{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T19:16:16Z","timestamp":1779909376396,"version":"3.53.1"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T00:00:00Z","timestamp":1762214400000},"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. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Although treatment for acute lymphoblastic leukemia (ALL) has advanced considerably, adults with relapsed or refractory (R\/R) disease continue to face a grave prognosis. Inotuzumab ozogamicin (InO), a CD22-directed antibody\u2013drug conjugate, represents a promising development for B-cell ALL. This systematic review and meta-analysis aims to define the precise efficacy and safety profile of InO-based therapies\u2014both monotherapy and combination regimens\u2014in adults with newly diagnosed and R\/R ALL.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A systematic literature search was conducted in PubMed, Web of Science, Embase, the Cochrane Library, and clinical trial registries through 2 December 2024. The primary outcomes were overall response (OR), complete remission (CR), minimal residual disease (MRD) negativity, overall survival (OS), and the rate of stem cell transplantation (SCT). Secondary outcomes comprised adverse events (AEs) and relapse.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The meta-analysis included 1 randomized controlled trial (RCT), 14 single-arm studies, and 1 clinical trial, encompassing 1,068 patients. The pooled efficacy outcomes were as follows: OR rate:89.0% [95% confidence interval (CI): 85.8%\u201392.2%, 95% prediction interval (PI): 1.2%\u201399.9%;\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sup>2<\/jats:sup>\n                      = 90.1%,\n                      <jats:italic>p<\/jats:italic>\n                      &amp;lt;0.001], CR rate: 70.5% (95% CI: 58.6%\u201382.5%, 95% PI: 3.3%\u201376.9%;\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sup>2<\/jats:sup>\n                      = 94.0%,\n                      <jats:italic>p<\/jats:italic>\n                      &amp;lt;0.001), MRD\u2212 rate: 84.6% (95% CI: 79.5%\u201389.6%, 95% PI: 0.4%\u201399.8%;\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sup>2<\/jats:sup>\n                      = 80.9%,\n                      <jats:italic>p<\/jats:italic>\n                      &amp;lt;0.001), 1-year OS rate: 61.7% (95% CI: 44.9%\u201378.5%;\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sup>2<\/jats:sup>\n                      = 94.1%,\n                      <jats:italic>p<\/jats:italic>\n                      &amp;lt;0.001), 2-year OS rate: 51.4% (95% CI: 32.2%\u201370.7%;\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sup>2<\/jats:sup>\n                      = 93.8%,\n                      <jats:italic>p<\/jats:italic>\n                      &amp;lt;0.001), 3-year OS rate: 46.9% (95% CI: 22.5%\u201371.4%, 95%;\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sup>2<\/jats:sup>\n                      = 95.2%,\n                      <jats:italic>p<\/jats:italic>\n                      &amp;lt;0.001), 5-year OS rate: 44.9% (95% CI: 39.2%\u201350.5%, 95%;\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sup>2<\/jats:sup>\n                      = 0.0%,\n                      <jats:italic>p<\/jats:italic>\n                      =0.482), SCT rate: 27.5% (95% CI: 16.6%\u201338.4%, 95% PI: 1.2%\u201379.4%;\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sup>2<\/jats:sup>\n                      = 95.2%,\n                      <jats:italic>p<\/jats:italic>\n                      &amp;lt;0.001), relapse rate: 23.6% (95% CI: 16.6%\u201330.6%, 95% PI: 16.6%\u201399.6%;\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sup>2<\/jats:sup>\n                      = 78.2%,\n                      <jats:italic>p<\/jats:italic>\n                      &amp;lt;0.001), and incidence of veno-occlusive disease (VOD): 6.2% (95% CI: 3.8%\u20138.6%, 95% PI: 6.6%\u201354.5%;\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sup>2<\/jats:sup>\n                      = 68.0%,\n                      <jats:italic>p<\/jats:italic>\n                      &amp;lt;0.001).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>InO demonstrates significant efficacy and a manageable safety profile in adult patients with ALL, supporting its use as a viable therapeutic option. Further randomized studies are needed to validate these findings.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Systematic review registration<\/jats:title>\n                    <jats:p>\n                      <jats:uri>https:\/\/www.crd.york.ac.uk\/prospero\/<\/jats:uri>\n                      , identifier CRD42024619042.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2025.1613777","type":"journal-article","created":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T05:22:35Z","timestamp":1762233755000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Efficacy and safety of inotuzumab ozogamicin and its combination therapies in acute lymphoblastic leukemia: a systematic review and meta-analysis"],"prefix":"10.3389","volume":"15","author":[{"given":"Changtao","family":"Lao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiange","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuezhen","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,11,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1007\/s00428-022-03448-8","article-title":"International Consensus Classification of acute lymphoblastic leukemia\/lymphoma","volume":"482","author":"Duffield","year":"2023","journal-title":"Virchows Arch"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(19)33018-1","article-title":"Acute lymphoblastic leukaemia","volume":"395","author":"Malard","year":"2020","journal-title":"Lancet"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2022.2398","article-title":"Treatment of adults with philadelphia chromosome-positive acute lymphoblastic leukemia-from intensive chemotherapy combinations to chemotherapy-free regimens: A review","volume":"8","author":"Jabbour","year":"2022","journal-title":"JAMA Oncol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"755","DOI":"10.1186\/s12885-018-4670-5","article-title":"Influence of pre-transplant minimal residual disease on prognosis after Allo-SCT for patients with acute lymphoblastic leukemia: systematic review and meta-analysis","volume":"18","author":"Shen","year":"2018","journal-title":"BMC Cancer"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.clml.2022.12.009","article-title":"Efficacy and safety of blinatumomab for the treatment of relapsed\/refractory acute lymphoblastic leukemia: A systemic review and meta-analysis","volume":"23","author":"Liu","year":"2023","journal-title":"Clin Lymphoma Myeloma Leuk"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines11102693","article-title":"CAR T-cells in acute lymphoblastic leukemia: current status and future prospects","volume":"11","author":"Almaeen","year":"2023","journal-title":"Biomedicines"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.4413","article-title":"Comparison of allogeneic hematopoietic stem cell transplantation and TKI combined with chemotherapy for adult philadelphia chromosome positive acute lymphoblastic leukemia: a systematic review and meta-analysis","volume":"10","author":"Zeng","year":"2021","journal-title":"Cancer Med"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.19250","article-title":"Durable responses in acute lymphoblastic leukaemia with the use of FLT3 and IDH inhibitors","volume":"204","author":"Madero-Marroquin","year":"2024","journal-title":"Br J Haematol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2020.03.006","article-title":"Response and resistance to BCR-ABL1-targeted therapies","volume":"37","author":"Braun","year":"2020","journal-title":"Cancer Cell"},{"key":"B10","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1186\/s13045-024-01552-7","article-title":"Inotuzumab ozogamicin for the treatment of adult acute lymphoblastic leukemia: past progress, current research and future directions","volume":"17","author":"Short","year":"2024","journal-title":"J Hematol Oncol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1237738","article-title":"Inotuzumab ozogamicin in B-cell precursor acute lymphoblastic leukemia: efficacy, toxicity, and practical considerations","volume":"14","author":"Rubinstein","year":"2023","journal-title":"Front Immunol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.clml.2020.12.008","article-title":"Efficacy and safety of inotuzumab ozogamicin (CMC-544) for the treatment of relapsed\/refractory acute lymphoblastic leukemia and non-hodgkin lymphoma: A systematic review and meta-analysis","volume":"21","author":"Li","year":"2021","journal-title":"Clin Lymphoma Myeloma Leuk"},{"key":"B13","volume-title":"Cochrane handbook for systematic reviews of interventions, version 5.1","author":"Higgins","year":"2011"},{"key":"B14","doi-asserted-by":"publisher","first-page":"e1000097","DOI":"10.1371\/journal.pmed.1000097","article-title":"Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement","volume":"6","author":"Moher","year":"2009","journal-title":"PloS Med"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1053\/jhep.2002.31354","article-title":"Endoscopic treatment versus endoscopic plus pharmacologic treatment for acute variceal bleeding: a meta-analysis","volume":"35","author":"Ba\u00f1ares","year":"2002","journal-title":"Hepatology"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1046\/j.1445-2197.2003.02748.x","article-title":"Methodological index for non-randomized studies (minors): development and validation of a new instrument","volume":"73","author":"Slim","year":"2003","journal-title":"ANZ J Surg"},{"key":"B17","unstructured":""},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.32116","article-title":"Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia: Final report and long-term survival follow-up from the randomized, phase 3 INO-VATE study","volume":"125","author":"Kantarjian","year":"2019","journal-title":"Cancer"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2016001925","article-title":"Inotuzumab ozogamicin in adults with relapsed or refractory CD22-positive acute lymphoblastic leukemia: a phase 1\/2 study","volume":"1","author":"DeAngelo","year":"2017","journal-title":"Blood Adv"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2024.0967","article-title":"Dose-adjusted EPOCH plus inotuzumab ozogamicin in adults with relapsed or refractory B-cell ALL: A phase 1 dose-escalation trial","volume":"10","author":"Kopmar","year":"2024","journal-title":"JAMA Oncol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.24.00490","article-title":"Inotuzumab ozogamicin and low-intensity chemotherapy in older patients with newly diagnosed CD22+ Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia","volume":"42","author":"Chevallier","year":"2024","journal-title":"J Clin Oncol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(18)30011-1","article-title":"Inotuzumab ozogamicin in combination with low-intensity chemotherapy for older patients with Philadelphia chromosome-negative acute lymphoblastic leukaemia: a single-arm, phase 2 study","volume":"19","author":"Kantarjian","year":"2018","journal-title":"Lancet Oncol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.31720","article-title":"Chemoimmunotherapy with inotuzumab ozogamicin combined with mini-hyper-CVD, with or without blinatumomab, is highly effective in patients with Philadelphia chromosome-negative acute lymphoblastic leukemia in first salvage","volume":"124","author":"Jabbour","year":"2018","journal-title":"Cancer"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.23.00546","article-title":"Inotuzumab ozogamicin as induction therapy for patients older than 55 years with philadelphia chromosome-negative B-precursor ALL","volume":"42","author":"Stelljes","year":"2024","journal-title":"J Clin Oncol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2022-157937","article-title":"Gimema ALL2418: interim analysis of a phase iia study of feasibility and effectiveness of inotuzumab ozogamicin in adult patients with B-cell acute lymphoblastic leukemia with positive minimal residual disease before any hematopoietic stem cell transplantation","volume":"140","author":"Marconi","year":"2022","journal-title":"Blood"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2023.41.16_suppl.e19008","article-title":"Inotuzumab ozogamicin (INO) for the treatment of measurable residual disease (MRD) in patients with B-cell acute lymphoblastic leukemia (B-ALL): Results from a phase II study","volume":"41","author":"Nasr","year":"2023","journal-title":"JCO"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2023.41.16_suppl.7006","article-title":"Chemotherapy-free treatment with inotuzumab ozogamicin and blinatumomab for older adults with newly diagnosed, Ph-negative, CD22-positive, B-cell acute lymphoblastic leukemia: Alliance A041703","volume":"41","author":"Wieduwilt","year":"2023","journal-title":"JCO"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V124.21.2255.2255","article-title":"A phase II study of weekly inotuzumab ozogamicin (InO) in adult patients with CD22-positive acute lymphoblastic leukemia (ALL) in second or later salvage","volume":"124","author":"Advani","year":"2014","journal-title":"Blood"},{"key":"B29","doi-asserted-by":"publisher","first-page":"2878","DOI":"10.1182\/blood-2023-182982","article-title":"Phase 2 trial of mini-hyper-CVD plus inotuzumab ozogamicin, with or without blinatumomab, in older patients with newly diagnosed philadelphia chromosomeNegative B-cell acute lymphoblastic leukemia","author":"Jen","year":"2023","journal-title":"Blood"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2022-168052","article-title":"A phase II study of mini-hyper-CVD plus inotuzumab ozogamicin, with or without blinatumomab, in older adults with newly diagnosed philadelphia chromosome-negative B-cell acute lymphoblastic leukemia: updated results and predictors for outcomes","author":"Nasnas","year":"2022","journal-title":"Blood"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2020-143386","article-title":"Sequential combination of inotuzumab ozogamicin (InO) with low-intensity chemotherapy (mini-hyper-CVD) with or without blinatumomab (Blina) as salvage therapy for patients (Pts) with acute lymphoblastic leukemia (ALL) in first relapse","author":"Rafei","year":"2020","journal-title":"Blood"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2020-138569","article-title":"Reduced-intensity chemotherapy with mini-hyper-CVD plus inotuzumab ozogamicin, with or without blinatumomab, in older adults with newly diagnosed philadelphia chromosome-negative acute lymphoblastic leukemia: results from a phase II study","author":"Short","year":"2020","journal-title":"Blood"},{"key":"B33","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1080\/17474086.2023.2298732","article-title":"Comparison of blinatumomab and CAR T-cell therapy in relapsed\/refractory acute lymphoblastic leukemia:a systematic review and meta-analysis","volume":"17","author":"Zhai","year":"2024","journal-title":"Expert Rev Hematol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/S2352-3026(23)00073-X","article-title":"Mini-hyper-CVD plus inotuzumab ozogamicin, with or without blinatumomab, in the subgroup of older patients with newly diagnosed Philadelphia chromosome-negative B-cell acute lymphocytic leukaemia: long-term results of an open-label phase 2 trial","volume":"10","author":"Jabbour","year":"2023","journal-title":"Lancet Haematol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1007\/s12098-023-04635-4","article-title":"Relapsed acute lymphoblastic leukemia","volume":"91","author":"Sidhu","year":"2024","journal-title":"Indian J Pediatr"},{"key":"B36","doi-asserted-by":"publisher","first-page":"590","DOI":"10.3324\/haematol.2010.035675","article-title":"The Ph-positive and Ph-negative myeloproliferative neoplasms: some topical pre-clinical and clinical issues","volume":"96","author":"Van Etten","year":"2011","journal-title":"Haematologica"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12020303","article-title":"CD22 expression in B-cell acute lymphoblastic leukemia: biological significance and implications for inotuzumab therapy in adults","volume":"12","author":"Lanza","year":"2020","journal-title":"Cancers (Basel)"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-20-2399","article-title":"Inotuzumab ozogamicin for relapsed\/refractory acute lymphoblastic leukemia in the INO-VATE trial: CD22 pharmacodynamics, efficacy, and safety by baseline CD22","volume":"27","author":"Kantarjian","year":"2021","journal-title":"Clin Cancer Res"},{"key":"B39","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1182\/blood.2024023930","article-title":"Genomic determinants of response and resistance to inotuzumab ozogamicin in B-cell ALL","volume":"144","author":"Zhao","year":"2024","journal-title":"Blood"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/S2352-3026(17)30103-5","article-title":"Hepatic adverse event profile of inotuzumab ozogamicin in adult patients with relapsed or refractory acute lymphoblastic leukaemia: results from the open-label, randomised, phase 3 INO-VATE study","volume":"4","author":"Kantarjian","year":"2017","journal-title":"Lancet Haematol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.12558","article-title":"Haemato-oncology Task Force of British Committee for Standards in Haematology; British Society for Blood and Marrow Transplantation. BCSH\/BSBMT guideline: diagnosis and management of veno-occlusive disease (sinusoidal obstruction syndrome) following haematopoietic stem cell transplantation","volume":"163","author":"Dignan","year":"2013","journal-title":"Br J Haematol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1080\/10428194.2021.1933475","article-title":"Hematopoietic cell transplantation for acute lymphoblastic leukemia: review of current indications and outcomes","volume":"62","author":"Khazal","year":"2021","journal-title":"Leuk Lymphoma"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2025.1613777\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T05:22:36Z","timestamp":1762233756000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2025.1613777\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,4]]},"references-count":42,"alternative-id":["10.3389\/fonc.2025.1613777"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2025.1613777","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,4]]},"article-number":"1613777"}}