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• W3204287454 abstract "ImmunotherapyVol. 13, No. 17 CommentaryFree AccessLights and shadows on the role of rhG-CSF in cancer patients during the COVID-19 pandemic and future perspectives of researchAngioletta Lasagna, Marta Muzzana & Paolo PedrazzoliAngioletta Lasagna *Author for correspondence: Tel.: +39 038 250 2287; E-mail Address: a.lasagna@smatteo.pv.ithttps://orcid.org/0000-0002-9611-1164Medical Oncology Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, 27100, ItalySearch for more papers by this author, Marta MuzzanaMedical Oncology Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, 27100, ItalyDepartment of Internal Medicine and Medical Therapy, University of Pavia, Pavia, 27100, ItalySearch for more papers by this author & Paolo PedrazzoliMedical Oncology Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, 27100, ItalyDepartment of Internal Medicine and Medical Therapy, University of Pavia, Pavia, 27100, ItalySearch for more papers by this authorPublished Online:29 Sep 2021https://doi.org/10.2217/imt-2021-0219AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Keywords: cancer patientsCOVID-19cytokine stormfebrile neutropeniaproteomic profilingrecombinant human granulocyte-colony stimulating factors (rhG-CSFs)IntroductionSince the early phase of the COVID-19 pandemic, a principal international panel of experts from European Society for Medical Oncology (ESMO) [1] and Multinational Association of Supportive Care in Cancer (MASCC) [2], have drawn up recommendations for every aspect of the management of cancer patients.In managing febrile neutropenia (FN), supportive care indications have driven to an expanded use of rhG-CSFs to accelerate absolute neutrophil count recovery; in particular, they have also recommended its use in patients with intermediate risk (10–20%) and all patients with FN antecedents without risk factors [1,2].G-CSF is a glycoprotein that stimulates granulopoiesis and leads to proliferation, maturation and mobilisation of neutrophils [3]. It is mainly expressed by myeloid cells, but most recent studies have reported its expression in fibroblasts, endothelial cells, bone marrow stromal cells, placenta, adult neural stem cells, B cells and cardiomyocytes [3]. Filgrastim, the first rhG-CSF approved by the US FDA in 1991, has renal- and neutrophil-mediated clearance pathways, while the serum concentrations of long-acting rhG-CSF are due to the neutrophil-mediated clearance [4]. Thus, in case of chemotherapy-induced neutropenia, the circulating concentrations of a single dose of long-acting rhG-CSF persist elevated until there is an increase in the absolute neutrophil counts (ANCs), which increases the self-regulated clearance [4].In this paper, the authors analyze the role of rhG-CSF. Even though it was initally emphasized, later it was considered with caution because of the risk of acute lung injury [5]. However, it is now proven to be effective because of its immunomodulatory action on the molecular pathophysiology of sepsis.What is rhG-CSF for & why is it used during the COVID-19 pandemic?Before the COVID-19 pandemic, the prophylactic use of rhG-CSF [6] has been recommended by all guidelines when the overall risk of FN from the prescribed chemotherapy regimen is ≥20% [6]. Starting rhG-CSF treatment earlier during the COVID-19 pandemic may shorten hospital stay [7], and self-administration of rhG-CSF or the use of long-acting agents (e.g., pegfilgrastim) may reduce outpatient visits [8].Some authors highlighted that the rhG-CSF administration may counteract with COVID-19-related lymphocytopenia and improve the outcome of the infection in patients without cancer [9,10]. Cheng et al. reported that rhG-CSF led to a sustained increase in lymphocyte, but they excluded patients with comorbidities such as cancer from the analysis, to minimise their potential adverse effects on the immune responses of the subjects [10].We also found three case reports of agranulocytosis following COVID-19 infection responding to rhG-CSF without apparent adverse events [11–13]. Spencer described a case of pancytopenia in a 51-year-old man with natural killer (NK) cell large granular lymphocytic leukemia and mild COVID-19 treated with two doses of rhG-CSF on the first day and 5 days after the diagnosis of COVID-19 real time PCR (RT-PCR) positivity [11]. Lutfi et al. reported a case of profound neutropenia 23 days from the beginning of COVID-19 infection, treated with a course of six doses of rhG-CSF from day 23 to 28 [12].Finally, Hernandez et al. described a case with FN successfully managed with a 7-day course of rhG-CSF 53 days from the beginning of COVID-19 infection [13]. The favorable use of rhG-CSF in these cases may depend on the time elapsed since the onset of acute COVID-19 when the cytokine activation phase has been resolved.Is rhG-CSF use dangerous in COVID-19?Soon after the onset of the pandemic, some authors described the possibility of worsening of clinical conditions in cancer patients following the use of rhG-CSF during FN [14–17]. In particular, Nawar et al. illustrated the respiratory worsening of three cancer patients within 72 h after rhG-CSF administration [15]. These patients developed an increase in neutrophil-to-lymphocyte ratio (NLR), which suggests an imbalance in inflammatory response [15]. Taha et al. reported a clinical deterioration within 24 h after rhG-CSF administration in a patient with COVID-19 and leukopenia [16]. Malek suggested that concomitant COVID-19 infection in patients treated with rhG-CSF after hematopoietic cell transplantation (HCT) may lead to a worse clinical outcome [17].rhG-CSF-induced neutropenia recovery may trigger off respiratory deterioration due to acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) in neutropenic cancer patients with viral pneumonia [5]. ALI is due to the compartmentalisation of neutrophils in the lung with the formation of neutrophil extracellular traps (NETs), release of cytokines, reactive oxygen species and proteinases [18]. In COVID-19, excessive NETosis (a unique type of apoptosis caused by neutrophils), induced by epithelial and endothelial cells affected by the virus, is involved in the development of the ‘cytokine storm' with the elevation of plasma levels of chemokine such as IL-6, IL-7, IL-8, TNF-α and G-CSF [19].Therefore, as remarked by Taha et al., rhG-CSFs therapy might worsen the overwhelming inflammatory reaction in COVID-19 and lead to worse outcomes [16].Recently, Zhang et al. have reported a higher risk of hospitalisation, respiratory failure and death in cancer patients recovered from neutropenia through the administration of rhG-CSF [20]. In particular, among hospitalised patients, the administration of rhG-CSF was linked to an increased need for high levels of oxygen supplementation and death (hazard ratio [HR]: 3.56, 95% CI: 1.19–10.2, p = 0.024). This effect was predominantly observed among the patients showing a robust neutrophil response (HR: 7.78, 95% CI: 2.05–27.9, p = 0.004) compared to those with less robust levels of response to G-CSF (HR: 4.04, 95% CI: 0.80–16.7, p = 0.086) [20].This paper has confirmed our conclusion in the early phase of pandemic [14–17] that the use of rhG-CSF could worsen the clinical conditions of the patients with cancer in case of concomitant COVID-19 infection [14].Future perspectiveThe particular sequence of events, triggered by a hyperinflammatory mechanism, makes COVID-19 management particularly difficult and general rules often do not apply to COVID-19 patients. The complex interplay between cytokines and cellular response interaction with G-CSF metabolism as well as the use of rhG-CSF remains a dilemma in cancer patients with COVID-19 infection. The question remains as to whether it is better to force neutrophil count recovery or to run the risk of severe respiratory complications. The available data are not sufficient to confirm this.Answering this question may be the object of both biological and clinical studies. Identifying the patients' risk by using analytical quick technologies with more sensitive biomarkers of cellular activation is an ideal field for precision medicine research. Targeting G-CSF might be a therapeutic option, and knowledge of the serum level of G-CSF in patients with sepsis might indicate whether its administration may benefit patients with low G-CSF level or harmful for those with a higher G-CSF level [21]. Moreover, the primary role of neutrophils associated with critical illness in COVID-19 has been highlighted by a recent literature [22]. Meizlish et al. demonstrated, through the use of proteomic profiling and a machine learning prediction algorithm, that elevations in circulating markers of neutrophil activation precede the onset of critical illness. They have identified that a group of proteins are early transcribed in neutrophil development, then stored into cytoplasmic granules, and released from mature neutrophils. High levels of G-CSF may stimulate emergency granulopoiesis, and IL-8 drives neutrophil migration into the lungs. Here, neutrophils are activated and release RETN, LCN2 and HGF, as well as other proteins with antimicrobial and inflammatory functions. Testing of these proteins, by utilizing a more precise medicine approach, may help to distinguish earlier subjects with an increased risk of developing complications related to the administration of rhG-CSF. This strategy should integrate the standard procedures of COVID-19 diagnosis, in order to distinguish the patients with possible complications.Another research goal is to study different ways of immune stimulation and G-CSF release following short-acting and long-acting rhG-CSF administration to establish which one has better safety profile.ConclusionIn this commentary, we would like to emphasise the importance of obtaining more clinical and preclinical data to understand the complexity of G-CSF and its interaction with the immune system in cancer patients with COVID-19 disease.We recognize as a limitation of this commentary that most of the references are anecdotal case reports. However, we would like to underline that in neutropenic cancer patients with COVID-19 infection, the possible risks versus the benefits of the rhG-CSF administration should be weighed carefully, as rhG-CSF may lead to worsening clinical and respiratory status.The balance between the potential increased use of rhG-CSF in patients with cancer receiving chemotherapy and the concerns raised by some of the studies quoted might be addressed by prospective trials by utilizing a more precision medicine approach. Therefore, big data analysis on a large number of patients may be useful to correlate ANC, inflammatory marker trend and disease outcome.Author contributionsThe authors contributed equally to the present manuscript. All authors approved the submitted version of the manuscript.Financial & competing interests disclosureThis work was supported by Fondazione IRCCS Policlinico San Matteo, Ricerca Corrente (grant no. 08067620). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilised in the production of this manuscript.Papers of special note have been highlighted as: • of interest; •• of considerable interestReferences1. Curigliano G, Banerjee S, Cervantes A et al. Managing cancer patients during the COVID-19 pandemic: an ESMO multidisciplinary expert consensus. Ann. Oncol. 31(10), 1320–1335 (2020).Crossref, Medline, CAS, Google Scholar2. Cooksley T, Font C, Scotte F et al. Emerging challenges in the evaluation of fever in cancer patients at risk of febrile neutropenia in the era of COVID-19: a MASCC position paper. Support Care Cancer 23, 1–10 (2020).Google Scholar3. Karagiannidis I, Salataj E, Said Abu Egal E, Beswick EJ. G-CSF in tumors: aggressiveness, tumor microenvironment and immune cell regulation. Cytokine 142, 155479 (2021). • Represents an overview of the multiple roles of G-CSF in tumors.Crossref, Medline, CAS, Google Scholar4. Arvedson T, O'Kelly J, Yang B-B. Design rationale and development approach for pegfilgrastim as a long-acting granulocyte colony-stimulating factor. BioDrugs 29(3), 185–198 (2015).Crossref, Medline, CAS, Google Scholar5. Karlin L, Darmon M, Thiéry G et al. Respiratory status deterioration during G-CSF-induced neutropenia recovery. Bone Marrow Transplant 36(3), 245–250 (2005).Crossref, Medline, CAS, Google Scholar6. Smith TJ, Bohlke K, Lyman GH et al. Recommendations for the use of WBC growth factors: American Society of Clinical Oncology Clinical Practice Guideline Update. J. Clin. Oncol. 33, 3199–3212 (2015).Crossref, Medline, CAS, Google Scholar7. Griffiths EA, Alwan LM, Bachiashvili K et al. Considerations for use of hematopoietic growth factors in patients with cancer related to the COVID-19 pandemic. J. Natl. Compr. Canc. Netw. 1, 1–4 (2020).Crossref, Google Scholar8. NCCN. NCCN Hematopoietic growth factors. Short-term recommendations specific to issues with COVID-19 (SARS-CoV-2). https://www.iononline.com/-/media/assets/ion/pdf/covid19-resources/nccn_hgf_covid-19_19may20.pdf?la=en&hash=9FB98741E9E83D354F8FEFF66AC5F5188E139471Google Scholar9. Chen GB, Lin JT, Zhang Z, Liu L. Effect of recombinant human granulocyte colony-stimulating factor on lymphocyte subsets in patients with COVID-19. Infect. Dis. (Lond.) 52(10), 759–761 (2020).Crossref, Google Scholar10. Cheng LL, Guan WJ, Duan CY et al. Effect of recombinant human granulocyte colony-stimulating factor for patients with coronavirus disease 2019 (COVID-19) and lymphopenia: a randomized clinical trial. JAMA Intern. Med. 181(1), 71–78 (2021).Crossref, Medline, CAS, Google Scholar11. Spencer HC, Wurzburger R. COVID-19 presenting as neutropenic fever. Ann. Hematol. 99(8), 1939–1940 (2020).Crossref, Medline, CAS, Google Scholar12. Lutfi F, Benyounes A, Farrukh N, Bork J, Duong V. Agranulocytosis following COVID-19 recovery. Cureus. 12(7), e9463 (2020).Medline, Google Scholar13. Hernandez JM, Quarles R, Lakshmi S et al. Pancytopenia and profound neutropenia as a sequela of severe SARS-CoV-2 infection (COVID-19) with concern for bone marrow involvement. Open Forum Infect. Dis. 8(2), ofab017 (2021).Crossref, Medline, Google Scholar14. Lasagna A, Zuccaro V, Ferraris E, Rizzo G, Tancredi RJ, Pedrazzoli P. How to use prophylactic G-CSF in the time of COVID-19. JCO Oncol Pract. 16(11), 771–772 (2020).Crossref, Medline, Google Scholar15. Nawar T, Morjaria S, Kaltsas A et al. Granulocyte-colony stimulating factor in COVID-19: is it stimulating more than just the bone marrow? Am. J. Hematol. 95(8), E210–E213 (2020).Crossref, Medline, CAS, Google Scholar16. Taha M, Sharma A, Soubani A. Clinical deterioration during neutropenia recovery after G-CSF therapy in a patient with COVID-19. Respir. Med. Case Rep. 31, 101231 (2020).Medline, Google Scholar17. Malek AE. Time to revisit the use of G-CSF after allogeneic haematopoietic cell transplantation in COVID-19 era? Br. J. Cancer 124(7), 1183 (2021).Crossref, Medline, CAS, Google Scholar18. Geissler K, Gunzer M, Ostermann H. How safe is the administration of long-acting granulocyte colony-stimulating factor in cancer patients? Oncol. Res. Treat. 41, 316–326 (2018).Crossref, Medline, CAS, Google Scholar19. Vorobjeva NV, Chernyak BV. NETosis: molecular mechanisms, role in physiology and pathology. Biochemistry (Mosc.) 85(10), 1178–1190 (2020).Crossref, Medline, CAS, Google Scholar20. Zhang AW, Morjaria S, Kaltsas A et al. The effect of neutropenia and filgrastim (G-CSF) in cancer patients with COVID-19 infection. Clin. Infect. Dis. doi:10.1093/cid/ciab534 (2021) (Epub ahead of print). •• This is the first cohort study published about the clinical impact of neutropenia and G-CSF use in cancer patients with COVID-19.Google Scholar21. Suratt BT, Eisner MD, Calfee CS et al. Plasma granulocyte colony-stimulating factor levels correlate with clinical outcomes in patients with acute lung injury. Crit. Care Med. 37(4), 1322–1328 (2009).Crossref, Medline, CAS, Google Scholar22. Meizlish ML, Pine AB, Bishai JD et al. A neutrophil activation signature predicts critical illness and mortality in COVID-19. Blood Adv. 5(5), 1164–1177 (2021). •• The authors identified a prominent signature of neutrophil activation, which may be the strongest predictors of critical illness.Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetailsCited ByCurrent state and future opportunities in granulocyte colony-stimulating factor (G-CSF)24 June 2022 | Supportive Care in Cancer, Vol. 30, No. 9Case report: Successful outcome of COVID-19 in the context of autologous hematopoietic stem cell transplantation: The impact of the anti-SARS-CoV-2 vaccine and early remdesivir22 July 2022 | Frontiers in Medicine, Vol. 9G-CSF zur Prophylaxe der Neutropenie und der febrilen Neutropenie, Anämie bei Krebserkrankung20 June 2022 | best practice onkologie, Vol. 17, No. 6G-CSF zur Prophylaxe der Neutropenie und der febrilen Neutropenie, Anämie bei Krebserkrankung27 April 2022 | Der Urologe, Vol. 61, No. 5COVID-19 in Patients with Hematologic Malignancies: Clinical Manifestations, Persistence, and Immune Response2 March 2022 | Acta Haematologica, Vol. 145, No. 3 Vol. 13, No. 17 STAY CONNECTED Metrics History Received 10 August 2021 Accepted 3 September 2021 Published online 29 September 2021 Published in print December 2021 Information© 2021 Future Medicine LtdKeywordscancer patientsCOVID-19cytokine stormfebrile neutropeniaproteomic profilingrecombinant human granulocyte-colony stimulating factors (rhG-CSFs)Author contributionsThe authors contributed equally to the present manuscript. All authors approved the submitted version of the manuscript.Financial & competing interests disclosureThis work was supported by Fondazione IRCCS Policlinico San Matteo, Ricerca Corrente (grant no. 08067620). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilised in the production of this manuscript.PDF download" @default.
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