title: Selective ablation of acute myeloid leukemia using antibody-targeted chemotherapy: a phase I study of an anti-CD33 calicheamicin immunoconjugate.
abstract: Leukemic blast cells express the CD33 antigen in most patients with acute myeloid leukemia (AML), but this antigen is not expressed by hematopoietic stem cells. We conducted a study to determine whether normal hematopoiesis could be restored in patients with AML by selective ablation of cells expressing the CD33 antigen. In a dose escalation study, 40 patients with relapsed or refractory CD33(+) AML were treated with an immunoconjugate (CMA-676) consisting of humanized anti-CD33 antibody linked to the potent antitumor antibiotic calicheamicin. The capacity of leukemic cells to efflux 3, 3'-diethyloxacarbocyanine iodide (DiOC2) was used to estimate pretreatment functional drug resistance. Leukemia was eliminated from the blood and marrow of 8 (20%) of the 40 patients; blood counts returned to normal in three (8%) patients. A high rate of clinical response was observed in leukemias characterized by low dye efflux in vitro. Infusions of CMA-676 were generally well tolerated, and a postinfusion syndrome of fever and chills was the most common toxic effect. Two patients who were treated at the highest dose level (9 mg/m2) were neutropenic >5 weeks after the last dose of CMA-676. These results show that an immunoconjugate targeted to CD33 can selectively ablate malignant hematopoiesis in some patients with AML.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. esievers@fhcrc.org
authors.forename: E L
authors.initials: EL
authors.lastname: Sievers
authors.forename: F R
authors.initials: FR
authors.lastname: Appelbaum
authors.forename: R T
authors.initials: RT
authors.lastname: Spielberger
authors.forename: S J
authors.initials: SJ
authors.lastname: Forman
authors.forename: D
authors.initials: D
authors.lastname: Flowers
authors.forename: F O
authors.initials: FO
authors.lastname: Smith
authors.forename: K
authors.initials: K
authors.lastname: Shannon-Dorcy
authors.forename: M S
authors.initials: MS
authors.lastname: Berger
authors.forename: I D
authors.initials: ID
authors.lastname: Bernstein
mesh_terms: D000328:Adult; D000368:Aged; D000617:Aminoglycosides; D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D015703:Antigens, CD / Q000276:immunology*; D015214:Antigens, Differentiation, Myelomonocytic / Q000276:immunology*; D001772:Blood Cell Count / Q000187:drug effects; D053281:Enediynes; D005260:Female; D006410:Hematopoiesis / Q000187:drug effects; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage* / Q000276:immunology; D007275:Injections, Intravenous; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D063268:Sialic Acid Binding Ig-like Lectin 3; D016896:Treatment Outcome
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; C571163:CD33 protein, human; D053281:Enediynes; D018796:Immunoconjugates; D063268:Sialic Acid Binding Ig-like Lectin 3; C055955:calicheamicin gamma(1)I