{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T01:35:05Z","timestamp":1792028105980,"version":"4.4.0"},"reference-count":37,"publisher":"American Society of Hematology","issue":"9","license":[{"start":{"date-parts":[[2022,11,18]],"date-time":"2022-11-18T00:00:00Z","timestamp":1668729600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,3,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Activated phosphoinositide 3-kinase delta (PI3K\u03b4) syndrome (APDS) is an inborn error of immunity with clinical manifestations including infections, lymphoproliferation, autoimmunity, enteropathy, bronchiectasis, increased risk of lymphoma, and early mortality. Hyperactive PI3K\u03b4 signaling causes APDS and is selectively targeted with leniolisib, an oral, small molecule inhibitor of PI3K\u03b4. Here, 31 patients with APDS aged \u226512 years were enrolled in a global, phase 3, triple-blinded trial and randomized 2:1 to receive 70 mg leniolisib or placebo twice daily for 12 weeks. Coprimary outcomes were differences from baseline in the index lymph node size and the percentage of na\u00efve B cells in peripheral blood, assessed as proxies for immune dysregulation and deficiency. Both primary outcomes were met: the difference in the adjusted mean change (95% confidence interval [CI]) between leniolisib and placebo for lymph node size was\u00a0\u22120.25 (\u22120.38,\u00a0\u22120.12; P\u00a0= .0006; N\u00a0= 26) and for percentage of na\u00efve B cells, was 37.30 (24.06, 50.54; P\u00a0= .0002; N\u00a0= 13). Leniolisib reduced spleen volume compared with placebo (adjusted mean difference in 3-dimensional volume [cm3],\u00a0\u2212186; 95% CI,\u00a0\u2212297 to\u00a0\u221276.2; P\u00a0= .0020) and improved key immune cell subsets. Fewer patients receiving leniolisib reported study treatment-related adverse events (AEs; mostly grades 1-2) than those receiving placebo (23.8% vs 30.0%). Overall, leniolisib was well tolerated and significant improvement over placebo was notable in the coprimary endpoints, reducing lymphadenopathy and increasing the\u00a0percentage of na\u00efve B cells, reflecting a favorable impact on the immune dysregulation and deficiency seen in\u00a0patients\u00a0with APDS. This trial was registered at www.clinicaltrials.gov as #NCT02435173.<\/jats:p>","DOI":"10.1182\/blood.2022018546","type":"journal-article","created":{"date-parts":[[2022,11,18]],"date-time":"2022-11-18T21:16:23Z","timestamp":1668806183000},"page":"971-983","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":137,"title":["A randomized, placebo-controlled phase 3 trial of\u00a0the PI3K\u03b4 inhibitor leniolisib for activated PI3K\u03b4 syndrome"],"prefix":"10.1182","volume":"141","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7881-6902","authenticated-orcid":false,"given":"V. Koneti","family":"Rao","sequence":"first","affiliation":[{"name":"1National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon","family":"Webster","sequence":"additional","affiliation":[{"name":"1National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7730-2304","authenticated-orcid":false,"given":"Anna","family":"\u0160ediv\u00e1","sequence":"additional","affiliation":[{"name":"2Department of Immunology, 2nd Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Plebani","sequence":"additional","affiliation":[{"name":"3Pediatrics Clinic, Department of Clinical and Experimental Sciences, University of Brescia, Azienda Socio Sanitaria Territoriale Spedali Civili di Brescia, Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8731-8924","authenticated-orcid":false,"given":"Catharina","family":"Schuetz","sequence":"additional","affiliation":[{"name":"4Department of Pediatric Immunology, University Hospital Carl Gustav Carus, Technische Universit\u00e4t Dresden, Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Shcherbina","sequence":"additional","affiliation":[{"name":"5Department of Immunology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1102-0758","authenticated-orcid":false,"given":"Niall","family":"Conlon","sequence":"additional","affiliation":[{"name":"6Wellcome Trust Clinical Research Facility, St. James\u2019s Hospital, and Department of Clinical Immunology, Trinity College Dublin, Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanya","family":"Coulter","sequence":"additional","affiliation":[{"name":"7Regional Immunology Services of Northern Ireland, Belfast Health and Social Care Trust, Belfast, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virgil A.","family":"Dalm","sequence":"additional","affiliation":[{"name":"8Division of Allergy and Clinical Immunology, Department of Internal Medicine, and Department of Immunology, Erasmus Medical Center University Medical Center, Rotterdam, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonino","family":"Trizzino","sequence":"additional","affiliation":[{"name":"9Department of Pediatric Hematology and Oncology, ARNAS Ospedali Civico Di Cristina Benfratelli Hospital, Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yulia","family":"Zharankova","sequence":"additional","affiliation":[{"name":"10Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Minsk, Belarus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaine","family":"Kulm","sequence":"additional","affiliation":[{"name":"11Clinical Research Directorate, Frederick National Laboratory for Cancer Research, Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6313-4434","authenticated-orcid":false,"given":"Julia","family":"K\u00f6rholz","sequence":"additional","affiliation":[{"name":"4Department of Pediatric Immunology, University Hospital Carl Gustav Carus, Technische Universit\u00e4t Dresden, Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vassilios","family":"Lougaris","sequence":"additional","affiliation":[{"name":"3Pediatrics Clinic, Department of Clinical and Experimental Sciences, University of Brescia, Azienda Socio Sanitaria Territoriale Spedali Civili di Brescia, Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9857-4456","authenticated-orcid":false,"given":"Yulia","family":"Rodina","sequence":"additional","affiliation":[{"name":"5Department of Immunology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kath","family":"Radford","sequence":"additional","affiliation":[{"name":"12Novartis Pharmaceuticals UK Limited, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason","family":"Bradt","sequence":"additional","affiliation":[{"name":"13Pharming Healthcare Inc, Warren, NJ"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus","family":"Kucher","sequence":"additional","affiliation":[{"name":"14Novartis Institutes for Biomedical Research, Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5521-4538","authenticated-orcid":false,"given":"Anurag","family":"Relan","sequence":"additional","affiliation":[{"name":"13Pharming Healthcare Inc, Warren, NJ"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven M.","family":"Holland","sequence":"additional","affiliation":[{"name":"1National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1584-468X","authenticated-orcid":false,"given":"Michael J.","family":"Lenardo","sequence":"additional","affiliation":[{"name":"1National Institute of Allergy and Infectious Diseases, National 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Clinical studies index: Seletalisib (UCB5857). Accessed 5 October 2022. https:\/\/www.ucb.com\/clinical-studies\/Clinical-studies-index\/Seletalisib-UCB5857."},{"issue":"11","key":"2023030216271833500_","doi-asserted-by":"crossref","first-page":"2979","DOI":"10.4049\/jimmunol.2000326","article-title":"Seletalisib for activated PI3K\u03b4 syndromes: open-label phase 1b and extension studies","volume":"205","author":"Diaz","year":"2020","journal-title":"J\u00a0Immunol"}],"container-title":["Blood"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/141\/9\/971\/2036280\/blood_bld-2022-018546-main.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/141\/9\/971\/2036280\/blood_bld-2022-018546-main.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,3,13]],"date-time":"2023-03-13T02:06:09Z","timestamp":1678673169000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/141\/9\/971\/493284\/A-randomized-placebo-controlled-phase-3-trial-of"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,2]]},"references-count":37,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2023,3,2]]}},"URL":"https:\/\/doi.org\/10.1182\/blood.2022018546","relation":{},"ISSN":["0006-4971","1528-0020"],"issn-type":[{"value":"0006-4971","type":"print"},{"value":"1528-0020","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,2]]}}}