{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T01:45:14Z","timestamp":1791942314762,"version":"4.3.4"},"reference-count":39,"publisher":"American Society of Hematology","issue":"6","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,3,25]]},"abstract":"<jats:sec>\n                  <jats:title>Abstract<\/jats:title>\n                  <jats:p>The prognosis for patients with acute promyelocytic leukemia (APL) has improved dramatically since the introduction of all-trans retinoic acid and IV arsenic trioxide (ATO). However, ATO administration requires daily infusions over several months, representing an onerous burden for hospitals and patients. We evaluated the bioavailability of a novel encapsulated oral ATO formulation in patients with APL in first complete remission during standard-of-care consolidation. After a pilot study exploring the likely oral dose requirement, total arsenic pharmacokinetics were evaluated in 20 patients after both IV and oral ATO 0.15\u00a0mg\/kg per day, with exposure to oral ATO restricted to the first week in 2\u00a0of 4 ATO cycles. The primary end point was bioequivalence of area under the curve from 0 to 24 hours (AUC0-24), with bioequivalence of maximum concentration achieved (Cmax) as the key secondary end point. The 90% confidence intervals (CIs) around point estimates of the geometric means of the oral-to-IV ratios for AUC0-24 and Cmax were compared with bioequivalence limits specified by the European Medicines Agency (0.80-1.25). The estimated oral-to-IV ratios and 90%\u00a0CIs for AUC0-24 in whole blood and plasma were 0.993 (0.954-1.034) and 1.030 (0.977-1.087) respectively; data for Cmax also satisfied bioequivalence requirements. Exploratory studies of arsenic species in plasma showed bioequivalence for AUC0-24 with As(III) (oral-to-IV ratio, 0.966 [0.879-1.063]). The adverse event profiles of oral and IV ATO were comparable for cycles commencing with the IV and oral formulations. In conclusion, this novel oral ATO formulation is bioequivalent with IV ATO and offers a convenient alternative for patients with APL. This trial was registered at www.anzctr.org.au as #ACTRN12616001022459.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1182\/bloodadvances.2024015397","type":"journal-article","created":{"date-parts":[[2025,1,28]],"date-time":"2025-01-28T21:00:20Z","timestamp":1738098020000},"page":"1476-1484","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":7,"title":["ALLG APML5: bioavailability and safety of oral arsenic trioxide assessed during consolidation therapy for APL"],"prefix":"10.1182","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9787-5908","authenticated-orcid":false,"given":"Harry J.","family":"Iland","sequence":"first","affiliation":[{"name":"1Institute of Haematology, Royal Prince Alfred Hospital, Sydney, Australia"},{"name":"2Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8825-8625","authenticated-orcid":false,"given":"John","family":"Reynolds","sequence":"additional","affiliation":[{"name":"3Biostatistics Consulting Platform, Monash University, Melbourne, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8920-9286","authenticated-orcid":false,"given":"Alan V.","family":"Boddy","sequence":"additional","affiliation":[{"name":"4UniSA Clinical and Health Sciences, University of South Australia, Adelaide, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8856-0317","authenticated-orcid":false,"given":"Hayley B.","family":"Schultz","sequence":"additional","affiliation":[{"name":"4UniSA Clinical and Health Sciences, University of South Australia, Adelaide, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liane","family":"Khoo","sequence":"additional","affiliation":[{"name":"1Institute of Haematology, Royal Prince Alfred Hospital, Sydney, Australia"},{"name":"2Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaun","family":"Fleming","sequence":"additional","affiliation":[{"name":"5Department of Clinical Haematology, Alfred Hospital, Melbourne, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8050-6209","authenticated-orcid":false,"given":"Steven W.","family":"Lane","sequence":"additional","affiliation":[{"name":"6Cancer Care Services, Royal Brisbane and Women\u2019s Hospital, Brisbane, Australia"},{"name":"7School of Medicine, University of Queensland, Brisbane, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6341-2537","authenticated-orcid":false,"given":"Nicholas","family":"Weber","sequence":"additional","affiliation":[{"name":"6Cancer Care Services, Royal Brisbane and Women\u2019s Hospital, Brisbane, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1225-8757","authenticated-orcid":false,"given":"Robin","family":"Gasiorowski","sequence":"additional","affiliation":[{"name":"2Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, Australia"},{"name":"8Haematology, Concord Hospital, Sydney, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tasman","family":"Armytage","sequence":"additional","affiliation":[{"name":"9Haematology, Gosford Hospital, Gosford, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosemary","family":"Harrup","sequence":"additional","affiliation":[{"name":"10Cancer and Blood Services, Royal Hobart Hospital, Hobart, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Marie","family":"Watson","sequence":"additional","affiliation":[{"name":"11Haematology, Liverpool Hospital, Sydney, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Tan","sequence":"additional","affiliation":[{"name":"12Haematology, Royal Perth Hospital, Perth, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin","family":"Filshie","sequence":"additional","affiliation":[{"name":"13Haematology, St Vincent\u2019s Hospital, Melbourne, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiona","family":"Kwok","sequence":"additional","affiliation":[{"name":"14Haematology, Westmead Hospital, Sydney, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Stevenson","sequence":"additional","affiliation":[{"name":"2Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, Australia"},{"name":"15Haematology, Royal North Shore Hospital, Sydney, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sam","family":"Yuen","sequence":"additional","affiliation":[{"name":"16Haematology, Calvary Mater Hospital, Newcastle, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9690-0879","authenticated-orcid":false,"given":"Ashley P.","family":"Ng","sequence":"additional","affiliation":[{"name":"17Department of Clinical Haematology, Peter MacCallum Cancer Centre and The Royal Melbourne Hospital, Melbourne, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leesa","family":"Rowley","sequence":"additional","affiliation":[{"name":"18Australasian Leukaemia and Lymphoma Group, Melbourne, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"Marlton","sequence":"additional","affiliation":[{"name":"7School of Medicine, University of Queensland, Brisbane, Australia"},{"name":"19Haematology, Princess Alexandra Hospital, Brisbane, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7514-3298","authenticated-orcid":false,"given":"Andrew H.","family":"Wei","sequence":"additional","affiliation":[{"name":"17Department of Clinical Haematology, Peter MacCallum Cancer Centre and The Royal Melbourne Hospital, Melbourne, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","published-online":{"date-parts":[[2025,3,25]]},"reference":[{"issue":"1","key":"2025041018370925800_bib1","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1111\/j.1365-2141.2011.08922.x","article-title":"The pathogenesis and management of the coagulopathy of acute promyelocytic leukaemia","volume":"156","author":"Breen","year":"2012","journal-title":"Br J Haematol"},{"issue":"8010","key":"2025041018370925800_bib2","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/S0140-6736(77)91415-5","article-title":"15\/17 translocation, a consistent chromosomal change in acute promyelocytic leukaemia","volume":"1","author":"Rowley","year":"1977","journal-title":"Lancet"},{"issue":"12","key":"2025041018370925800_bib3","first-page":"802","article-title":"The retinoic acid receptor alpha gene is rearranged in retinoic acid-sensitive promyelocytic leukemias","volume":"4","author":"Chomienne","year":"1990","journal-title":"Leukemia"},{"issue":"4","key":"2025041018370925800_bib4","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1016\/0092-8674(91)90112-C","article-title":"Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RAR alpha with a novel putative transcription factor, PML","volume":"66","author":"Kakizuka","year":"1991","journal-title":"Cell"},{"issue":"2","key":"2025041018370925800_bib5","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1182\/blood.V72.2.567.567","article-title":"Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia","volume":"72","author":"Huang","year":"1988","journal-title":"Blood"},{"issue":"9","key":"2025041018370925800_bib6","doi-asserted-by":"crossref","first-page":"3354","DOI":"10.1182\/blood.V89.9.3354","article-title":"Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients","volume":"89","author":"Shen","year":"1997","journal-title":"Blood"},{"issue":"33","key":"2025041018370925800_bib7","doi-asserted-by":"crossref","first-page":"4215","DOI":"10.1200\/JCO.2013.48.8312","article-title":"Oral tetra-arsenic tetra-sulfide formula versus intravenous arsenic trioxide as first-line treatment of acute promyelocytic leukemia: a multicenter randomized controlled trial","volume":"31","author":"Zhu","year":"2013","journal-title":"J\u00a0Clin Oncol"},{"issue":"2","key":"2025041018370925800_bib8","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1097\/MOH.0000000000000025","article-title":"Optimal approach for high-risk acute promyelocytic leukemia","volume":"21","author":"Iland","year":"2014","journal-title":"Curr Opin Hematol"},{"issue":"15","key":"2025041018370925800_bib9","doi-asserted-by":"crossref","first-page":"1630","DOI":"10.1182\/blood-2019-01-894980","article-title":"Management of acute promyelocytic leukemia: updated recommendations from an expert panel of the European LeukemiaNet","volume":"133","author":"Sanz","year":"2019","journal-title":"Blood"},{"issue":"2","key":"2025041018370925800_bib10","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1056\/NEJMoa1300874","article-title":"Retinoic acid and arsenic trioxide for acute promyelocytic leukemia","volume":"369","author":"Lo-Coco","year":"2013","journal-title":"N\u00a0Engl J Med"},{"key":"2025041018370925800_bib11","unstructured":"National Comprehensive Cancer Network\n          . Acute myeloid leukemia (version 2.2025). Accessed 11 February 2025. https:\/\/www.nccn.org\/professionals\/physician_gls\/pdf\/aml.pdf."},{"issue":"3","key":"2025041018370925800_bib12","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1182\/blood-2007-07-099978","article-title":"Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results","volume":"111","author":"Ades","year":"2008","journal-title":"Blood"},{"issue":"17","key":"2025041018370925800_bib13","doi-asserted-by":"crossref","first-page":"3171","DOI":"10.1182\/blood-2010-03-276196","article-title":"Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation for adults younger than 61 years: results of the AIDA-2000 trial of the GIMEMA Group","volume":"116","author":"Lo-Coco","year":"2010","journal-title":"Blood"},{"issue":"25","key":"2025041018370925800_bib14","doi-asserted-by":"crossref","first-page":"5137","DOI":"10.1182\/blood-2010-01-266007","article-title":"Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high-risk patients: further improvements in treatment outcome","volume":"115","author":"Sanz","year":"2010","journal-title":"Blood"},{"issue":"9","key":"2025041018370925800_bib15","doi-asserted-by":"crossref","first-page":"e357","DOI":"10.1016\/S2352-3026(15)00115-5","article-title":"Use of arsenic trioxide in remission induction and consolidation therapy for acute promyelocytic leukaemia in the Australasian Leukaemia and Lymphoma Group (ALLG) APML4 study: a non-randomised phase 2 trial","volume":"2","author":"Iland","year":"2015","journal-title":"Lancet Haematol"},{"issue":"13","key":"2025041018370925800_bib16","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.1016\/S1470-2045(15)00193-X","article-title":"Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a randomised, controlled, phase 3 trial","volume":"16","author":"Burnett","year":"2015","journal-title":"Lancet Oncol"},{"key":"2025041018370925800_bib17","author":"Platzbecker","year":"15  2024"},{"issue":"2","key":"2025041018370925800_bib18","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1182\/blood.2024026186","article-title":"Acute promyelocytic leukemia: long-term outcomes from the HARMONY project","volume":"145","author":"Voso","year":"2025","journal-title":"Blood"},{"issue":"1","key":"2025041018370925800_bib19","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1001\/jamaoncol.2021.5206","article-title":"Assessment of arsenic trioxide and all-trans retinoic acid for the treatment of pediatric acute promyelocytic leukemia: a report from the Children's Oncology Group AAML1331 trial","volume":"8","author":"Kutny","year":"2022","journal-title":"JAMA Oncol"},{"issue":"7","key":"2025041018370925800_bib20","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1016\/S1470-2045(18)30295-X","article-title":"Oral arsenic plus retinoic acid versus intravenous arsenic plus retinoic acid for non-high-risk acute promyelocytic leukaemia: a non-inferiority, randomised phase 3 trial","volume":"19","author":"Zhu","year":"2018","journal-title":"Lancet Oncol"},{"issue":"25","key":"2025041018370925800_bib21","doi-asserted-by":"crossref","first-page":"6535","DOI":"10.1182\/blood-2011-05-354530","article-title":"Oral arsenic trioxide-based maintenance regimens for first complete remission of acute promyelocytic leukemia: a 10-year follow-up study","volume":"118","author":"Au","year":"2011","journal-title":"Blood"},{"issue":"1","key":"2025041018370925800_bib22","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1182\/blood-2003-01-0298","article-title":"Oral arsenic trioxide in the treatment of relapsed acute promyelocytic leukemia","volume":"102","author":"Au","year":"2003","journal-title":"Blood"},{"issue":"6","key":"2025041018370925800_bib23","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.3324\/haematol.2019.229583","article-title":"Oral arsenic trioxide ORH-2014 pharmacokinetic and safety profile in patients with advanced hematologic disorders","volume":"105","author":"Ravandi","year":"2020","journal-title":"Haematologica"},{"issue":"8","key":"2025041018370925800_bib24","doi-asserted-by":"crossref","first-page":"1570","DOI":"10.1182\/blood-2012-02-410746","article-title":"All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4)","volume":"120","author":"Iland","year":"2012","journal-title":"Blood"},{"key":"2025041018370925800_bib25","unstructured":"European Medicines Agency\n          . Guideline on the investigation of bioequivalence (Rev.1). Committee for Medicinal Products for Human Use (CHMP). 2010;CPMP\/EWP\/QWP\/1401\/98 Rev. Accessed 11 February 2025. https:\/\/www.ema.europa.eu\/en\/investigation-bioequivalence-scientific-guideline."},{"issue":"4","key":"2025041018370925800_bib26","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1084\/jem.20122337","article-title":"Uncoupling RARA transcriptional activation and degradation clarifies the bases for APL response to therapies","volume":"210","author":"Ablain","year":"2013","journal-title":"J\u00a0Exp Med"},{"issue":"1","key":"2025041018370925800_bib27","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.molmed.2011.10.001","article-title":"Curing APL through PML\/RARA degradation by As2O3","volume":"18","author":"Lallemand-Breitenbach","year":"2012","journal-title":"Trends Mol Med"},{"issue":"1","key":"2025041018370925800_bib28","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1083\/jcb.201112044","article-title":"The cell biology of disease: acute promyelocytic leukemia, arsenic, and PML bodies","volume":"198","author":"de The","year":"2012","journal-title":"J\u00a0Cell Biol"},{"issue":"12","key":"2025041018370925800_bib29","doi-asserted-by":"crossref","first-page":"2548","DOI":"10.1158\/2159-8290.CD-23-0453","article-title":"Structural basis of PML-RARA oncoprotein targeting by arsenic unravels a cysteine rheostat controlling PML body assembly and function","volume":"13","author":"Bercier","year":"2023","journal-title":"Cancer Discov"},{"issue":"28","key":"2025041018370925800_bib30","doi-asserted-by":"crossref","first-page":"25646","DOI":"10.18632\/oncotarget.4662","article-title":"Methylated arsenic metabolites bind to PML protein but do not induce cellular differentiation and PML-RAR\u03b1 protein degradation","volume":"6","author":"Wang","year":"2015","journal-title":"Oncotarget"},{"issue":"3","key":"2025041018370925800_bib31","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1111\/j.0954-6820.1957.tb00124.x","article-title":"Acute promyelocytic leukemia","volume":"159","author":"Hillestad","year":"1957","journal-title":"Acta Med Scand"},{"issue":"1","key":"2025041018370925800_bib32","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1007\/s40487-018-0091-5","article-title":"Acute promyelocytic leukemia: a history over 60 years - from the most malignant to the most curable form of acute leukemia","volume":"7","author":"Thomas","year":"2019","journal-title":"Oncol Ther"},{"issue":"1","key":"2025041018370925800_bib33","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1182\/hematology.2023000477","article-title":"How to avoid early mortality in acute promyelocytic leukemia","volume":"2023","author":"Odetola","year":"2023","journal-title":"Hematology"},{"issue":"7","key":"2025041018370925800_bib34","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1182\/blood.2019000760","article-title":"The simpler, the better: oral arsenic for acute promyelocytic leukemia","volume":"134","author":"Zhu","year":"2019","journal-title":"Blood"},{"issue":"12","key":"2025041018370925800_bib35","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1182\/blood.2024023890","article-title":"Clinical networking results in continuous improvement of the outcome of patients with acute promyelocytic leukemia","volume":"144","author":"Koury","year":"2024","journal-title":"Blood"},{"issue":"8","key":"2025041018370925800_bib36","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1111\/j.1445-5994.2012.02852.x","article-title":"Oral administration of arsenic trioxide in the treatment of acute promyelocytic leukaemia and accelerated phase chronic myeloid leukaemia: an Australian single-centre study","volume":"42","author":"Firkin","year":"2012","journal-title":"Intern Med J"},{"key":"2025041018370925800_bib37","doi-asserted-by":"crossref","first-page":"1294","DOI":"10.3389\/fonc.2020.01294","article-title":"Resurrection of oral arsenic trioxide for treating acute promyelocytic leukaemia: a historical account from bedside to bench to bedside","volume":"10","author":"Kumana","year":"2020","journal-title":"Front Oncol"},{"issue":"8","key":"2025041018370925800_bib38","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1007\/s00228-002-0514-x","article-title":"Systemic availability of arsenic from oral arsenic-trioxide used to treat patients with hematological malignancies","volume":"58","author":"Kumana","year":"2002","journal-title":"Eur\u00a0J Clin Pharmacol"},{"issue":"1","key":"2025041018370925800_bib39","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1182\/blood-2006-01-0054","article-title":"Effects of oral arsenic trioxide therapy on QT intervals in patients with acute promyelocytic leukemia: implications for long-term cardiac safety","volume":"108","author":"Siu","year":"2006","journal-title":"Blood"}],"container-title":["Blood Advances"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ashpublications.org\/bloodadvances\/article-pdf\/9\/6\/1476\/2362122\/blooda_adv-2024-015397-main.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/ashpublications.org\/bloodadvances\/article-pdf\/9\/6\/1476\/2362122\/blooda_adv-2024-015397-main.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,10]],"date-time":"2025-04-10T18:37:21Z","timestamp":1744310241000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/bloodadvances\/article\/9\/6\/1476\/535305\/ALLG-APML5-bioavailability-and-safety-of-oral"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,25]]},"references-count":39,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2025,3,25]]}},"URL":"https:\/\/doi.org\/10.1182\/bloodadvances.2024015397","relation":{},"ISSN":["2473-9529","2473-9537"],"issn-type":[{"value":"2473-9529","type":"print"},{"value":"2473-9537","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,25]]}}}