{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T20:29:12Z","timestamp":1782851352216,"version":"3.54.5"},"reference-count":14,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T00:00:00Z","timestamp":1769731200000},"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>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Thrombopoietin receptor agonists combined with anti-thymocyte globulin (ATG) and cyclosporine (CsA) are the standard immunosuppressive therapy (IST) for severe\/very severe aplastic anemia (SAA\/VSAA). However, early response rates remain suboptimal. Cyclophosphamide (CTX) has shown efficacy in relapsed\/refractory AA. Therefore, we designed a clinical trial to evaluate low-dose CTX combined with the standard IST as a first-line treatment for SAA\/VSAA to improve early response rates.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This study was a single-arm, prospective, phase II clinical trial using a Simon\u2019s two-stage design, and 43 patients were enrolled. The primary endpoint was the overall response rate (ORR) at 3 months. Newly diagnosed SAA\/VSAA patients received a combination treatment as follows: porcine ATG at 25 mg\/kg\/day from days 1 to 5, CsA at 3\u20135 mg\/kg\/day continuously, hetrombopag at 15 mg\/day starting from day 1 and continued for 6 months, low-dose CTX at 20 mg\/kg\/day on days 29\u201330 and days 43-44.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>All 43 patients achieved the primary endpoint, demonstrating 3-month and 6-month ORR of 65.1% (28\/43) and 69.8% (30\/43) respectively. Complete response (CR) rates were 9.3% (4\/43) at 3-month and 27.9% (12\/43) at 6-month. CTX associated toxicities comprised 100% grade 1\u20132 gastrointestinal reactions, grade 3\u20134 neutropenia in 62.8% of patients (median duration 6 days, range 4-33). Infectious events occurred in 60.5% (26\/43) of patients within the first 3 months of treatment, while no mortality observed during this period.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Low-dose CTX combined with standard IST appears to improve the early response rate in SAA\/VSAA patients with manageable toxicity.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1741042","type":"journal-article","created":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T07:37:23Z","timestamp":1769758643000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Low-dose cyclophosphamide combined with standard immunosuppressive therapy improves early response rates in severe aplastic anemia"],"prefix":"10.3389","volume":"17","author":[{"given":"Hong","family":"Pan","sequence":"first","affiliation":[{"name":"State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Tianjin, China"]},{"name":"Tianjin Institutes of Health Science","place":["Tianjin, China"]},{"name":"Red Blood Cell Diseases Center & Regenerative Medicine Clinic, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Gao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Tianjin, China"]},{"name":"Tianjin Institutes of Health Science","place":["Tianjin, China"]},{"name":"Red Blood Cell Diseases Center & Regenerative Medicine Clinic, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lele","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Tianjin, China"]},{"name":"Tianjin Institutes of Health Science","place":["Tianjin, China"]},{"name":"Red Blood Cell Diseases Center & Regenerative Medicine Clinic, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiwang","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Tianjin, China"]},{"name":"Tianjin Institutes of Health Science","place":["Tianjin, China"]},{"name":"Red Blood Cell Diseases Center & Regenerative Medicine Clinic, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruonan","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Tianjin, China"]},{"name":"Tianjin Institutes of Health Science","place":["Tianjin, China"]},{"name":"Red Blood Cell Diseases Center & Regenerative Medicine Clinic, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyu","family":"Zhao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Tianjin, China"]},{"name":"Tianjin Institutes of Health Science","place":["Tianjin, China"]},{"name":"Red Blood Cell Diseases Center & Regenerative Medicine Clinic, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Yu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Tianjin, China"]},{"name":"Tianjin Institutes of Health Science","place":["Tianjin, China"]},{"name":"Red Blood Cell Diseases Center & Regenerative Medicine Clinic, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhexiang","family":"Kuang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Tianjin, China"]},{"name":"Tianjin Institutes of Health Science","place":["Tianjin, China"]},{"name":"Red Blood Cell Diseases Center & Regenerative Medicine Clinic, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neng","family":"Nie","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Tianjin, China"]},{"name":"Tianjin Institutes of Health Science","place":["Tianjin, China"]},{"name":"Red Blood Cell Diseases Center & Regenerative Medicine Clinic, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianping","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Tianjin, China"]},{"name":"Tianjin Institutes of Health Science","place":["Tianjin, China"]},{"name":"Red Blood Cell Diseases Center & Regenerative Medicine Clinic, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Tianjin, China"]},{"name":"Tianjin Institutes of Health Science","place":["Tianjin, China"]},{"name":"Red Blood Cell Diseases Center & Regenerative Medicine Clinic, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingxin","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Tianjin, China"]},{"name":"Tianjin Institutes of Health Science","place":["Tianjin, China"]},{"name":"Red Blood Cell Diseases Center & Regenerative Medicine Clinic, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinbo","family":"Huang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Tianjin, China"]},{"name":"Tianjin Institutes of Health Science","place":["Tianjin, China"]},{"name":"Red Blood Cell Diseases Center & Regenerative Medicine Clinic, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Zhao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Tianjin, China"]},{"name":"Tianjin Institutes of Health Science","place":["Tianjin, China"]},{"name":"Red Blood Cell Diseases Center & Regenerative Medicine Clinic, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Tianjin, China"]},{"name":"Tianjin Institutes of Health Science","place":["Tianjin, China"]},{"name":"Red Blood Cell Diseases Center & Regenerative Medicine Clinic, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meili","family":"Ge","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Tianjin, China"]},{"name":"Tianjin Institutes of Health Science","place":["Tianjin, China"]},{"name":"Red Blood Cell Diseases Center & Regenerative Medicine Clinic, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yizhou","family":"Zheng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Tianjin, China"]},{"name":"Tianjin Institutes of Health Science","place":["Tianjin, China"]},{"name":"Red Blood Cell Diseases Center & Regenerative Medicine Clinic, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liwei","family":"Fang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Tianjin, China"]},{"name":"Tianjin Institutes of Health Science","place":["Tianjin, China"]},{"name":"Red Blood Cell Diseases Center & Regenerative Medicine Clinic, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Shi","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Tianjin, China"]},{"name":"Tianjin Institutes of Health Science","place":["Tianjin, China"]},{"name":"Red Blood Cell Diseases Center & Regenerative Medicine Clinic, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(88)90388-1","article-title":"Criteria for severe aplastic anaemia","volume":"331","author":"Camitta Bruce","year":"1988","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V85.11.3058.bloodjournal85113058","article-title":"Intensive immunosuppression with antithymocyte globulin and cyclosporine as treatment for severe acquired aplastic anemia","volume":"85","author":"Rosenfeld","year":"1995","journal-title":"Blood"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199105093241901","article-title":"Treatment of aplastic anemia with antilymphocyte globulin and methylprednisolone with or without cyclosporine","volume":"324","author":"Frickhofen","year":"1991","journal-title":"N Engl J Med"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1103975","article-title":"Horse versus rabbit antithymocyte globulin in acquired aplastic anemia","volume":"365","author":"Scheinberg","year":"2011","journal-title":"N Engl J Med"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1613878","article-title":"Eltrombopag added to standard immunosuppression for aplastic anemia","volume":"376","author":"Townsley","year":"2017","journal-title":"N Engl J Med"},{"key":"B6","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1056\/NEJMoa2109965","article-title":"Eltrombopag added to immunosuppression in severe aplastic anemia","volume":"386","author":"Peffault de Latour","year":"2022","journal-title":"N Engl J Med"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2024-206377","article-title":"Hetrombopag added to immunosuppressive therapy in first-line treatment of severe aplastic anemia: A randomized, double-blind, placebo-controlled phase 3 trial","volume":"144","author":"Zhang","year":"2024","journal-title":"Blood"},{"key":"B8","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1186\/s40164-023-00377-3","article-title":"Hetrombopag plus porcine ATG and cyclosporine for the treatment of aplastic anaemia: early outcomes of a prospective pilot study","volume":"12","author":"Yang","year":"2023","journal-title":"Exp Hematol Oncol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-135-7-200110020-00006","article-title":"Durable treatment-free remission after high-dose cyclophosphamide therapy for previously untreated severe aplastic anemia","volume":"135","author":"Brodsky","year":"2001","journal-title":"Ann Intern Med"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V87.2.491.bloodjournal872491","article-title":"Complete remission in severe aplastic anemia after high-dose cyclophosphamide without bone marrow transplantation","volume":"87","author":"Brodsky","year":"1996","journal-title":"Blood"},{"key":"B11","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1182\/blood.2021012130","article-title":"Long-term outcomes in patients with severe aplastic anemia treated with immunosuppression and eltrombopag: a phase 2 study","volume":"139","author":"Patel","year":"2022","journal-title":"Blood"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1080\/08880018.2021.1900475","article-title":"Efficacy and safety of eltrombopag in the first-line therapy of severe aplastic anemia in children","volume":"38","author":"Jie","year":"2021","journal-title":"Pediatr Hematol Oncol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-06-225375","article-title":"High-dose cyclophosphamide for severe aplastic anemia: long-term follow-up","volume":"115","author":"Brodsky","year":"2010","journal-title":"Blood"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-05-573642","article-title":"Moderate-dose cyclophosphamide for severe aplastic anemia has significant toxicity and does not prevent relapse and clonal evolution","volume":"124","author":"Scheinberg","year":"2014","journal-title":"Blood"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1741042\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T07:37:24Z","timestamp":1769758644000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1741042\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,30]]},"references-count":14,"alternative-id":["10.3389\/fimmu.2026.1741042"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1741042","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,30]]},"article-number":"1741042"}}