@article{798ba3a7fe5e4769888dd622c87d0ae5,
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 = "Funding Information: Eligibility criteria. This study was sponsored by Polaris Group and registered with ClinicalTrials.gov as NCT01910012 on 10/07/2013. Patients≥18 years old with relapsed/refractory or poor-risk AML and not candidates for stem cell transplantation were eligible. Poor-risk AML included treatment-related AML, antecedent hematologic disease (e.g., myelodysplastic syndrome, myelofibrosis, and polycythemia vera), unfavorable cytogenetics regardless of age and de novo AML at ≥60 years of age. Patients who had uncontrolled concomitant illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure (New York Heart Association Class III or IV), cardiac arrhythmia, psychiatric illness, social situations that would limit compliance with study requirements, disseminated intravascular coagulation or a history of another active primary cancer, except curatively resected skin cancer or treated cervical carcinoma in situ, were excluded. The study was approved by the institutional review board of each participating institution, and all of the patients provided signed informed consent. In addition, this trial was approved by the Institutional Review Boards of National Cheng Kung University Hospital, Tainan, Taiwan; Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; University of Texas M.D. Anderson Cancer Center, Houston, TX, USA; Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; Linkou Chang Gung Memorial Hospital, Linkou, Taiwan; China Medical University Hospital, Taichung, Taiwan and performed in accordance with their guidelines and regulations of each participating hospital. Funding Information: The whole transcriptome sequencing was supported by National Cheng Kung University Hospital, DOH102-TD-C-111-003. Publisher Copyright: {\textcopyright} 2017 The Author(s).",
year = "2017",
month = dec,
day = "1",
doi = "10.1038/s41598-017-10542-4",
language = "English",
volume = "7",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
number = "1",
}