ABCB1 SNP predicts outcome in patients with acute myeloid leukemia treated with Gemtuzumab ozogamicin: a report from Children’s Oncology Group AAML0531 Trial

Roya Rafiee, Lata Chauhan, Todd A. Alonzo, Yi Cheng Wang, Ahlam Elmasry, Michael R. Loken, Jessica Pollard, Richard Aplenc, Susana Raimondi, Betsy A Hirsch, Irwin D. Bernstein, Alan S. Gamis, Soheil Meshinchi, Jatinder K. Lamba

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number51
JournalBlood cancer journal
Volume9
Issue number6
DOIs
StatePublished - Jun 1 2019

Fingerprint

Acute Myeloid Leukemia
Single Nucleotide Polymorphism
Genotype
DNA Damage
gemtuzumab
Alleles
HL-60 Cells
Pharmaceutical Preparations
Disease-Free Survival
Anti-Idiotypic Antibodies
Cell Survival
Cell Death
Recurrence
Antibodies
DNA

Cite this

ABCB1 SNP predicts outcome in patients with acute myeloid leukemia treated with Gemtuzumab ozogamicin : a report from Children’s Oncology Group AAML0531 Trial. / Rafiee, Roya; Chauhan, Lata; Alonzo, Todd A.; Wang, Yi Cheng; Elmasry, Ahlam; Loken, Michael R.; Pollard, Jessica; Aplenc, Richard; Raimondi, Susana; Hirsch, Betsy A; Bernstein, Irwin D.; Gamis, Alan S.; Meshinchi, Soheil; Lamba, Jatinder K.

In: Blood cancer journal, Vol. 9, No. 6, 51, 01.06.2019.

Research output: Contribution to journalArticle

Rafiee, R, Chauhan, L, Alonzo, TA, Wang, YC, Elmasry, A, Loken, MR, Pollard, J, Aplenc, R, Raimondi, S, Hirsch, BA, Bernstein, ID, Gamis, AS, Meshinchi, S & Lamba, JK 2019, '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 journal, vol. 9, no. 6, 51. https://doi.org/10.1038/s41408-019-0211-y
Rafiee, Roya ; Chauhan, Lata ; Alonzo, Todd A. ; Wang, Yi Cheng ; Elmasry, Ahlam ; Loken, Michael R. ; Pollard, Jessica ; Aplenc, Richard ; Raimondi, Susana ; Hirsch, Betsy A ; Bernstein, Irwin D. ; Gamis, Alan S. ; Meshinchi, Soheil ; Lamba, Jatinder K. / ABCB1 SNP predicts outcome in patients with acute myeloid leukemia treated with Gemtuzumab ozogamicin : a report from Children’s Oncology Group AAML0531 Trial. In: Blood cancer journal. 2019 ; Vol. 9, No. 6.
@article{c0ef311f36914dce9e9edba5a9e8b8fc,
title = "ABCB1 SNP predicts outcome in patients with acute myeloid leukemia treated with Gemtuzumab ozogamicin: a report from Children’s Oncology Group AAML0531 Trial",
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.",
author = "Roya Rafiee and Lata Chauhan and Alonzo, {Todd A.} and Wang, {Yi Cheng} and Ahlam Elmasry and Loken, {Michael R.} and Jessica Pollard and Richard Aplenc and Susana Raimondi and Hirsch, {Betsy A} and Bernstein, {Irwin D.} and Gamis, {Alan S.} and Soheil Meshinchi and Lamba, {Jatinder K.}",
year = "2019",
month = "6",
day = "1",
doi = "10.1038/s41408-019-0211-y",
language = "English (US)",
volume = "9",
journal = "Blood Cancer Journal",
issn = "2044-5385",
publisher = "Nature Publishing Group",
number = "6",

}

TY - JOUR

T1 - ABCB1 SNP predicts outcome in patients with acute myeloid leukemia treated with Gemtuzumab ozogamicin

T2 - a report from Children’s Oncology Group AAML0531 Trial

AU - Rafiee, Roya

AU - Chauhan, Lata

AU - Alonzo, Todd A.

AU - Wang, Yi Cheng

AU - Elmasry, Ahlam

AU - Loken, Michael R.

AU - Pollard, Jessica

AU - Aplenc, Richard

AU - Raimondi, Susana

AU - Hirsch, Betsy A

AU - Bernstein, Irwin D.

AU - Gamis, Alan S.

AU - Meshinchi, Soheil

AU - Lamba, Jatinder K.

PY - 2019/6/1

Y1 - 2019/6/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85065968856&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85065968856&partnerID=8YFLogxK

U2 - 10.1038/s41408-019-0211-y

DO - 10.1038/s41408-019-0211-y

M3 - Article

VL - 9

JO - Blood Cancer Journal

JF - Blood Cancer Journal

SN - 2044-5385

IS - 6

M1 - 51

ER -