expansion and cell cycle entry (Schuettpelz et al., 2014), and CH have decreased MPPs (LSKCD150 -CD48 -) and common myeloid progenitors (CMPs) (Lin −Sca1 −Kit +FcγR −CD34 +) (Soukup et al., 2021), we asked if mobilization defects reflected decreased functional HSPCs in bone marrow. CH had 2.2-fold fewer colony forming units (CFU) from bone marrow (p = 0.007) than wild type (WT), reflecting a paucity of functional HSPCs. 16 hours following a single G-CSF dose, WT bone marrow immunophenotypic HSCs (LSKCD150 +CD48 -) and MPPs expanded 1.8-fold (p = 0.001 and 0.01, respectively); CH HSCs and MPPs were unchanged. CH led to decreased HSPCs and failed to induce rapid HSPC expansion post-G-CSF. We tested whether Gata2 variation impairs mobilization in response to different stimuli, or if select pathways are impacted via disrupting the CXCR4/CXCL12 chemokine axis with the CXCR4 antagonist plerixafor, stromal/neutrophil CXCR2 activation with rhIL-8, or VLA-4/VCAM1 binding with VLA-4 inhibitor BIO5192. IL-8 or BIO5192 resulted in 3.9- and 2.2-fold increased WT CFU, respectively (p &amp;lt; 0.0001 and 0.0014) without altering CH CFU. By contrast, mobilization with plerixafor resulted in a 4.3-fold increase in WT CFU (p &amp;lt; 0.0001) and 4.5-fold increase in CH CFU (p = 0.004). Targeting these pathways collectively with G-CSF was insufficient to restore normal mobilization in CH. Competitive transplantations with peripheral blood revealed G-CSF + plerixafor increased WT donor-derived hematopoiesis 24- and 20-fold at 8 and 12 weeks, respectively, versus vehicle control. Treatment of CH did not increase donor-derived contributions. Since GATA2 deficiency syndrome and somatic GATA2 variation involve heterozygous alleles, we tested whether monoallelic +9.5 Ets motif variation disrupts mobilization. G-CSF increased CFU 28.5-fold (p &amp;lt; 0.0001) relative to vehicle-treated WT. Mobilization of Gata2 Ets +/- HSPCs were reduced significantly (p = 0.003). CH variation severely disrupted mobilization, with 7.3-fold fewer CFU than Gata2 Ets +/- (p = 0.02). Synergistic G-CSF/plerixafor treatment increased CFU 89-fold in WT versus untreated (p &amp;lt; 0.0001), and Gata2 Ets +/- mobilization was reduced (p = 0.006) and not improved relative to Gata2 Ets -/- or CH, resembling G-CSF/BIO5192. Thus, Gata2 heterozygosity impaired G-CSF-induced HSPC mobilization with all regimens. Although GATA2 noncoding variation is not commonly evaluated, analysis of human data will be performed to assess relationships between variation and poor mobilization outcomes. Gata2 variation depletes functional HSPCs in the bone marrow, reducing the available HSPCs to mobilize and rendering most mobilization regimens inefficient. Ongoing studies are elucidating molecular mechanisms underlying the mobilization blockade. Our mobilization-defective system offers unique utility for elucidating fundamental HSPC mechanisms e.g., in the context of additional environmental and/or genetic insults. Future knowledge linking functionality of mobilization regimens in these contexts may unveil insights into mechanisms operational in poor mobilizers.

Granulocyte Colony-Stimulating Factor Use in Patients with Hemophagocytic Lymphohistiocytosis: A Single Center Experience

Background: Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening syndrome caused by activation of T cells that results in extreme inflammation. HLH is commonly associated with underlying conditions such as infection, autoimmune disease, or malignancy. HLH management includes treatment directed at the specific trigger, suppression of maladaptive cytokines, and inhibition of T cell and macrophage proliferation. Granulocyte colony-stimulating factor (GCSF) is a myeloid growth factor that stimulates the production, maturation, and activation of neutrophils. GCSF may theoretically promote production of inflammatory cytokines and enhance hemophagocytosis, thereby intensifying HLH. By contrast, GCSF could play a vital role in the treatment of granulocytopenia caused by HLH and thus limit the development of infections. There is a paucity of data examining the role of GCSF in patients with HLH. Current literature is limited to case reports of HLH exacerbated by GCSF administration. Practice patterns of GCSF use in HLH are highly variable, both within and between institutions. Aim: To compare the clinical course and overall survival of patients with HLH who received GCSF treatment and those who did not. Methods: We performed a retrospective, single-center cohort study of patients admitted with a diagnosis code of HLH from July 1997 through February 2023. Patients at least 18 years old with active HLH were included. Each case was reviewed to confirm the diagnosis of HLH based on available diagnostic evaluation and the final discharge diagnoses as documented by the primary treating team. In cases indeterminate for HLH, a second independent reviewer performed additional evaluation to reach consensus. The primary outcome was overall survival as determined by the Kaplan Meier method with statistical comparison using the log-rank test. Other examined outcomes included: incidence of infection, length of hospital stay (LOS), incidence of intensive care unit (ICU) admissions, length of ICU stay, incidence of 30-day re-admissions due to HLH, and time to first change in HLH-directed therapy. Results: Database analysis revealed 130 patients with a diagnosis code of HLH, of which 68 patients met inclusion criteria. The study cohort comprised 26 patients that received GCSF treatment and 42 patients that did not. The median follow-up time was 3.1 months (interquartile range [IQR] 0.6-29.4). The most common HLH triggers were infection (30.8% GCSF group vs 45.2% control, p=0.31) and malignancy (65.5% GCSF group vs 19% control, p&amp;lt;0.001). A median of 10 doses (IQR 6-16) of GCSF were administered per patient in the GCSF group, and the median time between diagnosis and the first administered dose was 6.5 days (IQR 2.25-18.75). Median overall survival in the GCSF group was 122.6 months compared to 1.5 months in the control group (p=0.02, Figure 1). There was a higher but statistically insignificant difference in infection rate in the GCSF arm (92.3%) compared to the control arm (71.4%, p=0.06). The median LOS was higher in the GCSF group (38 days vs 15 days, p&amp;lt;0.001). Rates of ICU admission (53.4% vs 62%, p=0.69), intubation and mechanical ventilation (34.6% vs 33.3%, p=1.0), and initiation of renal replacement therapy (23.1% vs 16.7%, p=0.74) were similar across the GCSF and control groups, respectively. Two patients in each group were re-admitted for HLH within 30 days of initial discharge. The median time to change in HLH-directed therapy was not reached in either group, and there was no significant difference in incidence of therapy change between groups at 1, 3, or 6 months (Figure 2). Conclusions: In this single center, retrospective cohort study of patients with HLH, treatment with GCSF was not associated with inferior overall survival. While over-representation of a malignancy-associated trigger in the GCSF group may confound interpretation of this result, it nevertheless reflects an important clinical finding that contradicts previously published case report-level evidence. This study highlights the need for further prospective investigation of GCSF administration in HLH.

Granulocyte colony-stimulating factor plus pentoxifylline increases short-term survival in patients with severe alcoholic hepatitis: a network meta-analysis

ABSTRACT Background: Optimal treatments for severe alcoholic hepatitis (SAH) remain controversial. Previous network meta-analysis showed that corticosteroid (CS) combined with N-acetylcysteine (NAC) was superior in reducing short-term mortality of patients with SAH. Recently, granulocyte colony-stimulating factor (G-CSF) treatments for SAH yielded promising results. Objectives: To determine how currently available treatments affect the survival and complications of patients with SAH. Methods: The study was conducted following the guidelines of PRISMA. The data from PubMed, Embase, MEDLINE, Cochrane Library, and clinicaltrials.gov to October 2022 were searched, and patients with SAH with pharmacotherapy were included in our study. The primary outcome was short-term survival, and the other outcomes were medium- (3/6 months) or long-term (12 months) survival and complications after treatment. R software was used to establish network meta-analysis models and the result was expressed by the odd ratio (OR) value and 95% credible interval (Crls). Results: A total of 31 randomized controlled trials, including 19 treatment regimens, were enrolled in our study. As the primary outcome, G-CSF+ pentoxifylline (PTX) ranked first in one-month survival and showed significant superiority when compared with the placebo (OR 8.60, 95% Crls 1.92–45.10) and CS (OR 4.95, 95% Crls 1.11–25.53). Also, G-CSF+PTX ranked first in improving three-month survival and reducing the occurrence of infection. PTX+MTD ranked first in six-month survival, and G-CSF ranked first in twelve-month survival. CS+MTD ranked first in the occurrence of gastrointestinal bleeding and hepatorenal syndrome. Conclusions: The combination of G-CSF and PTX showed a significant benefit in improving the short-term survival of SAH patients.

Efficacy of Granulocyte Colony-Stimulating Factor in Acute on Chronic Liver Failure: A Systematic Review and Survival Meta-Analysis.

Acute-on-chronic liver failure (ACLF) mostly occurs when there is an acute insult to the liver in patients with pre-existing liver disease, and it is characterized by a high mortality rate. Various therapeutic approaches have been used thus far, with orthotopic liver transplantation being the only definitive cure. Clinical trials and meta-analyses have investigated the use of granulocyte colony-stimulating factor (G-CSF) to mobilize bone marrow-derived stem cells. Some studies have suggested that G-CSF may have a significant role in the management and survival of patients with ACLF. However, the results are conflicting, and the efficacy of G-CSF still needs to be confirmed. The aim was to assess the efficacy of G-CSF in patients with ACLF. Electronic databases were searched until May 2023 for randomized controlled trials investigating the use of G-CSF in adult patients with ACLF. Outcome measures were the effects of G-CSF on overall survival, changes in liver disease severity scores, complications of cirrhosis, other G-CSF-related adverse effects, and all-cause mortality. The study's protocol has been registered with Prospero (CRD42023420273). Five double-blind randomized controlled trials involving a total of 421 participants met the inclusion criteria. The use of G-CSF demonstrated a significant effect on overall survival (HR 0.63, 95% CI 0.41 to 0.95, and I2 48%), leading to a decreased mortality (LogOR-0.97, 95% CI -1.57 to -0.37, and I2 37.6%) and improved Model for End-Stage Liver Disease (MELD) scores (SMD -0.87, 95% CI -1.62 to -0.13, and I2 87.3%). There was no correlation between the improvement of the Child-Pugh score and the use of G-CSF(SMD -2.47, 95% CI -5.78 to 0.83, and I2 98.1%). The incidence of complications of cirrhosis did not decrease significantly with G-CSF treatment (rate ratio 0.51, 95% CI 0.26 to 1.01, and I2 90%). A qualitative synthesis showed that the use of G-CSF is safe. The administration of G-CSF has demonstrated a positive impact on overall survival, liver function, and the MELD score. The presence of heterogeneity in the included studies prohibits conclusive recommendations.

Assessment of the diagnosis, treatment, and follow-up of a group of Turkish pediatric glycogen storage disease type 1b patients with varying clinical presentations and a novel mutation.

Glycogen storage disease (GSD) type 1b is a multisystemic disease in which immune and infectious complications are present, different from GSD type 1a. Treatment with granulocyte-colony stimulating factor (G-CSF) is often required in the management of neutropenia and inflammatory bowel disease. Recently, an alternative treatment option to G-CSF has been preferred, like empagliflozin. To report on the demographics, genotype, clinical presentation, management, and complications of pediatric patients with glycogen storage disease type 1b (GSD 1b). A retrospective analysis of the clinical course of eight patients with GSD type 1b whose diagnosis was confirmed by molecular testing. The mean age at referral was four months. The diagnosis of GSD 1b was based on clinical and laboratory findings and supported by genetic studies. One patient presented with an atypical clinical finding in the form of hydrocephalus at the time of first admission. The first symptom was abscess formation on the scalp due to neutropenia in another patient. Other patients had hypoglycemia at the time of admission. All patients presented suffered from neutropenia, which was managed with G-CSF, except one. Hospitalizations for infections were frequent. One patient developed chronic diarrhea and severe infections, which have been brought under control with empagliflozin. Neutropenia is an essential finding in GSD 1b and responsible for complications. The coexistence of hypoglycemia and neutropenia should bring to mind GSD 1b. Empagliflozin can be a treatment option for neutropenia, which is resistant to G-CSF treatment.

Successful Steroid Treatment of Pembrolizumab-induced Agranulocytosis That Developed after Splenectomy in a Patient with Non-small-cell Lung Cancer.

Neutropenia, a rare immune-related adverse event, affects patients receiving treatment with immune checkpoint inhibitors (ICIs). We herein report a case of pembrolizumab-induced agranulocytosis. An 83-year-old man was diagnosed with advanced-stage lung carcinoma concomitant with splenomegaly complicated by hypersplenism, causing pancytopenia. To avoid the risk of bone marrow suppression due to cytotoxic chemotherapy, pembrolizumab monotherapy was chosen. However, the patient developed agranulocytosis despite the resolution of pancytopenia through splenectomy performed after the fourth pembrolizumab cycle. Neutrophil counts improved after steroid treatment but not after granulocyte colony-stimulating factor treatment. This case demonstrated that neutropenia can sometimes develop abruptly after several ICI therapy cycles.

Application of G-CSF in high-leukocyte acute myeloid leukemia is a poor prognostic factor

ABSTRACTObjectiveTo analyze the effect of granulocyte colony-stimulating factor (G-CSF) on outcomes in patients with acute myeloid leukemia (AML).MethodsA total of 526 patients with AML in the Haematology Department were enrolled. They were divided into a G-CSF treatment group and a no G-CSF group according to whether G-CSF was administered in the induction chemotherapy period, with 355 cases in the G-CSF group and 171 cases in the no G-CSF group. Cox regression analysis and Kaplan-Meier curve analysis were used to analyze the effect of G-CSF on the first complete remission (CR1) phase and overall survival (OS). In addition, further analysis was performed based on an initial white blood cell count of 50 * 10^9/L.ResultsThe application of G-CSF significantly shortened the CR1 phase and OS in patients with high leukocytes.ConclusionsG/GM-CSF should be used with caution in patients with AML, especially those with high leukocytes.

Treatment-Induced Bone Marrow Enhancement at MRI in Breast Cancer Patients Receiving Granulocyte-Colony Stimulating Factor Adjunct to Chemotherapy

Granulocyte-colony stimulating factor (G-CSF) induces the reconversion of fatty bone marrow to hematopoietic bone marrow. The bone marrow changes are detectable as signal intensity changes at MRI. The aim of this study was to evaluate sternal bone marrow enhancement following G-CSF and chemotherapy treatment in women with breast cancer. This retrospective study included breast cancer patients who received neoadjuvant chemotherapy with adjunct G-CSF. The signal intensity of sternal bone marrow at MRI on T1-weighted contrast-enhanced subtracted images was measured before treatment, at the end of treatment, and at 1-year follow-up. The bone marrow signal intensity (BM SI) index was calculated by dividing the signal intensity of sternal marrow by the signal intensity of the chest wall muscle. Data were collected between 2012 and 2017, with follow-up until August 2022. Mean BM SI indices were compared before and after treatment, and at 1-year follow-up. Differences in bone marrow enhancement between time points were analyzed using a one-way repeated measures ANOVA. A total of 109 breast cancer patients (mean age 46.1±10.4 years) were included in our study. None of the women had distal metastases at presentation. A repeated-measures ANOVA determined that mean BM SI index scores differed significantly across the three time points(F[1.62, 100.67]=44.57, p<.001). At post hoc pairwise comparison using the Bonferroni correction BM SI index significantly increased between initial assessment and following treatment (2.15 vs 3.33, p<.001), and significantly decreased at 1-yearfollow-up (3.33 vs 1.45, p<.001). In a subgroup analysis, while women younger than 50 years had a significant increase in marrow enhancement after G-CSF treatment, in women aged 50 years and older, the difference was not statistically significant. Treatment with G-CSF as an adjunct to chemotherapy can result in increased sternal bone marrow enhancement due to marrow reconversion. Radiologists should be aware of this effect in order to avoid misinterpretation as false marrow metastases.

Provider barriers in uptake of biosimilars: case study on filgrastim.

In this article, we used administrative claims data from the OptumLabs Data Warehouse and American Hospital Association Annual Survey data to examine associations between hospital characteristics and uptake of biosimilar granulocyte colony-stimulating factor treatments. We found that 340B-participating hospitals and non-rural referral center (RRC) hospitals that reported owning rural health clinics were less likely to administer the lower-cost biosimilars, whereas the opposite was true for hospitals that are RRCs. To our knowledge, our study offers a first look at an underappreciated source of disparities in access to lower-cost medications such as biosimilars. Results from our study reveal opportunities for targeted policies to encourage adoption of lower-cost treatments, particularly among hospitals that serve rural communities where patients often have fewer choices in care site.