A Phase II Study of Arginine Deiminase (ADI-PEG20) in Relapsed/Refractory or Poor-Risk Acute Myeloid Leukemia Patients

Hui Jen Tsai, Shih Sheng Jiang, Wen Chun Hung, Gautam Borthakur, Sheng Fung Lin, Naveen Pemmaraju, Elias Jabbour, John S. Bomalaski, Ya-Ping Chen, Hui Hua Hsiao, Ming Chung Wang, Ching Yuan Kuo, Hung Chang, Su Peng Yeh, Jorge Cortes, Li Tzong Chen, Tsai-Yun Chen

研究成果: Article

9 引文 (Scopus)

摘要

Exogenous arginine is required for growth in some argininosuccinate synthetase (ASS)-deficient cancers. Arginine deiminase (ADI) inhibits growth in various ASS-deficient cancers by depleting arginine. The efficacy of pegylated ADI (ADI-PEG20) in relapsed/refractory/poor-risk acute myeloid leukemia (AML) was evaluated in 43 patients in a prospective, phase II trial (NCT01910012 (10/07/2013), https://clinicaltrials.gov/ct2/show/NCT01910012?term = ADI-PEG20&rank = 12). Despite almost all pre-treatment tumor samples showing ASS deficiency, the best response among 21 evaluable patients was complete response (CR) in 2 (9.5%) and stable disease in 7 (33.3%), yielding a disease control rate (DCR) of 42.9%. The response durations of the two patients with CR were 7.5 and 8.8 months. DCR was correlated with a median of 8 weeks of arginine depletion to ≤10 μM. Using whole transcriptome sequencing, we compared gene expression profiling of pre- and post-treatment bone marrow samples of the two responders and three non-responders. The expression levels of some markers for AML subtypes and c-MYC regulated genes were considered potential predictors of response to ADI-PEG20. These results suggest that ASS deficiency is a prerequisite but not a sufficient condition for response to ADI-PEG20 monotherapy in AML. Predictive biomarkers and mechanistic explorations will be critical for identifying appropriate patients for future AML trials of ADI-PEG20.

原文English
文章編號11253
期刊Scientific reports
7
發行號1
DOIs
出版狀態Published - 2017 十二月 1

指紋

Acute Myeloid Leukemia
Citrullinemia
Argininosuccinate Synthase
Arginine
Neoplasms
Gene Expression Profiling
Growth
Transcriptome
arginine deiminase
Therapeutics
Biomarkers
Bone Marrow
Genes

All Science Journal Classification (ASJC) codes

  • General

引用此文

Tsai, Hui Jen ; Jiang, Shih Sheng ; Hung, Wen Chun ; Borthakur, Gautam ; Lin, Sheng Fung ; Pemmaraju, Naveen ; Jabbour, Elias ; Bomalaski, John S. ; Chen, Ya-Ping ; Hsiao, Hui Hua ; Wang, Ming Chung ; Kuo, Ching Yuan ; Chang, Hung ; Yeh, Su Peng ; Cortes, Jorge ; Chen, Li Tzong ; Chen, Tsai-Yun. / A Phase II Study of Arginine Deiminase (ADI-PEG20) in Relapsed/Refractory or Poor-Risk Acute Myeloid Leukemia Patients. 於: Scientific reports. 2017 ; 卷 7, 編號 1.
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title = "A Phase II Study of Arginine Deiminase (ADI-PEG20) in Relapsed/Refractory or Poor-Risk Acute Myeloid Leukemia Patients",
abstract = "Exogenous arginine is required for growth in some argininosuccinate synthetase (ASS)-deficient cancers. Arginine deiminase (ADI) inhibits growth in various ASS-deficient cancers by depleting arginine. The efficacy of pegylated ADI (ADI-PEG20) in relapsed/refractory/poor-risk acute myeloid leukemia (AML) was evaluated in 43 patients in a prospective, phase II trial (NCT01910012 (10/07/2013), https://clinicaltrials.gov/ct2/show/NCT01910012?term = ADI-PEG20&rank = 12). Despite almost all pre-treatment tumor samples showing ASS deficiency, the best response among 21 evaluable patients was complete response (CR) in 2 (9.5{\%}) and stable disease in 7 (33.3{\%}), yielding a disease control rate (DCR) of 42.9{\%}. The response durations of the two patients with CR were 7.5 and 8.8 months. DCR was correlated with a median of 8 weeks of arginine depletion to ≤10 μM. Using whole transcriptome sequencing, we compared gene expression profiling of pre- and post-treatment bone marrow samples of the two responders and three non-responders. The expression levels of some markers for AML subtypes and c-MYC regulated genes were considered potential predictors of response to ADI-PEG20. These results suggest that ASS deficiency is a prerequisite but not a sufficient condition for response to ADI-PEG20 monotherapy in AML. Predictive biomarkers and mechanistic explorations will be critical for identifying appropriate patients for future AML trials of ADI-PEG20.",
author = "Tsai, {Hui Jen} and Jiang, {Shih Sheng} and Hung, {Wen Chun} and Gautam Borthakur and Lin, {Sheng Fung} and Naveen Pemmaraju and Elias Jabbour and Bomalaski, {John S.} and Ya-Ping Chen and Hsiao, {Hui Hua} and Wang, {Ming Chung} and Kuo, {Ching Yuan} and Hung Chang and Yeh, {Su Peng} and Jorge Cortes and Chen, {Li Tzong} and Tsai-Yun Chen",
year = "2017",
month = "12",
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doi = "10.1038/s41598-017-10542-4",
language = "English",
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Tsai, HJ, Jiang, SS, Hung, WC, Borthakur, G, Lin, SF, Pemmaraju, N, Jabbour, E, Bomalaski, JS, Chen, Y-P, Hsiao, HH, Wang, MC, Kuo, CY, Chang, H, Yeh, SP, Cortes, J, Chen, LT & Chen, T-Y 2017, 'A Phase II Study of Arginine Deiminase (ADI-PEG20) in Relapsed/Refractory or Poor-Risk Acute Myeloid Leukemia Patients', Scientific reports, 卷 7, 編號 1, 11253. https://doi.org/10.1038/s41598-017-10542-4

A Phase II Study of Arginine Deiminase (ADI-PEG20) in Relapsed/Refractory or Poor-Risk Acute Myeloid Leukemia Patients. / Tsai, Hui Jen; Jiang, Shih Sheng; Hung, Wen Chun; Borthakur, Gautam; Lin, Sheng Fung; Pemmaraju, Naveen; Jabbour, Elias; Bomalaski, John S.; Chen, Ya-Ping; Hsiao, Hui Hua; Wang, Ming Chung; Kuo, Ching Yuan; Chang, Hung; Yeh, Su Peng; Cortes, Jorge; Chen, Li Tzong; Chen, Tsai-Yun.

於: Scientific reports, 卷 7, 編號 1, 11253, 01.12.2017.

研究成果: Article

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T1 - A Phase II Study of Arginine Deiminase (ADI-PEG20) in Relapsed/Refractory or Poor-Risk Acute Myeloid Leukemia Patients

AU - Tsai, Hui Jen

AU - Jiang, Shih Sheng

AU - Hung, Wen Chun

AU - Borthakur, Gautam

AU - Lin, Sheng Fung

AU - Pemmaraju, Naveen

AU - Jabbour, Elias

AU - Bomalaski, John S.

AU - Chen, Ya-Ping

AU - Hsiao, Hui Hua

AU - Wang, Ming Chung

AU - Kuo, Ching Yuan

AU - Chang, Hung

AU - Yeh, Su Peng

AU - Cortes, Jorge

AU - Chen, Li Tzong

AU - Chen, Tsai-Yun

PY - 2017/12/1

Y1 - 2017/12/1

N2 - Exogenous arginine is required for growth in some argininosuccinate synthetase (ASS)-deficient cancers. Arginine deiminase (ADI) inhibits growth in various ASS-deficient cancers by depleting arginine. The efficacy of pegylated ADI (ADI-PEG20) in relapsed/refractory/poor-risk acute myeloid leukemia (AML) was evaluated in 43 patients in a prospective, phase II trial (NCT01910012 (10/07/2013), https://clinicaltrials.gov/ct2/show/NCT01910012?term = ADI-PEG20&rank = 12). Despite almost all pre-treatment tumor samples showing ASS deficiency, the best response among 21 evaluable patients was complete response (CR) in 2 (9.5%) and stable disease in 7 (33.3%), yielding a disease control rate (DCR) of 42.9%. The response durations of the two patients with CR were 7.5 and 8.8 months. DCR was correlated with a median of 8 weeks of arginine depletion to ≤10 μM. Using whole transcriptome sequencing, we compared gene expression profiling of pre- and post-treatment bone marrow samples of the two responders and three non-responders. The expression levels of some markers for AML subtypes and c-MYC regulated genes were considered potential predictors of response to ADI-PEG20. These results suggest that ASS deficiency is a prerequisite but not a sufficient condition for response to ADI-PEG20 monotherapy in AML. Predictive biomarkers and mechanistic explorations will be critical for identifying appropriate patients for future AML trials of ADI-PEG20.

AB - Exogenous arginine is required for growth in some argininosuccinate synthetase (ASS)-deficient cancers. Arginine deiminase (ADI) inhibits growth in various ASS-deficient cancers by depleting arginine. The efficacy of pegylated ADI (ADI-PEG20) in relapsed/refractory/poor-risk acute myeloid leukemia (AML) was evaluated in 43 patients in a prospective, phase II trial (NCT01910012 (10/07/2013), https://clinicaltrials.gov/ct2/show/NCT01910012?term = ADI-PEG20&rank = 12). Despite almost all pre-treatment tumor samples showing ASS deficiency, the best response among 21 evaluable patients was complete response (CR) in 2 (9.5%) and stable disease in 7 (33.3%), yielding a disease control rate (DCR) of 42.9%. The response durations of the two patients with CR were 7.5 and 8.8 months. DCR was correlated with a median of 8 weeks of arginine depletion to ≤10 μM. Using whole transcriptome sequencing, we compared gene expression profiling of pre- and post-treatment bone marrow samples of the two responders and three non-responders. The expression levels of some markers for AML subtypes and c-MYC regulated genes were considered potential predictors of response to ADI-PEG20. These results suggest that ASS deficiency is a prerequisite but not a sufficient condition for response to ADI-PEG20 monotherapy in AML. Predictive biomarkers and mechanistic explorations will be critical for identifying appropriate patients for future AML trials of ADI-PEG20.

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