Document Type
Article
Publication Date
5-21-2019
Identifier
DOI: 10.1038/s41408-019-0211-y; PMCID: PMC6529443
Abstract
Gemtuzumab-ozogamicin (GO), a humanized-anti-CD33 antibody linked with the toxin-calicheamicin-γ is a reemerging and promising drug for AML. Calicheamicin a key element of GO, induces DNA-damage and cell-death once the linked CD33-antibody facilitates its uptake. Calicheamicin efflux by the drug-transporter PgP-1 have been implicated in GO response thus in this study, we evaluated impact of ABCB1-SNPs on GO response. Genomic-DNA samples from 942 patients randomized to receive standard therapy with or without addition of GO (COG-AAML0531) were genotyped for ABCB1-SNPs. Our most interesting results show that for rs1045642, patients with minor-T-allele (CT/TT) had better outcome as compared to patients with CC genotype in GO-arm (Event-free survival-EFS: p = 0.022; and risk of relapse-RR, p = 0.007). In contrast, no difference between genotypes was observed for any of the clinical endpoints within No-GO arm (all p > 0.05). Consistent results were obtained when genotype groups were compared by GO and No-GO arms. The in vitro evaluation using HL60-cells further demonstrated consistent impact of rs1045642-T-allele on calicheamicin induced DNA-damage and cell-viability. Our results show the significance of ABCB1 SNPs on GO response in AML and warrants the need to investigate this in other cohorts. Once validated, ABCB1-SNPs in conjunction with CD33-SNPs can open up opportunities to personalize GO-therapy.
Journal Title
Blood Cancer J
Volume
9
Issue
6
First Page
51
Last Page
51
MeSH Keywords
ATP Binding Cassette Transporter, Subfamily B; Adolescent; Adult; Alleles; Antineoplastic Agents, Immunological; Biomarkers, Tumor; Child; Child, Preschool; Female; Gemtuzumab; Genotype; Humans; Infant; Infant, Newborn; Leukemia, Myeloid, Acute; Male; Polymorphism, Single Nucleotide; Prognosis; Recurrence; Treatment Outcome; Young Adult
Keywords
ATP Binding Cassette Transporter, Subfamily B; Adolescent; Adult; Alleles; Antineoplastic Agents, Immunological; Biomarkers, Tumor; Child; Child, Preschool; Female; Gemtuzumab; Genotype; Humans; Infant; Infant, Newborn; Leukemia, Myeloid, Acute; Male; Polymorphism, Single Nucleotide; Prognosis; Recurrence; Treatment Outcome; Young Adult
Recommended Citation
Rafiee R, Chauhan L, Alonzo TA, et al. ABCB1 SNP predicts outcome in patients with acute myeloid leukemia treated with Gemtuzumab ozogamicin: a report from Children's Oncology Group AAML0531 Trial. Blood Cancer J. 2019;9(6):51. Published 2019 May 21. doi:10.1038/s41408-019-0211-y
Comments
Grant support
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Publisher's Access: https://doi.org/10.1038/s41408-019-0211-y