A Novel 12-Step Subcutaneous Desensitization Protocol to Pegfilgrastim

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Estrada-Mendizabal, Alfonso J. Castillo-Ivon, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4433659/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Pegfilgrastim is a sustained-duration form of the granulocyte colony-stimulating factor filgrastim to which a polyethylene glycol molecule is covalently bound to the N-terminal methionine residue. Although rare, anaphylaxis to pegfilgrastim has been reported. Desensitization is a safe management option for drug hypersensitivity. To date, no desensitization protocols to pegfilgrastim have been reported. We present the case of a 36-year-old female diagnosed with breast cancer who was treated with paclitaxel and carboplatin every two weeks plus pegfilgrastim, to which she developed anaphylaxis. The lack of alternative treatment options led to the decision to proceed with desensitization, which was carried out successfully with a novel 12-step, 1-bag protocol, allowing the safe resumption of the medication. Although the mechanisms underlying hypersensitivity to pegfilgrastim remain unknown, clinicians must be aware of the possibility of anaphylaxis to this medication and of the available treatment options, such as desensitization. To our knowledge, this is the first report of a desensitization protocol to pegfilgrastim. pegfilgrastim G-CSF desensitization immunotherapy anaphylaxis Introduction Granulocyte colony-stimulating factor (G-CSF) products are used as adjuvant therapy in patients undergoing myelosuppressive chemotherapy to increase the number of neutrophils and prevent febrile neutropenia. (De Oliveira Brandao et al., 2023 ) Pegfilgrastim is a sustained-duration form of the G-CSF filgrastim, to which a polyethylene glycol molecule is covalently bound to the N-terminal methionine residue. This results in a predominant neutrophil-mediated clearance (as opposed to the renal-predominant clearance of filgrastim), causing longer-sustained concentrations in patients with profound neutropenia. (Dadla et al., 2015 ) Anaphylaxis is an acute, potentially life-threatening allergic reaction most commonly mediated by the degranulation of mast cells. (Simons et al., 2012 ) Drug hypersensitivity is one of the most frequent causes of anaphylaxis, especially in adults and hospitalized patients. (Muraro et al., 2014 ) Desensitization is an effective and safe management option for drug hypersensitivity, which allows the safe resumption of the offending medication. This procedure consists of a controlled and gradual increase in the dose of the culprit drug under strict supervision until a temporary tolerance has been developed and a full therapeutic dose has been achieved. However, a desensitization protocol with specific concentrations and time intervals is required. (Adkinson, 2008 ) Although rare, anaphylaxis to pegfilgrastim has been reported, and standardized desensitization protocols are still lacking. (Bustillo et al., 2009 ; Dadla et al., 2015 ; Hanna et al., 2008 ) We present the case of a patient with breast cancer who developed anaphylaxis after the administration of pegfilgrastim and underwent successful subcutaneous desensitization, allowing the resumption of the medication. To our knowledge, this is the first report of a desensitization protocol to pegfilgrastim. Case report A 36-year-old female diagnosed with breast cancer was treated with paclitaxel and carboplatin every two weeks plus pegfilgrastim for prevention of neutropenia. Twenty-four hours after receiving the first and second doses of pegfilgrastim, she experienced intense muscle and bone pain, but 2 hours after the third dose, she experienced foreign body sensation in the throat, dysphonia, rhinitis, generalized urticaria, shortness of breath and laryngeal stridor, which prompted her admission to the emergency department. After treatment with steroids and antihistamines, the patient was discharged and referred to an allergy consultation. Due to the risk of neutropenia that would have required either dose reduction or schedule delay of chemotherapy, and therefore, compromised the efficacy of chemotherapy and overall outcome of the disease, the decision to proceed with desensitization to pegfilgrastim was made. Skin testing was cost-prohibited, and alternative agents such as filgrastim or lenogastrim were not an option because pegfilgrastim was given through government aid. A 12-step single-bag desensitization protocol to pegfilgrastim was performed using sequential 15-minute doses (mg) subcutaneously: 0.001, 0.002, 0.004, 0.01, 0.02, 0.04, 0.1, 0.2, 0.4, 0.8, 1.4, and 3 to a final cumulative dose of 5.97 mg over 3 hours (Table I). The desensitization protocol is described in Table 1 . Table 1 Twelve-step desensitization protocol to pegfilgrastim Pegfilgrastim (Neulastim® 6 mg/0.6 mL); Solution A (1/100), Solution B (1/10), Solution C (1/1). Step/bag Time (min) Dose administered at step (mg) Cumulative dose (mg) 1 A 15 0.001 0.001 2 A 15 0.002 0.003 3 A 15 0.004 0.007 4 B 15 0.01 0.017 5 B 15 0.02 0.037 6 B 15 0.04 0.077 7 C 15 0.1 0.177 8 C 15 0.2 0.377 9 C 15 0.4 0.777 10 C 15 0.8 1.577 11 C 15 1.4 2.977 12 C 15 3 5.977 Total 3 hrs 5.977 mg The first desensitization was performed in the ED under Allergy supervision. Premedications included dexamethasone (6 mg IV), bilastine (20 mg), montelukast (10 mg), and acetaminophen (1000 mg). Vital signs were monitored every 15 minutes during the desensitization and 1 hour after the desensitization. After successfully completing the first desensitization in 3 hours without adverse events, the protocol was initiated 24 hours after each cycle of chemotherapy; however, after the second desensitization, the patient developed diffuse hives, which resolved with cetirizine (20 mg) and in the further 2 cycles, no reaction was found. Discussion Global cancer incidence continues to rise, and current chemotherapy regimens, while improving survival, pose a significant risk of hematological toxicity. (Nguyen et al., 2022 ) G-CSF is an endogenous hematopoietic growth factor that stimulates neutrophil proliferation, differentiation, maturation, and survival. Pegfilgrastim and filgrastim mimic G-CSF’s biological actions, representing a significant advancement in the supportive care of cancer patients. (Neumann & Foote, 2012 ) They provide primary prophylaxis for chemotherapy-induced neutropenia, reducing infections, related hospitalizations, and early deaths. The use of G-CSFs also decreases chemotherapy delays and dose reductions, potentially impacting disease-free and overall survival. (Blayney & Schwartzberg, 2022 ) Neutrophil recovery requires several injections of filgrastim because of its short half-life. Adding a polyethylene glycol molecule (‘pegylation’) to the amino-terminal of filgrastim - pegfilgrastim - reduces its renal clearance and extends its half-life (3.5h vs 42h respectively). Pegfilgrastim has a predominant neutrophil-mediated clearance, making its biological effect longer when the neutrophil count is lower. (Arvedson et al., 2015 ) This allows for a single injection per cycle plus longer intervals between administrations and, consequently, improved compliance. The underlying mechanism of hypersensitivity to G-CSF remains unknown. Although one study found positive immediate intradermal test to G-CSF at 0.3 mg/ml, suggesting IgE-mediated sensitization, the inaccuracy and lack of published data on skin testing with G-CSF limits its use for confirming IgE-mediated reactions. (Stone Jr et al., 1998 ) Other studies suggest possible sensitization and cross-reactivity to bacterial component-derived products or polyethylene glycol and polysorbate products. (Dadla et al., 2015 ; Neumann & Foote, 2012 ) Moreover, as reactions have been reported during the first drug exposure and skin testing is predominantly negative, other non-IgE mechanisms may be involved, such as nonspecific histamine release, complement activation, or the production of cytokines. Another proposed alternative is the production of G-CSF by the tumor itself, which could lead to the production of antibodies that cross-react with exogenous G-CSF. (Bustillo et al., 2009 ) On the other hand, cross-reactivity between G-CSF agents has yet to be elucidated. Pegfilgrastim is generally well tolerated, with bone pain as the main adverse effect. Although rare, post-marketing surveillance has reported some cases of acute anaphylaxis, but no reports exist regarding desensitization protocols. (Bustillo et al., 2009 ; Hanna et al., 2008 ; Stone Jr et al., 1998 ) Our patient developed urticaria 18 hours after the second desensitization, but it was mild and responded promptly to antihistamines. Clinicians must be aware of the possibility of anaphylaxis to pegfilgrastim and of the available and safe management options, such as desensitization. To our knowledge, this is the first desensitization protocol to pegfilgrastim. Declarations Author Contribution AC: Conceptualization, supervision, writing, and editing.RE: Writing, supervision and editing.AC: Writing and editing.EDL: Writing and editing.AGE: Editing and reviewing. Consent to publish declaration: No patient-identifiable information or images are included in this manuscript. The patient provided consent for publication of this case. Competing interest declaration: The authors have no relevant financial or non-financial interests to disclose. No funding was received for the creation of this manuscript. Data availability declaration: Not applicable. This manuscript does not report data generation or analysis. References Adkinson NF (2008) Desensitization for drug hypersensitivity. J allergy Clin Immunol 122(3):581–582 Arvedson T, O’Kelly J, Yang B-B (2015) Design rationale and development approach for pegfilgrastim as a long-acting granulocyte colony-stimulating factor. BioDrugs 29:185–198 Blayney DW, Schwartzberg L (2022) Chemotherapy-induced neutropenia and emerging agents for prevention and treatment: a review. Cancer Treat Rev 109:102427 Bustillo I, Kaley K, Saif MW (2009) Rash associated with the use of pegylated filgrastim in a patient with advanced pancreatic cancer. Cutan Ocul Toxicol 28(4):181–184 Dadla A, Tannenbaum S, Yates B, Holle L (2015) Delayed hypersensitivity reaction related to the use of pegfilgrastim. J Oncol Pharm Pract 21(6):474–477 De Oliveira Brandao C, Lewis S, Sandschafer D, Crawford J (2023) Two decades of pegfilgrastim: what have we learned? Where do we go from here? Curr Med Res Opin 39(5):707–718 Hanna G, Edgar D, Clarke J (2008) A case of prolonged type 1 hypersensitivity reaction to pegfilgrastim. Clin Oncol 20(4):315–316 Muraro A, Roberts G, Worm M, Bilò M, Brockow K, Fernández Rivas M, Santos AF, Zolkipli Z, Bellou A, Beyer K (2014) Anaphylaxis: guidelines from the E uropean A cademy of A llergy and C linical I mmunology. Allergy 69(8):1026–1045 Neumann TA, Foote M (2012) The safety profile of filgrastim and pegfilgrastim. Twenty Years of G-CSF: Clinical and Nonclinical Discoveries , 395–408 Nguyen SM, Pham AT, Nguyen LM, Cai H, Tran TV, Shu X-O, Tran HT (2022) Chemotherapy-induced toxicities and their associations with clinical and non-clinical factors among breast cancer patients in Vietnam. Curr Oncol 29(11):8269–8284 Simons FER, Ardusso LR, Bilo MB, Dimov V, Ebisawa M, El-Gamal YM, Ledford DK, Lockey RF, Ring J, Sanchez-Borges M (2012) 2012 Update: World Allergy Organization Guidelines for the assessment and management of anaphylaxis. Curr Opin Allergy Clin Immunol 12(4):389–399 Stone HD Jr, DiPiro C, Davis PC, Meyer CF, Wray BB (1998) Hypersensitivity reactions to Escherichia coli–derived polyethylene glycolated–asparaginase associated with subsequent immediate skin test reactivity to E. coli–derived granulocyte colony-stimulating factor. J allergy Clin Immunol 101(3):429–431 Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4433659","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":309311759,"identity":"c05bd825-eb56-4093-8367-40dfed3bdda2","order_by":0,"name":"Alejandra Canel-Paredes","email":"data:image/png;base64,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","orcid":"","institution":"Monterrey Institute of Technology and Higher Education","correspondingAuthor":true,"prefix":"","firstName":"Alejandra","middleName":"","lastName":"Canel-Paredes","suffix":""},{"id":309311760,"identity":"4dd2dab4-2fd2-474c-b3ff-6cb5f62a9197","order_by":1,"name":"Ricardo J. Estrada-Mendizabal","email":"","orcid":"","institution":"Monterrey Institute of Technology and Higher Education","correspondingAuthor":false,"prefix":"","firstName":"Ricardo","middleName":"J.","lastName":"Estrada-Mendizabal","suffix":""},{"id":309311761,"identity":"7ad91435-3ae1-431b-90f5-5bd87e32a272","order_by":2,"name":"Alfonso J. 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(De Oliveira Brandao et al., \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2023\u003c/span\u003e) Pegfilgrastim is a sustained-duration form of the G-CSF filgrastim, to which a polyethylene glycol molecule is covalently bound to the N-terminal methionine residue. This results in a predominant neutrophil-mediated clearance (as opposed to the renal-predominant clearance of filgrastim), causing longer-sustained concentrations in patients with profound neutropenia. (Dadla et al., \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2015\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eAnaphylaxis is an acute, potentially life-threatening allergic reaction most commonly mediated by the degranulation of mast cells. (Simons et al., \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2012\u003c/span\u003e) Drug hypersensitivity is one of the most frequent causes of anaphylaxis, especially in adults and hospitalized patients. (Muraro et al., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2014\u003c/span\u003e) Desensitization is an effective and safe management option for drug hypersensitivity, which allows the safe resumption of the offending medication. This procedure consists of a controlled and gradual increase in the dose of the culprit drug under strict supervision until a temporary tolerance has been developed and a full therapeutic dose has been achieved. However, a desensitization protocol with specific concentrations and time intervals is required. (Adkinson, \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2008\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eAlthough rare, anaphylaxis to pegfilgrastim has been reported, and standardized desensitization protocols are still lacking. (Bustillo et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2009\u003c/span\u003e; Dadla et al., \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Hanna et al., \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2008\u003c/span\u003e) We present the case of a patient with breast cancer who developed anaphylaxis after the administration of pegfilgrastim and underwent successful subcutaneous desensitization, allowing the resumption of the medication. To our knowledge, this is the first report of a desensitization protocol to pegfilgrastim.\u003c/p\u003e"},{"header":"Case report","content":"\u003cp\u003eA 36-year-old female diagnosed with breast cancer was treated with paclitaxel and carboplatin every two weeks plus pegfilgrastim for prevention of neutropenia. Twenty-four hours after receiving the first and second doses of pegfilgrastim, she experienced intense muscle and bone pain, but 2 hours after the third dose, she experienced foreign body sensation in the throat, dysphonia, rhinitis, generalized urticaria, shortness of breath and laryngeal stridor, which prompted her admission to the emergency department. After treatment with steroids and antihistamines, the patient was discharged and referred to an allergy consultation.\u003c/p\u003e \u003cp\u003eDue to the risk of neutropenia that would have required either dose reduction or schedule delay of chemotherapy, and therefore, compromised the efficacy of chemotherapy and overall outcome of the disease, the decision to proceed with desensitization to pegfilgrastim was made. Skin testing was cost-prohibited, and alternative agents such as filgrastim or lenogastrim were not an option because pegfilgrastim was given through government aid. A 12-step single-bag desensitization protocol to pegfilgrastim was performed using sequential 15-minute doses (mg) subcutaneously: 0.001, 0.002, 0.004, 0.01, 0.02, 0.04, 0.1, 0.2, 0.4, 0.8, 1.4, and 3 to a final cumulative dose of 5.97 mg over 3 hours (Table I). The desensitization protocol is described in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cb\u003eTwelve-step desensitization protocol to pegfilgrastim\u003c/b\u003e Pegfilgrastim (Neulastim\u0026reg; 6 mg/0.6 mL); Solution A (1/100), Solution B (1/10), Solution C (1/1).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" 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\u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2 A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3 A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.007\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4 B\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.017\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5 B\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.037\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6 B\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.077\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7 C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.177\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8 C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.377\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9 C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.777\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10 C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.577\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11 C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.977\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12 C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.977\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTotal\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 hrs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.977 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe first desensitization was performed in the ED under Allergy supervision. Premedications included dexamethasone (6 mg IV), bilastine (20 mg), montelukast (10 mg), and acetaminophen (1000 mg). Vital signs were monitored every 15 minutes during the desensitization and 1 hour after the desensitization. After successfully completing the first desensitization in 3 hours without adverse events, the protocol was initiated 24 hours after each cycle of chemotherapy; however, after the second desensitization, the patient developed diffuse hives, which resolved with cetirizine (20 mg) and in the further 2 cycles, no reaction was found.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eGlobal cancer incidence continues to rise, and current chemotherapy regimens, while improving survival, pose a significant risk of hematological toxicity. (Nguyen et al., \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2022\u003c/span\u003e) G-CSF is an endogenous hematopoietic growth factor that stimulates neutrophil proliferation, differentiation, maturation, and survival. Pegfilgrastim and filgrastim mimic G-CSF\u0026rsquo;s biological actions, representing a significant advancement in the supportive care of cancer patients. (Neumann \u0026amp; Foote, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2012\u003c/span\u003e) They provide primary prophylaxis for chemotherapy-induced neutropenia, reducing infections, related hospitalizations, and early deaths. The use of G-CSFs also decreases chemotherapy delays and dose reductions, potentially impacting disease-free and overall survival. (Blayney \u0026amp; Schwartzberg, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2022\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eNeutrophil recovery requires several injections of filgrastim because of its short half-life. Adding a polyethylene glycol molecule (\u0026lsquo;pegylation\u0026rsquo;) to the amino-terminal of filgrastim -\u003cem\u003epegfilgrastim\u003c/em\u003e- reduces its renal clearance and extends its half-life (3.5h vs 42h respectively). Pegfilgrastim has a predominant neutrophil-mediated clearance, making its biological effect longer when the neutrophil count is lower. (Arvedson et al., \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2015\u003c/span\u003e) This allows for a single injection per cycle plus longer intervals between administrations and, consequently, improved compliance.\u003c/p\u003e \u003cp\u003eThe underlying mechanism of hypersensitivity to G-CSF remains unknown. Although one study found positive immediate intradermal test to G-CSF at 0.3 mg/ml, suggesting IgE-mediated sensitization, the inaccuracy and lack of published data on skin testing with G-CSF limits its use for confirming IgE-mediated reactions. (Stone Jr et al., \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e1998\u003c/span\u003e) Other studies suggest possible sensitization and cross-reactivity to bacterial component-derived products or polyethylene glycol and polysorbate products. (Dadla et al., \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Neumann \u0026amp; Foote, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2012\u003c/span\u003e) Moreover, as reactions have been reported during the first drug exposure and skin testing is predominantly negative, other non-IgE mechanisms may be involved, such as nonspecific histamine release, complement activation, or the production of cytokines. Another proposed alternative is the production of G-CSF by the tumor itself, which could lead to the production of antibodies that cross-react with exogenous G-CSF. (Bustillo et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2009\u003c/span\u003e) On the other hand, cross-reactivity between G-CSF agents has yet to be elucidated.\u003c/p\u003e \u003cp\u003ePegfilgrastim is generally well tolerated, with bone pain as the main adverse effect. Although rare, post-marketing surveillance has reported some cases of acute anaphylaxis, but no reports exist regarding desensitization protocols. (Bustillo et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2009\u003c/span\u003e; Hanna et al., \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2008\u003c/span\u003e; Stone Jr et al., \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e1998\u003c/span\u003e) Our patient developed urticaria 18 hours after the second desensitization, but it was mild and responded promptly to antihistamines. Clinicians must be aware of the possibility of anaphylaxis to pegfilgrastim and of the available and safe management options, such as desensitization. To our knowledge, this is the first desensitization protocol to pegfilgrastim.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eAC: Conceptualization, supervision, writing, and editing.RE: Writing, supervision and editing.AC: Writing and editing.EDL: Writing and editing.AGE: Editing and reviewing.\u003c/p\u003e\u003ch2\u003eConsent to publish declaration: \u003c/h2\u003e\n\u003cp\u003eNo patient-identifiable information or images are included in this manuscript. The patient provided consent for publication of this case.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eCompeting interest declaration: \u003c/h2\u003e\n\u003cp\u003eThe authors have no relevant financial or non-financial interests to disclose. No funding was received for the creation of this manuscript.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eData availability declaration: \u003c/h2\u003e\n\u003cp\u003eNot applicable. This manuscript does not report data generation or analysis.\u003cstrong\u003e\u0026nbsp; \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAdkinson NF (2008) Desensitization for drug hypersensitivity. J allergy Clin Immunol 122(3):581\u0026ndash;582\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eArvedson T, O\u0026rsquo;Kelly J, Yang B-B (2015) Design rationale and development approach for pegfilgrastim as a long-acting granulocyte colony-stimulating factor. BioDrugs 29:185\u0026ndash;198\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBlayney DW, Schwartzberg L (2022) Chemotherapy-induced neutropenia and emerging agents for prevention and treatment: a review. Cancer Treat Rev 109:102427\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBustillo I, Kaley K, Saif MW (2009) Rash associated with the use of pegylated filgrastim in a patient with advanced pancreatic cancer. Cutan Ocul Toxicol 28(4):181\u0026ndash;184\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDadla A, Tannenbaum S, Yates B, Holle L (2015) Delayed hypersensitivity reaction related to the use of pegfilgrastim. J Oncol Pharm Pract 21(6):474\u0026ndash;477\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDe Oliveira Brandao C, Lewis S, Sandschafer D, Crawford J (2023) Two decades of pegfilgrastim: what have we learned? Where do we go from here? Curr Med Res Opin 39(5):707\u0026ndash;718\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHanna G, Edgar D, Clarke J (2008) A case of prolonged type 1 hypersensitivity reaction to pegfilgrastim. Clin Oncol 20(4):315\u0026ndash;316\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMuraro A, Roberts G, Worm M, Bil\u0026ograve; M, Brockow K, Fern\u0026aacute;ndez Rivas M, Santos AF, Zolkipli Z, Bellou A, Beyer K (2014) Anaphylaxis: guidelines from the E uropean A cademy of A llergy and C linical I mmunology. Allergy 69(8):1026\u0026ndash;1045\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNeumann TA, Foote M (2012) The safety profile of filgrastim and pegfilgrastim. \u003cem\u003eTwenty Years of G-CSF: Clinical and Nonclinical Discoveries\u003c/em\u003e, 395\u0026ndash;408\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNguyen SM, Pham AT, Nguyen LM, Cai H, Tran TV, Shu X-O, Tran HT (2022) Chemotherapy-induced toxicities and their associations with clinical and non-clinical factors among breast cancer patients in Vietnam. Curr Oncol 29(11):8269\u0026ndash;8284\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSimons FER, Ardusso LR, Bilo MB, Dimov V, Ebisawa M, El-Gamal YM, Ledford DK, Lockey RF, Ring J, Sanchez-Borges M (2012) 2012 Update: World Allergy Organization Guidelines for the assessment and management of anaphylaxis. Curr Opin Allergy Clin Immunol 12(4):389\u0026ndash;399\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStone HD Jr, DiPiro C, Davis PC, Meyer CF, Wray BB (1998) Hypersensitivity reactions to Escherichia coli\u0026ndash;derived polyethylene glycolated\u0026ndash;asparaginase associated with subsequent immediate skin test reactivity to E. coli\u0026ndash;derived granulocyte colony-stimulating factor. J allergy Clin Immunol 101(3):429\u0026ndash;431\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"pegfilgrastim, G-CSF, desensitization, immunotherapy, anaphylaxis","lastPublishedDoi":"10.21203/rs.3.rs-4433659/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4433659/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePegfilgrastim is a sustained-duration form of the granulocyte colony-stimulating factor filgrastim to which a polyethylene glycol molecule is covalently bound to the N-terminal methionine residue. Although rare, anaphylaxis to pegfilgrastim has been reported. Desensitization is a safe management option for drug hypersensitivity. To date, no desensitization protocols to pegfilgrastim have been reported. We present the case of a 36-year-old female diagnosed with breast cancer who was treated with paclitaxel and carboplatin every two weeks plus pegfilgrastim, to which she developed anaphylaxis. The lack of alternative treatment options led to the decision to proceed with desensitization, which was carried out successfully with a novel 12-step, 1-bag protocol, allowing the safe resumption of the medication. Although the mechanisms underlying hypersensitivity to pegfilgrastim remain unknown, clinicians must be aware of the possibility of anaphylaxis to this medication and of the available treatment options, such as desensitization. To our knowledge, this is the first report of a desensitization protocol to pegfilgrastim.\u003c/p\u003e","manuscriptTitle":"A Novel 12-Step Subcutaneous Desensitization Protocol to Pegfilgrastim","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-04 09:47:54","doi":"10.21203/rs.3.rs-4433659/v1","editorialEvents":[{"type":"communityComments","content":1}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b7f761af-a5ed-44ac-955c-a9b41ea18a3a","owner":[],"postedDate":"June 4th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-06-04T09:47:54+00:00","versionOfRecord":[],"versionCreatedAt":"2024-06-04 09:47:54","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4433659","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4433659","identity":"rs-4433659","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}