Immediate hypersensitivity reaction to pegylated liposomal doxorubicin: management and outcome in four patients

Ingen‐Housz‐Oro, Saskia; Pham‐Ledard, Anne; Brice, Pauline; Lebrun‐Vignes, Bénédicte; Zehou, O.; Reitter, Delphine; Ram‐Wolff, Caroline; Dupin, Nicolas; Bagot, M.; Chosidow, Olivier; Beylot‐Barry, M.

doi:10.1684/ejd.2017.2986

Cited by 13 publications

(10 citation statements)

References 17 publications

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“…In a 4-patient study, grade 3 HSR induced by Doxil occurred almost immediately after the start of infusion in all patients and treatment was stopped. Premedication with ranitidine and hydroxyzine prior to the resumption of Doxil infusion eliminated HSR in 3 of the 4 patients [166]. Similarly, data analysis performed by Chanan-Khan et al showed that, on average, 8% of people who received Doxil experienced HSR [162].…”

Section: Hypersensitivity Reactionsmentioning

confidence: 91%

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Immunological and Toxicological Considerations for the Design of Liposomes

et al. 2020

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Liposomes hold great potential as gene and drug delivery vehicles due to their biocompatibility and modular properties, coupled with the major advantage of attenuating the risk of systemic toxicity from the encapsulated therapeutic agent. Decades of research have been dedicated to studying and optimizing liposomal formulations for a variety of medical applications, ranging from cancer therapeutics to analgesics. Some effort has also been made to elucidate the toxicities and immune responses that these drug formulations may elicit. Notably, intravenously injected liposomes can interact with plasma proteins, leading to opsonization, thereby altering the healthy cells they come into contact with during circulation and removal. Additionally, due to the pharmacokinetics of liposomes in circulation, drugs can end up sequestered in organs of the mononuclear phagocyte system, affecting liver and spleen function. Importantly, liposomal agents can also stimulate or suppress the immune system depending on their physiochemical properties, such as size, lipid composition, pegylation, and surface charge. Despite the surge in the clinical use of liposomal agents since 1995, there are still several drawbacks that limit their range of applications. This review presents a focused analysis of these limitations, with an emphasis on toxicity to healthy tissues and unfavorable immune responses, to shed light on key considerations that should be factored into the design and clinical use of liposomal formulations.

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Section: Hypersensitivity Reactionsmentioning

confidence: 91%

“…Liposomes have also been shown to induce HSR [163][164][165][166][167][168][169][170]. HSR are non-IgE-mediated pseudo-allergic immune responses, which usually develop immediately after IV infusion when the body is exposed to an antigen or liposomes [162].…”

Section: Hypersensitivity Reactionsmentioning

confidence: 99%

Immunological and Toxicological Considerations for the Design of Liposomes

et al. 2020

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“…An unresolved issue with such PEGylated nanopharmaceuticals is their recognition by the immune system manifested in non-IgE-mediated (pseudoallergic) hypersensitivity reactions (HSRs), an adverse event commonly called infusion reaction. − PEGylated nanomedicines that have been reported to cause such reactions include PEGylated liposomal doxorubicin (Doxil/Caelyx), PEGylated G-CSF (pegfilgrastim, Neulasta), PEGylated erythropoetin (mono-mPEG-epoetin-β, Mircera), PEGylated recombinant human factor VIII (Adynovate), and PEGylated phenylalanine ammonia lyase (pegvaliase-pqpz, Palynziq), with at least three formulations withdrawn from clinical use partly because of severe HSRs: PEGylated EPO-mimetic peptide (peginesatide, Omontys), PEGylated urate oxidase (pegloticase, Krystexxa), and a PEGylated IXa blocker RNA aptamer (pegnivacogin, Revolixys) …”

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confidence: 99%

Pseudo-anaphylaxis to Polyethylene Glycol (PEG)-Coated Liposomes: Roles of Anti-PEG IgM and Complement Activation in a Porcine Model of Human Infusion Reactions

et al. 2019

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Polyethylene glycol (PEG)-coated nanopharmaceuticals can cause mild to severe hypersensitivity reactions (HSRs), which can occasionally be life threatening or even lethal. The phenomenon represents an unsolved immune barrier to the use of these drugs, yet its mechanism is poorly understood. This study showed that a single i.v. injection in pigs of a low dose of PEGylated liposomes (Doxebo) induced a massive rise of anti-PEG IgM in blood, peaking at days 7−9 and declining over 6 weeks. Bolus injections of PEG-liposomes during seroconversion resulted in anaphylactoid shock (pseudo-anaphylaxis) within 2−3 min, although similar treatments of naı ̈ve animals led to only mild hemodynamic disturbance. Parallel measurement of pulmonary arterial pressure (PAP) and sC5b-9 in blood, taken as measures of HSR and complement activation, respectively, showed a concordant rise of the two variables within 3 min and a decline within 15 min, suggesting a causal relationship between complement activation and pulmonary hypertension. We also observed a rapid decline of anti-PEG IgM in the blood within minutes, increased binding of PEGylated liposomes to IgM + B cells in the spleen of immunized animals compared to control, and increased C3 conversion by PEGylated liposomes in the serum of immunized pigs. These observations taken together suggest rapid binding of anti-PEG IgM to PEGylated liposomes, leading to complement activation via the classical pathway, entailing anaphylactoid shock and accelerated blood clearance of liposome−IgM complexes. These data suggest that complement activation plays a causal role in severe HSRs to PEGylated nanomedicines and that pigs can be used as a hazard identification model to assess the risk of HSRs in preclinical safety studies.

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“…However, some reports have described the occurrence of HSR to PLD, despite premedication. Ingen et al reported that three patients with T‐cell lymphoma and one patient with Kaposi sarcoma showed HSR during PLD administration, despite using methylprednisolone 80 mg and dexchlorpheniramine 5 mg as premedication 10 . Chan et al reported that patients with ovarian cancer showed a HSR to PLD after intravenous administration of ondansetron 8 mg, dexamethasone 8 mg, and diphenhydramine 25 mg. Close monitoring during the first 15 min of infusion for signs of HSR should be mandatory for patients receiving their first dose of PLD 11 .…”

Section: Discussionmentioning

confidence: 99%

Hypersensitivity reaction to pegylated liposomal doxorubicin administration for Mullerian carcinoma in Japanese women

Yamaguchi

Yahata

Okugawa

et al. 2021

J of Obstet and Gynaecol

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Aim PEGylated liposomal doxorubicin (PLD) is a therapeutic agent for gynecological malignancy. Hypersensitivity reaction (HSR) is a major adverse effect that usually disappears after halting administration of PLD. Premedication is usually not necessary before administration of PLD to prevent HSR. Here, we evaluated the frequency of HSR during administration of PLD following premedication in Japanese women. Methods We performed PLD administration in 78 patients (386 cycles) between 2013 and 2018. Granisetron hydrochloride and dexamethasone sodium phosphate were administered 30 min before PLD administration. Then, PLD (40 or 30 mg/m2 combined usage with carboplatin) was administered. We retrospectively reviewed the medical records of 78 patients and examined the frequency of HSR. Results Seven of 78 (9%) patients showed HSR by PLD administration following premedication. One patient showed cardiopulmonary arrest in 13 min after PLD administration (grade 4). The other six patients showed grade 2 HSR. All patients developed HSR in the first course. The incidence of HSR was significantly higher in patients with allergic history than in patients without allergic history (p = 0.0151). Conclusions Clinicians should be aware of the potential for HSR in patients administered PLD, particularly those with allergic history and those receiving the first cycle of PLD, even following premedication.

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Immediate hypersensitivity reaction to pegylated liposomal doxorubicin: management and outcome in four patients

Cited by 13 publications

References 17 publications

Immunological and Toxicological Considerations for the Design of Liposomes

Immunological and Toxicological Considerations for the Design of Liposomes

Pseudo-anaphylaxis to Polyethylene Glycol (PEG)-Coated Liposomes: Roles of Anti-PEG IgM and Complement Activation in a Porcine Model of Human Infusion Reactions

Hypersensitivity reaction to pegylated liposomal doxorubicin administration for Mullerian carcinoma in Japanese women

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