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

doi: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

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 › 同行評審

59 引文斯高帕斯（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
卷	7
發行號	1
DOIs	https://doi.org/10.1038/s41598-017-10542-4
出版狀態	Published - 2017 12月 1

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10.1038/s41598-017-10542-4

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Tsai, H. J., Jiang, S. S., Hung, W. C., Borthakur, G., Lin, S. F., Pemmaraju, N., Jabbour, E., Bomalaski, J. S., Chen, Y. P., Hsiao, H. H., Wang, M. C., Kuo, C. Y., Chang, H., Yeh, S. P., Cortes, J., Chen, L. T., & 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, 7(1), 文章 11253. https://doi.org/10.1038/s41598-017-10542-4

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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 Chen, {Ya Ping} 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 Chen, {Tsai Yun}",

note = "Publisher Copyright: {\textcopyright} 2017 The Author(s).",

year = "2017",

month = dec,

day = "1",

doi = "10.1038/s41598-017-10542-4",

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Tsai, HJ, Jiang, SS, Hung, WC, Borthakur, G, Lin, SF, Pemmaraju, N, Jabbour, E, Bomalaski, JS, Chen, YP, Hsiao, HH, Wang, MC, Kuo, CY, Chang, H, Yeh, SP, Cortes, J, Chen, LT & Chen, TY 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

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

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