Recombinant Human Granulocyte Colony-stimulating Factor Research Articles

Exploring optimal administration timing of pegylated recombinant human granulocyte colony-stimulating factor for chemotherapy-induced neutropenia in early breast cancer treated with pharmorubicin and endoxan: a prospective randomized controlled clinical trial.

Pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) is a treatment for preventing febrile neutropenia (FN) in patients with early breast cancer. However, the optimal injection timing of PEG-rhG-CSF after chemotherapy is obscure. The trial was designed to explore the best administration timing of PEG-rhG-CSF when breast cancer patients could benefit most. Patients with early breast cancer were randomly assigned to receive a preventive injection on the 7th or 3rd day following chemotherapy. The experimental group (n = 80) received PEG-rhG-CSF treatment on day 7 after chemotherapy, whereas the control group (n = 80) received it on day 3. The occurrence of grades 3-4 neutropenia and FN in the first cycle was the primary endpoint. The secondary endpoint was the frequency of PEG-rhG-CSF dose reduction. In comparison to the control group, the experimental group exhibited higher white blood cell count (WBC) and absolute neutrophil count (ANC) on the 9th and 13th days following chemotherapy (P < 0.05). Additionally, the incidence of grade 3-4 neutropenia was significantly lower in the experimental group (P = 0.038). Furthermore, a greater proportion of patients in the experimental group met the criteria for reducing the PEG-rhG-CSF dose compared to the control group (69.74% vs. 35.06%, P < 0.001). In comparison with PEG-rhG-CSF injection on day 3 after chemotherapy, the incidence of grade 3-4 myelosuppression is lower, and the safety is more manageable after the injection on day 7. This approach potentially allows for a wider adoption of PEG-rhG-CSF dose reduction, leading to a consequential decrease in overall medical costs for patients. Clinical Trials: NCT04477616. Registered July 16, 2020.

The Efficacy Research of Prophylactic PEG-rhG-CSF in Preventing Neutropenia in Early-Stage Breast Cancer Patients Treated With Docetaxel-Based Chemotherapy: A Retrospective Analysis

PurposeDocetaxel-based chemotherapy regimens (DBRs) are commonly used in the treatment of early-stage breast cancer (EBC). The prophylactic use of pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) has been shown to reduce the incidence of neutropenia induced by DBRs. However, the clinical usage of PEG-rhG-CSF in EBC patients undergoing DBRs in China remains unclear. MethodsThis retrospective study was conducted in 137 EBC patients receiving DBRs from September 2022 to February 2024. We compared the incidence of chemotherapy-induced neutropenia (CIN) between patients who was treated with prophylactic PEG-rhG-CSF or not by complete blood counts, evaluating the effectiveness of PEG-rhG-CSF in preventing CIN. Prophylactic PEG-rhG-CSF was given at 100 μg/kg body weight (maximum total dosage of 6 mg) once 24–48 h following chemotherapy. Meanwhile, we also collected basic patient information, the area under time-concentration curve of docetaxel, and liver and kidney function indicators. Multivariate logistic regression and Receiver operating characteristic (ROC) curve analysis were employed to explore independent factors influencing neutropenia. FindingsIn this study, 87 of 137 EBC patients were administrated with prophylactic PEG-rhG-CSF, while 50 were not. Compared to patients who did not receive PEG-rhG-CSF, those who received prophylactic injections had a significantly lower incidence of grade 3–4 CIN (20% vs. 4.6%, P < 0.05). Higher body surface area (BSA), lower body mass index (BMI), elevated alanine aminotransferase (ALT), and nonprophylactic use of PEG-rhG-CSF were found to be positively correlated with CIN occurrence. ROC curve analysis indicated an area under the curve of 0.756 for predicting CIN in EBC patients when BSA was 1.66 m², BMI was 24.8 kg/m², and ALT was 41 U/L, with a sensitivity of 73.08% and specificity of 73.87%. ImplicationsProphylactic use of PEG-rhG-CSF significantly reduces the incidence of CIN, particularly grades 3 and 4. BSA, BMI, ALT, and PEG-rhG-CSF prophylaxis are independent influencing factors for the occurrence of neutropenia.

Efficacy and safety of same-day versus next-day administration of PEG-rhG-CSF for the prophylaxis of chemotherapy-induced neutropenia and febrile neutropenia in patients with breast cancer: a retrospective cohort study

: Objectives Polyethylene glycol recombinant human granulocyte colony-stimulating factors (PEG-rhG-CSFs) are used to prevent or treat chemotherapy-induced neutropenia (CIN) and febrile neutropenia (FN). This study aimed to compare the efficacy and safety of same-day versus next-day PEG-rhG-CSF administration following chemotherapy and the effects of 3 mg versus 6 mg dosages. Methods We retrospectively analyzed cohort data of patients with breast cancer who underwent chemotherapy and received PEG-rhG-CSF either within 24 h (same-day group) or 24 h (next-day group) after chemotherapy. The incidences of CIN and FN were assessed in each chemotherapy cycle between the two groups. The primary endpoint was the incidence of FN in the first cycle and throughout all cycles. The secondary endpoints included the incidences of various grades of CIN (CIN1–CIN4), antibiotic use, chemotherapy regimen modifications, and overall safety. Results Among the 2385 chemotherapy cycles with prophylactic PEG-rhG-CSF in 620 patients, 798 and 1587 cycleswere in the same-day and next-day group, respectively. No statistically significant differences were observed in the incidence of FN in the first cycle or across all cycles, CIN1-4, or adverse reactions between the two groups. However, the same-day group exhibited significantly higher rates of antibiotic use (2.88% vs. 0.42%, P = 0.03) and chemotherapy regimen modification (4.68% vs. 1.45%, P < 0.001). Subgroup analysis indicated no differences in outcomes for the 6 mg dosage, but a significantly lower incidence of CIN was observed in the same-day group receiving 3 mg (P = 0.025). Conclusions These findings suggest that same-day administration of PEG-rhG-CSF is as effective and safe as next-day administration in preventing FN and CIN during chemotherapy.

Differential impact of pegfilgrastim, a recombinant human granulocyte colony stimulating factor, on the neutrophil count of male and female deer mice (Peromyscus maniculatus bairdii)

BackgroundAn increasing body of research implicates inflammatory processes, including alterations in the neutrophil-lymphocyte ratio (NLR), in the pathophysiology of psychiatric illness. The deer mouse (Peromyscus maniculatus bairdii) is commonly studied for its naturalistic expression of compulsive-like behaviour. Towards future efforts to gain an understanding of how innate and adaptive immune processes might be involved in this model, we aimed to study the effects of pegfilgrastim, a pegylated recombinant human granulocyte colony-stimulating factor (g-CSF) analogue, on the NLR of both male and female deer mice.MethodsBriefly, 54 deer mice (equally distributed between sexes) were exposed to a single injection with either control or pegfilgrastim (0.1 or 1 mg/kg) (n = 18 per group). Six mice of each group (three per sex) were euthanized on days two, four and seven post-administration, their blood collected and the NLR calculated. Data were analysed by means of ordinary three-way ANOVA, followed by Bonferroni post-hoc testing.ResultsIrrespective of dose, pegfilgrastim resulted in higher NLR values in mice of both sexes at days four and seven of testing. However, female mice exposed to the higher dose, presented with significantly higher NLR values irrespective of time, compared to male mice exposed to the same.ConclusionThe data generated from this work highlight important dose- and sex-specific aspects of pegfilgrastim with female mice showing heighted elevation of the NLR in response to high-dose pegfilgrastim administration only. Since the innate immune components of male and female deer mice is differentially sensitive to g-CSF stimulation, our results provide a useful basis for further study of sex-specific immunological processes in deer mice.

Population pharmacokinetic and exposure-toxicity analyses of nab-paclitaxel after pegylated recombinant human granulocyte colony-stimulating factor administration in patients with metastatic breast cancer.

This study aimed to establish a population pharmacokinetic (PK) model to evaluate the dynamic relationship between the concentrations of total and unbound paclitaxel, and the exposure-response analysis of albumin-bound paclitaxel (nab-paclitaxel) after pegylated recombinant human granulocyte colony-stimulating factor (PEG-G-CSF) administration in patients with metastatic breast cancer. A total of 653 concentrations corresponding to total paclitaxel and 334 concentrations corresponding to unbound paclitaxel were analyzed in 24 subjects who randomized received a single 260 mg/m2 dose of two nab-paclitaxel formulations with a 21-35-day washout period. PEG-G-CSF was administered to all the patients in each cycle to prevent neutropenia. The exposure-response relationships were evaluated using the exposure to total, albumin-coated, and unbound paclitaxel, as well as the reduction in neutrophil count. The exposure data were analyzed using nonlinear mixed-effect modeling. A linear regression model was used to test the statistical significance of the correlation between percentage of reduction in neutrophil count and exposure. The PK characteristics of total paclitaxel were described using a three-compartment model with first-order elimination, and a mechanism-based model incorporating linear release of nab-paclitaxel and the saturated binding of unbound paclitaxel to plasma components was established. The release ratio of paclitaxel from nab-paclitaxel was estimated to be 4.60% and the maximum unbound fraction (2.76%) was reached at the end of the infusion. The study found that a longer duration of total paclitaxel concentration > 0.19 µmol/L was significantly correlated with a reduction in neutrophil count (r2 = 0.23, P = 0.00062). Specifically, a duration of > 8.6h was a predictor of a decreased neutrophil count. The decrease in neutrophils induced by nab-paclitaxel was significantly correlated with the duration above a total paclitaxel concentration of 0.19 µmol/L despite the use of PEG-G-CSF.

Efficacy, safety, and cost-effectiveness of pegylated PEG-rhg-CSF in pediatric patients receiving high-intensity chemotherapy: results from a phase II study.

High-intensity chemotherapy can cause life-threatening complications in pediatric patients. Therefore, this study investigated safety and efficacy of long-acting pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF; Jinyouli®) in children undergoing high-intensity chemotherapy. Treatment-naive patients received post-chemotherapy PEG-rhG-CSF as primary prophylaxis for two cycles. The primary endpoints were drug-related adverse events (AEs) and bone pain scores. Secondary endpoints included grade 3-4 neutropenia, duration of neutropenia recovery, absolute neutrophil count changes, febrile neutropenia (FN), reduced chemotherapy intensity, antibiotic usage, and AE severity. The cost-effectiveness of PEG-rhG-CSF was compared with that of rhG-CSF (Ruibai®). Here, 307 and 288 patients underwent one and two PEG-rhG-CSF cycles, respectively. Ninety-one patients experienced drug-related AEs, primarily bone pain (12.7%). Moreover, Grade 3-4 neutropenia and FN were observed. Median FN durations were 3.0 days in both cycles. No drug-related delays were observed during chemotherapy. One patient experienced grade 4 neutropenia-induced reduction in chemotherapy intensity during cycle 2. In total, 138 patients received antibiotics. PEG-rhG-CSF exhibited superior cost-effectiveness compared to rhG-CSF. Our findings indicate that PEG-rhG-CSF is safe, efficient, and cost-effective in pediatric patients undergoing high-intensity chemotherapy, providing preliminary evidence warranting further randomized controlled trials.

Pegylated recombinant human granulocyte colony-stimulating factor for primary prophylaxis of neutropenia in patients with cervical cancer receiving concurrent chemoradiotherapy: a prospective study

BackgroundThis study aimed to investigate the efficacy and safety of pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) for primary prophylaxis of neutropenia in patients with cervical cancer receiving concurrent chemoradiotherapy.MethodsIn this prospective, single-center, single-arm study, we enrolled patients (18–70 years) with 2018 International Federation of Gynecology and Obstetrics (FIGO) stage IIIC1r-IVA and IVB (distant metastasis only with inguinal lymph node metastasis) cervical cancer. Eligible patients should have normal function of the bone marrow (absolute neutrophil count (ANC) ≥ 2.0 × 109/L) and adequate hepatic and renal functions. Key exclusion criteria included: previous chemotherapy and/or radiotherapy; a history of bone marrow dysplasia or other hematopoietic abnormalities. All patients underwent radical radiotherapy (pelvic radiotherapy or extended-field irradiation) plus brachytherapy. The chemotherapy regimen included four cycles of 3-weekly paclitaxel and cisplatin. PEG-rhG-CSF was administered 48–72 h after each treatment cycle. Salvage granulocyte colony-stimulating factor (G-CSF) was only permitted in certain circumstances. The primary endpoint was the incidence of grade 3–4 neutropenia. The secondary endpoints included frequency of febrile neutropenia (FN), chemotherapy completion rate in cycles 2–4, time to complete radiotherapy, and safety.ResultsOverall, 52 patients were enrolled in this study from July 2019 to October 2020. The incidence of grade 3–4 neutropenia was 28.8%, with an average duration of grade 3–4 neutropenia persistence of 3.85 days (1–7 days). The incidence rate of FN was 3.8%. The chemotherapy completion rate was 94.2%, 82.7%, and 75.0% for cycles 2–4, respectively. The incidences of grade 3–4 neutropenia for cycles 1–4 were 9.6% (5/52), 8.2% (4/49), 14.0% (6/43), and 2.6% (1/39), respectively. All patients completed radiotherapy within 8 weeks (median, 48 days; range: 41–56 days), except one patient who withdrew consent and did not receive radiotherapy. Severe non-hematologic toxicity was not observed in any patient.ConclusionPEG-rhG-CSF is an effective and safe prophylactic treatment for neutropenia in patients with cervical cancer undergoing concurrent chemoradiotherapy.Trial registrationChinese Clinical Trial Registry, ChiCTR1900024494. Date of Registration:13/July/2019.

Low-dose pegylated recombinant human granulocyte-colony stimulating factor as hematopoietic support for adjuvant chemotherapy in Chinese patients with breast cancer: An open-label, randomized, non-inferiority trial.

The recommended dosage of pegylated recombinant human granulocyte-colony stimulating factor (PEG-rhG-CSF) for Western chemotherapy patients is 6mg per cycle. However, for Eastern Asians, the optimal dose remains unknown. This open-label, randomized, non-inferiority trial (NCT05283616) enrolled Chinese female breast cancer patients receiving adjuvant chemotherapy. Participants were randomized to receive either 3 or 6mg of PEG-rhG-CSF per cycle, stratified by body weight (BW; ≤60 kg vs. >60 kg). The primary endpoint was timely absolute neutrophil count (ANC) recovery before the second cycle of chemotherapy. A total of 122 patients were randomized and 116 were included for efficacy analyses. The timely ANC recovery rate in the 3mg arm was 89.8%, compared to 93.0% in the 6mg arm (one-sided 95% confidence interval [CI] lower limit for difference: -11.7%), meeting the prespecified non-inferiority margin of 15%. The rate was 93.3% with PEG-rhG-CSF 3mg and 96.6% with 6mg in patients with BW ≤ 60 kg, and 86.2% and 89.3%, respectively, in those with BW > 60 kg. Although the incidence of severe neutropenia was similar across arms, the occurrence of excessively high ANC and white blood cell counts was higher in the 6mg arm. No grade ≥3 adverse events related to PEG-rhG-CSF occurred. Three milligrams of PEG-rhG-CSF per cycle provided non-inferior neutrophil protection and attenuated neutrophil overshoot compared to 6mg doses. This low-dose regimen could be a new supportive care option for Chinese breast cancer patients receiving anthracycline-based adjuvant chemotherapy.

Prospective clinical study of the efficacy and safety of different doses of PEG recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) for preventing leukopenia/neutropenia caused by concurrent chemoradiotherapy for cervical cancer

ObjectiveThe efficacy and safety of different doses of PEG recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) in the prevention of leukopenia/neutropenia during concurrent chemoradiotherapy for cervical cancer were investigated.MethodsThe patients who received concurrent radiotherapy and chemotherapy for cervical cancer from June 2020 to January 2023 were selected to evaluate the difference in efficacy, adverse reactions, and treatment cost of PEG-rhG-CSF in the prevention of leukopenia/neutropenia between the test group and the control group.ResultsThe minimum value of leukopenia/neutropenia in the test group was significantly higher than that in the control group (P < 0.05). The incidence of grade ≥ 3 leukopenia/neutropenia was significantly lower than that of the control group (P < 0.05). The number of interrupted days of radiotherapy was less than that of the control group (P < 0.05). PEG-rhG-CSF of different prophylactic doses (100 μg/kg dose or 50 μg/kg dose) had similar prophylactic effects in the test group, OR=1.192 (0.761, 1.868), P=0.443.ConclusionProphylactic application of PEG-rhG-CSF could reduce the incidence of leukopenia/neutropenia in cervical cancer during concurrent chemoradiotherapy. There was no significant difference in efficacy and safety with prophylactic use of drug at doses of 100 μg/kg and 50 μg/kg.

The Preventive Effect of Levofloxacin Combined with G-CSF or Only G-CSF Supportive Therapy on Infection in Autologous Hematopoietic Stem Cell Transplantation

To investigate the role of levofloxacin combined with recombinant human granulocyte colony-stimulating factor (G-CSF) or only G-CSF supportive therapy in preventing infection in autologous hematopoietic stem cell transplantation(ASCT), and to analyze the length of hospital stay, hospitalization cost and post-transplant survival of the patients. A retrospective analysis was performed in the patients with hematological malignancies who accepted ASCT at our hospital from January 2012 to July 2022, the febrile neutropenia, the incidence of bacterial infection and the use rate of intravenous antibiotics in the levofloxacin+G-CSF group and only G-CSF support group during ASCT were observed. The length of hospital stay, total cost during hospitalization and survival after 90 days of transplantation between the two groups were compared. A total of 102 cases were included in this study, including 57 cases of multiple myeloma, 36 cases of acute leukaemia, 7 cases of lymphoma, 3 cases of myelodysplastic syndrome, 1 case of light chain amyloidosis, and 1 case of POEMS syndrome. 47 patients received levofloxacin+ G-CSF antibacterial prophylaxis, and 55 patients received G-CSF supportive therapy. In the levofloxacin+ G-CSF group, 40 cases (85.11%) developed febrile neutropenia, and 13 cases (27.66%) were confirmed as bacterial infection. In the G-CSF group, 44 cases (80.00%) developed febrile neutropenia, and 16 cases (29.09%) were bacterial infection. There was no statistically significant difference in the incidence of febrile neutropenia and bacterial infection between the two groups (χ2=0.46，P =0.50; χ2=0.03，P =0.87). The use rate of intravenous antibiotics in the levofloxacin+ G-CSF group was 85.11% (40/47), which was not statistically different from 85.45% (47/55) in the G-CSF group (χ2=0.04，P =0.84). The detection rates of levofloxacin-resistant bacteria in the levofloxacin+ G-CSF group and G-CSF group were 8.57% (3/35) and 21.43% (6/28), respectively, with no statistical difference (χ2=0.65, P >0.05). The median length and median cost of hospitalization in the levofloxacin+ G-CSF group and G-CSF group were 25 d vs 22 d and 78 216.24 yuan vs 80 724.38 yuan, with no statistically significant differences ( t =3.00，P =0.09; t =0.94，P =0.09). Within 90 days after transplantation, two cases (4.26%) died in the levofloxacin+ G-CSF group and one case (1.82%) died in the G-CSF group, with no statistically significant difference between the two groups (χ2=0.53，P =0.47). Application of levofloxacin+ G-CSF showed no significant benefit compared to G-CSF support for the prevention of bacterial infections during ASCT.

Safety and efficacy of PEG-rhG-CSF as primary prophylaxis against neutropenia induced by combination chemotherapy regimens involving oral chemotherapy agents in gastrointestinal cancer patients: A prospective, exploratory, non-randomized controlled study.

e24107 Background: The safety and efficacy of PEGylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) for prevention of chemotherapy-induced neutropenia (CIN) in patients undergoing oral chemotherapy remain unclear. This study investigated the safety and efficacy of PEG-rhG-CSF as primary prophylaxis against CIN in gastrointestinal (GI) cancer patients receiving combination chemotherapy regimens involving oral chemotherapy agents. Methods: This is a prospective, single-center, open-label, exploratory, non-randomized controlled study. GI cancer patients receiving two consecutive cycles of IV oxaliplatin (150mg/m2 on day 1) combined with oral capecitabine 1000mg/m2 or tegafur gimeracil oteracil potassium capsule 40-60mg twice daily on days 1-14 every 3 weeks. PEG-rhG-CSF (6mg) was administered subcutaneously 24 hours post-oxaliplatin treatment in the PEG-rhG-CSF group, while the control group did not receive it. The primary endpoint was safety, and secondary endpoints included CIN incidence and neutropenic complications. The study was registered with the Chinese Clinical Trial Registry (registration number ChiCTR2100054854). Results: Between March 2022 and January 2023, a total of 49 patients was screened, and 43 patients completed the treatment (26 in PEG-rhG-CSF group and 17 in control group). The average age was 61.4 years, with 90.7% males and 83.7% having gastric cancer. Baseline characteristics were similar between the two groups. The overall adverse events (AE) did not differ statistically (88.5% vs. 88.2%, p = 1.000), with grade £2 fatigue and nausea being the most common AEs. Grade 3 platelet reduction showed no significant difference between the two groups (7.69% vs. 17.65%, p = 0.432). Four cases of bone pain (15.4%) and five cases of injection site reactions below grade 3 (19.2%) were observed in the PEG-rhG-CSF group. Grade ≥2 CIN was significantly lower in the PEG-rhG-CSF group (3.84% vs. 58.82%, p &lt; 0.001). One case in the PEG-rhG-CSF group required antibiotic treatment due to febrile neutropenia. Regarding neutropenic complications, the PEG-rhG-CSF group exhibited lower proportion of chemotherapy delay (3.85% vs. 35.29%, p &lt; 0.001) and dose reduction (1.92% vs. 23.53%, p = 0.002). Rescue treatment with rhG-CSF for grade 3/4 CIN was significantly less frequent in the PEG-rhG-CSF group (1.92% vs. 23.53%, p = 0.002). Conclusions: Primary prophylaxis with PEG-rhG-CSF in GI cancer patients undergoing oral capecitabine/tegafur gimeracil oteracil potassium may be safe, without an increased chemotherapy-related AEs, and is associated with a reduced grade ≥2 CIN. Clinical trial information: ChiCTR2100054854.

Abstract PO4-20-02: A prospective, randomized, controlled clinical trial comparing different PEG-rhG-CSF administration times to treat chemotherapy-induced neutropenia and febrile neutropenia in early breast cancer

Abstract Background: Pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) injection time is still referred as recombinant human granulocyte CSF (rhG-CSF) as a treatment for preventing febrile neutropenia (FN) in patients with early breast cancer. The trial examined whether PEG-rhG-CSF injection on day 7 following chemotherapy was superior to injection on day 3. Patients and methods: Patients with early breast cancer were randomly assigned to receive a preventive injection on days 7 or 3 following chemotherapy. The experimental group (n = 80) received PEG-rhG-CSF treatment on day 7 after chemotherapy, whereas the control group (n=80) received it on day 3. The occurrence of grades 3–4 neutropenia and FN was the primary endpoint. The secondary endpoint was the frequency of PEG-rhG-CSF dose reduction. Results: Compared with the control group, the white blood count (WBC) or absolute neutrophil count (ANC) in the experimental group was higher on days 9 and 13 (P &amp;lt; 0.05) after chemotherapy, and the incidence of grade 3–4 neutropenia was lower (P = 0.038). The experimental group met the standard for lowering the PEG-rhG-CSF dose were more than that in the control group (69.74% vs. 35.06%, P &amp;lt; 0.001). Patients receiving a lower PEG-rhG-CSF dose had higher WBC count and ANC after chemotherapy, but were more likely to suffer from mild arthralgia. (P &amp;lt; 0.05). Conclusion: In comparison with PEG-rhG-CSF injection on day 3 after chemotherapy, the incidence of grade 3–4 myelosuppression is lower, and the safety is more manageable after the injection on day 7. Thus, more patients will receive dose reduction and lower patient medical costs. Citation Format: Xiaoming Zha, Jue Wang, Yinggang Xu, Jinzhi He, Ye Wang, Weiwei Zhang, Xinyu Wan, Wenjie Shi. A prospective, randomized, controlled clinical trial comparing different PEG-rhG-CSF administration times to treat chemotherapy-induced neutropenia and febrile neutropenia in early breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-20-02.

A retrospective study of ovarian tissue cryopreservation in female patients with hematological diseases for fertility preservation.

To investigate the effect and safety of ovarian tissue cryopreservation (OTC) for fertility preservation in female patients with hematological diseases. We designed a retrospective study. The clinical data of patients with hematological diseases undergoing OTC admitted to Peking University People's Hospital from April 2017 to January 2023 were analyzed and summarized. A total of 24 patients were included in the study, including 19 patients with malignant hematological diseases and 5 patients with non-malignant hematological diseases. The former included 14 patients with acute leukemia, 1 patient with chronic leukemia, and 4 patients with myelodysplastic syndrome, while the latter 5 patients were aplastic anemia (AA). 16 patients had received chemotherapy before OTC. The average age of 24 patients was 22.80 ± 6.81years. The average anti-Mullerian hormone (AMH) was 1.97 ± 2.12ng/mL, and the average follicle-stimulating hormone (FSH) was 7.01 ± 4.24IU/L in examination before OTC. FSH was greater than 10.0IU/L in 4 cases. The pre-OTC laboratory tests showed that the average white blood cell (WBC) count was (3.33 ± 1.35) × 109/L, the average hemoglobin was 91.42 ± 22.84g/L, and the average platelet was (147.38 ± 114.46) × 109/L. After injection of recombinant human granulocyte colony-stimulating factor (rhG-CSF), blood transfusion, and iron supplementation in pre-OTC treatment, the average WBC count was (4.91 ± 3.07) × 109/L, the average hemoglobin was 98.67 ± 15.43g/L, and the average platelet was (156.38 ± 103.22) × 109/L. Of the 24 patients, 22 underwent laparoscopic bilateral partial oophorectomy and oophoroplasty, and 2 underwent laparoscopic unilateral oophorectomy. The average duration of OTC was 59.54 ± 17.58min, and the average blood loss was 32.1 ± 41.6mL. The maximum blood loss was 200mL. There was no significant difference in WBC count and hemoglobin concentration after OTC compared to pre-OTC period. Only the platelet count after OTC surgery was significantly different from that before surgery ([134.54 ± 80.84 vs. 156.38 ± 103.22] × 109/L, p < 0.05). None of the 24 patients had serious complications after OTC. 2 patients had mild infection symptoms, but both recovered well. 23 patients underwent hematopoietic stem cell transplantation (HSCT) after OTC. The median and interquartile range from OTC to the pretreatment of HSCT was 33 (57) days, and the median and interquartile range from OTC to HSCT was 41 (57) days. Seven of them began pretreatment of HSCT within 20days and began HSCT within 30days after OTC. All patients were followed up. Of the 23 patients who underwent HSCT after surgery, 22 presented with amenorrhea and 1 with scanty menstrual episodes. Seven patients underwent hormone replacement therapy (HRT) after HSCT. A patient with AA underwent ovarian tissue transplantation (OTT) 3years after HSCT and resumed regular menstruation 6months after OTT. Ovarian tissue cryopreservation has a promising future in fertility protection in patients with hematological diseases. However, patients with hematological malignancies often have received gonadotoxic therapy before OTC, which may be accompanied by myelosuppression while patients with non-malignant hematological diseases often present with severe hemocytopenia. So perioperative complete blood count of patients should be paid attention to. There was no significant difference in the WBC count and hemoglobin concentration in patients with hematological diseases before and after OTC surgery, and the platelet count decreased slightly within the normal range. Infection is the most common post-OTC complication, and HSCT pretreatment can be accepted as early as the 10th day after OTC. OTC has no adverse effects on patients with hematological diseases and does not delay HSCT treatment. For young patients with hematological diseases, OTC is an effective method of fertility preservation.

Clinical outcomes of coronavirus disease in patients with breast cancer treated with granulocyte colony-stimulating factor following chemotherapy: Triangulation of evidence using population-based cohort and Mendelian randomization analyses.

Recombinant human granulocyte colony-stimulating factor (G-CSF) administration in patients with cancer and coronavirus disease (COVID-19) remains controversial. Concerns exist that it may worsen COVID-19 outcomes by triggering an inflammatory cytokine storm, despite its common use for managing chemotherapy-induced neutropenia (CIN) or febrile neutropenia post-chemotherapy. Here, we determined whether prophylactic or therapeutic G-CSF administration following chemotherapy exacerbates COVID-19 progression to severe/critical conditions in breast cancer patients with COVID-19. Between December 2022 and February 2023, all 503 enrolled breast cancer patients had concurrent COVID-19 and received G-CSF post-chemotherapy, with most being vaccinated pre-chemotherapy. We prospectively observed COVID-19-related adverse outcomes, conducted association analyses, and subsequently performed Mendelian randomization (MR) analyses to validate the causal effect of genetically predicted G-CSF or its associated granulocyte traits on COVID-19 adverse outcomes. Only 0.99% (5/503) of breast cancer patients experienced COVID-19-related hospitalization following prophylactic or therapeutic G-CSF administration after chemotherapy. No mortality or progression to severe/critical COVID-19 occurred after G-CSF administration. Notably, no significant associations were observed between the application, dosage, or response to G-CSF and COVID-19-related hospitalization (all p >.05). Similarly, the MR analyses showed no evidence of causality of genetically predicted G-CSF or related granulocyte traits on COVID-19-related hospitalization or COVID-19 severity (all p >.05). There is insufficient evidence to substantiate the notion that the prophylactic or therapeutic administration of G-CSF after chemotherapy for managing CIN in patients with breast cancer and COVID-19 would worsen COVID-19 outcomes, leading to severe or critical conditions, or even death, especially considering the context of COVID-19 vaccination.

CRISPR-Cas9n-mediated ELANE promoter editing for gene therapy of severe congenital neutropenia

Severe congenital neutropenia (CN) is an inherited pre-leukemia bone marrow failure syndrome commonly caused by autosomal-dominant ELANE mutations (ELANE-CN). ELANE-CN patients are treated with daily injections of recombinant human granulocyte colony-stimulating factor (rhG-CSF). However, some patients do not respond to rhG-CSF, and approximately 15% of ELANE-CN patients develop myelodysplasia or acute myeloid leukemia. Here, we report the development of a curative therapy for ELANE-CN through inhibition of ELANE mRNA expression by introducing two single-strand DNA breaks at the opposing DNA strands of the ELANE promoter TATA-box using CRISPR/Cas9D10A nickases - termed MILESTONE. This editing effectively restored defective neutrophil differentiation of ELANE-CN CD34+ hematopoietic stem and progenitor cells (HSPCs) in vitro and in vivo, without affecting the functions of the edited neutrophils. CRISPResso analysis of the edited ELANE-CN CD34+ HSPCs revealed on-target efficiencies of over 90%. Simultaneously, GUIDE-seq, CAST-Seq, and rhAmpSeq indicated a safe off-target profile with no off-target sites or chromosomal translocation. Taken together, ex vivo gene editing of ELANE-CN HSPCs using MILESTONE in the setting of autologous stem cell transplantation could be a universal, safe, and efficient gene therapy approach for ELANE-CN patients.

Safety of Docetaxel in a Patient with Metastatic Castration-Resistant Prostate Cancer After Kidney Transplantation: A Case Report

There are limitations in treating advanced prostate cancer (PC), especially castration-resistant (CR) cases, in renal transplant recipients (RTRs). We describe the case of RTR with metastatic CRPC (mCRPC) treated with docetaxel. A 60-year-old man with end-stage renal disease due to autosomal-dominant polycystic kidney disease (ADPKD) underwent living-related kidney transplantation. A year later, he was diagnosed with PC (prostate-specific antigen level: 998 ng/mL). Prostate biopsy revealed prostatic adenocarcinoma with a Gleason score of 4 + 4 = 8. Radiographic examination revealed seminal vesicle invasion and multiple bone and lymph node metastases. Combined androgen blockade therapy was initiated; however, the patient was diagnosed with CRPC 6 months later. Triweekly docetaxel therapy was administered 28 months after diagnosis. The patient successfully completed 7 cycles of this therapy without major adverse events. However, after the 7th cycle, he developed a high fever caused by an infection of ADPKD-associated renal cysts. Therefore, docetaxel was discontinued, and enzalutamide was started, followed by abiraterone, but without any effect. We then introduced cabazitaxel but discontinued it because of hepatic dysfunction. Hence, the patient underwent a docetaxel rechallenge. He was administered the PEGylated form of the recombinant human granulocyte colony-stimulating factor for neutropenia prophylaxis. After 6 cycles of rechallenge docetaxel therapy, the patient accidentally fell, resulting in a cervical spine fracture and subsequent death due to respiratory failure. Docetaxel can be safely delivered to patients with CRPC after renal transplantation who are taking oral immunosuppressants. It can be a good treatment option for them.

Site-selective fatty acid chain conjugation of the N-terminus of the recombinant human granulocyte colony-stimulating factor.

The clinical application of the recombinant human granulocyte colony-stimulating factor (rhG-CSF) is restricted by its short serum half-life. Herein, site-selective modification of the N-terminus of rhG-CSF with PAL-PEG3-Ph-CHO was used to develop a long-acting rhG-CSF. The optimized conditions for rhG-CSF modification with PAL-PEG3-Ph-CHO were: reaction solvent system of 3% (w/v) Tween 20 and 30mM NaCNBH3 in acetate buffer (20mmol/L, pH 5.0), molar ratio of PAL-PEG3-Ph-CHO to rhG-CSF of 6:1, temperature of 20°C, and reaction time of 12h, consequently, achieving a PAL-PEG3-Ph-rhG-CSF product yield of 70.8%. The reaction mixture was purified via preparative liquid chromatography, yielding the single-modified product PAL-PEG3-Ph-rhG-CSF with a HPLC purity exceeding 95%. The molecular weight of PAL-PEG3-Ph-rhG-CSF was 19297Da by MALDI-TOF-MS, which was consistent with the theoretical value. The circular dichroism analysis revealed no significant change in its secondary structure compared to unmodified rhG-CSF. The PAL-PEG3-Ph-rhG-CSF retained 82.0% of the in vitro biological activity of unmodified rhG-CSF. The pharmacokinetic analyses showed that the serum half-life of PAL-PEG3-Ph-rhG-CSF was 7.404 ± 0.777h in mice, 4.08 times longer than unmodified rhG-CSF. Additionally, a single subcutaneous dose of PAL-PEG3-Ph-rhG-CSF presented comparable in vivo efficacy to multiple doses of rhG-CSF. This study demonstrated an efficacious strategy for developing long-acting rhG-CSF drug candidates.

Effect of M0 macrophage-derived exosome miR-181d-5p targeting BCL-2 to regulate NLRP3/caspase-1/GSDMD pathway on human renal mesangial cells pyroptosis

BackgroundLupus nephritis (LN) is a type of autoimmune disease that impacts the kidneys. Exosomes are valuable for in-depth studies of the pathogenesis of LN. This study aimed to explore miR-181d-5p expression levels in M0 macrophage-derived exosomes and their role in human renal mesangial cells (HRMC) pyroptosis through binding to BCL-2. MethodsPeripheral blood mononuclear cells (PBMCs) were collected from patients with lupus nephritis (LN) and healthy subjects. Monocytes isolated from these samples were induced into M0 macrophages using recombinant human granulocyte colony-stimulating factor (rhG-CSF). In a parallel process, THP-1 cells were induced into M0 macrophages using Phorbol Myristate Acetate (PMA). LPS- and ATP-stimulated HRMC were used to construct a cell pyroptosis model. We then introduced different miR-181d-5p mimic fragments into the M0 macrophages derived from the THP-1 cells. Subsequently, exosomes from these macrophages were co-cultured with HRMC. To evaluate the impact on HRMC, we conducted proliferation and apoptosis assessments using CellCountingKit-8assay and flow cytometry. The effect of exosomal miR-181d-5p on HRMC pyroptosis was assessed using western blot. The miR-181d-5p and BCL-2 targeting relationship was detected using real-time fluorescence quantitative PCR. IL-6, IL-1β, and TNF-α levels in cell supernatants were detected using ELISA kits. ResultsIn this study, we observed an increase in miR-181d-5p levels within exosomes secreted from M0 macrophages obtained by induction of monocytes from LN patients. It was found that miR-181d-5p can target binding to BCL-2. Exosomes with elevated levels of miR-181d-5p contributed to a significant increase in miR-181d-5p within HRMC, facilitating its proliferation and inhibiting apoptosis. Furthermore, exosomes expressing high levels of miR-181d-5p were observed to promote an inflammatory response and pyroptosis in HRMC. Notably, these effects were reversed when the levels of miR-181d-5p in the exosomes were reduced. ConclusionInhibition of miR-181d-5p, derived from M0 macrophage exosomes, effectively suppresses inflammation and pyroptosis in HRMC. This discovery indicates that miR-181d-5p holds the potential as a valuable target in the development of treatments for Lupus Nephritis (LN).

Cost-effectiveness analysis of mecapegfilgrastim and recombinant human granulocyte stimulating factor for primary prophylaxis of chemotherapy-induced neutropenia innon-small cell lung cancer.

To evaluate the efficacy, safety, and economics of mecapegfilgrastim and recombinant human granulocyte colony-stimulating factor (rhG-CSF) in the primary prevention of chemotherapy-related neutropenia in non-small cell lung cancer (NSCLC). Data from 181 patients with NSCLC who received intermediate risk chemotherapy were collected from the information system of a tertiary hospital in China. Patients were categorized into two groups: those treated with mecapegfilgrastim (n=91) and those treated with rhG-CSF (n=90). The clinical efficacy rates of neutropenia prevention were used as effect indicators, and a cost-effectiveness analysis was conducted from the perspective of the Chinese healthcare system. Logistic regression, generalized linear regression, and bootstrap methods were used for sensitivity analyses. There was no statistical difference between the mecapegfilgrastim and rhG-CSF groups in clinical efficacy rates (98.9 vs. 97.8%). However, the total cost in the mecapegfilgrastim group was significantly higher than that in the rhG-CSF group (16,341.6 CNY vs. 14,371.1 CNY, p=0.03). The cost-minimization analysis shows that mecapegfilgrastim is not cost-effective. The sensitivity analyses confirm that these results are robust. Compared with rhG-CSF, mecapegfilgrastim is not a cost-effective strategy for NSCLC patients in neutropenia prevention in China.

On-demand plerixafor added to high-dose cyclophosphamide and pegylated recombinant human granulocyte colony-stimulating factor in the mobilization of patients with multiple myeloma: a treatment with high effectiveness, convenient, and affordable cost.

The combination of high-dose cyclophosphamide (HD-Cy) (3g/m2) plus granulocyte colony-stimulating factor (G-CSF) and on-demand plerixafor (PXF) has been considered an effective mobilization regimen of patients with multiple myeloma(MM). However, the daily multi-injection regimen of G-CSF poses challenges. This study delves into the efficiency and cost implications of a novel approach, using HD-Cy alongside pegylated G-CSF (PEG G-CSF) and on-demand PXF. Unlike G-CSF, which necessitates daily injections, the half-life of PEG G-CSF extended allows for a single injection. A retrospective analysis was conducted on 350 MM patients, which were categorized based on their mobilization regimens: Cy+PEG G-CSF+/-PXF (n=66), Cy+PEG G-CSF (n=91), Cy+ G-CSF (n=169), and G-CSF+PXF (n=24). Mobilization with Cy+PEG G-CSF+/-PXF(8.79)yielded a notably higher median CD34+ cell count compared to the other regimens: Cy+PEG G-CSF(4.96), Cy+G-CSF (4.65), and G-CSF+PXF (2.99) (P<0.001). The percentage of patients who achieved >6×106/kg CD34+ cells was significantly higher in the Cy+PEG G-CSF+/-PXF group (77.3%) than in the other mobilization regimens: Cy+PEG G-CSF (41.8%), Cy+ G-CSF (37.3%), and G-CSF+PXF (8.3%) (P<0.001). From a cost perspective, the Cy+PEG G-CSF+/-PXF approach was more economical than the G-CSF+PXF strategy but was marginally costlier than the other two methods. A multivariate assessment highlighted that the combination of Cy+PEG G-CSF with on-demand PXF had a superior potential to achieve the desired harvest (6×106/kg) compared to the Cy+PEG G-CSF protocol without PXF. The incremental cost-effectiveness ratio for each 1% increase in the probability of achieving a successful optimal harvest was $ 97.02 per patient. The incidence of neutropenic fever was 3.0% in the Cy+PEG G-CSF+/-PXF group. The combination of on-demand PXF with HD-Cy and PEG G-CSF offers a cost-effective approach with a high mobilization success rate, manageable side effects, and the convenience of fewer injections. It stands as a promising mobilization strategy for MM patients.