CD33 Splicing Polymorphism and Response to Gemtuzumab Ozogamicin in AML
In an analysis of the phase III Children’s Oncology Group AAML0531 trial, published by Lambda et al in the Journal of Clinical Oncology, the CD33-targeted immunoconjugate gemtuzumab ozogamicin was shown to have benefit among patients with de novo acute myeloid leukemia (AML) who carry the CC genotype at rs12459419 in the CD33 splice enhancer region.
Study Details
The single nucleotide polymorphism rs12459419 C>T in the CD33 splice enhancer region regulates expression of a CD33 isoform that lacks exon 2 (D2-CD33), with this alteration eliminating the CD33 IgV domain that serves as the antibody-binding site for gemtuzumab ozogamicin. In the AAML0531 trial, the addition of gemtuzumab ozogamicin (one dose during induction and one during intensification) to standard chemotherapy was associated with modest improvement in outcomes overall, with benefit appearing to be limited to patients with higher CD33 expression. The current analysis assessed outcomes according to the genotype of the splicing polymorphism in the study population.
Genotype Frequency and Response
Among 408 patients receiving gemtuzumab ozogamicin and 408 patients in the control group, 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 presence of the T allele was associated with higher levels of D2-CD33 transcript (P < 1.0E-6) and lower diagnostic leukemic cell–surface CD33 intensity (P < 1.0E-6).
For gemtuzumab ozogamicin vs control patients, the 5-year risk of relapse was significantly lower among those with the CC genotype (26% vs 49%, P < .001) but not among those with the CT (38% vs 37%, P = .975) or TT genotype (46% vs 46%, P = .798). Five-year disease-free survival was significantly better among those with the CC genotype (65% vs 46%, P = .004) but not among those with the CT (56% vs 60%, P = .821) or TT genotype (51% vs 54%, P = .972). On multivariate analysis, the CC genotype was an independent predictor of gemtuzumab ozogamicin benefit in relapse risk (hazard ratio [HR] = 0.45, P < .001) and disease-free survival (HR = 0.57, P = .003).
The investigators concluded: “Our results suggest that patients with the CC genotype for rs12459419 have a substantial response to [gemtuzumab ozogamicin], making this a potential biomarker for the selection of patients with a likelihood of significant response to [gemtuzumab ozogamicin].”
The study was supported by grants from the National Institutes of Health.
Jatinder K. Lamba, MSc, PhD, of the Department of Pharmacotherapy and Translational Research at the University of Florida, Gainesville, is the corresponding author of the Journal of Clinical Oncology article.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
