Granulocyte Colony-stimulating Factor Group 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.

Comparison between a single dose of PEG G-CSF and multiple doses of non-PEG G-CSF: a systematic review and meta-analysis from Clinical Practice Guidelines for the use of G-CSF 2022.

Granulocyte colony-stimulating factor (G-CSF) is widely used for the primary prophylaxis of febrile neutropenia (FN). Two types of G-CSF are available in Japan, namely G-CSF chemically bound to polyethylene glycol (PEG G-CSF), which provides long-lasting effects with a single dose, and non-polyethylene glycol-bound G-CSF (non-PEG G-CSF), which must be sequentially administrated for several days. This current study investigated the utility of these treatments for the primary prophylaxis of FN through a systematic review of the literature. A detailed literature search for related studies was performed using PubMed, Ichushi-Web, and the Cochrane Library. Data were independently extracted and assessed by two reviewers. A qualitative analysis or meta-analysis was conducted to evaluate six outcomes. Through the first and second screenings, 23 and 18 articles were extracted for qualitative synthesis and meta-analysis, respectively. The incidence of FN was significantly lower in the PEG G-CSF group than in the non-PEG G-CSF group with a strong quality/certainty of evidence. The differences in other outcomes, such as overall survival, infection-related mortality, the duration of neutropenia (less than 500/μL), quality of life, and pain, were not apparent. A single dose of PEG G-CSF is strongly recommended over multiple-dose non-PEG G-CSF therapy for the primary prophylaxis of FN.

Associations of granulocyte colony-stimulating factor with toxicities and efficacy of chimeric antigen receptor T-cell therapy in relapsed or refractory B-cell acute lymphoblastic leukemia

Few studies have reported the associations of granulocyte colony-stimulating factor (G-CSF) with cytokine release syndrome (CRS), neurotoxic events (NEs) and efficacy after chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). We present a retrospective study of 67 patients with R/R B-ALL who received anti-CD19 CAR T-cell therapy, 41 (61.2%) patients received G-CSF (G-CSF group), while 26 (38.8%) did not (non-G-CSF group). Patients had similar duration of grade 3–4 neutropenia between the two groups. The incidences of CRS and NEs were higher in G-CSF group, while no differences in severity were found. Further stratified analysis showed that the incidence and severity of CRS were not associated with G-CSF administration in patients with low bone marrow (BM) tumor burden. None of the patients with low BM tumor burden developed NEs. However, there was a significant increase in the incidence of CRS after G-CSF administration in patients with high BM tumor burden. The duration of CRS in patients who used G-CSF was longer. There were no significant differences in response rates at 1 and 3 months after CAR T-cell infusion, as well as overall survival (OS) between the two groups. In conclusion, our results showed that G-CSF administration was not associated with the incidence or severity of CRS in patients with low BM tumor burden, but the incidence of CRS was higher after G-CSF administration in patients with high BM tumor burden. The duration of CRS was prolonged in G-CSF group. G-CSF administration was not associated with the efficacy of CAR T-cell therapy.

Clinical Analysis of PEG-rhG-CSF in Mobilization of Autologous Hematopoietic Stem Cells in Hematological Tumors

To investigate the efficiency and optimal time of stem cell apheresis mobilized by pegylated recombinant human granulocyte colony stimulating factor (PEG-rhG-CSF) in autologous stem cell transplantation (ASCT) for hematological malignancies without monitoring pre-collection CD34+ cells. Forty-six patients underwent stem cell mobilization were retrospectively analyzed between August 2017 and January 2022 at the First Affiliated Hospital of Fujian Medical University. 27 patients using high dose chemotherapy combined with PEG-rhG-CSF mobilization were enrolled in the PEG-rhG-CSF group, and other 19 patients mobilized with recombinant human granulocyte colony stimulating factor (G-CSF) were enrolled in G-CSF group. The mobilization and collection effects of the patients in two groups were compared. A total of 46 patients underwent 86 apheresis procedures, the median amount of mononuclear cell (MNC) in the PEG-rhG-CSF group and G-CSF group was 6.54（3.85-12.61）×108/kg and 6.15（1.13-11.58）×108/kg, respectively (P >0.05), the total CD34+ cells of the grafts were 11.44(1.33-65.02)×106/kg and 4.95(0.30-24.02)×106/kg (P < 0.05), with harvest timing of 14(10-20) days and 14(4-22) days, respectively (P >0.05). In the PEG-rhG-CSF group, there was a significant difference between the number of CD34+ cells collected when white blood cells (WBC) ≥10×109/L and WBC<10×109 /L, 19.04(2.85-65.02)×106/kg and 6.22(0.81-34.86)×106/kg, respectively (P < 0.05). Stem cells mobilization with PEG-rhG-CSF was highly efficient with a median mobilization time of 14 days. In the absence of peripheral blood CD34 monitoring, peripheral blood WBC≥10×109/L can be considered as a threshold for a single stem cell apheresis to collect sufficient stem cells.

The efficacy and safety of granulocyte colony-stimulating factor in the treatment of acute-on-chronic liver failure: A systematic review and meta-analysis.

The safety and efficacy of granulocyte-colony stimulating factor (G-CSF) for the treatment of acute-on-chronic liver failure (ACLF) remain controversial. This meta-analysis aimed to evaluate the effectiveness and safety of G-CSF in treating ACLF. The estimated pooled risk ratio (RR) and 95% confidence interval (CI) assessed the treatment effects of G-CSF. Mean differences (MD) and 95% confidence intervals were used to analyze continuous data. Heterogeneity was explored by sensitivity analysis. Potential publication bias was assessed using Egger's test. Ten studies, comprising a total of 603 participants, were included in the analysis. The G-CSF group showed significantly lower MELD scores at 7-day (MD = -2.39, 95%CI: -3.95 to -0.82), CTP scores at 7-day (MD = -0.77, 95%CI: -1.41 to -0.14), and MELD scores at 30-day (MD = -3.01, 95%CI: -5.36 to -0.67) compared to the control group. Furthermore, the G-CSF group was associated with a reduced risk of sepsis (RR = 0.53, 95%CI: 0.35-0.80). The 30-day survival (RR = 1.26, 95%CI:1.10-1.43), 60-day survival (RR = 1.47, 95%CI:1.17-1.84, and 90-day survival (RR = 1.73, 95%CI: 1.27-2.35) of patients with ACLF treated with G-CSF were significantly higher than those of the control group. Our meta-analysis suggests that G-CSF therapy may be a promising treatment for ACLF, with significant improvements in liver function and survival rates, however, further studies are needed to verify this conclusion.

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.

On-Demand Plerixafor Added to High-Dose Cyclophosphamide and Pegylated Recombinant Human Granulocyte Colony-Stimulating Factorin the Mobilization of Patients with Multiple Myeloma: High Effectiveness and Affordable Cost

Background Autologous stem cell transplantation(ASCT) still represents an integral part of treatment for patients with eligible newly diagnosed multiple myeloma. It is important to collect enough stem cells for two transplants in the first mobilization.The combination of high-dose cyclophosphamide(Cy) (3g/m 2) plus granulocyte colony-stimulating factor(G-CSF)and on-demand plerixafor has been considered the effective method as mobilization regimen, but G-CSF requires daily, multi-injection administration. Here, we performed a real-world analysis to evaluate the efficacy and cost of high-dose Cy combination pegylated recombinant human granulocyte colony-stimulating factor（PEG-rhG-CSF）and on-demand plerixafor for the first time, allowing for a single injection given the long half-life and slow elimination of PEG-rhG-CSF. Methods We retrospectively compared 343 patients whith MM mobilized between August 2008 and December 2022 using the following mobilization strategies: Cy+PEG-rhG-CSF+/-plerixafor(n=61), Cy+PEG-rhG-CSF(n=89),Cy+ G-CSF( n=169), G-CSF+plerixafor(n=24). Then the stem cell mobilization and collection results of the four groups were compared. Results Mobilization with Cy+PEG-rhG-CSF+/-plerixafor resulted in a significantly higher total CD34+ cells ( ×10 6/kg )collected( 8.81) compared to patients mobilized with other mobilization regimens：Cy+PEG-rhG-CSF(5.47；p＜0.001),Cy+ G-CSF(4.65; p＜0.001), G-CSF+plerixafor( 2.99; p＜0.001). Day1+Day 2 CD34+ cells ( ×10 6/kg ) collected were higher in Cy+PEG-rhG-CSF+/-plerixafor group too (Cy+PEG-rhG-CSF+/-plerixafor, 7.87 vs. Cy+PEG-rhG-CSF, 4.96 vs. Cy+ G-CSF,3.92 vs. G-CSF+plerixafor, 2.43) (p＜0.001).The percentage of patients who achieved＞6×10 6/kg CD34+ cells were significantly higher in Cy+PEG-rhG-CSF+/-plerixafor group group (77.0%) than other mobilization regimens：Cy+PEG-rhG-CSF (42.7% ；p＜0.001),Cy+ G-CSF( 37.3% ;p＜0.001）, G-CSF+plerixafor( 8 % ;p＜0.001). Apheresis sessions were fewer in Cy+PEG-rhG-CSF+/-plerixafor group ( Cy+PEG-rhG-CSF+/-plerixafor, 2 vs. Cy+PEG-rhG-CSF,3 vs. Cy+ G-CSF ,3 vs. G-CSF+plerixafor,4)(p＜0.001). Patients proceeded to ASCT with a mean of 2.94 CD34+cell (×10 6/kg ) infused for PEG-rhG-CSF+/-plerixafor , 2.94 infused for Cy+PEG-rhG-CSF, 2.61infused for G-CSF+plerixafor, 3.17 infused for Cy+ G-CSF (p=0.057) . The median time to neutrophil and platelet engraftment not different in the four groups. The total cost of mobilization and apheresis using Cy+PEG-rhG-CSF+/-plerixafor was significant lower ($5670.64) compared to G-CSF+plerixafor group($11098.61), and significant higher than Cy+PEG-rhG-CSF group ($3842.23)and Cy+ G-CSF group($3727.82)（p＜0.001）. Multivariate analysis showed that patients who received Cy+PEG-rhG-CSF +/-plerixafor treatment had significantly higher likelihoods of successfully achieving the optimal harvest (6×10 6/kg) in respect to Cy+PEG-rhG-CSF group mobilized without any plerixafor. The incremental cost-effectiveness ratio, for each 1% increase in probability of achieving a successful optimal harvest, was $62.57 per patient. The incidence of neutropenic fever not different in the Cy+PEG-rhG-CSF+/-plerixafor group(4%), Cy+PEG-rhG-CSF group (10%) and Cy+ G-CSF group(18%)(p=0.051). There was no patients suffered with neutropenic fever in G-CSF+plerixafor group. Conclusion Given higher rates of successful mobilization, affordable cost and toxicity, on-demand plerixafor added to high-dose Cy and PEG-rhG-CSF may be preferable in the mobilization of patients with multiple myeloma.

Comparison of different plerixafor-based strategies for adequate hematopoietic stem cell collection in poor mobilizers

Objectives: The main objective of the present study was to evaluate whether the use of plerixafor in combination with granulocyte colony-stimulating factor (G-CSF) or subsequent use of isolated G-CSF and then plerixafor following disease-specific chemotherapy, and whether it would allow for adequate peripheral stem cell collection in patients. Methods: The retrospective study evaluated 54 patients with previous mobilization failure who were administered plerixafor in 2 centers. In patients without any side effects, CD 34+ cell counts, the percentage of patients who were found eligible for autologous transplantation, the engraftment kinetics of the patients who underwent transplantation, and their overall survival results were compared between the two groups where G-CSF was used with plerixafor, or where plerixafor was used after isolated G-CSF following chemotherapy. Results: The median age of the patients was 49 years (range: 17-70), and 64.8% (n = 35) were males. It was identified that 31 (57.4%) patients underwent mobilization treatment with isolated G-CSF and plerixafor, and 23 (42.6%) patients underwent mobilization treatment with chemotherapy plus G-CSF and plerixafor. In all patients, mean hemoglobin level (11.3 ± 1.5 g/dL vs. 9.3 ± 1.3 g/dL; p &amp;lt; 0.001) and median platelet level (129.2 ×103/µL vs. 58.4 ×103/µL) were found to be higher, while febrile neutropenia rate (3.3% vs. 60.9%), the percentage of replacement patients (6.7% vs. 65.2%), and median days of G-CSF (6 vs. 9) were found to be lower on the day of plerixafor administration in the isolated G-CSF and plerixafor group compared to the chemotherapy and G-CSF and plerixafor group. Conclusions: In conclusion, our study demonstrated that administration of plerixafor is generally safe and well-tolerated. Regardless of the underlying disease, it offers an effective alternative for patients with previous failed mobilization attempts using conventional regimens, and allows stem cell collection with fewer apheresis sessions.

Comparison of Plerixafor or Cyclophosphamide Combined with G-CSF in Mobilization of Peripheral Blood Stem Cells in Multiple Myeloma

To compare the efficacy of plerixafor (PXF) combined with granulocyte colony-stimulating factor (G-CSF) (PXF+G-CSF) and cyclophosphamide (Cy) combined with G-CSF (Cy+G-CSF) in the mobilization of peripheral blood stem cells (PBSCs) in patients with multiple myeloma (MM). The clinical data of 41 MM patients who underwent PBSC mobilization using PXF+G-CSF (18 cases) or Cy+G-CSF (23 cases) in Shanxi Bethune Hospital from January 2019 to December 2021 were retrospectively analyzed, including the count of collected CD34+ cells, acquisition success rate, failure rate, and optimal rate. The correlation of sex, age, disease type, DS staging, ISS staging, number of chemotherapy cycle, disease status before mobilization, and mobilization regimen with the collection results was analyzed, and the adverse reactions, length of hospital stay, and hospitalization costs were compared between the two mobilization regimens. The 41 patients underwent 97 mobilization collections, and the median number of CD34+ cells collected was 6.09 (0-34.07)×106/kg. The acquisition success rate, optimal rate, and failure rate was 90.2%, 56.1%, and 9.8%, respectively. Univariate analysis showed that sex, age, disease type, and disease stage had no significant correlation with the number of CD34+ cells collected and acquisition success rate (P >0.05), but the patients with better disease remission than partial remission before mobilization were more likely to obtain higher CD34+ cell count (P <0.05). The PXF+G-CSF group had a larger number of CD34+ cells and higher acquisition success rate in the first collection than Cy+G-CSF group (both P <0.05), and had lower infection risk and shorter length of hospital stay during mobilization (both P <0.05), but the economic burden increased (P <0.05). PXF+G-CSF used for PBSC mobilization in MM patients has high first acquisition success rate, large number of CD34+ cells, less number of collection times, and short length of hospital stay, but the economic cost is heavy.

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.

Early granulocyte colony stimulating factor administration increases the risk of cytokine release syndrome in acute lymphoblastic leukemia patients receiving anti-CD19 chimeric antigen receptor T-cell therapy.

Cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS) and neutropenia are common toxicities associated with chimeric antigen receptor T (CAR-T) cell therapy. The role of granulocyte colony stimulating factor (G-CSF) in CAR-T-cell-treated patients remains unclear. To explore the efficacy and safety of early G-CSF administration in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) who were receiving autologous anti-CD19 CAR-T cells, we retrospectively collected and summarized clinical data to compare patients receiving G-CSF within 14days (early G-CSF group) to patients receiving later or no G-CSF (control group) after their CART infusion. The results showed that there was no significant difference in the incidence and duration of neutropenia between the early G-CSF group and the control group (77% vs. 63%, p=0.65; 8 vs. 4days, p=0.37, respectively). However, the incidence and duration of CRS were significantly higher in the early G-CSF group than in the control group (81% vs. 38%, p=0.03; 3 vs. 0days, p=0.004, respectively). Moreover, early G-CSF application had no significant effect on the expansion and efficacy of CAR-T cells. In conclusion, our study suggested that early G-CSF administration did not reduce the incidence and duration of neutropenia but rather increased the incidence and duration of CRS.

Granulocyte colony-stimulating factor inhibits apoptosis of substantia nigra dopamine neurons in Parkinson’s disease mice model

Granulocyte colony-stimulating factor (G-CSF) can effectively improve body’s immunity. This study explored G-CSF’s role in dopaminergic neurons apoptosis in Parkinson’s disease mice model. In this study, Oxidopamine, also known as 6-hydroxydopamine (6-OHDA) drugs were used to establish mouse models, and 2,3,5-Triphenyltetrazolium chloride (TTC) measurement of brain nerve cell apoptosis and mouse motor function scores methods were used to analyze and clarify whether G-CSF’s role in inflammatory process is through regulating monocyte chemoattractant protein 1 (MCP-1) expression and T cell immune function. Meanwhile, neutrophil infiltration in apoptotic and surrounding areas was also assessed. Nerve cell apoptosis was significantly reduced After a single dose of G-CSF treatment in the model 24 h after successful modeling, compared with PBS control group (P &lt;0.05). The motor function of mice in the G-CSF treatment group was significantly improved (P &lt;0.05) on days 7 and 14. Moreover, the expressions of MCP-1, IL-10, TNF-α, and TGF-β were significantly decreased through therapeutic intervention, and inflammation was controlled (P &lt; 0.05). The number of CD11b infiltration in the apoptotic area in the G-CSF group did not increase, suggesting that intervention did not reduce apoptosis of nerve cells. Bcl-2 expression in the treatment group was significantly higher than in the control group, and Bax expression was lower (P &lt;0.05). In addition, the number of dopamine BrdU+ cells in the substantia nigra was significantly increased (P &lt;0.05). G-CSF can thus promote bone marrow hematopoiesis, thereby stimulating endogenous nerve cell proliferation, resisting nerve damage in Parkinson’s mice, and promoting neuron regeneration to help preserve neuronal function in mice and improve prognosis.

Granulocyte-colony stimulating factor does not prevent in vitro cisplatin-induced germ cell reduction in immature human and mouse testis

BackgroundCurrently there are no established fertility preservation options for pre-pubertal boys facing cancer treatment. Granulocyte-colony stimulating factor (G-CSF) treatment has been proposed to be chemoprotective against spermatogonial cell loss in an alkylating chemotherapy model of busulfan treated adult mice. Having previously shown that exposure to the alkylating-like chemotherapy cisplatin resulted in a reduction in germ cell numbers in immature human testicular tissues, we here investigate whether G-CSF would prevent cisplatin-induced germ cell loss in immature human and mouse (fetal and pre-pubertal) testicular tissues.MethodsOrganotypic in vitro culture systems were utilised to determine the effects of clinically-relevant concentrations of G-CSF in cisplatin-exposed immature testicular tissues. Human fetal (n = 14 fetuses) and mouse pre-pubertal (n = 4 litters) testicular tissue pieces were cultured and exposed to cisplatin or vehicle control for 24 hrs and analysed at 72 and 240 hrs post-exposure. Combined G-CSF and cisplatin exposure groups explored varying concentrations and duration of G-CSF supplementation to the culture medium (including groups receiving G-CSF before, during and after cisplatin exposure). In addition, effects of G-CSF supplementation alone were investigated. Survival of total germ cell and sub-populations were identified by expression of AP2γ and MAGE-A4 for human gonocytes and (pre)spermatogonia, respectively, and MVH and PLZF, for mouse germ cells and putative spermatogonial stem cells (SSCs) respectively, were quantified.ResultsExposure to cisplatin resulted in a reduced germ cell number in human fetal and mouse pre-pubertal testicular tissues at 240 hrs post-exposure. Germ cell number was not preserved by combined exposure with G-CSF using any of the exposure regimens (prior to, during or after cisplatin exposure). Continuous supplementation with G-CSF alone for 14 days did not change the germ cell composition in either human or mouse immature testicular tissues.ConclusionsThis study demonstrates that exposure to G-CSF does not prevent cisplatin-induced germ cell loss in immature human and mouse testicular tissues in an in vitro system.

Associations of granulocyte colony-stimulating factor with toxicities and efficacy of chimeric antigen receptor T-cell therapy in relapsed or refractory multiple myeloma

Background aimsFew studies have reported the associations of granulocyte colony-stimulating factor (G-CSF) with cytokine release syndrome (CRS), neurotoxic events (NEs) and efficacy after chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory (R/R) multiple myeloma (MM). We present a retrospective study performed on 113 patients with R/R MM who received single anti-BCMA CAR T-cell, combined with anti-CD19 CAR T-cell or anti-CD138 CAR T-cell therapy. MethodsEight patients were given G-CSF after successful management of CRS, and no CRS re-occurred thereafter. Of the remaining 105 patients that were finally analyzed, 72 (68.6%) received G-CSF (G-CSF group), and 33 (31.4%) did not (non G-CSF group). We mainly analyzed the incidence and severity of CRS or NEs in two groups of patients, as well as the associations of G-CSF timing, cumulative dose and cumulative time with CRS, NEs and efficacy of CAR T-cell therapy. ResultsBoth groups of patients had similar duration of grade 3–4 neutropenia, and the incidence and severity of CRS or NEs.There were also no differences in the incidence and severity of CRS or NEs between patients with the timing of G-CSF administration ≤3 days and those >3 days after CAR T-cell infusion. The incidence of CRS was greater in patients receiving cumulative doses of G-CSF >1500 μg or cumulative time of G-CSF administration >5 days. Among patients with CRS, there was no difference in the severity of CRS between patients who used G-CSF and those who did not. The duration of CRS in anti-BCMA and anti-CD19 CAR T-cell–treated patients was prolonged after G-CSF administration. There were no significant differences in the overall response rate at 1 and 3 months between the G-CSF group and the non–G-CSF group. ConclusionsOur results showed that low-dose or short-time use of G-CSF was not associated with the incidence or severity of CRS or NEs, and G-CSF administration did not influence the antitumor activity of CAR T-cell therapy.

A retrospective review of primary prophylaxis with granulocyte-colony stimulating factor (G-CSF) for patients with genitourinary malignancies receiving chemotherapy during the COVID-19 pandemic and implications for the future.

115 Background: To mitigate the risks of chemotherapy associated neutropenia, during the COVID-19 pandemic, all genitourinary (GU) cancer patients treated with chemotherapy at the Princess Margaret Cancer Centre (PMCC) were offered primary prophylaxis with GCSF. We hypothesize that this reduced rates of febrile neutropenia, hospitalizations, healthcare costs and improved overall outcomes, compared to GU cancer patients treated with chemotherapy without GCSF in the 2 years prior to the pandemic. Methods: We performed a retrospective review of GU cancer patients, receiving curative or palliative intent chemotherapy, with or without primary GCSF prophylaxis between January 2018 and June 2022. GCSF was given either as a single dose or as consecutive doses post chemotherapy. Main outcomes were incidence of febrile neutropenia, hospitalization, health care expenditures as well as disease specific outcomes. Results: Overall, 248 patients with prostate cancer (44%), urothelial cancers (33%) germ cell (21%), and rare GU cancers (4%) were identified. Median age was 70 (range 19-91), 92% were male, 65% were ECOG 0/1. Treatment intent was neoadjuvant (13%), adjuvant (20%), or palliative (67%). Main regimens used were docetaxel, cabazitaxel, carboplatin, cisplatin/etoposide, gemcitabine/cisplatin and BEP. Median follow-up was 10.5 months (0.23-52.3 months). A total of 206/248 received primary GCSF prophylaxis. During chemotherapy, the median white blood cell levels were higher in the GCSF group compared to the non-GCSF group (14.1*10*9/L vs 2.90*10*9/L, p&lt;0.0001); and neutropenia rates were markedly lower (2% vs. 93%, P=&lt;0.0001). Hospital admission rates were significantly lower in G-CSF users compared to non-users (19% vs. 69%, P&lt;0.0001). Symptomatic disease progression 13% was the leading cause of admission in the G-CSF group. Infectious causes such as UTI, pneumonia, COVID-19, and sepsis were seen in only 12% of the G-CSF group compared to 31% in the non-users. G-CSF was generally well tolerated with just 0.97% discontinuing G-CSF. Conclusions: During the COVID-19 pandemic, primary prophylactic G-CSF use in GU cancer patients, undergoing chemotherapy significantly lowered rates of both febrile neutropenia and hospitalizations and could be a cost-effective strategy in this patient population that warrants further study.

The effect of granulocyte-colony stimulating factor, decitabine, and busulfan–cyclophosphamide versus busulfan–cyclophosphamide conditioning on relapse in patients with myelodysplastic syndrome or secondary acute myeloid leukaemia evolving from myelodysplastic syndrome undergoing allogeneic haematopoietic stem-cell transplantation: an open-label, multicentre, randomised, phase 3 trial

Relapse remains high in patients with myelodysplastic syndrome-refractory anaemia with excess blasts (RAEB) or secondary acute myeloid leukaemia evolving from myelodysplastic syndrome undergoing allogeneic haematopoietic stem-cell transplantation (HSCT). We aimed to investigate whether granulocyte-colony stimulating factor (G-CSF) and decitabine plus busulfan-cyclophosphamide conditioning reduced relapse compared with busulfan-cyclophosphamide in this population. We did an open-label, randomised, phase 3 trial at six hospitals in China. Eligible patients (aged 14-65 years) had myelodysplastic syndrome-RAEB or secondary acute myeloid leukaemia evolving from myelodysplastic syndrome, and an Eastern Cooperative Oncology Group performance status of 0-2 and HSCT comorbidity index of 0-2. Patients were randomly assigned (1:1) to receive G-CSF, decitabine, and busulfan-cyclophosphamide conditioning or busulfan-cyclophosphamide conditioning. Randomisation was done with permuted blocks (block size four) with no stratification and was implemented through an interactive web-based response system, which was independent of study site staff and investigators. G-CSF, decitabine, and busulfan-cyclophosphamide conditioning comprised G-CSF 5 μg/kg daily subcutaneously (days -17 to -10), decitabine 20 mg/m2 daily intravenously (days -14 to -10), busulfan 3·2 mg/kg daily intravenously (days -7 to -4), and cyclophosphamide 60 mg/kg daily intravenously (days -3 and -2). Busulfan-cyclophosphamide conditioning comprised the same dose and duration of busulfan and cyclophosphamide. The primary endpoint was 2 year cumulative incidence of relapse. All efficacy and safety endpoints were assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02744742; the trial is complete. Between April 18, 2016, and Sept 30, 2019, 297 patients were screened for eligibility, 202 of whom were randomly assigned to G-CSF, decitabine, and busulfan-cyclophosphamide (n=101) or busulfan-cyclophosphamide (n=101) conditioning. 123 (61%) participants were male and 79 (31%) were female. Median follow-up was 32·4 months (IQR 10·0-43·0). The 2-year cumulative incidence of relapse was 10·9% (95% CI 5·8-17·9) in the G-CSF, decitabine, and busulfan-cyclophosphamide group and 24·8% (16·8-33·5) in the busulfan-cyclophosphamide group (hazard ratio 0·39 [95% CI 0·19-0·79]; p=0·011). Within 100 days after transplantation, the most common grade 3-4 adverse events in the G-CSF, decitabine, and busulfan-cyclophosphamide group and the busulfan-cyclophosphamide group were infections (34 [34%] and 32 [32%]), acute graft-versus-host disease (30 [30%] and 30 [30%]), and gastrointestinal toxicity (28 [28%] and 29 [29%]). 11 (11%) patients in the G-CSF, decitabine, and busulfan-cyclophosphamide group and 13 (13%) in the busulfan-cyclophosphamide group died of adverse events. There were no treatment related deaths. Our results suggest that G-CSF, decitabine, and busulfan-cyclophosphamide conditioning is a better choice than busulfan-cyclophosphamide conditioning for patients with myelodysplastic syndrome-RAEB or secondary acute myeloid leukaemia evolving from myelodysplastic syndrome undergoing allogeneic HSCT. This conditioning could be a suitable therapuetic option for this patient population. None. For the Chinese translation of the abstract see Supplementary Materials section.

G‑CSF delays tooth extraction socket bone healing via the inhibition of bone turnover in mice.

Granulocyte colony-stimulating factor (G-CSF) regulates the survival, proliferation and differentiation of all cells in the neutrophil lineage, and is consequently used for neutropenic conditions. Upon G-CSF administration, osteoblasts and osteocytes are suppressed, and the support system allowing hematopoietic stem cells to remain in the microenvironment is diminished. The present study focused on and investigated G-CSF as a regulatory factor of bone remodeling. The aim of the present study was to investigate the effect of G-CSF administration on the bone healing of tooth extraction sockets. Significant differences in the bone volume fraction, and trabecular separation of the proximal femurs and alveolar septa were observed between the G-CSF and control (saline-treated) groups. The trabecular bone of the femur and alveolar septa was reduced in the G-CSF group compared with that in the control group. In addition, serum procollagen type 1 N-terminal propeptide levels, a marker of bone formation, were lower in the G-CSF group compared with in the control group. Fibrous connective tissues and immature bone were observed in the extraction socket, and bone healing was delayed in the G-CSF group compared with that in the control group. The bone area in the extraction socket 6 days after tooth extraction was significantly smaller in the G-CSF group (23.6%) than that in the control group (45.1%). Furthermore, G-CSF administration reduced the number of canaliculi per osteocyte and inhibited the connection of osteocyte networks. Consequently, osteoblast activation was inhibited and bone remodeling changed to a state of low bone turnover in the G-CSG group. Analysis of bone formation parameters revealed that the G-CSF group exhibited a lower mineral apposition rate compared with in the control group. In conclusion, these findings indicated that G-CSF may delay bone healing of the socket after tooth extraction.

Comparison of Adjunctive Use of G-CSF Vs Autologous PRP in IVF Patients with a Refractory Thin Endometrium: A Retrospective Record Review

Background: In Vitro Fertilization (IVF) is an important treatment option in the management of couples with infertility. Sadly, however, failure to achieve a pregnancy through IVF is not uncommon. Amongst the many causes of IVF failure, implantation failure has emerged as one of the more common and important factors. The refractory thin endometrium as a cause of recurrent IVF failure has been well documented. The use of either Granulocyte Colony Stimulating Factor (G-CSF) or autologous Platelet Rich Plasma (PRP) has emerged as potential adjunctive treatments that may mitigate the rate of implantation failure; however, no conclusive evidence exists to favour the use of one over the other. Objective: To compare the measured change in endometrial thickness and pregnancy rates in patients with Recurrent implantation Failure (RIF) and/or thin endometrium following the intrauterine administration of either G-CSF or autologous PRP. In addition, to compare the pregnancy rates in patients with fluid in the endometrial cavity who underwent either therapy. Design: A retrospective analysis was conducted on patients who underwent endometrial therapy (either G-CSF or PRP) between January and June 2020. The measured change in endometrial thickness and the clinical pregnancy outcome of the two groups were compared. Subjects: 36 patients with a mean age of 40.36 years met the inclusion criteria of the study. 20 received autologous intrauterine PRP treatment and 16 received intrauterine G-CSF treatment. Both groups were well matched for age, pre-intervention endometrial thickness and embryo quality. Intervention: Administration of G-CSF (One ampoule Neupogen® (filgrastim)) or PRP (1ml) into the uterine cavity transcervical 48 hours prior to embryo transfer. Main Outcome Measures: The change in endometrial thickness measured 48 hours prior to embryo transfer and at the time of embryo transfer (ET) was compared. Positive clinical pregnancy outcome was determined by a positive serum B-HCG test 10 days post insertion. A statistically significant difference was set at p=0.05. Results: There was a statistically significant difference in endometrial expansion post intervention in both the G-CSF and PRP groups. However, the difference between the two groups did not reach statistical significance (p=0.077). Additionally, the collective pregnancy rate of the total study population was 44.4% (16 of 36), a significant increase over the expected pregnancy rate in the published literature [1,2]. Of the positive pregnancies, 9 (56.25%) were in the autologous PRP group and 7 (43.75%) in the G-CSF group. This difference was, however, determined not to be statistically significant (p=0.603). Conclusion: Both G-CSF and PRP are effective interventions in the management of the thin refractory endometrium. Both result in significant endometrial expansion and increased pregnancy rates. Despite a marginally higher endometrial response and pregnancy rate in the PRP group, the differences in these metrics between the two groups were not statistically significant.

The Effectiveness of Granulocyte Colony-Stimulating Factor (G-CSF) Against Experimental Ischemia-Reperfusion Injury in Rat Ovaries and Its Effect on In Vitro Fertilization Outcomes.

Local ischemic damage resulting from ovarian torsion is a common cause of decreased follicular activity and infertility. It was aimed to evaluate the effect of granulocyte colony-stimulating factor (G-CSF) protection on in vitro fertilization (IVF) results against experimental ischemic (I) and ischemic-reperfusion (I/R) injury in rat ovaries. The study consisted of 35 adult female Sprague-Dawley albino rats (sham, ischemia, I/R, I + G-CSF, and I/R + G-CSF) randomly assigned to 5 groups, each containing 7 rats. While bilateral adnexal torsion was applied to the ischemia groups for 3h, detorsion was applied to the reperfusion groups. Intraperitoneal 100IU/kg G-CSF was administered 30min prior to ischemia (I + G-CSF) or reperfusion (I/R + G-CSF). After ovulation induction (intraperitoneal 150-300IU/kg PMSG), the oocytes were collected and IVF was applied. Statistically significant differences were observed between the collected oocyte numbers in I and I + G-CSF, I/R, and I/R + G-CSF groups (P values were P = 0.001 for the I-I + G-SCF groups and P = 0.003 for I/R-IR + G-CSF, respectively). An increase in the number of MII oocytes obtained was observed in the I + G-CSF and I/R + G-CSF groups compared to the I and I/R groups. Grade 1 and grade 2 embryo numbers were statically different between the I/R and I/R + G-CSF groups (P values were P = 0.023 for grade 1 embryos and P = 0.045 for grade 2 embryos, respectively). G-CSF treatment was found to be effective in reducing I- and I/R-induced ovarian damage.

Is There any Role for Granulocyte Colony Stimulating Factor in Improvement of Implantation in Intrauterine Insemination? A Prospective Double-Blind Randomized Control Trial.

Granulocyte colony stimulating factor (GCSF) has been introduced as an immunomodulatory agent by increasing implantation rate in vitro fertilization (IVF) patients but it has not been studied in intrauterine insemination (IUI) patients. The aim of this study is to answer the role of GCSF in implantation rate of IUI. In this prospective double-blind randomized control trial, 320 eligible patients were enrolled, who were referred to the referral infertility clinic of Shiraz University of Medical Sciences from February 2018 till the end of 2019. They were divided into two groups randomly. After collecting the demographic data, all patients received clomiphene citrate from the 5th day of the menstruation cycle for 5 days. 50-150 units of recombinant purified follicle-stimulating factor (FSH) were started from the 8th day of the cycle. Follicle monitoring was done by transvaginal sonography till a mature follicle of 18 mm or more was developed. Human chorionic gonadotropin (HCG) injection was done in both groups with intrauterine administration of 300 μg GCSF in the case group and normal saline in the control group simultaneously. After 36 hours, IUI was performed. The clinical pregnancy, miscarriage, and ongoing pregnancy rates of both groups were calculated by SPSS software. The results showed improvement of clinical pregnancy rate [15.38% vs. 13.81% OR=1.17 (0.62-2.21)], miscarriage rate [3.84% vs. 5.26% OR=0.74 (0.25-2.20)] and ongoing pregnancy rate [11.53% vs. 8.55% OR=1.37 (0.65-2.92)] in the GCSF group compared to the control. However, the results revealed no statistically significance (P>0.05). Although it was not statistically significant, 300 μg Intrauterine GCSF administration simultaneously with hCG injection in standard IUI procedure might increase the pregnancy outcomes. Further studies are warranted (registration number: IRCT201212079281N2).