ABCB1 SNP predicts outcome in patients with acute myeloid leukemia treated with Gemtuzumab ozogamicin: a report from Children's Oncology Group AAML0531 Trial.
Roya RafieeLata ChauhanTodd A AlonzoYi-Cheng WangAhlam ElmasryMichael R LokenJessica PollardRichard AplencSusana RaimondiBetsy A HirschIrwin D BernsteinAlan S GamisSoheil MeshinchiJatinder Kaur LambaPublished in: Blood cancer journal (2019)
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.
Keyphrases
- genome wide
- acute myeloid leukemia
- dna damage
- free survival
- cell death
- acute lymphoblastic leukemia
- end stage renal disease
- oxidative stress
- cell cycle arrest
- genome wide association
- newly diagnosed
- phase iii
- ejection fraction
- dna repair
- escherichia coli
- allogeneic hematopoietic stem cell transplantation
- induced apoptosis
- chronic kidney disease
- magnetic resonance
- young adults
- phase ii
- drug induced
- open label
- diabetic rats
- stem cells
- minimally invasive
- gene expression
- bone marrow
- study protocol
- adverse drug
- dual energy
- single molecule
- patient reported
- emergency department
- positron emission tomography
- circulating tumor
- endothelial cells
- high density