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


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.
Chanan-Khan
A
A
Kaplan Comprehensive Cancer Center, New York University, New York, NY, USA. asher.chanan-khan@roswellpark.org
Szebeni
J
J
Savay
S
S
Liebes
L
L
Rafique
N M
NM
Alving
C R
CR
Muggia
F M
FM
D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D003167:Complement Activation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000009:adverse effects*; D004342:Drug Hypersensitivity / Q000276:immunology*; D005260:Female; D006801:Humans; D006969:Hypersensitivity, Immediate / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy
D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin