CD33 splicing polymorphism determines gemtuzumab ozogamicin response in de novo acute myeloid leukemia: Report from randomized phase III children’s oncology group trial AAML0531

Jatinder K. Lamba, Lata Chauhan, Miyoung Shin, Michael R. Loken, Jessica A. Pollard, Yi Cheng Wang, Rhonda E. Ries, Richard Aplenc, Betsy A. Hirsch, Susana C. Raimondi, Roland B. Walter, Irwin D. Bernstein, Alan S. Gamis, Todd A. Alonzo, Soheil Meshinchi

Research output: Contribution to journalArticle

53 Scopus citations

Abstract

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, 1.0E26) and with lower diagnostic leukemic cell surface CD33 intensity (P, 1.0E26). Patients with the CC genotype had significantly lower relapse risk in the GO arm than in the No-GO arm (26% v 49%; P, .001). However, in patients with the CT or TT genotype, exposure to GO did not influence relapse risk (39% v 40%; P = .85). Disease-free survival was higher in patients with the CC genotype in the GO arm than in the No-GO arm (65% v 46%, respectively; P = .004), but this benefit of GO addition was not seen in patients with the CT or TT genotype. Conclusion Our results suggest that patients with the CC genotype for rs12459419 have a substantial response to GO, making this a potential biomarker for the selection of patients with a likelihood of significant response to GO.

Original languageEnglish (US)
Pages (from-to)674-2682
Number of pages2009
JournalJournal of Clinical Oncology
Volume35
Issue number23
DOIs
StatePublished - Aug 10 2017

Fingerprint Dive into the research topics of 'CD33 splicing polymorphism determines gemtuzumab ozogamicin response in de novo acute myeloid leukemia: Report from randomized phase III children’s oncology group trial AAML0531'. Together they form a unique fingerprint.

  • Cite this

    Lamba, J. K., Chauhan, L., Shin, M., Loken, M. R., Pollard, J. A., Wang, Y. C., Ries, R. E., Aplenc, R., Hirsch, B. A., Raimondi, S. C., Walter, R. B., Bernstein, I. D., Gamis, A. S., Alonzo, T. A., & Meshinchi, S. (2017). 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, 35(23), 674-2682. https://doi.org/10.1200/JCO.2016.71.2513