Recombinant Human Granulocyte Colony-stimulating Factor Research Articles

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

Role of recombinant human granulocyte colony-stimulating factor in development of cancer-associated venous thromboembolism in lung cancer patients who undergo chemotherapy.

The role of recombinant human granulocyte colony-stimulating factor (rhG-CSF), especially the long-acting factor in the development of cancer-associated venous thromboembolism (VTE) in lung cancer patients who undergo chemotherapy has been understudied, although the use of rhG-CSF has been reported to be associated with an increased risk of VTE. We retrospectively reviewed 1,673 lung cancer patients who underwent hospitalized chemotherapy. We performed propensity score matching to offset confounding factors related to cancer-associated VTE development and classified the patients into short-acting (N = 273), long-acting (N = 273), and no rhG-CSF (N = 273) groups. The primary outcome was cumulative cancer-associated VTE development three months after all cycles of chemotherapy. The overall VTE incidence in the short-acting, long-acting, and no rhG-CSF groups was 5.5%, 10.3%, and 2.2%, respectively (P <0.001). The VTE incidence in the long-acting rhG-CSF group was higher than that in the short-acting (P = 0.039) and no rhG-CSF groups (P <0.001). The VTE incidence in the short-acting rhG-CSF group was higher than that in the no rhG-CSF group (P = 0.045). The use of rhG-CSF (hazard ratio [HR] 2.337; 95% confidence interval [CI] [1.236-5.251], P = 0.006) was positively correlated with VTE development among all patients, whereas the use of long-acting rhG-CSF (HR 1.917, 95% CI [1.138-4.359]; P = 0.016), was positively correlated with VTE development in patients receiving rhG-CSF. The use of rhG-CSF, especially long-acting rhG-CSF, increases the risk of cancer-associated VTE development compared to no rhG-CSF use in lung cancer patients who undergo hospitalized chemotherapy.

Demonstration of physicochemical and functional similarity between Stimufend (pegfilgrastim-fpgk) and Neulasta (pegfilgrastim): A comparative analytical assessment.

Pegfilgrastim is a long-acting recombinant human granulocyte colony-stimulating factor biologic that is indicated to reduce the incidence of infections, manifested by febrile neutropenia, in patients receiving myelosuppressive anti-cancer drugs and to increase survival in patients acutely exposed to myelosuppressive doses of radiation. Due to the high cost of biologic therapy and the scarcity of biosimilar alternatives, there is an unmet medical need for targeted biologics. This comparative analytical investigation aimed to confirm the similarity of biosimilar Stimufend® (pegfilgrastim-fpgk) to reference product Neulasta® (pegfilgrastim). The analysis was designed using state-of-the-art orthogonal techniques and side-by-side testing to compare the physicochemical and biological properties of these two products. The measured quality attributes included the primary structure and higher order structure of the molecule, purity/impurity profiles, product variants, process-related impurities, composition, content, and biological activity. The statistical analysis was based on risk ranking of the critical quality attributes (very low, low, moderate, high, very high), and scientific considerations in combination with the characteristics of the assay (sensitivity, selectivity, and variability). In addition, non-quantitative parameters were compared using a descriptive assessment of the product profile. Analytical similarity was concluded by quality attributes falling within the defined range of the originator product. The results of this study confirm that Stimufend® is biosimilar to Neulasta® for all measured quality attributes. There are no clinically significant differences between Stimufend® and Neulasta®, which was confirmed by the marketing approval for Stimufend® by the Food and Drug Administration and the European Medicines Agency. The findings of this study provide robust evidence supporting the structural and functional biosimilarity between Stimufend® and Neulasta®.

Optimization of human recombinant granulocyte-colony stimulating factor supplementation during in vitro production of porcine embryos to improve the efficiency of resource utilization of poor-quality cumulus-oocyte complexes

Granulocyte colony-stimulating factor (G-CSF), a pleiotropic cytokine, is secreted by the reproductive tract. Furthermore, our previous study indicated that human recombinant G-CSF (hrG-CSF) supplementation during porcine oocyte in vitro maturation (IVM) or during embryo in vitro culture (IVC) improved their quality and development potential when using cumulus-oocyte complexes (COCs) with more than three cumulus cell layers (CCL >3). Thus, in this study, we investigate the optimal conditions of hrG-CSF supplementation throughout the in vitro production (IVP: IVM + IVC) system to improve the embryo production efficiency of “poor-quality (CCL ≤3)” oocytes. COCs were classified into two groups according to the number of CCL (>3 and ≤3) and embryonic viability was analyzed after treatment with hrG-CSF during IVC. The mRNA transcription levels of G-CSF in COCs were compared based on their type and the period of IVM. Finally, developmental capacity and quality were evaluated after treatment with hrG-CSF for different periods of IVP. No marked effects on the developmental potential of embryos when using CCL ≤3 type COCs were observed after supplementing hrG-CSF only during IVC. Moreover, the mRNA transcription level of G-CSF increased gradually with IVM culture time and was higher in CCL ≤3 COCs than in >3. Supplementing hrG-CSF only during the IVM period resulted in the best embryo developmental potential, while supplementing hrG-CSF during the IVP period resulted in the best quality embryos, reflected in the increased total cell number and decreased apoptotic nuclei index of blastocysts. These findings indicate that “poor-quality” COCs may have a greater demand for G-CSF than “good-quality”, meanwhile hrG-CSF supplementation throughout IVP improves resource utilization efficiency in poor-quality COCs.

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,...

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.

The Combination of Pegfilgrastim and Filgrastim Improves the Outcomes of Mobilization and Engraftment after Transplantation of Autologous Hematopoietic Stem Cells for the Treatment of Lymphoma

BACKGROUND : Hematopoietic stem cell transplantation (HSCT) is broadly utilized for the treatment of lymphoma. Autologous peripheral blood stem cell (PBSC) transplantation (ASCT) requires mobilization of hematopoietic stem cell/ hematopoietic progenitor cell (HSC/HPC) in peripheral blood (PB) to collect HSCs. The high mobilization failure rate with the mobilization strategy of combining chemotherapy and filgrastim (rhG-CSF, recombinant human granulocyte colony-stimulating factor) in ASCT is one of the unresolved issues. Whether the combination of polyethylene glycol filgrastim [pegfilgrastim (PEG-FIL), PEG-rhG-CSF] and filgrastim (FIL) improves the mobilization success rate and the timing of combination therapy has not been studied. METHODS: To test the hypothesis that the combination of pegfilgrastim and filgrastim schedule has superiority, we retrospectively investigated a cohort of 107 lymphoma patients who received auto-HSCT and collection in the First Hospital of Jilin University from Jan 1st 2015 to Dec 1st 2022. These patients were categorized into PEG+FIL group and FIL group. The group of PEG+FIL received pegfilgrastim (9 mg) on the third day of the chemotherapy, followed by filgrastim (10 μg/kg/day) based on the counts of peripheral blood stem cells (PBSC). The group of FIL received filgrastim 10 μg /kg/day depending on the number PBSCs. Demographic information, laboratory results, and treatment plans were collected for these two groups of patients. RESULTS：We compared their mobilization efficacy (mononuclear cell [MNC] and CD34 + cell counts) and transplantation efficacy (days to leukocyte and platelet recovery post-transplantation). Successful ASCT mobilization was achieved in 93 patients (86.9%), with the PEG+FIL group exhibiting a higher success rate compared to the FIL group (89.2% [58/65] vs. 83.3% [35/42], p = 0.032). The PEG+FIL group also demonstrated significantly higher CD34+ cell counts [MNC: 8.9 (6.9, 11.2) vs. 7.8 (6.2, 9.8) × 10 8 cells/kg, p = 0.024; CD34 + cell count: 7.5 (5.6, 13.0) vs. 4.9 (3.2, 9.2) × 10 6 cells/kg, p = 0.008] and a lower incidence of neutropenic fever compared to the FIL group (11.8% vs. 24.3%, p = 0.038). The PEG+FIL group also demonstrated a shorter mean leukocyte recovery time in autologous stem cell transplantation than the FIL group (10.02 ± 0.73 vs. 10.9 ± 1.1 days, p &amp;lt; 0.001). To delve deeper into the safety considerations of both groups, we evaluated the advantages of each regimen and the methodologies for selecting time windows. A bone marrow aspiration and biopsy were performed on all patients before stem cell collection. Among 18 patients who had a hematopoietic area less than 30% and a fat area greater than 40%, 10 were in the PEG+FIL group and 8 in the FIL group. For patients who required only one collection, the durability was 80% in the PEG+FIL group compared to 0% in the FIL group (p &amp;lt; 0.01), indicating a superior recommendation for patients with a bone marrow hematopoietic area of less than 30%. In the PEG+FIL group, monitoring was carried out for PB CD34 + percentage and WBC count following pegfilgrastim administration, with subsequent computation of CD34 + cells in PB. Filgrastim administration was found to be optimal 5-6 days post-pegfilgrastim administration. CONCLUSIONS: In conclusion, relative to conventional filgrastim mobilization, the conjunctive use of pegfilgrastim and filgrastim demonstrates superior efficacy, non-inferior safety during ASCT. The schedule enhanced the the outcomes of mobilization in the patients of less hematopoietic area. KEY WORDS: Pegylated recombinant human granulocyte-stimulating factor (pegfilgrastim, PEG-rhG-CSF), recombinant human granulocyte-colony stimulating factor (filgrastim, rhG-CSF), lymphoma, hematopoietic stem cell transplantation (HSCT) autologous hematopoietic stem cell mobilization.

Clinical approval of intra-peritoneal instilation of recombinant human granulocyte colony-stimulating factor for the treatment of acute peritonitis

To conduct a preliminary evaluation of the clinical use of recombinant human granulocyte colony-stimulating factor (G-CSF) for the treatment of acute peritonitis (AP).Material and methods. 20 patients. The causes of AP were perforated gastroduodenal ulcers – 7, colon perforation – 7, acute appendicitis – 3, small bowel perforation – 2, one case each of mesenteric thrombosis and uterine perforation. Diffuse AP was detected in 4 (20%) patients, generalized – in 16 (80%). The 1st, control, group and the 2nd, experimental groupб included 10 patients each. Similar basic treatment was used in both groups. Patients of the 2nd group at the end of the operation were injected intraperitoneally with a solution of G-CSF with 0.9% NaCl (5 μg/1 ml) at a dose of 10 μg per 1 kg of body weight. After the operation, the amount of glucose (AG), creatinine (AC) in blood plasma, prothrombin index (PI), nuclear index (NI), stress index (SI), leukocyte intoxication index (LII), neutrophil-lymphocyte index (NLI), neutrophil-mononuclear index (NMI), lymphocyte-monocyte index (LMI), immunological reactivity index (IRI).The results. NI in the 2nd group increased after a day (p&lt;0.01), then prevailed almost all the time. SI after a day in both groups was almost not different. On the 3rd day, the SI in the 1st group significantly increased, and in the 2nd group, it decreased. Later there were opposite changes. After a day, LII decreased in both groups. After 3 days, LII decreased in the 1st group (p&lt;0.05). In the 2nd group, after 3 days, LII increased significantly (p&lt;0.01) and decreased after 7 days. NLI indicators changed similarly. In the 1st group, NMI significantly (p&lt;0.05) decreased after 3 days and remained low. NMI significantly prevailed in the 2nd group, increased (p&lt;0.01) after 5 days. In the 1st group, LMI decreased all the time. In the 2nd group, LMI increased (p&lt;0.01) after 2 days, decreased after 3 days, and increased (p&lt;0.05) after 5 days. IRI in the 1st group, after it increased for 3-5 days, then decreased. In the 2nd group, IRI changed like LMI. AG in the 1st group prevailed all the time. In the 1st group, AC increased for 5 days, in the 2nd group - it constantly decreased. PI in the 1st group decreased for 5 days, in the 2nd group it normalized after 3 days, then increased.Conclusions. 1. According to the complex of integral evaluation criteria, in patients with AP who underwent intraperitoneal instillation of G-CSF solution, signs of adequate functioning of cellular components of immune protection were found after the operation. 2. According to the complex of biochemical criteria, signs of an early reduction in the manifestations of intoxication and recovery of kidney and liver function were found in such patients. 3. The results of clinical approbation indicate the possibility and perspective of using this method of treatment for patients with AP.

A Universal CRISPR/Cas9n-Mediated Genome Editing Approach for ELANE-Related Severe Congenital Neutropenia

Severe congenital neutropenia (CN) is an inherited bone marrow failure syndrome characterized by impaired maturation of neutrophil granulocytes. Due to the lack or very low levels of neutrophils in the peripheral blood, patients experience severe, life-threatening bacterial infections as early as birth. Autosomal-dominant ELANE mutations are the most common cause of CN. Although most patients respond to daily treatment with recombinant human granulocyte colony-stimulating factor, about 15% of patients do not respond to this cytokine, and approximately 20% of patients develop myelodysplasia or acute myeloid leukemia. The only curative treatment available thus far is allogenic hematopoietic stem cell transplantation, which is associated with serious side effects. Autologous transplantation of gene-edited patients' HSPCs offers a novel curative therapy. Considering the wide range of mutations distributed throughout the ELANE gene, A universal, high-safety-profile approach could be advantageous for all ELANE-CN patients. Our group has already published a universal CRISPR/Cas9-mediated knockout approach for the ELANE gene; however, targeting the coding sequence region (CDS) of the ELANE gene could lead to the introduction of new disease-causing variants, so it may be harmful for patients. In order to address this concern, we reformatted our previously published knockout concept into a clinical-grade gene therapy strategy. We have screened cis-regulatory regions in the ELANE core promoter and, using CRISPR/Cas9n, introduced two nicks on opposing strands of the Goldberg-Hognes box region (TATA-box) to make the transcription starting process inefficient, as transcription factors and RNApol II cannot recognize the modified sequence. Theproposed strategy targets the non-coding region of the ELANE gene and thus does not generate new unwanted variants. Also, by replacing Cas9 with Cas9-ncikase, the off-target activity should decrease by up to 1000-fold. We have observed a markedly elevated neutrophil differentiation in gene-edited ELANE-CN patients HSPCs (n = 2), as assessed by the percentage of CD45 +CD11b +CD15 +, CD45 +CD15 +CD16 +, and CD45 +CD16 +CD66b + myeloid/granulocytic cells, compared to the mock electroporated ELANE-CN group, while no disruption of granulopoiesis in healthy donor HSPCs (n = 2) was detected. Results validated by the CFU assay. To have nucleotide-level resolution of on-target events, we performed targeted next-generation sequencing of edited loci on gene-edited healthy donors and ELANE-CN HSPCs. Next-generation sequencing results showed &amp;gt;90% on-target efficiency. CRISPR/Cas9n-mediated targeting of the TATA box rescued defective granulopoiesis in vivo, as gene-edited ELANE-CN HSPCs (n = 3) were transplanted in NSG mice and assessed by the percentage of neutrophils (hCD19 -hCD3 -hCD66b Int/lowhCD33 +hCD16 high) after 16 weeks. We have also observed efficient engraftment and preserved the multilineage potential of gene edited HSPCs in immunodeficient NSG mice. The strategy also depicted a safe profile upon applying gene editing to healthy donor CD34 + HSPCs and performing GUIDE-seq and CAST-seq. GUIDE-seq highlighted two potential off-target sites after &amp;gt;=6 mismatches, while no chromosomal translocations were detected by CAST-seq. RNA-sequencing of in vitro-generated neutrophils from gene-edited HSPCs of healthy donors (n = 2) confirmed a &amp;gt;9-fold reduction of ELANE gene expression level. Important to note, none of the other serine proteases or neighboring genes were down-regulated. Taken together, ex vivo CRISPR-Cas9n-based gene editing of ELANE's gene promoter in the setting of autologous stem cell transplantation could be a safe therapeutic approach for all ELANE-CN patients.

Using recombinant human G-CSF to treat chemotherapy-induced neutropenia over 3 decades: What is next?

Chemotherapy-Induced Neutropenia (CIN) is a potentially fatal side effect of cancer treatment, affecting &gt; 50% of cancer patients treated with chemotherapy. Clinical use of recombinant human granulocyte colony-stimulating factor (rhG-CSF) has allowed for primary and secondary prophylaxis of CIN and its sequela (i.e., febrile neutropenia, fatal infection) during myelosuppressive chemotherapy. Here, we review the translation and properties of first, second, and third-generation rhG-CSF molecules, including filgrastim (Neupogen, FDA approved in 1991) and biosimilars, pegfilgrastim (Neulasta, FDA approved in 2002) and biosimilars, and F-627 (Ryzneuta, NMPA approved in 2023), a novel long-acting rhG-CSF agent developed this past decade. Even with the development of increasingly personalized and targeted cancer therapy, chemotherapy, and stem cell transplantation remains a backbone for the majority of patients with advanced cancers, especially in the hematopoietic system. As such, more than 20 million cancer patients have been treated with rhG-CSF drugs since the first approval of filgrastim. In the next decade, we envision third-generation rhG-CSF products such as Ryzneuta lowering costs to patients and healthcare providers, expanding access to this essential medication for cancer patients worldwide, particularly for patients who require more aggressive chemotherapy treatment.

Efficacy and safety of PEG-rhG-CSF versus rhG-CSF in preventing chemotherapy-induced-neutropenia in early-stage breast cancer patients

BackgroundTo compare the clinical value of recombinant human granulocyte colony-stimulating factor (rhG-CSF) and pegylated rhG-CSF(PEG-rhG-CSF) in early-stage breast cancer (EBC) patients receiving adjuvant chemotherapy, compare the efficacy of PEG-rhG-CSF with different dose and explore the timing of rhG-CSF rescue treatment.MethodsPatients in two PEG-rhG-CSF subgroups were given 3 mg or 6 mg PEG-rhG-CSF within 24 ~ 48 h after chemotherapy for preventing myelosuppression, while patients in the rhG-CSF group were given rhG-CSF. Observation indicators include the incidence of febrile neutropenia (FN) and grade 3/4 chemotherapy-induced-neutropenia (CIN), the overall levels and nadir values of white blood cells (WBC) and absolute neutrophil count (ANC), comparison of WBC and ANC curves over time, the incidence of CIN-related complications, the incidence of adverse events in each group and the timing of rescue treatment for rhG-CSF.ResultsThere was no significant difference in the incidence of FN in the first cycle among the groups (P = 0.203). But the incidence of ≥ 3 grade CIN in two PEG-rhG-CSF subgroups was significantly lower than that in the rhG-CSF group (P < 0.001). The overall WBC and ANC levels in the PEG-rhG-CSF group were significantly higher than those in the rhG-CSF group (P < 0.001). In terms of CIN-related complications, less chemotherapy delay rate (1.1 vs. 7.5%, P = 0.092), less dose reduction rate (6.9 vs. 7.5%, P = 1.000), less antibiotic use rate (3.4 vs. 17.5%, P = 0.011) and less proportion of rhG-CSF rescue therapy (24.1 vs. 85.0%, P < 0.001) in the PEG-rhG-CSF group, and there were no significant differences between PEG-rhG-CSF subgroups. In the incidence of adverse events among the groups, there were no statistical differences. All patients undergoing rhG-CSF rescue treatment were mainly 4 grade (63.6%) and 3 grade (25.5%) CIN, and 10.9% of patients with 1 ~ 2 grade CIN who had high infection risk or had been infected.ConclusionPEG-rhG-CSF has better efficacy and equal tolerance compared with rhG-CSF in preventing CIN in EBC patients receiving EC regimen. Moreover, a half-dose 3 mg PEG-rhG-CSF also had good efficacy. Last, patients with ≥ 3 grade CIN and others who have been assessed to be at high risk of infection or have co-infection should consider rhG-CSF or even antibiotic rescue treatment.

A novel PEGylated form of granulocyte colony-stimulating factor, mecapegfilgrastim, for peripheral blood stem cell mobilization in patients with hematologic malignancies.

The Pegylated recombinant human granulocyte colony stimulating factor (PEG-rhG-CSF) has longer half-life and is given once only, which is more comfortable for patients. We aimed to evaluate the efficacy of mecapegfilgrastim for hematopoietic stem cell (HSC) mobilization in patients with hematologic malignancies and to explore the potential factors related to HSC mobilization. A retrospective analysis was performed on patients who underwent HSC mobilization in the hematology department of Mianyang Central Hospital from April 2016 to November 2022. The number of CD34 + cells collected was compared between the patients receiving mecapegfilgrastim (PEG group) and those receiving recombinant human granulocyte colony-stimulating factor (rhG-CSF group), and the possible factors for mobilization failure were analyzed. The success rates of collecting CD34 + cells in the PEG group and rhG-CSF group were 80.6% and 67.7%, respectively (χ = 1.444, P = 0.229). The median CD34 + cell counts were 3.62 × 10^6/kg and 2.92 × 10^6/kg (P = 0.178), respectively. After combination with plerixafor for mobilization, the median number of CD34 + cells collected in the PEG group and rhG-CSF group were 3.64 × 10^6/kg and 3.92 × 10^6/kg, respectively, with no significant difference (P = 0.754). There was no significant difference in hematopoietic cell recovery or infection between the groups (P > 0.05). Multivariate analysis showed that more than 5 cycles of chemotherapy (OR = 15.897, 95% CI: 1.766-143.127, P = 0.014), a precollection WBC count < 32 × 10^9/L (OR = 14.441, 95% CI: 2.180-95.657, P = 0.006) and a precollection to premobilization lymphocyte ratio < 1.7 (OR = 11.388, 95% CI: 2.129-60.915, P = 0.004) were independent risk factors for HSC mobilization failure. The HSC mobilization efficacy of mecapegfilgrastim in patients with hematologic malignancies was comparable to that of rhG-CSF, and combination with plerixafor for mobilization was feasible and effective. Patients with more than 5 cycles of chemotherapy before HSC mobilization, a precollection WBC count lower than 32 × 10^9/L, and a precollection lymphocyte count less than 1.7 times the premobilization lymphocyte count have a high probability of HSC mobilization failure.

Efficacy and safety of anlotinib combined with anthracycline and ifosfamide followed by anlotinib maintenance in advanced soft tissue sarcoma: A single-arm, phase 2 trial.

11553 Background: Anthracycline plus ifosfamide is the standard first line treatment regime for advanced soft tissue sarcoma (STS). Anlotinib, a multikinase angiogenesis inhibitor, has evolved as a standard second line treatment option in Chinese advanced STS patients. This study was performed to evaluate the efficacy and safety of anlotinib combined with anthracycline and ifosfamide followed by anlotinib maintenance in the first line treatment of patients with advanced STS. Methods: This prospective, open-label, single-arm, phase 2 trial was conducted in Shandong Cancer Hospital and Institute (ChiCTR2100054711). The key inclusion criteria included: (a) age was 18-70 years; (b) ECOG performance state of 0-1; (c) histologically confirmed high-grade STS; (d) unresectable or metastatic STS; (e) previously untreated, and sensitive to chemotherapy; (f) having measurable lesions according to RECIST 1.1. All patients received up to 6 cycles of anlotinib (12 mg QD on day1-14, 21 days per cycle) combined with anthracycline (epirubicin 40mg/m2/d on day 1-2, 21 days per cycle; or liposomal doxorubicin 30mg/m2/d on day 1, 21 days per cycle) and ifosfamide (2g/m2/d on day 1-3, 21 days per cycle) followed by anlotinib maintenance until disease progression, unacceptable toxicity or death. Pegylated recombinant human granulocyte colony-stimulating factor was administered following chemotherapy. The primary endpoint was objective response rate (ORR). The secondary endpoints included progression-free survival (PFS), overall survival (OS), and adverse effect (AE). Results: From December 2021 to December 2022, 31 patients (median [range] age, 53 [18-69] years; 20 [64.5%] male) were enrolled. 29 were evaluable for objective response, and the ORR and DCR were 31.03% (95%CI, 17.28-49.23%) and 82.76% (95%CI, 65.45-92.4%), respectively. With a median follow-up duration of 6.3 months (range, 0.8–14.0), the median PFS for all 31 patients was 6.9 months (95% CI, 2.62-11.17). The median OS was not reached. Treatment-related AEs of any grade occurred in all patients. The most common AEs included nausea/vomiting (88.46%), anemia (23.08%), leukopenia (19.23%), venous thrombosis (15.38%), hand-foot syndrome (11.54%) and elevated alanine aminotransferase or aspartate aminotransferase (11.54%). The most frequent ≥ grade 3 AEs were leukopenia (11.54%) and thrombocytopenia (7.69%). 2 serious AEs (1 left heart failure and 1 intestinal obstruction) were recorded. No treatment-related death occurred. Conclusions: This study suggested that anlotinib combined with anthracycline and ifosfamide followed by anlotinib maintenance demonstrated encouraging efficacy with a manageable safety profile in the first line treatment of patients with advanced STS. Clinical trial information: ChiCTR2100054711 .

A multicenter phase II trial of primary prophylactic PEG-rhG-CSF in pediatric patients with solid tumors and non-Hodgkin lymphoma after chemotherapy: An interim analysis.

Pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) can be used in pediatric patients. This study assessed the safety and efficacy of PEG-rhG-CSF as a primary prophylactic drug against neutropenia after chemotherapy in pediatric patients with solid tumors or non-Hodgkin lymphoma (NHL). This phase II study (between October 2020 and March 2022) enrolled pediatric patients with solid tumors or NHL treated with high-intensity chemotherapy and with grade ≥3 myelosuppression for at least 14 days during chemotherapy. Prophylactic PEG-rhG-CSF was given at 100 μg/kg body weight (maximum total dosage of 6 mg) once 24-48 h following chemotherapy for two cycles. The primary endpoint was the incidence of PEG-rhG-CSF-related adverse events (AEs). The key secondary endpoints were the rates of grade 3/4 neutropenia and febrile neutropenia (FN). This study included 160 pediatric patients with a median age of 6.22 (0.29, 18.00) years. Fifty-eight patients (36.25%) were diagnosed with sarcoma. AEs potentially related to PEG-rhG-CSF included bone pain (n = 32), fatigue (n = 21), pain at the injection site (n = 21), and myalgia (n = 20). The rates of grade 3/4 neutropenia and FN during treatment were 57.28% and 29.45%, respectively. PEG-rhG-CSF is well tolerated and effective in pediatric patients with solid tumors or NHL. These findings should be substantiated with further trials. ClinicalTrials.gov identifier: NCT04547829.

Application of Mecapegfilgrastim for Peripheral Blood Hematopoietic Stem Cell Mobilization in Patients With Hematologic Neoplasms and Analysis of Predictors for Poor Mobilization

To evaluate the efficacy of applying mecapegfilgrastim for peripheral blood hematopoietic stem cell (PBSC) mobilization in patients with hematologic neoplasms, and to investigate the influencing factors of PBSC collection. Patients who underwent PBSC mobilization in the Department of Hematology, Mianyang Central Hospital between April 2016 and May 2022 were retrospectively analyzed. The CD34 + cell collection results of two groups, the mecapegfilgrastim group ( n=28), or the PEG group, and the recombinant human granulocyte colony-stimulating factor (rhG-CSF) group ( n=30), were compared, and the influencing factors of collection failure were analyzed. The success rates of CD34 + cells collection in the PEG group and the rhG-CSF group were 75.0% and 63.3%, respectively ( P>0.05). The median CD34 + cell counts were 3.37×10 6/kg and 2.68×10 6/kg, respectively, showing no significant difference. After combined mobilization with plerixafor, the median counts of CD34 + cells collected in the PEG group and rhG-CSF group were 4.23×10 6/kg and 3.26×10 6/kg, respectively, showing no significant difference ( P>0.05). There was no significant difference in hematopoietic system reconstruction and infections between the two groups ( P>0.05). Multivariate analysis found non-plasma cell disease (odds ratio [ OR]=19.697, 95% confidence interval [ CI] : 1.501-258.537, P=0.023), anemia before collection ( OR=18.571, 95% CI: 1.354-254.775, P=0.029) and white blood cell count before collection under 32×10 9 L -1 ( OR=85.903, 95% CI: 4.947-1491.807, P=0.002) to be independent risk factors for PBSC collection failure. The effect of PBSC mobilization with mecapegfilgrastim was comparable to that of rhG-CSF in patients with hematologic neoplasms. Furthermore, combined mobilization with plerixafor was feasible and effective. Patients with leukemia or lymphoma, anemia, and WBC<32×10 9 L -1 before stem cell collection have a high probability of PBSC collection failure.

Effects of pegylated recombinant human granulocyte colony-stimulating factor on lymphocytes and white blood cells of patients with malignant tumor.

We investigated the effect of pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) on lymphocytes and white blood cells of patients with malignant tumors. After PEG-rhG-CSF treatment, the count of lymphocytes increased in 66 cases, remained unchanged in 2 cases, and decreased in 20 cases. The difference in lymphocyte count before and after treatment was statistically significant (P < 0.001). White blood cell changes were positively correlated with lymphocyte changes (r = 0.36, P = 0.001). In the subgroup with increased white blood cells (n = 80), there were 62 cases with increased lymphocytes, 1 case with unchanged lymphocytes, and 17 cases with decreased lymphocytes after PEG-rhG-CSF treatment. There was significant difference in the count of lymphocytes and white blood cells (P < 0.001). In the subgroup with 6 mg of PEG-rhG-CSF (n = 66) and the subgroup with 3 mg of PEG-rhG-CSF (n = 22), the changes of white blood cell and lymphocyte counts before and after treatment were statistically significant (P < 0.001). The two were positively correlated in the 6 mg PEG-rhG-CSF subgroup, with correlation coefficient r = 0.34 (P = 0.002). PEG-rhG-CSF can increase the count of lymphocytes and white blood cells in patients with malignant tumors, and the increase of lymphocytes is positively correlated with the increase of white blood cells.

Efficacy and safety of recombinant human granulocyte colony-stimulating factor in patients with unexplained recurrent spontaneous abortion: A systematic review and meta-analysis

IntroductionPublished data regarding efficacy of intrauterine perfusion of recombinant human granulocyte colony-stimulating factor for patients with unexplained recurrent spontaneous abortion (URSA) is inconclusive. This study aims at evaluating the efficacy and safety of G-CSF in URSA. Materials and methodsElectronic databases were searched including Cochrane Library, PubMed, Embase, China Biology Medicine disc, China Science and Technology Journal Database, Wanfang Database and China National Knowledge Infrastructure Database (last search was performed on Sep 10th, 2022). A systematic review and meta-analysis was conducted with R-language software. Combined relative risk (RRs), and 95% confidence intervals (CIs) were calculated to estimate efficacy and safety. ResultsCompared with placebo, the efficacy of G-CSF in the treatment of URSA patients was significant in conception rate (RR=1.34, 95%CI: 1.03–1.74, P = 0.028), and was none of significance in live birth rate (RR=1.35, 95%CI: 0.99–1.84, P = 0.06). Subgroup analysis showed that the ovulation-period-medication was the protective factor for conception rate, while "Ethnicity Asian" and "ovulation-period medication" were the protective factors for live birth rate. When it comes to the safety of rhG-CSF on URSA, meta-analysis showed that rhG-CSF had no significant effect on the incidence of adverse events (AEs) (RR=1.13, 95% CI: 0.89–1.43, P = 0.322), and subgroup analysis showed that the incidence of AEs in each subgroup did not increase significantly (P > 0.05). ConclusionBased on our meta-analysis, intrauterine perfusion of rhG-CSF in ovulation period is an effective and safe way to improve conception rate in URSA.

Clinical Applications of Recombinant Human Granulocyte Colony-Stimulating Factor in Reproductive Medicine: Expert Consensus

The primary clinical indication for recombinant human granulocyte-stimulating factor (rhG-CSF) is neutropenia of multiple etiologies. In recent years, rhG-CSF has been proved to be effective and safe for mothers and fetus in the clinical application in some reproductive disorders. Until recently, there has been no reliable evidence of authoritative expert consensus or standards. In order to regulate the research and rational application of rhG-CSF in the fields of reproductive medicine, the Committee on Reproductive Immunity of the China Society for the Promotion of Human Health Science and Technology (the Committee) organized experts from relevant disciplines to formulate the Expert Consensus, which is based on the latest international basic study and clinical research evidence. According to evidence-based data, recommendations were established on the applicable population, starting method, and duration of rhG-CSF administration in reproductive medicine. It is recommended that rhG-CSF could be applicated in the patients with thin endometrium which was ineffective to standard treatments, in unexplained recurrent spontaneous abortion (RSA), in unexplained recurrent implantation failure (RIF), and could attempt to be applicated in unexplained RSA with slow rise of human chorionic gonadotropin and/or embryo growth retardation. Meanwhile, the patients are demand of ineffective to the standard therapy and need to sign informed consent for the off-label use of rhG-CSF before treatment. Comprehensive communication between OB/GYN and patients before therapy is essential according to that the rhG-CSF treatment would be inefficient when genetic abnormality, gamete damage, heterotopic pregnancy and other unknown disorder exist.

Impact of rhG-CSF on Clinical Efficacy and Immune Cell Subsets after Initial Induction Chemotherapy in AML.

The impact of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in acute myeloid leukemia (AML) is still controversial. The purpose of this study is to explore the impact of rhG-CSF administration on clinical efficacy and immune cell subsets after initial induction chemotherapy in AML. The clinical efficacy and immune cell subsets were compared in the newly diagnosed patients with AML according to whether rhG-CSF was used after initial induction chemotherapy. Next, rhG-CSF stimulation experi-ments on leukemia cell lines and primary leukemia blasts were performed in vitro. There was no statistical difference between control group and rhG-CSF therapy group in complete remission rate and relapse free survival. The duration of agranulocytosis was significantly shortened in rhG-CSF therapy group compared with control group. The percentage of circulating monocytic myeloid-derived suppressor cells (M-MDSCs) and regulatory T cells (Tregs) were significantly increased after the administration of rhG-CSF. Furthermore, it was found that rhG-CSF did not promote the proliferation of leukemia cell lines and primary leukemia blasts, but increased the proportion of M-MDSCs and Tregs in vitro. Administration of rhG-CSF after initial induction therapy of AML does not affect the clinical remission and relapse rate, but reduces the duration of agranulocytosis and increases the proportion of M-MDSCs and Tregs.

MATHEMATICAL SOLUTION OF A PHARMACOKINETIC MODEL WITH SIMULTANEOUS FIRST-ORDER AND HILL-TYPE ELIMINATION

Mathematical studies on pharmacokinetic models are essentially important for drug development and optimal dose design. Considering the interaction between drug molecules and their receptors, the elimination of drug molecules can exhibit Hill-type kinetics. In this paper, motivated by the recombinant human granulocyte colony-stimulating factor (G-CSF) and the transcendent Lambert <i>W</i> function, we have studied the mathematical solutions of a one-compartment nonlinear pharmacokinetic model with simultaneous first-order and Hill-type (<i>n</i> = 2) elimination for the case of intravenous bolus administration. By introducing three well-defined transcendental functions depending on three different scenarios, we have established the closedform precise solutions of time course of drug concentration, which is a method to calculate drug concentrations at any time point. As a result, we also have derived the explicit expressions of some key pharmacokinetic surrogates such as the elimination half-life <i>t</i>_1/2 and total drug exposure (i.e. area under the concentration curve (AUC)), which are found as dose-dependent. Finally, a case study of a G-CSF drug is quantitatively illustrated to delineate our theoretical results, including the elimination half-life and AUC for different dosages. Our findings can provide an effective guidance for drugs with simultaneous first-order and Hill-type (<i>n</i> = 2) elimination in clinical pharmacology