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Hematopoietic progenitor cell collection (HPC-C) by apheresis after granulocyte-colony stimulating factor (G-CSF) stimulation is a routine worldwide procedure. The first apheresis procedure is typically performed on Day 5 of G-CSF administration. We aimed to evaluate whether initiating the apheresis procedure on Day 4, with 1 day shorter G-CSF exposure for the donor, affects collection outcomes. This study included healthy, unrelated donors who underwent HPC-C by apheresis after G-CSF administration between April 2022 and February 2024 at our center. Of 182 unrelated donors, 34.6% underwent apheresis on Day 4 of G-CSF treatment and 65.4% on Day 5. There was no significant difference between the two groups in terms of collected CD34+ cell yield (p = 0.369) or the need for a second apheresis procedure (p = 0.74). Successful mobilization was achieved in 93.7% of donors who underwent a single apheresis procedure on Day 4 and in 95% of those who underwent a single apheresis procedure on Day 5 (p = 0.477). In donors requiring two consecutive apheresis procedures, the collected CD34+ cell yield was higher in those who initiated apheresis on Day 4, although this difference was not statistically significant (p = 0.067). This is the first study comparing HPC-C outcomes on Days 4 and 5 of G-CSF administration exclusively in unrelated donors. Our data indicate no difference in the collected CD34+ cell yield or the need for a second apheresis procedure between the two groups. Initiating apheresis on Day 4 may allow for 1 day less G-CSF exposure without compromising collection outcomes.
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Remoção de Componentes Sanguíneos , Fator Estimulador de Colônias de Granulócitos , Mobilização de Células-Tronco Hematopoéticas , Células-Tronco de Sangue Periférico , Doadores não Relacionados , Humanos , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas/métodos , Masculino , Feminino , Adulto , Remoção de Componentes Sanguíneos/métodos , Células-Tronco de Sangue Periférico/citologia , Antígenos CD34 , Fatores de Tempo , Pessoa de Meia-Idade , Células-Tronco HematopoéticasRESUMO
Promoter-proximal pausing of RNA polymerase II (Pol II) primes genes for rapid activation, yet how Pol II dynamics are temporally organized in adult stem cells to enable fast and flexible responses to environmental cues remain unknown. To address this, we developed sciCUT&Tag2in1 for joint profiling of Pol II and histone modifications in single cells. By profiling over 200,000 CD34+ hematopoietic stem cells (HSCs) and progenitors, we identify a Pol II regulatory cascade that directs the response to granulocyte colony-stimulating factor (G-CSF)-induced inflammatory stress. HSCs are activated by elevated Pol II occupancy and reduced Polycomb repression of immune response genes. Lineage commitment proceeds through sequential modes of Pol II activation, beginning with rapid pause-and-release genes, followed by slower initiate-and-release of Polycomb-repressed targets. sciCUT&Tag2in1 defines the temporal logic of how adult stem cells use paused Pol II to enable flexible lineage decisions, providing a powerful tool for studying the intersection of development, inflammation, and disease.
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BACKGROUND: Granulocyte colony-stimulating factor (G-CSF) is a crucial hematopoietic growth factor essential for granulopoiesis, inflammation, and immune responses in humans and animals. Although widely used in human medicine for neutropenia and transplantation support, its applications in feline medicine, encompassing neutropenia, infection management, and transplantation, remain underexplored, with limited comprehensive reviews. A significant limitation of recombinant human G-CSF (rhG-CSF) treatment in cats is the risk of developing neutralizing antibodies, which can target G-CSF and potentially reduce its efficacy. Developing feline-specific or long-acting variants offers potential solutions. METHODS: A comprehensive literature search was performed using PubMed and other databases up to August 1, 2025. Search terms included "G-CSF", "granulocyte colony-stimulating factor", "feline", and "cat". Studies reporting the clinical use of G-CSF in cats were included. RESULTS: rhG-CSF administration elevated neutrophil and lymphocyte counts but could induce transient neutropenia and immunogenicity. In contrast, recombinant feline G-CSF (rfG-CSF) demonstrated improved bioactivity and did not generate anti-drug antibodies in small-scale studies with follow-up periods extending beyond one year. Novel long-acting variants, including PEGylated rfG-CSF (PEG-rfG-CSF) and a fusion protein, exhibited prolonged half-life and enhanced efficacy compared to standard forms. CONCLUSION: rfG-CSF represents a promising therapeutic alternative to rhG-CSF for managing neutropenia in cats, primarily due to its lack of immunogenicity. Future development efforts should focus on optimizing these long-acting formulations and maximizing bioactivity to facilitate widespread clinical adoption and commercialization in veterinary medicine.
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Doenças do Gato , Fator Estimulador de Colônias de Granulócitos , Neutropenia , Animais , Gatos , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/imunologia , Doenças do Gato/tratamento farmacológico , Doenças do Gato/imunologia , Proteínas Recombinantes/uso terapêutico , Proteínas Recombinantes/imunologia , Neutropenia/veterinária , Neutropenia/tratamento farmacológicoRESUMO
Platelet-targeted gene therapy for hemophilia entails modifying a patient's hematopoietic stem cells (HSCs) ex vivo to produce platelets containing coagulation factors, offering a potential cure by localized factor release at injury sites. However, the associated bone marrow transplantation carries significant risks, underscoring the critical need for low-toxicity conditioning regimens to enable clinical translation. This study evaluated G-CSF and 5-FU as conditioning regimens to facilitate the engraftment of HSCs expressing platelet-targeted FIX Padua. Hemophilia B (HB) mice were conditioned with G-CSF, 5-FU alone, or a combination of G-CSF, plerixafor, and 5-FU. Bone marrow mononuclear cells (BM-MNCs) from transgenic donors (2bF9-R338L) expressing platelet-stored FIX Padua were transplanted. G-CSF conditioning enabled long-term engraftment with 1 × 108 BM-MNCs; however, the efficacy declined significantly with lower cell doses. A single-dose of 5-FU (150 mg/kg) administered one day pre-transplant achieved optimal FIX expression and minimal toxicity. Critically, a combined regimen of G-CSF/plerixafor plus timed 5-FU (day -1) yielded stable, long-term platelet FIX expression and phenotypic rescue. The success of 5-FU underscores the importance of creating a transient niche vacancy for donor HSC engraftment. These results demonstrate that this mobilization-based, non-myeloablative conditioning strategy is a promising approach for platelet-targeted gene therapy for hemophilia.
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Plaquetas , Fluoruracila , Terapia Genética , Fator Estimulador de Colônias de Granulócitos , Hemofilia B , Condicionamento Pré-Transplante , Animais , Terapia Genética/métodos , Hemofilia B/terapia , Hemofilia B/genética , Fluoruracila/farmacologia , Camundongos , Plaquetas/metabolismo , Plaquetas/efeitos dos fármacos , Condicionamento Pré-Transplante/métodos , Fator Estimulador de Colônias de Granulócitos/farmacologia , Fator IX/genética , Transplante de Células-Tronco Hematopoéticas , Camundongos Transgênicos , Humanos , Modelos Animais de DoençasRESUMO
Filgrastim, a therapeutic protein for the treatment of neutropenia, exerts its biological activity by interacting with the granulocyte colony-stimulating factor receptor. However, the affinity of filgrastim to its receptor is usually overlooked during characterization and comparability tests, since its biological activity is assessed only by in vitro proliferation assays. In this work, we propose the use of a cell-based colorimetric method to determine the relative affinity of filgrastim to its receptor expressed in murine myeloid leukemia cells. After performing a validation exercise, the method proved to be accurate, specific, and linear within an affinity interval of 75 to 130%; precise with a confidence interval of 93.6 to 114.2% and a coefficient of variation of 12.6%. The validation exercise proved that the proposed cell-based method is a viable alternative to evaluate the biological activity of filgrastim via the affinity for its receptor and it is suitable to be included as part of its biological characterization exercises as well as in comparability exercises for products coming from distinct manufacturing processes.
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Background: Severe congenital neutropenia (SCN) is commonly treated with granulocyte colony-stimulating factor (G-CSF) to reduce neutropenia and the associated risk of infections. Pegfilgrastim, a long-acting form of G-CSF, provides the benefit of less frequent dosing; however, its application in SCN has not been extensively studied. This study aims to assess the long-term safety and effectiveness of transitioning SCN patients from standard G-CSF therapy to pegfilgrastim. Methods: We followed eight patients with severe congenital neutropenia (five males, average age 17.8 years) who had been on G-CSF treatment for at least five years. They were switched to pegfilgrastim injections (3-6 mg every 7-14 days). Dosing was individualized to obtain an absolute neutrophil count (ANC) above 1000/µL in all patients. Over a five-year follow-up under treatment with pegfilgrastim, patients were evaluated for ANC levels, infection frequency, adverse effects, and quality of life using the Functional Assessment of Cancer Therapy-Neutropenia (FACT-N) questionnaire. In addition, yearly abdominal ultrasounds, bone density every two years, and genetic screening for RUNX1 and the G-CSF receptor mutations were performed. Results: Pegfilgrastim significantly improved ANC levels compared to prior G-CSF treatment (p = 0.008). Quality of life (QoL) significantly improved in six patients (p = 0.016). Varying maintenance dosages were required based on the therapeutic response. Bone pain was common, leading to discontinuation in one patient. Two patients developed hip osteopenia, and one showed progressive splenomegaly. Hospitalization rates and infection frequency remained unchanged. Oral ulcers were decreased overall. Conclusion: Pegfilgrastim can be used as an alternative to daily G-CSF in SCN, providing stable ANC and QoL improvements with individualized dosing. Larger studies are warranted to evaluate its long-term safety and efficacy. Clinical trial registration: This trial is registered at https://irct.behdasht.gov.ir/ in Iranian Registry of Clinical Trials (IRCT) # IRCT20150125020786N3.
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BACKGROUND: Primary Graft Dysfunction (PGD) is an early post-lung transplant (LTx) inflammatory condition primarily driven by lung ischemia-reperfusion injury (LIRI). Neutrophils are key mediators of LIRI, but their phenotypic diversity and maturation state remain poorly characterized. In other inflammatory settings, early expansion of immature neutrophils has been linked to increased tissue injury and worse clinical outcomes. Whether immature neutrophils increase following LTx and contribute to PGD severity remains unclear. METHODS: Circulating neutrophil heterogeneity was analyzed by flow cytometry in 20 LTx candidates with advanced lung disease and 30 LTx recipients. Matched plasma samples were used for cytokine profiling. The role of immature neutrophils in LIRI was studied using a murine left pulmonary hilar clamp model with or without anti-G-CSF treatment. The differentiation and effector functions of immature neutrophils derived from murine hematopoietic progenitors were studied in vitro. RESULTS: LTx recipients exhibited an early rise in circulating immature neutrophils, correlated with higher G-CSF levels and PGD severity. In mice, LIRI was linked to increased G-CSF levels, significant mobilization, and lung infiltration of immature neutrophils with an activated, ROS-producing phenotype. These cells showed prolonged survival, strong ROS activity, but impaired phagocytosis. Preoperative anti-G-CSF treatment decreased lung injury while reducing immature neutrophil mobilization and recruitment to the lung. CONCLUSIONS: Our findings underscore the clinical significance of neutrophil heterogeneity in the early perioperative setting following LTx. Targeting the G-CSF-immature neutrophil axis may offer a novel strategy to improve early lung allograft outcomes.
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Background and Objectives: There are limited data on the requirement and duration of white blood cell (WBC) growth factor (GF) administration in patients receiving biweekly docetaxel, oxaliplatin, leucovorin, 5 Fluorouracil (mFLOT) or modified FOLFIRINOX (oxaliplatin, irinotecan, leucovorin, 5 Fluorouracil (mFOLFIRINOX) regimens. Methods: The data of 749 patients with pancreatic, gastric, and colorectal adenocarcinomas treated with mFOLFIRINOX or mFLOT for at least three cycles between January 2018 and December 2022 were retrieved. Results: Of the 749 patients, 387 (52%) received mFLOT, while 362 (48%) received mFOLFIRINOX. Increased use of GF was seen in patients with diabetes mellitus (70 vs. 53%; p < 0.001), prior chemotherapy (82 vs. 49%; p < 0.001), prior pelvic radiotherapy (89 vs. 54%; p < 0.001), prior surgery (70 vs. 49%; p < 0.001), and stage I to III cancers as opposed to stage IV cancers (61 vs. 48%; p = 0.006). The use of GF resulted in a statistically lesser incidence of all-grades neutropenia (2.6 vs. 18.4%; p < 0.001), grade 3/4 neutropenia (1.2 vs. 12.5%; p < 0.001), and the primary endpoint of febrile neutropenia (FN; 1.2 vs. 6.1%; p = 0.001). There were no differences in the incidence of all grades of neutropenia (3.7 vs. 1.9%; p = 0.527), grade 3/4 neutropenia, and the primary endpoint of FN (1.2 vs. 1.1%; p = 0.079) in patients receiving single-day versus multiday GF, respectively. Interpretation and Conclusion: The use of GF reduces the rates of FN by approximately 80% in patients receiving mFLOT and mFOLFIRINOX, although incidences of FN are low with these regimens. The incidence of febrile neutropenia was similar with single-dose versus multiday GF in efficacy when administered with mFLOT and mFOLFIRINOX chemotherapy.
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Pulmonary sarcomatoid carcinoma (PSC) is a rare and aggressive subtype of non-small cell lung cancer, and granulocyte colony-stimulating factor (G-CSF)-producing PSC is associated with particularly poor prognosis and inconsistent responses to immune checkpoint inhibitors (ICIs). We report the case of a 67-year-old man presented with leukocytosis, systemic inflammation, and a right upper lobe mass diagnosed as PSC with positive G-CSF expression and a high programmed death-ligand 1 (PD-L1) tumor proportion score (95 %). Despite stage IIIB disease with mediastinal lymph node involvement and poor performance status, the patient was treated with chemoradiotherapy (CRT), in which radiotherapy was initiated first and subsequently combined with weekly carboplatin and paclitaxel. Durvalumab consolidation was initiated but discontinued because of radiation pneumonitis requiring corticosteroids. Nevertheless, he achieved durable disease control, exceeding 12 months, with normalization of inflammatory markers and improved performance status. This case suggests that multimodal therapy, including CRT and feasible use of consolidation durvalumab, may provide clinical benefit in G-CSF-producing PSC, for which optimal management remains undefined.
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Background: Current immunotherapies for type 1 diabetes (T1D) have shown limited success in durably preserving ß-cell function. We tested a novel strategy that repurposes allogeneic islet transplantation not for metabolic replacement, but as a platform for antigen-specific immune education. Methods: In this monocentric, open-label pilot study (April 2015-April 2023), six patients with recent-onset T1D received a minimal islet mass (median 3452 IEQ/kg; range 2980-4050) combined with short-term immunomodulation (ATG, transient mTOR inhibition, and G-CSF). The transplanted islet mass was intentionally insufficient for metabolic replacement. The primary endpoint was the change in stimulated 2-h C-peptide AUC at 52 weeks. Exploratory endpoints included immune cell phenotyping, cytokine/chemokine profiling, miR-375 release kinetics, analysis of islet-related autoantibodies, and monitoring of donor-specific HLA antibodies. ClinicalTrials.gov Identifier: NCT02505893. Findings: The protocol was safe and well-tolerated. At 12 months, the median stimulated C-peptide AUC was preserved at 91-100% of baseline with all participants achieving a partial clinical remission (IDAA1c ≤ 9). At 5 years, median C-peptide AUC declined to 44-56% of baseline, with 2 patients maintaining stable secretion and 2 retaining â¼50% of initial function. Exploratory analyses demonstrated a structured pattern of immune resetting, with early lymphodepletion followed by memory and regulatory T-cell expansion; transient increases in IL-2 and IL-10; sustained early elevation of sCD25; biphasic miR-375 peaks indicating early ß-cell stress; transient increases in autoantibodies without epitope spreading; and donor-specific class I HLA antibodies in five patients, with persistent class II DSA in two. No expansion of CD3+CD8+ T cells specific for GAD65 was detected. Interpretation: This study introduces a paradigm shift in the use of islet transplantation-transforming it from a metabolic intervention into a tolerogenic stimulus through controlled antigen exposure. Further potentiation with stem-cell-derived islets may enable improved matching, graft modification, and iterative antigen delivery. Funding: Supported by Fondazione Italiana Diabete (FID). The funder had no role in study design, data collection, data analysis, interpretation, manuscript preparation, or decision to publish.
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Filgrastim, a granulocyte colony-stimulating factor (G-CSF), is widely used for the mobilization of peripheral blood stem cells in donors and is generally considered safe. While transient side effects such as bone pain and arthralgia are well-documented, chronic musculoskeletal complications are rarely reported, particularly in otherwise healthy individuals. Herein, we describe the case of a 43-year-old physically active female who developed prolonged musculoskeletal symptoms following stem cell mobilization with filgrastim. The patient initially experienced severe flu-like symptoms and diffuse myalgia, which progressed post-collection and significantly impaired daily function. Despite partial spontaneous improvement, symptoms recurred after physiotherapy and persisted nine months later, prompting hospital admission. Clinical findings included joint pain, swelling, and restricted shoulder mobility. Laboratory tests showed elevated inflammatory markers and positive ANA, while creatine kinase levels remained normal. Imaging revealed Klippel-Feil syndrome and mild degenerative changes. A single dose of intramuscular betamethasone led to gradual recovery of muscular function. This case underscores the importance of recognizing potential long-term iatrogenic effects of G-CSF, even in healthy donors, and highlights the need for individualized follow-up and management.
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Filgrastim , Fator Estimulador de Colônias de Granulócitos , Mobilização de Células-Tronco Hematopoéticas , Doenças Musculares , Humanos , Feminino , Adulto , Filgrastim/efeitos adversos , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Mobilização de Células-Tronco Hematopoéticas/efeitos adversos , Resultado do Tratamento , Doenças Musculares/induzido quimicamente , Proteínas Recombinantes/efeitos adversos , Doadores de TecidosRESUMO
PURPOSE: We performed post-marketing surveillance of the safety and effectiveness of 3.6 mg pegfilgrastim to prevent chemotherapy-induced febrile neutropenia (FN) in real-world conditions in Japan. METHODS: Patients were registered between June 2015 and May 2017 and followed prospectively. Pegfilgrastim was administered once every chemotherapy cycle (maximum 6 cycles). Use of pegfilgrastim, safety, and effectiveness in reducing FN were evaluated. RESULTS: From 300 institutions, 1,597 patients were registered and 1,479 patients were analyzed. Pegfilgrastim was given as primary prophylaxis (750 patients), as secondary prophylaxis (727 patients), or for therapeutic purposes (2 patients). The most common primary diseases were breast cancer (51.4%) and non-Hodgkin lymphoma (25.6%). Adverse events (AEs) occurred in 36.4% of patients and adverse drug reactions (ADR) in 18.5%. Common ADRs included back pain (3.6%), pyrexia (3.1%), arthralgia (2.1%), hepatic function abnormal (1.5%), myalgia (1.4%), and bone pain (1.0%). All back and/or bone pain-related ADRs were non-serious and well-controlled with non-steroidal anti-inflammatory drugs. Docetaxel-cyclophosphamide therapy among breast cancer patients was a factor influencing bone and/or back pain-related AEs by multivariate logistic regression analysis (odds ratios vs. fluorouracil-epirubicin-cyclophosphamide therapy: 2.32, P = 0.031). FN was observed in 5.3% (primary prophylaxis) and 2.5% (secondary prophylaxis) of the effectiveness analysis set in cycle 1 and decreased with increasing cycles. CONCLUSION: This survey confirmed that both primary and secondary prophylaxis using pegfilgrastim reduced FN in the real-world setting. No new safety concerns were identified. This survey was retrospectively registered on 26 April 2024 in the University Hospital Medical Information Network Clinical Trial Registry (UMIN000054267).
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Antineoplásicos , Neutropenia Febril Induzida por Quimioterapia , Filgrastim , Neoplasias , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Antineoplásicos/efeitos adversos , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Neutropenia Febril Induzida por Quimioterapia/prevenção & controle , Neutropenia Febril Induzida por Quimioterapia/etiologia , Filgrastim/efeitos adversos , Filgrastim/uso terapêutico , Filgrastim/administração & dosagem , Japão , Neoplasias/tratamento farmacológico , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/uso terapêutico , Vigilância de Produtos Comercializados , Estudos ProspectivosRESUMO
IntroductionTrifluridine-tipiracil (FTD/TPI) is approved as monotherapy and in combination with bevacizumab for the treatment of metastatic colorectal cancer (mCRC). This UK real-world retrospective analysis aimed to evaluate the use of granulocyte colony stimulating factor (G-CSF) to prevent FTD/TPI induced neutropenia in patients with mCRC.MethodsRetrospective data were collected across five UK Healthcare sites. Consecutive patients with mCRC having received at least 2 cycles of FTD/TPI in addition to G-CSF administered as primary or secondary prophylaxis were included. The study assessed the timing and duration of G-CSF treatment, incidence of neutropenia, and subsequent dose delays/reductions. Time on FTD/TPI treatment, Progression free Survival (PFS), and Overall Survival (OS) were also calculated for this patient cohort.ResultsThe data set included 55 mCRC patients in total; 25 receiving primary prophylaxis, and 30 receiving secondary prophylaxis. 68% of G-CSF prophylaxis commenced on day 15, with 99% initiated between days 14 and 22. Following G-CSF use, 25% of patients experienced a dose delay and 18% a dose reduction due to neutropenia. 14.5% of patients reported grade ≥3 neutropenia. In patients receiving primary prophylaxis a mean of 18.4 weeks of FTD/TPI were completed, whereas in those receiving secondary prophylaxis the mean was 28.8 weeks. Primary prophylaxis patients exhibited a median PFS of 3 months, and a median OS of 9.7 months. In secondary prophylaxis patients the median PFS was 7.2 months and the median OS 17.5 months.ConclusionG-CSF prophylaxis reduced the incidence of neutropenia, improved dose intensity, and extended PFS and OS in this real-world study of mCRC patients on FTD/TPI. G-CSF prophylaxis was commonly administered as a 5-day course of filgrastim starting on day 15.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Colorretais , Fator Estimulador de Colônias de Granulócitos , Neutropenia , Trifluridina , Humanos , Estudos Retrospectivos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Colorretais/mortalidade , Masculino , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Trifluridina/efeitos adversos , Trifluridina/administração & dosagem , Feminino , Pessoa de Meia-Idade , Idoso , Reino Unido/epidemiologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Timina/efeitos adversos , Timina/análogos & derivados , Timina/administração & dosagem , Combinação de Medicamentos , Neutropenia/induzido quimicamente , Neutropenia/prevenção & controle , Pirrolidinas/efeitos adversos , Pirrolidinas/administração & dosagem , Adulto , Idoso de 80 Anos ou maisRESUMO
Metastasis is the leading cause of cancer-related mortality. During metastatic progression, distant organs form a pre-metastatic niche (PMN), creating a permissive microenvironment that facilitates circulating tumor cell (CTC) colonization. To investigate pulmonary PMN formation in breast cancer, a micro-organ chip is employed that enables contact-independent coculture of tumor and lung tissues. This model reveals that PMN formation is governed by tumor-secreted factors without requiring direct tumor cell contact and exhibits non-tumor-type specificity. It is found that coculture with tumor tissue upregulates vascular endothelial growth factor (VEGF) receptor-2 (VEGFR2/KDR) in lung capillary cells. Through integrated single-cell RNA sequencing and cytokine array analysis, granulocyte colony stimulating factor (G-CSF) is identified as a key tumor-derived mediator that modulates the pre-metastatic niche through activating the VEGFA-KDR signaling axis in the lung, thereby promoting angiogenesis and PMN development. This study highlights the G-CSF-KDR axis as a potential therapeutic target for inhibiting breast cancer metastasis.
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Background: Primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) in diffuse large B-cell lymphoma (DLBCL) patients undergoing rituximab-cyclophosphamide-doxorubicin-vincristine-prednisolone every 21 d (R-CHOP-21) chemotherapy varies based on physician discretion. Objectives: The present study aims to investigate the impact of primary G-CSF prophylaxis on febrile neutropenia (FN) and other outcomes in DLBCL patients receiving R-CHOP-21 in real-world practice. Methods: Medical records of 103 newly diagnosed DLBCL patients, aged 18-80 years, were retrospectively analyzed. Seventy-four patients received primary G-CSF prophylaxis (prophylaxis group), while 29 patients did not receive prophylaxis (non-prophylaxis group). The occurrence of FN and other outcomes was compared between the two groups. Results: The prophylaxis group had older patients (median ± interquartile ranges [IQR], 63 ± 12 years vs. 50 ± 15 years, P < 0.001). The incidence of FN after the first R-CHOP was not statistically significant between groups (8.3% vs. 17.2%, P = 0.177). However, FN events were significantly higher in non-prophylaxis cycles (7.40%) compared with prophylaxis cycles (2.70%) (P = 0.027). Cumulative FN events were lower in the prophylaxis group (14.9%) than in the non-prophylaxis group (27.6%) (P = 0.134). FN-free survival was not significantly different between prophylaxis and non-prophylaxis groups (hazard ratio [HR], 0.48; 95% confidence interval [95%CI], 0.17-1.35), while primary G-CSF prophylaxis significantly improved event-free survival (HR, 0.36; 95%CI, 0.16-0.84). Conclusions: Primary G-CSF prophylaxis may reduce the risk of FN in DLBCL patients undergoing R-CHOP-21 treatment. The present study highlights the importance of primary G-CSF prophylaxis, especially for those at high risk of FN.
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Autologous hematopoietic stem cell (HSC) gene therapy has gone through remarkable advancements in recent years, especially for the treatment of sickle cell disease (SCD). However, the collection of HSCs from SCD patients requires unique considerations, as granulocyte colony-stimulating factor (G-CSF)-mediated mobilization is contraindicated, and plerixafor-only mobilization is highly variable. Consequently, alternative mobilization regimens that are safe for SCD patients and generate better cell yields are desirable for SCD HSC gene therapy. Here, we evaluated a combination of plerixafor (AMD3100, a CXCR4 antagonist) with GroßT (MGTA-145/GroßT, a CXCR2 agonist) against the current gold-standard G-CSF for HSC gene therapy in nonhuman primates (NHPs) for HSC mobilization, leukapheresis, ex vivo gene editing to reactivate fetal hemoglobin, and transplantation. AMD3100/GroßT rapidly and reliably mobilized phenotypically primitive HSCs within hours even in a G-CSF non-responder. Average CD34/CD90 frequency in the blood and yields after enrichment were comparable in both mobilization regimens. Rapid recovery and robust multilineage long-term engraftment of gene-modified HSCs was achieved in the bone marrow and blood of animals. In summary, AMD3100/GroßT allows highly efficient and reliable mobilization of HSCs, providing a G-CSF-free regimen specifically for SCD but also any other hematological disease or disorder treatable with HSC gene therapy.
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Purpose: Anti-tumor drugs have developed rapidly in recent years. Antibody-drug conjugates (ADCs), as a novel class of targeted biologics, demonstrate significant survival benefits but inevitably cause treatment-related toxicities, with hematologic toxicity-particularly severe neutropenia (grade ≥3)-representing the most prevalent and clinically consequential adverse effect. Currently, no standardized ADC-specific neutropenia management guidelines exist, resulting in fragmented prevention strategies where clinical practice relies on extrapolation from chemotherapy protocols and reactive approaches (e.g., post-onset growth factor support). This study aims to address this gap by proposing a structured preventive framework for ADC-induced neutropenia. Materials and Methods: We conducted a systematic meta-summary of neutropenia data from clinical trials involving ADCs. This evidence was integrated with established principles from chemotherapy-induced neutropenia guidelines and expert consensus. The analysis focused on drug-specific risk profiles, patient-related factors, and evidence-based interventional strategies. Results: We developed a risk-adapted preventive strategy centered on a "planning for a rainy day" approach. The framework incorporates: (1) risk stratification based on the specific ADC drug and patient factors; (2) primary prophylaxis with long-acting granulocyte colony-stimulating factor (G-CSF) for high-risk patients; (3) secondary prevention strategies for subsequent treatment cycles; and (4) dynamic monitoring of absolute neutrophil counts (ANC) around days 5-7 post-infusion. Conclusion: Shifting from a reactive to a proactive, personalized prevention paradigm can potentially reduce the incidence of severe neutropenia, subsequent treatment interruptions, and infection-related mortality. This framework provides actionable guidance for standardizing ADC toxicity management and underscores the importance of prioritizing hematologic safety in future ADC development.
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Pegfilgrastim (pegylated granulocyte colony-stimulating factor, PEG-G-CSF) is commonly used as prophylaxis for febrile neutropenia (FN) in high-risk chemotherapy regimens for breast cancer. However, the optimal timing of PEG-G-CSF injections has not been established, despite several investigations into the subject. In this study, patients received epirubicin-based breast cancer chemotherapy and underwent routine blood tests on days seven or eight of initial chemotherapy to assess the risk of FN. Four patients experienced significant decreases in white blood cell (WBC) and neutrophil (NE) counts. To maintain patient safety and relative dose intensity (RDI), the dose was reduced in the second cycle, and PEG-G-CSF administration was moved from day three to day four, as administering PEG-G-CSF within 24 hours to prevent FN is thought to be ineffective. This theory is based on the fact that the WBC and NE expanded by PEG-G-CSF were killed by the remaining chemotherapy. Therefore, we hypothesized that in the next second cycle, administering PEG-G-CSF one day later (day four) after chemotherapy might be effective for these patients. Furthermore, for patients whose blood tests on days seven or eight of the second cycle showed an increase in WBC and NE counts, the chemotherapy dose was increased in the third cycle. Patients with breast cancer (age range: 41-71 years) were assigned to receive PEG-G-CSF on day three or four of a three-week epirubicin and cyclophosphamide-based chemotherapy regimen (dose-dense epirubicin and cyclophosphamide; 5-fluorouracil, epirubicin, and cyclophosphamide; or basic epirubicin and cyclophosphamide) using heterochronic timing. We then compared WBC and NE counts in the same individuals over time. In all four cases, WBC and NE counts on day seven or eight were much greater with PEG-G-CSF injection on day four than with injection on day three. As per heterochronic follow-up, which has not been reported previously, day four injection of PEG-G-CSF appears more effective than day three injection for preventing neutropenia. However, due to the small number of cases in this series and the confounding factor of the chemotherapy dose in the third cycle being approximately 8% less than that in the first cycle in Case 2, it is difficult to generalize our findings. Hence, future studies with a longitudinal follow-up involving a larger number of cases are required.
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Colony-stimulating factor 3 (CSF3), additionally called granulocyte colony-stimulating factor (G-CSF), is the major cytokine regulating neutrophil production and also impacting their function. The actions of this cytokine are mediated through its unique receptor, the colony-stimulating factor 3 receptor (CSF3R). Several classes of pathogenic mutations in the CSF3R gene have been identified that have distinct biological properties and clinical impacts. This review provides an overview of CSF3R, the various pathogenic CSF3R mutations/variants and their biological effects. It also details the diseases to which they contribute, notably including chronic neutrophilic leukemia (CNL) and other myeloproliferative neoplasms (MPNs), myelodysplastic neoplasms (MDS), combined MDS/MPN disorders such as atypical chronic myeloid leukemia (aCML) and chronic myelomonocytic leukemia (CMML), as well as acute myeloid leukemia (AML) and lymphoid malignancies.