title: Continuous infusion of the anti-CD22 immunotoxin IgG-RFB4-SMPT-dgA in patients with B-cell lymphoma: a phase I study.
abstract: IgG-RFB4-SMPT-dgA consists of deglycosylated ricin A chain (dgA) coupled to the monoclonal antihuman CD22 antibody, RFB4. This study determined the maximally tolerated dose (MTD) of this immunotoxin (IT) administered as a continuous 8-day infusion to 18 patients with B-cell lymphoma (30% CD22+ tumor cells) over 8 days. The MTD was 19.2 mg/m2/192 h (maximum toxicity grade 1), with vascular leak syndrome (VLS) as dose-limiting toxicity (DLT) at 28.8 mg/m2/192 h (grades 3 through 5 in 7 of 11 patients). Predictors of severe VLS included serum IT concentrations greater than 1,000 ng/mL and the absence of circulating tumor cells. Decreased urine sodium excreted in 24 hours provided evidence for mild VLS without notable changes in serum albumin. Four partial responses, 3 minor responses, 6 stable disease, and 3 progression of disease were observed. The mean maximal serum concentration (Cmax) in initial courses at the MTD (19.2 mg/m2) was 443 +/- 144 ng/mL (n = 3; range, 326 to 604). At 28.8 mg/m2/192 h, the Cmax was highly variable (n = 11; mean, 1,102 +/- 702; range, 9.6 to 2,032 ng/mL). Human antimouse or antiricin antibodies developed in 6 of 16 (37.5%) patients after one course of IT. However, 10 eligible patients received multiple courses of IT. Changes in serum cytokines and cytokine receptors did not correlate with toxicity but decreased soluble interleukin-2 receptor concentrations correlated with clinical response. Comparison to a prior study with the same IT administered by intermittent bolus infusions (Amlot et al, Blood 82:2624, 1993) suggests similar clinical response, toxicity, and immunogenicity.
authors.affiliation: Laboratory of Biological Chemistry, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Sausville
authors.forename: D
authors.initials: D
authors.lastname: Headlee
authors.forename: M
authors.initials: M
authors.lastname: Stetler-Stevenson
authors.forename: E S
authors.initials: ES
authors.lastname: Jaffe
authors.forename: D
authors.initials: D
authors.lastname: Solomon
authors.forename: W D
authors.initials: WD
authors.lastname: Figg
authors.forename: J
authors.initials: J
authors.lastname: Herdt
authors.forename: W C
authors.initials: WC
authors.lastname: Kopp
authors.forename: H
authors.initials: H
authors.lastname: Rager
authors.forename: S M
authors.initials: SM
authors.lastname: Steinberg
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D015703:Antigens, CD / Q000276:immunology*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology*; D015815:Cell Adhesion Molecules; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D007260:Infusion Pumps; D037102:Lectins; D016393:Lymphoma, B-Cell / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D012276:Ricin / Q000008:administration & dosage; D051918:Sialic Acid Binding Ig-like Lectin 2
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; C497867:CD22 protein, human; D015815:Cell Adhesion Molecules; D000922:Immunotoxins; D037102:Lectins; D051918:Sialic Acid Binding Ig-like Lectin 2; D012276:Ricin