Coding polymorphisms in CD 33 and response to gemtuzumab ozogamicin in pediatric patients with AML

Gemtuzumab ozogamicin (GO) is an anti-CD33 antibody conjugated with calicheamicin (a cytotoxic antibiotic) that is used for the treatment of acute myeloid leukemia (AML). The relationship between the CD33 expression in leukemic cells and response to GO treatment has been controversial. We studied CD33 transcript and protein expression as well as polymorphisms in the CD33 gene in 22 uniformly treated pediatric AML patients and correlated the results with minimal residual disease (MRD) findings before and after GO. We found that a nonsynonymous coding change (Ala14Val) in CD33 was significantly associated with response to GO (P = .02) whereas CD33 transcript and protein expression were not (P > .2). The results suggest a novel mechanism of resistance to GO, one that may extend to other immunotoxins.

[1]  E. Schuetz,et al.  Pharmacogenetics of Deoxycytidine Kinase: Identification and Characterization of Novel Genetic Variants , 2007, Journal of Pharmacology and Experimental Therapeutics.

[2]  I. Bernstein,et al.  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. , 2007, Blood.

[3]  D. Campana,et al.  Improved Remission Induction Rate of Childhood AML: Preliminary Results of the AML02 Trial. , 2005 .

[4]  J. Korth-Bradley,et al.  Pharmacokinetics of Gemtuzumab Ozogamicin as a Single‐Agent Treatment of Pediatric Patients With Refractory or Relapsed Acute Myeloid Leukemia , 2004, Journal of clinical pharmacology.

[5]  J. Downing,et al.  Clinical significance of residual disease during treatment in childhood acute myeloid leukaemia , 2003, British journal of haematology.

[6]  M. Berger,et al.  Pharmacokinetics of Gemtuzumab Ozogamicin, an Antibody‐Targeted Chemotherapy Agent for the Treatment of Patients with Acute Myeloid Leukemia in First Relapse , 2001, Journal of clinical pharmacology.

[7]  E. Sievers.  Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukaemia in first relapse , 2001, Expert opinion on biological therapy.

[8]  X. H. Chen,et al.  Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[9]  N. Casadevall,et al.  The immunophenotype of 177 adults with acute myeloid leukemia: proposal of a prognostic score. , 2000, Blood.

[10]  D. Patel,et al.  Calicheamicin-DNA complexes: warhead alignment and saccharide recognition of the minor groove. , 1995, Proceedings of the National Academy of Sciences of the United States of America.