{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T22:09:49Z","timestamp":1793830189470,"version":"4.6.1"},"reference-count":114,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T00:00:00Z","timestamp":1672790400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Duvelisib is the first FDA-approved oral dual inhibitor of phosphatidylinositol-3-kinase PI3K-delta (PI3K-\u03b4) and PI3K-gamma (PI3K-\u03b3). Although many clinical studies support the efficacy of duvelisib, the safety of duvelisib remains with great attention. This systematic review and meta-analysis aimed to evaluate the safety and efficacy of duvelisib in treating different relapsed or refractory (RR) lymphoid neoplasm types.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We searched prospective clinical trials from PUBMED, EMBASE, Cochrane Library, and ClinicalTrials.gov. For efficacy analysis, Overall response rate (ORR), complete response rate (CR), partial response rate (PR), rate of stable disease (SDR), rate of progressive disease (PDR), median progression-free survival (mPFS), 12-\/24-month PFS, and 12-month overall survival (OS) were assessed. For safety analysis, the incidences of any grade and grade \u22653 adverse events (AEs), serious AEs, and treatment-related discontinuation and death were evaluated. Subgroup analysis based on the disease type was performed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We included 11 studies and 683 patients, including 305 chronic lymphocytic leukemia\/small lymphocytic lymphoma (CLL\/SLL), 187 B-cell indolent non-Hodgkin lymphoma (iNHL), 39 B-cell aggressive non-Hodgkin lymphoma (aNHL), and 152 T-cell non-Hodgkin lymphoma (T-NHL) patients. The pooled ORR in CLL\/SLL, iNHL, aNHL and T-NHL was 70%, 70%, 28% and 47%, respectively. Additionally, the pooled ORR in CLL\/SLL patients with or without TP53 mutation\/17p-deletion (62% vs. 74%, p=0.45) and in follicular lymphoma (FL) or other iNHL (69% vs. 57%, p=0.38) had no significant differences. Mantle cell lymphoma (MCL) patients had higher pooled ORR than other aNHL (68% vs. 17%, p=0.04). Angioimmunoblastic TCL (AITL) patients had higher pooled ORR than other PTCL patients (67% vs. 42%, p=0.01). The pooled incidence of any grade, grade \u22653, serious AEs, treatment-related discontinuation and death was 99%, 79%, 63%, 33% and 3%, respectively. The most frequent any-grade AEs were diarrhea (47%), ALT\/AST increase (39%), and neutropenia (38%). The most frequent grade \u22653 AEs were neutropenia (25%), ALT\/AST increased (16%), diarrhea (12%), and anemia (12%).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Generally, duvelisib could offer favorable efficacy in patients with RR CLL\/SLL, iNHL, MCL, and AITL. Risk and severity in duvelisib treatment may be mitigated through proper identification and management.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2022.1070660","type":"journal-article","created":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T13:30:15Z","timestamp":1672839015000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":29,"title":["Safety and efficacy of dual PI3K-\u03b4, \u03b3 inhibitor, duvelisib in patients with relapsed or refractory lymphoid neoplasms: A systematic review and meta-analysis of prospective clinical trials"],"prefix":"10.3389","volume":"13","author":[{"given":"Zhongwang","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinjin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Niu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,1,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"7","DOI":"10.3322\/caac.21708","article-title":"Cancer statistics, 2022","volume":"72","author":"Siegel","year":"2022","journal-title":"CA Cancer J Clin"},{"key":"B2","first-page":"1975","volume-title":"SEER cancer statistics review","author":"Howlader","year":"2021"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-022-01620-2","article-title":"The 5th edition of the world health organization classification of haematolymphoid tumours: Lymphoid neoplasms","volume":"36","author":"Alaggio","year":"2022","journal-title":"Leukemia"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djk152","article-title":"Immunochemotherapy with rituximab and overall survival in patients with indolent or mantle cell lymphoma: a systematic review and meta-analysis","volume":"99","author":"Schulz","year":"2007","journal-title":"J Natl Cancer Inst"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1177\/107327481201900303","article-title":"Follicular lymphoma: current management and future directions","volume":"19","author":"Bello","year":"2012","journal-title":"Cancer Control"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2020010029","article-title":"Exploring the pathways to chronic lymphocytic leukemia","volume":"138","author":"Stevenson","year":"2021","journal-title":"Blood"},{"key":"B7","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1186\/s13045-021-01054-w","article-title":"Current and future treatment strategies in chronic lymphocytic leukemia","volume":"14","author":"Patel","year":"2021","journal-title":"J Hematol Oncol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1186\/s13045-020-01018-6","article-title":"How we treat mature b-cell neoplasms (indolent b-cell lymphomas)","volume":"14","author":"Lumish","year":"2021","journal-title":"J Hematol Oncol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1038\/s41572-019-0132-x","article-title":"Follicular lymphoma","volume":"5","author":"Carbone","year":"2019","journal-title":"Nat Rev Dis Primers"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3884","article-title":"Targeting b cell receptor signaling with ibrutinib in diffuse large b cell lymphoma","volume":"21","author":"Wilson","year":"2015","journal-title":"Nat Med"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2007.15.3429","article-title":"Lenalidomide monotherapy in relapsed or refractory aggressive non-hodgkin\u2019s lymphoma","volume":"26","author":"Wiernik","year":"2008","journal-title":"J Clin Oncol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2016.70.4320","article-title":"Phase I first-in-Human study of venetoclax in patients with relapsed or refractory non-Hodgkin lymphoma","volume":"35","author":"Davids","year":"2017","journal-title":"J Clin Oncol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.14694\/EdBook_AM.2014.34.191","article-title":"Mantle cell lymphoma: biology, clinical presentation, and therapeutic approaches","author":"Dreyling","year":"2014","journal-title":"Am Soc Clin Oncol Educ Book"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-06-230250","article-title":"Molecular remission is an independent predictor of clinical outcome in patients with mantle cell lymphoma after combined immunochemotherapy: a European MCL intergroup study","volume":"115","author":"Pott","year":"2010","journal-title":"Blood"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdt366","article-title":"Long-term follow-up of lenalidomide in relapsed\/refractory mantle cell lymphoma: subset analysis of the NHL-003 study","volume":"24","author":"Zinzani","year":"2013","journal-title":"Ann Oncol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2005.13.466","article-title":"Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma","volume":"23","author":"Witzig","year":"2005","journal-title":"J Clin Oncol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-12-516245","article-title":"How I treat the peripheral T-cell lymphomas","volume":"123","author":"Moskowitz","year":"2014","journal-title":"Blood"},{"key":"B18","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1186\/s13045-020-01006-w","article-title":"Novel targeted therapies of T cell lymphomas","volume":"13","author":"I\u017cykowska","year":"2020","journal-title":"J Hematol Oncol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2012.44.7524","article-title":"Survival of patients with peripheral T-cell lymphoma after first relapse or progression: spectrum of disease and rare long-term survivors","volume":"31","author":"Mak","year":"2013","journal-title":"J Clin Oncol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2010.29.9024","article-title":"Pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma: results from the pivotal PROPEL study","volume":"29","author":"O\u2019Connor","year":"2011","journal-title":"J Clin Oncol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2014.59.2782","article-title":"Belinostat in patients with relapsed or refractory peripheral T-cell lymphoma: Results of the pivotal phase II BELIEF (CLN-19) study","volume":"33","author":"O\u2019Connor","year":"2015","journal-title":"J Clin Oncol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1186\/1756-8722-7-11","article-title":"Romidepsin for the treatment of relapsed\/refractory peripheral T-cell lymphoma: pivotal study update demonstrates durable responses","volume":"7","author":"Coiffier","year":"2014","journal-title":"J Hematol Oncol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.25243","article-title":"Duvelisib, an oral dual PI3K-\u03b4,\u03b3 inhibitor, shows clinical and pharmacodynamic activity in chronic lymphocytic leukemia and small lymphocytic lymphoma in a phase 1 study","volume":"93","author":"O\u2019Brien","year":"2018","journal-title":"Am J Hematol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2018-05-850461","article-title":"The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL\/SLL","volume":"132","author":"Flinn","year":"2018","journal-title":"Blood"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-19-3061","article-title":"Efficacy and safety of duvelisib following disease progression on ofatumumab in patients with Relapsed\/Refractory CLL or SLL in the DUO crossover extension study","volume":"26","author":"Davids","year":"2020","journal-title":"Clin Cancer Res"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.18.00915","article-title":"DYNAMO: A phase II study of duvelisib (IPI-145) in patients with refractory indolent non-Hodgkin lymphoma","volume":"37","author":"Flinn","year":"2019","journal-title":"J Clin Oncol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1007\/s12185-020-02929-3","article-title":"Phase I study of duvelisib in Japanese patients with relapsed or refractory lymphoma","volume":"112","author":"Izutsu","year":"2020","journal-title":"Int J Hematol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.25228","article-title":"Duvelisib, an oral dual PI3K-\u03b4, \u03b3 inhibitor, shows clinical activity in indolent non-Hodgkin lymphoma in a phase 1 study","volume":"93","author":"Flinn","year":"2018","journal-title":"Am J Hematol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-05-786566","article-title":"Duvelisib, a novel oral dual inhibitor of PI3K-\u03b4,\u03b3, is clinically active in advanced hematologic malignancies","volume":"131","author":"Flinn","year":"2018","journal-title":"Blood"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2021.39.15_suppl.e19532","article-title":"Efficacy and safety of duvelisib, a phosphoinositide 3 kinase (PI3K) \u03b4 and \u03b3 inhibitor, in Chinese patients (pts) with relapsed\/refractory follicular lymphoma (R\/R FL)","volume":"39","author":"Zheng","year":"2021","journal-title":"A single-arm open-label multicenter phase \u2161 Clin trial"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1002\/hon.33_2629","article-title":"Duvelisib, an oral dual PI3K-\u03b4,\u03b3 inhibitor, efficacy and safety in patients with relapsed or refractory (RR) peripheral T-cell lymphoma","volume":"37","author":"Horwitz","year":"2019","journal-title":"rationale phase 2 PRIMO trial"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1097\/01.HS9.0000847552.42271.7c","article-title":"P1172: DUVELISIB IN PATIENTS WITH RELAPSED\/REFRACTORY PERIPHERAL T-CELL LYMPHOMA FROM THE PHASE 2 PRIMO TRIAL","volume":"136","author":"Zinzani","year":"2002","journal-title":"Blood"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-08-802470","article-title":"Activity of the PI3K-\u03b4,\u03b3 inhibitor duvelisib in a phase 1 trial and preclinical models of T-cell lymphoma","volume":"131","author":"Horwitz","year":"2018","journal-title":"Blood"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20020805","article-title":"A crucial role for the p110delta subunit of phosphatidylinositol 3-kinase in b cell development and activation","volume":"196","author":"Clayton","year":"2002","journal-title":"J Exp Med"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1126\/science.1073560","article-title":"Impaired b and T cell antigen receptor signaling in p110delta PI 3-kinase mutant mice","volume":"297","author":"Okkenhaug","year":"2002","journal-title":"Science"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.8b01298","article-title":"Evolution of PI3K\u03b3 and \u03b4 inhibitors for inflammatory and autoimmune diseases","volume":"62","author":"Perry","year":"2019","journal-title":"J Med Chem"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2882","article-title":"The emerging mechanisms of isoform-specific PI3K signalling","volume":"11","author":"Vanhaesebroeck","year":"2010","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2010.10.002","article-title":"Phosphoinositide 3-kinase delta (PI3K\u03b4) in leukocyte signaling and function","volume":"23","author":"Fung-Leung","year":"2011","journal-title":"Cell signalling"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbalip.2014.12.006","article-title":"PI3K signalling in inflammation","volume":"1851","author":"Hawkins","year":"2015","journal-title":"Biochim Biophys Acta"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.173.4.2236","article-title":"Cutting edge: differential roles for phosphoinositide 3-kinases, p110gamma and p110delta, in lymphocyte chemotaxis and homing","volume":"173","author":"Reif","year":"2004","journal-title":"J Immunol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1038\/nature19834","article-title":"PI3K\u03b3 is a molecular switch that controls immune suppression","volume":"539","author":"Kaneda","year":"2016","journal-title":"Nature"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/nature20554","article-title":"Overcoming resistance to checkpoint blockade therapy by targeting PI3K\u03b3 in myeloid cells","volume":"539","author":"De Henau","year":"2016","journal-title":"Nature"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V124.21.328.328","article-title":"Duvelisib (IPI-145) inhibits malignant b-cell proliferation and disrupts signaling from the tumor microenvironment through mechanisms that are dependent on PI3K-\u03b4 and PI3K-\u03b3","volume":"124","author":"Peluso","year":"2014","journal-title":"Blood"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2015.105","article-title":"The phosphoinositide-3-kinase (PI3K)-delta and gamma inhibitor, IPI-145 (Duvelisib), overcomes signals from the PI3K\/AKT\/S6 pathway and promotes apoptosis in CLL","volume":"29","author":"Balakrishnan","year":"2015","journal-title":"Leukemia"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2015.33.15_suppl.8559","article-title":"High throughput in vitro combination sensitivity screen in hematologic malignancies with the phosphoinositide-3 kinase (PI3K)-\u03b4,\u03b3 inhibitor, duvelisib","volume":"33","author":"Faia","year":"2015","journal-title":"J Clin Oncol"},{"key":"B46","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1016\/j.ccell.2018.01.001","article-title":"RHOA G17V induces T follicular helper cell specification and promotes lymphomagenesis","volume":"33","author":"Cortes","year":"2018","journal-title":"Cancer Cell"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2019.07.009","article-title":"PI3K\/Akt\/mTOR inhibitors in cancer: At the bench and bedside","volume":"59","author":"Alzahrani","year":"2019","journal-title":"Semin Cancer Biol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2013.10","article-title":"Development of PI3K inhibitors: lessons learned from early clinical trials","volume":"10","author":"Rodon","year":"2013","journal-title":"Nat Rev Clin Oncol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2019.0034","article-title":"Safety, tolerability, and management of toxic effects of phosphatidylinositol 3-kinase inhibitor treatment in patients with cancer: A review","volume":"5","author":"Esposito","year":"2019","journal-title":"JAMA Oncol"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbcan.2019.03.003","article-title":"Targeting PI3K signaling in cancer: Challenges and advances","volume":"1871","author":"De Santis","year":"2019","journal-title":"Biochim Biophys Acta Rev Cancer"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(22)00200-5","article-title":"The saga of PI3K inhibitors in haematological malignancies: survival is the ultimate safety endpoint","volume":"23","author":"Richardson","year":"2022","journal-title":"Lancet Oncol"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201343812","article-title":"PI3K\u03b3 kinase activity is required for optimal T-cell activation and differentiation","volume":"43","author":"Ladygina","year":"2013","journal-title":"Eur J Immunol"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.176.1.589","article-title":"Class IB-phosphatidylinositol 3-kinase (PI3K) deficiency ameliorates IA-PI3K-induced systemic lupus but not T cell invasion","volume":"176","author":"Barber","year":"2006","journal-title":"J Immunol"},{"key":"B54","doi-asserted-by":"publisher","first-page":"798","DOI":"10.1038\/s41573-021-00300-7","article-title":"Author correction: PI3K inhibitors are finally coming of age","volume":"20","author":"Vanhaesebroeck","year":"2021","journal-title":"Nat Rev Drug Discovery"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-02-271171","article-title":"Phosphatidylinositol 3-kinase-\u03b4 inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals","volume":"116","author":"Herman","year":"2010","journal-title":"Blood"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-05-352492","article-title":"The phosphoinositide 3\u2019-kinase delta inhibitor, CAL-101, inhibits b-cell receptor signaling and chemokine networks in chronic lymphocytic leukemia","volume":"118","author":"Hoellenriegel","year":"2011","journal-title":"Blood"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2013.09.001","article-title":"B-cell receptor signaling as a driver of lymphoma development and evolution","volume":"23","author":"Niemann","year":"2013","journal-title":"Semin Cancer Biol"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-11-818617","article-title":"RhoA G17V is sufficient to induce autoimmunity and promotes T-cell lymphomagenesis in mice","volume":"132","author":"Ng","year":"2018","journal-title":"Blood"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20092042","article-title":"The fusion kinase ITK-SYK mimics a T cell receptor signal and drives oncogenesis in conditional mouse models of peripheral T cell lymphoma","volume":"207","author":"Pechloff","year":"2010","journal-title":"J Exp Med"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1209843","article-title":"Oncogenic tyrosine kinase NPM\/ALK induces activation of the MEK\/ERK signaling pathway independently of c-raf","volume":"26","author":"Marzec","year":"2007","journal-title":"Oncogene"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2018-09-872549","article-title":"Genetic drivers of oncogenic pathways in molecular subgroups of peripheral T-cell lymphoma","volume":"133","author":"Heavican","year":"2019","journal-title":"Blood"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-19-2787","article-title":"Dasatinib is an effective treatment for angioimmunoblastic T-cell lymphoma","volume":"80","author":"Nguyen","year":"2020","journal-title":"Cancer Res"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2020001584","article-title":"PI3K\u03b4 inhibition reshapes follicular lymphoma-immune microenvironment cross talk and unleashes the activity of venetoclax","volume":"4","author":"Serrat","year":"2020","journal-title":"Blood Adv"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.595818","article-title":"Phosphoinositide 3-kinase signaling in the tumor microenvironment: What do we need to consider when treating chronic lymphocytic leukemia with PI3K inhibitors","volume":"11","author":"Aydin","year":"2020","journal-title":"Front Immunol"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-06-227579","article-title":"Molecular signatures to improve diagnosis in peripheral T-cell lymphoma and prognostication in angioimmunoblastic T-cell lymphoma","volume":"115","author":"Iqbal","year":"2010","journal-title":"Blood"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1172\/JCI99386","article-title":"PI3K p110\u03b4 inactivation antagonizes chronic lymphocytic leukemia and reverses T cell immune suppression","volume":"129","author":"Dong","year":"2019","journal-title":"J Clin Invest"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-14-0095","article-title":"Selective inhibition of regulatory T cells by targeting the PI3K-akt pathway","volume":"2","author":"Abu-Eid","year":"2014","journal-title":"Cancer Immunol Res"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-16-1925","article-title":"Enhanced therapeutic efficacy and memory of tumor-specific CD8 T cells by ex vivo PI3K-\u03b4 inhibition","volume":"77","author":"Abu Eid","year":"2017","journal-title":"Cancer Res"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-16-1839","article-title":"Differential PI3K\u03b4 signaling in CD4(+) T-cell subsets enables selective targeting of T regulatory cells to enhance cancer immunotherapy","volume":"77","author":"Ahmad","year":"2017","journal-title":"Cancer Res"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1038\/nature13444","article-title":"Inactivation of PI(3)K p110\u03b4 breaks regulatory T-cell-mediated immune tolerance to cancer","volume":"510","author":"Ali","year":"2014","journal-title":"Nature"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2020-000693","article-title":"Enhanced antitumor immunity through sequential targeting of PI3K\u03b4 and LAG3","volume":"8","author":"Lauder","year":"2020","journal-title":"J Immunother Cancer"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.120631","article-title":"Compensation between CSF1R+ macrophages and Foxp3+ treg cells drives resistance to tumor immunotherapy","volume":"3","author":"Gyori","year":"2018","journal-title":"JCI Insight"},{"key":"B73","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1186\/s13045-021-01054-w","article-title":"Current and future treatment strategies in chronic lymphocytic leukemia","volume":"14","author":"Patel","year":"2021","journal-title":"J Hematol Oncol"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1400376","article-title":"Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia","volume":"371","author":"Byrd","year":"2014","journal-title":"N Engl J Med"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.18.01460","article-title":"Final results of a randomized, phase III study of rituximab with or without idelalisib followed by open-label idelalisib in patients with relapsed chronic lymphocytic leukemia","volume":"37","author":"Sharman","year":"2019","journal-title":"J Clin Oncol"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2013.09.017","article-title":"PI3K-\u03b4 and PI3K-\u03b3 inhibition by IPI-145 abrogates immune responses and suppresses activity in autoimmune and inflammatory disease models","volume":"20","author":"Winkler","year":"2013","journal-title":"Chem Biol"},{"key":"B77","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1016\/S1470-2045(16)30671-4","article-title":"Idelalisib or placebo in combination with bendamustine and rituximab in patients with relapsed or refractory chronic lymphocytic leukaemia: interim results from a phase 3, randomised, double-blind, placebo-controlled trial","volume":"18","author":"Zelenetz","year":"2017","journal-title":"Lancet Oncol"},{"key":"B78","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1101\/gad.340919.120","article-title":"mTOR inhibition acts as an unexpected checkpoint in p53-mediated tumor suppression","volume":"35","author":"Kon","year":"2021","journal-title":"Genes Dev"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-021-02147-z","article-title":"p53-mediated AKT and mTOR inhibition requires RFX7 and DDIT4 and depends on nutrient abundance","volume":"41","author":"Coronel","year":"2022","journal-title":"Oncogene"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1205662","article-title":"p53 activation results in rapid dephosphorylation of the eIF4E-binding protein 4E-BP1, inhibition of ribosomal protein S6 kinase and inhibition of translation initiation","volume":"21","author":"Horton","year":"2002","journal-title":"Oncogene"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0502857102","article-title":"The coordinate regulation of the p53 and mTOR pathways in cells","volume":"102","author":"Feng","year":"2005","journal-title":"Proc Natl Acad Sci U.S.A."},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(01)00323-9","article-title":"Regulation of PTEN transcription by p53","volume":"8","author":"Stambolic","year":"2001","journal-title":"Mol Cell"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2008.12.002","article-title":"PH domain-only protein PHLDA3 is a p53-regulated repressor of akt","volume":"136","author":"Kawase","year":"2009","journal-title":"Cell"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.1182\/asheducation-2010.1.481","article-title":"Understanding and managing ultra high-risk chronic lymphocytic leukemia","author":"Stilgenbauer","year":"2010","journal-title":"Hematol Am Soc Hematol Educ Program 2010"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-10-606038","article-title":"Three-year follow-up of treatment-na\u00efve and previously treated patients with CLL and SLL receiving single-agent ibrutinib","volume":"125","author":"Byrd","year":"2015","journal-title":"Blood"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1513257","article-title":"Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia","volume":"374","author":"Roberts","year":"2016","journal-title":"N Engl J Med"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1509388","article-title":"Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia","volume":"373","author":"Burger","year":"2015","journal-title":"N Engl J Med"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2021.279012","article-title":"First-line treatment of chronic lymphocytic leukemia with ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab: final analysis of the randomized, phase 3 iLLUMINATE trial","volume":"107","author":"Moreno","year":"2022","journal-title":"Haematologica"},{"key":"B89","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2017.76.6840","article-title":"Venetoclax for patients with chronic lymphocytic leukemia with 17p deletion: Results from the full population of a phase II pivotal trial","volume":"36","author":"Stilgenbauer","year":"2018","journal-title":"J Clin Oncol"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-020-01433-6","article-title":"Venetoclax: A review in previously untreated chronic lymphocytic leukaemia","volume":"80","author":"Blair","year":"2020","journal-title":"Drugs"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2016.382","article-title":"Duvelisib treatment is associated with altered expression of apoptotic regulators that helps in sensitization of chronic lymphocytic leukemia cells to venetoclax (ABT-199)","volume":"31","author":"Patel","year":"2017","journal-title":"Leukemia"},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-07-587279","article-title":"IPI-145 antagonizes intrinsic and extrinsic survival signals in chronic lymphocytic leukemia cells","volume":"124","author":"Dong","year":"2014","journal-title":"Blood"},{"key":"B93","doi-asserted-by":"publisher","first-page":"w14635","DOI":"10.4414\/smw.2018.14635","article-title":"Diagnosis and treatment of follicular lymphoma: an update","volume":"148","author":"Bargetzi","year":"2018","journal-title":"Swiss Med Wkly"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1314583","article-title":"PI3K\u03b4 inhibition by idelalisib in patients with relapsed indolent lymphoma","volume":"370","author":"Gopal","year":"2014","journal-title":"N Engl J Med"},{"key":"B95","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2017.75.4648","article-title":"Phosphatidylinositol 3-kinase inhibition by copanlisib in relapsed or refractory indolent lymphoma","volume":"35","author":"Dreyling","year":"2017","journal-title":"J Clin Oncol"},{"key":"B96","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.20.03433","article-title":"Umbralisib, a dual PI3K\u03b4\/CK1\u03f5 inhibitor in patients with relapsed or refractory indolent lymphoma","volume":"39","author":"Fowler","year":"2021","journal-title":"J Clin Oncol"},{"key":"B97","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdx289","article-title":"Phase II study of copanlisib, a PI3K inhibitor, in relapsed or refractory, indolent or aggressive lymphoma","volume":"28","author":"Dreyling","year":"2017","journal-title":"Ann Oncol"},{"key":"B98","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1146\/annurev-immunol-020711-075027","article-title":"Pathogenesis of human b cell lymphomas","volume":"30","author":"Shaffer","year":"2012","journal-title":"Annu Rev Immunol"},{"key":"B99","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.25634","article-title":"Combination trial of duvelisib (IPI-145) with rituximab or bendamustine\/rituximab in patients with non-Hodgkin lymphoma or chronic lymphocytic leukemia","volume":"94","author":"Flinn","year":"2019","journal-title":"Am J Hematol"},{"key":"B100","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2014.59.2782","article-title":"Belinostat in patients with relapsed or refractory peripheral T-cell lymphoma","volume":"33","author":"O\u2019Connor","year":"2015","journal-title":"Results Pivotal Phase II BELIEF (CLN-19) Study"},{"key":"B101","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2011.37.4223","article-title":"Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy","volume":"30","author":"Coiffier","year":"2012","journal-title":"J Clin Oncol"},{"key":"B102","doi-asserted-by":"crossref","DOI":"10.1002\/hon.56_2879","article-title":"The combination of duvelisib and romidepsin (Dr) is highly active against Relapsed\/Refractory peripheral T-cell lymphoma with low rates of transaminitis: Final Results","author":"Horwitz","year":"2021"},{"key":"B103","doi-asserted-by":"publisher","DOI":"10.3109\/10428194.2015.1022770","article-title":"Management of adverse events associated with idelalisib treatment: expert panel opinion","volume":"56","author":"Coutr\u00e9","year":"2015","journal-title":"Leuk Lymphoma"},{"key":"B104","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-04220-6_11","article-title":"Infections in patients with leukemia and lymphoma","volume":"161","author":"Morrison","year":"2014","journal-title":"Cancer Treat Res"},{"key":"B105","doi-asserted-by":"publisher","first-page":"e2012070","DOI":"10.4084\/mjhid.2012.070","article-title":"Infectious complications in chronic lymphocytic leukemia","volume":"4","author":"Nosari","year":"2012","journal-title":"Mediterr J Hematol Infect Dis"},{"key":"B106","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-06-722991","article-title":"Atypical pneumocystis jirovecii pneumonia in previously untreated patients with CLL on single-agent ibrutinib","volume":"128","author":"Ahn","year":"2016","journal-title":"Blood"},{"key":"B107","doi-asserted-by":"publisher","DOI":"10.1111\/ejh.13020","article-title":"Systematic review of infectious events with the bruton tyrosine kinase inhibitor ibrutinib in the treatment of hematologic malignancies","volume":"100","author":"Tillman","year":"2018","journal-title":"Eur J Haematol"},{"key":"B108","doi-asserted-by":"publisher","DOI":"10.1016\/S2352-3026(17)30019-4","article-title":"Efficacy and safety of idelalisib in combination with ofatumumab for previously treated chronic lymphocytic leukaemia: an open-label, randomised phase 3 trial","volume":"4","author":"Jones","year":"2017","journal-title":"Lancet Haematol"},{"key":"B109","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-11-818286","article-title":"Early-onset invasive aspergillosis and other fungal infections in patients treated with ibrutinib","volume":"131","author":"Ghez","year":"2018","journal-title":"Blood"},{"key":"B110","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2021-147564","article-title":"TEMPO: A phase 2, randomized, open-label, 2-arm study comparing 2 intermittent dosing schedules of duvelisib in subjects with indolent non Hodgkin lymphoma (iNHL)","volume":"138","author":"Vorobyev","year":"2021","journal-title":"Blood"},{"key":"B111","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04685-2","article-title":"Intermittent PI3K\u03b4 inhibition sustains anti-tumour immunity and curbs irAEs","volume":"605","author":"Eschweiler","year":"2022","journal-title":"Nature"},{"key":"B112","doi-asserted-by":"publisher","DOI":"10.1016\/j.clml.2020.12.016","article-title":"Retrospective analysis of the impact of adverse event-triggered idelalisib interruption and dose reduction on clinical outcomes in patients with Relapsed\/Refractory b-cell malignancies","volume":"21","author":"Ma","year":"2021","journal-title":"Clin Lymphoma Myeloma Leuk"},{"key":"B113","doi-asserted-by":"publisher","DOI":"10.1038\/nm1284","article-title":"Blockade of PI3Kgamma suppresses joint inflammation and damage in mouse models of rheumatoid arthritis","volume":"11","author":"Camps","year":"2005","journal-title":"Nat Med"},{"key":"B114","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2009.12.001","article-title":"Phosphatidylinositol 3-kinase gamma inhibition ameliorates inflammation and tumor growth in a model of colitis-associated cancer","volume":"138","author":"Gonz\u00e1lez-Garc\u00eda","year":"2010","journal-title":"Gastroenterology"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.1070660\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T13:30:19Z","timestamp":1672839019000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.1070660\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,4]]},"references-count":114,"alternative-id":["10.3389\/fimmu.2022.1070660"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.1070660","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,4]]},"article-number":"1070660"}}