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http://ir.nhri.org.tw/handle/3990099045/8638
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| Title: | Pegylated arginine deiminase (ADI-PEG20) in relapsed/refractory and/or elder Acute Myeloid Leukemia: The preliminary result of phase II trial |
| Authors: | Tsai, HJ;Wang, MC;Lin, SF;Chen, YP;Hsiao, HH;Kuo, CY;Chen, LT;Chen, TY |
| Contributors: | National Institute of Cancer Research |
| Abstract: | Background: Deprivation of circulating L-asparagine by L-asparaginase, which can lead to the inhibition of RNA and DNA synthesis and subsequent apoptosis of blastic cell, has been implemented as part of multidrug chemotherapy for acute lymphoblastic leukemia since decades ago. Arginine, a semi-essential amino acid in human, is involved in diverse aspects of tumor metabolism and plays critical role for the growth of human cancers. Deficiency of argininosuccinate synthase (ASS), the rate-limiting enzyme for endogenous arginine production in urea cycle, has been found in various cancer tissues. In preclinical studies, pegylated arginine deiminase (ADI-PEG20), which can rapidly convert arginine into citrulline and serve as an arginine depriving agent, was shown to exert in vitro and in vivo anti-proliferative effect on ASS-deficient cancers, such as hepatocellular carcinoma, melanoma, small cell lung cancer, lymphoma and acute myeloid leukemia (AML). The efficacy of ADI-PEG20 is currently under evaluation for various solid tumors in clinical trial setting, including a global phase III trial for hepatocellular carcinoma. Absence of ASS expression has been noted in 87% (46/53) of bone marrow biopsy samples of patients with AML.1 In xenograft model, ADI-PEG20 could reduce the leukemic burden in mice transplanted with primary AML cells.2Herein, we reported the preliminary result of a phase II trial evaluating the therapeutic efficacy of ADI-PEG20 in relapsed/refractory and/or elderly AML patients. Patients and Methods: Patients ≥ 18 years with ASS deficient (by western blotting of bone marrow leukemia cells and/or immunohistochemical staining of bone marrow biopsy), relapsed/refractory or poor-risk AML were eligible. The poor-risk AML includes treatment-related AML, antecedent hematologic disease, unfavorable cytogenetics and de novo AML ≥ 70 years of age. Patients received ADI-PEG20 at 320IU/m2IM weekly (4 weeks as one cycle). Bone marrow aspiration was performed at the time of enrollment, and after the first and second cycle of treatment to evaluate the response. Treatment was continued for each patient until the occurrence of disease progression, development of unacceptable toxicity, death, or withdrawal of consent for any reason. If patients achieved complete remission (CR) or CR with incomplete blood count recovery, the treatment was finished after another 4 cycles of ADI-PEG20. Results: Between October 2013 and May 2014, 9 patients were enrolled, with a male/female ratio of 5/4 and a median age of 62 years (ranged 27 to 79 years old). They were all de novo AML except for 1 with blast-transformed chronic myelomonocytic leukemia. All patients received at least one prior treatment regimen, except for two treatment-naïve elderly patients. After a mean 1.5 cycles of ADI-PEG20 treatment, 2 of 8 evaluable patients achieved CR after 3 and 1 cycles of ADI-PEG20, respectively, while 6 patients had disease progression after an average of 1 cycle of treatment. One patient was not evaluable for response due to withdrawal of consent after the first 2 doses of treatment. Two patients, who died within 2 weeks after the first dose of ADI-PEG20, were considered to have progressive disease. Of the 2 CR patients, 1 was 79 years old with chemo-naïve acute megakaryocytic leukemia (M7) and the other was 69 years old with low-dose Ara-C refractory M2. The most common treatment-related severe adverse events (AE) included grade 4 tumor lysis syndrome, grade 4 infection and treatment-related grade 4 neutropenia occurring in one patient each. The episode of grade 4 neutropenia occurred in the ADI-PEG20 responsive M7 patient. Minor AE included grade 1 hyperuricemia and skin rash in 2 and 1 patients, respectively. Conclusions: ADI-PEG20 is an effective treatment for some patients with ASS-deficient AML with minimal toxicities. Further investigation with genetic and epigenetic profiling to identify patients who will benefit from arginine deprivation therapy is warranted. |
| Date: | 2014-12 |
| Relation: | Blood. 2014 Dec;124(21):984. |
| Link to: | http://www.bloodjournal.org/content/124/21/984 |
| JIF/Ranking 2023: | http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0006-4971&DestApp=IC2JCR |
| Cited Times(WOS): | https://www.webofscience.com/wos/woscc/full-record/WOS:000349243500007 |
| Appears in Collections: | [陳立宗] 會議論文/會議摘要
[蔡慧珍] 會議論文/會議摘要
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