Complement activation following first exposure to pegylated liposomal doxorubicin (Doxil®): possible role in hypersensitivity reactions

• Published in: Annals of oncology Vol. 14; no. 9; pp. 1430 - 1437
• Main Authors: Chanan-Khan, A., Szebeni, J., Savay, S., Liebes, L., Rafique, N. M., Alving, C. R., Muggia, F. M.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.09.2003
• Subjects: Adult; Aged; anaphylatoxins; Antibiotics, Antineoplastic - adverse effects; Biological and medical sciences; cancer chemotherapy; Complement Activation - drug effects; Dose-Response Relationship, Drug; doxorubicin; Doxorubicin - adverse effects; Drug Hypersensitivity - immunology; Drug toxicity and drugs side effects treatment; Female; Humans; hypersensitivity reactions; Hypersensitivity, Immediate - immunology; Key words: allergy; liposomes; Male; Medical sciences; Middle Aged; Miscellaneous (drug allergy, mutagens, teratogens...); Neoplasms - drug therapy; Pharmacology. Drug treatments; Antineoplastic agent; anaphylatixins; Intravenous administration; Toxicity; Drug carrier; Complement; Doxorubicin; Ethylene oxide polymer; Isomerases; Immediate hypersensitivity; Human; DNA topoisomerase (ATP-hydrolysing); Immune response; Enzyme; liposomes; Single dose; Enzyme inhibitor; Liposome; allergy; Malignant tumor; Chemotherapy; Treatment; hypersensitivity reactions; cancer chemotherapy; Anthracyclins; Coating
• ISSN: 0923-7534; 1569-8041
• DOI: 10.1093/annonc/mdg374

Background: Pegylated liposomal doxorubicin (Doxil®) has been reported to cause immediate hypersensitivity reactions (HSRs) that cannot be explained as IgE-mediated (type I) allergy. Previous in vitro and animal studies indicated that activation of the complement (C) system might play a causal role in the process, a proposal that has not been tested in humans to date. Patients and methods: Patients with solid tumors (n = 29) treated for the first time with Doxil were evaluated for HSRs and concurrent C activation. HSRs were classified from mild to severe, while C activation was estimated by serial measurement of plasma C terminal complex (SC5b-9) levels. Increases in SC5b-9 were compared in patients with or without reactions, and were correlated with Doxil dose rate. Results: Moderate to severe HSRs occurred in 45% of patients. Plasma SC5b-9 at 10 min after infusion was significantly elevated in 92% of reactor patients versus 56% in the non-reactor group, and the rise was greater in reactors than in non-reactors. We found significant association between C activation and HSRs, both showing direct correlation with the initial Doxil dose rate. Conclusions: C activation may play a key role in HSRs to Doxil. However, low-level C activation does not necessarily entail clinical symptoms, highlighting the probable involvement of further, as yet unidentified, amplification factors.