title: CD33 expression and P-glycoprotein-mediated drug efflux inversely correlate and predict clinical outcome in patients with acute myeloid leukemia treated with gemtuzumab ozogamicin monotherapy.
abstract: Gemtuzumab ozogamicin (GO) contains an anti-CD33 antibody to facilitate uptake of a toxic calicheamicin-gamma(1) derivative. While recent in vitro data demonstrated a quantitative relationship between CD33 expression and GO cytotoxicity, previous correlative studies failed to identify a significant association between CD33 expression and clinical outcome. Studying patients undergoing GO monotherapy for relapsed acute myeloid leukemia (AML), we now find that AML blasts of responders have a significantly higher mean CD33 level and lower P-glycoprotein (Pgp) activity compared with nonresponders. CD33 expression and Pgp activity are inversely correlated. While both variables are associated with outcome, Pgp remains significantly associated with outcome even after adjusting for CD33, whereas CD33 does not show such an association after adjusting for Pgp. The inverse relationship between CD33 and Pgp suggests a maturation-stage-dependent expression of both proteins, and offers the rationale for using cell differentiation-promoting agents to enhance GO-induced cytotoxicity.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA. rwalter@fhcrc.org
authors.forename: Roland B
authors.initials: RB
authors.lastname: Walter
authors.forename: Ted A
authors.initials: TA
authors.lastname: Gooley
authors.forename: Vincent H J
authors.initials: VH
authors.lastname: van der Velden
authors.forename: Michael R
authors.initials: MR
authors.lastname: Loken
authors.forename: Jacques J M
authors.initials: JJ
authors.lastname: van Dongen
authors.forename: David A
authors.initials: DA
authors.lastname: Flowers
authors.forename: Irwin D
authors.initials: ID
authors.lastname: Bernstein
authors.forename: Frederick R
authors.initials: FR
authors.lastname: Appelbaum
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000208:Acute Disease; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000617:Aminoglycosides / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD / Q000378:metabolism*; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D017322:Clinical Trials, Phase II as Topic; D000079982:Gemtuzumab; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000378:metabolism*; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D012074:Remission Induction; D063268:Sialic Acid Binding Ig-like Lectin 3; D016896:Treatment Outcome
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000617:Aminoglycosides; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000970:Antineoplastic Agents; C571163:CD33 protein, human; D063268:Sialic Acid Binding Ig-like Lectin 3; D000079982:Gemtuzumab