CD33 Splicing Polymorphism Determines Gemtuzumab Ozogamicin Response in De Novo Acute Myeloid Leukemia: Report From Randomized Phase III Children's Oncology Group Trial AAML0531.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Adolescent, Adult, Alleles, Aminoglycosides, Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols, Child, Child, Preschool, Disease-Free Survival, Gemtuzumab, Heterozygote, Homozygote, Humans, Infant, Infant, Newborn, Leukemia, Myeloid, Acute, Polymorphism, Single Nucleotide, RNA, Messenger, Sialic Acid Binding Ig-like Lectin 3, Treatment Outcome, Young Adult
Purpose Gemtuzumab ozogamicin (GO), a CD33-targeted immunoconjugate, is a re-emerging therapy for acute myeloid leukemia (AML). CD33 single nucleotide polymorphism rs12459419 C>T in the splice enhancer region regulates the expression of an alternatively spliced CD33 isoform lacking exon2 (D2-CD33), thus eliminating the CD33 IgV domain, which is the antibody-binding site for GO, as well as diagnostic immunophenotypic panels. We aimed to determine the impact of the genotype of this splicing polymorphism in patients with AML treated with GO-containing chemotherapy. Patients and Methods CD33 splicing single nucleotide polymorphism was evaluated in newly diagnosed patients with AML randomly assigned to receive standard five-course chemotherapy alone (No-GO arm, n = 408) or chemotherapy with the addition of two doses of GO once during induction and once during intensification (GO arm, n = 408) as per the Children's Oncology Group AAML0531 trial. Results The rs12459419 genotype was CC in 415 patients (51%), CT in 316 patients (39%), and TT in 85 patients (10%), with a minor allele frequency of 30%. The T allele was significantly associated with higher levels of D2-CD33 transcript ( P < 1.0E
Lamba, Jatinder K; Chauhan, Lata; Shin, Miyoung; Loken, Michael R; Pollard, Jessica A; Wang, Yi-Cheng; Ries, Rhonda E; Aplenc, Richard; Hirsch, Betsy A; Raimondi, Susana C; Walter, Roland B; Bernstein, Irwin D; Gamis, Alan S; Alonzo, Todd A; and Meshinchi, Soheil, "CD33 Splicing Polymorphism Determines Gemtuzumab Ozogamicin Response in De Novo Acute Myeloid Leukemia: Report From Randomized Phase III Children's Oncology Group Trial AAML0531." (2017). Maine Medical Center. 1611.