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

doi:10.1038/s41408-019-0211-y

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

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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 language	English (US)
Article number	51
Journal	Blood cancer journal
Volume	9
Issue number	6
DOIs	https://doi.org/10.1038/s41408-019-0211-y
State	Published - Jun 1 2019

Bibliographical note

Funding Information:
This research was supported by NIH under the award numbers: U10CA180899, U10CA180886, U10CA98413, U10CA098543 as well as by NCI-R21CA155524, R01CA132946, and R01CA133881. The research was also supported by St. Baldrick’s Foundation. Authors would like to thank the patients and families for participating in AAML0531. We are also thankful to Dr. Roland Walter for provide insightful comments. We are thankful to Drs Gottesman and Wang for providing ABCB1 expression constructs.

Publisher Copyright:
© 2019, The Author(s).

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Rafiee, R., Chauhan, L., Alonzo, T. A., Wang, Y. C., Elmasry, A., Loken, M. R., Pollard, J., Aplenc, R., Raimondi, S., Hirsch, B. A., Bernstein, I. D., Gamis, A. S., Meshinchi, S., & Lamba, J. K. (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, 9(6), Article 51. https://doi.org/10.1038/s41408-019-0211-y

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

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title = "ABCB1 SNP predicts outcome in patients with acute myeloid leukemia treated with Gemtuzumab ozogamicin: a report from Children{\textquoteright}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.}",

note = "Funding Information: This research was supported by NIH under the award numbers: U10CA180899, U10CA180886, U10CA98413, U10CA098543 as well as by NCI-R21CA155524, R01CA132946, and R01CA133881. The research was also supported by St. Baldrick{\textquoteright}s Foundation. Authors would like to thank the patients and families for participating in AAML0531. We are also thankful to Dr. Roland Walter for provide insightful comments. We are thankful to Drs Gottesman and Wang for providing ABCB1 expression constructs. Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = jun,

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",

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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.

N1 - Funding Information: This research was supported by NIH under the award numbers: U10CA180899, U10CA180886, U10CA98413, U10CA098543 as well as by NCI-R21CA155524, R01CA132946, and R01CA133881. The research was also supported by St. Baldrick’s Foundation. Authors would like to thank the patients and families for participating in AAML0531. We are also thankful to Dr. Roland Walter for provide insightful comments. We are thankful to Drs Gottesman and Wang for providing ABCB1 expression constructs. Publisher Copyright: © 2019, The Author(s).

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.

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

Abstract

Bibliographical note

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