{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:39:10Z","timestamp":1792787950234,"version":"4.5.0"},"reference-count":21,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,3,26]],"date-time":"2024-03-26T00:00:00Z","timestamp":1711411200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,3,26]],"date-time":"2024-03-26T00:00:00Z","timestamp":1711411200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"BioNova Pharmaceuticals (Shanghai) Limited"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Med"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Chronic graft-versus-host disease (cGVHD) is an immune-related disorder that is the most common complication post-allogenic hematopoietic stem cell transplant. Corticosteroids with or without calcineurin inhibitors (CNIs) remain the mainstay of cGVHD treatment for first-line therapy. However, for many patients, cGVHD symptoms cannot be effectively managed and thus require second-line therapy. Currently, there is no approved treatment for second-line cGVHD treatment in China. In this study, belumosudil, a highly selective and potent rho-associated coiled-coil-containing protein kinase-2 inhibitor demonstrated to be effective for cGVHD in the United States and other Western countries, is investigated in patients with cGVHD in China for its overall benefit\u2013risk balance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This multicenter, open-label phase II study evaluated the safety, efficacy, and pharmacokinetics of oral belumosudil 200\u00a0mg once daily in cGVHD patients who had been treated with at least one line of systemic therapy in China. The primary endpoint was overall response rate (ORR); each individual patient\u2019s response was assessed by the investigator using the 2014 National Institutes of Health consensus criteria. Secondary endpoints were duration of response (DOR), time to response (TTR), changes in Lee Symptom Scale (LSS) score, organ response rate, corticosteroid dose change, CNI dose change, failure-free survival, time-to-next-treatment, overall survival, and safety.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Thirty patients were enrolled in the study with a median follow-up time of 12.9\u00a0months. ORR was 73.3% (95% confidence interval: 54.1\u201387.7%) and all responders achieved partial response. Median DOR among responders was not reached and median TTR was 4.3\u00a0weeks (range: 3.9\u201348.1). Fifteen patients (50.0%) achieved clinically meaningful response in terms of reduction in LSS score by\u2009\u2265\u20097 points from baseline. Corticosteroid and CNI dose reductions were reported in 56.7% (17\/30) and 35.0% (7\/20) of patients, respectively. Most treatment-emergent adverse events (TEAEs) were mild to moderate in severity, with 11 patients (36.7%) experiencing grade\u2009\u2265\u20093 TEAEs. The most common grade\u2009\u2265\u20093 TEAE was pneumonia (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u20095, 16.7%).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Belumosudil treatment demonstrated a favorable benefit\u2013risk balance in treating cGVHD patients who previously have had standard corticosteroid therapy in China where approved second-line setting is absent.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration<\/jats:title>\n                    <jats:p>ClinicalTrials.gov identifier NCT04930562.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12916-024-03348-5","type":"journal-article","created":{"date-parts":[[2024,3,26]],"date-time":"2024-03-26T08:02:49Z","timestamp":1711440169000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["A phase II study of belumosudil for chronic graft-versus-host disease in patients who failed at least one line of systemic therapy in China"],"prefix":"10.1186","volume":"22","author":[{"given":"Ying","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Depei","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhua","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanjie","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qifa","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Xuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenyu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kunming","family":"Qi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuqian","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunqing","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjian","family":"Mo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Hua","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,3,26]]},"reference":[{"issue":"26","key":"3348_CR1","doi-asserted-by":"publisher","first-page":"2565","DOI":"10.1056\/NEJMra1703472","volume":"377","author":"R Zeiser","year":"2017","unstructured":"Zeiser R, Blazar BR. Pathophysiology of chronic graft-versus-host disease and therapeutic targets. N Engl J Med. 2017;377(26):2565\u201379.","journal-title":"N Engl J Med"},{"issue":"10","key":"3348_CR2","doi-asserted-by":"publisher","first-page":"1781","DOI":"10.1016\/j.bbmt.2016.06.020","volume":"22","author":"M Grube","year":"2016","unstructured":"Grube M, Holler E, Weber D, Holler B, Herr W, Wolff D. Risk factors and outcome of chronic graft-versus-host disease after allogeneic stem cell transplantation-results from a single-center observational study. Biol Blood Marrow Transplant. 2016;22(10):1781\u201391.","journal-title":"Biol Blood Marrow Transplant"},{"key":"3348_CR3","volume-title":"StatPearls","author":"AA Justiz Vaillant","year":"2023","unstructured":"Justiz Vaillant AA, Modi P, Mohammadi O. Graft versus host disease. In: StatPearls. Treasure Island: StatPearls Publishing; 2023."},{"key":"3348_CR4","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1186\/1756-8722-5-10","volume":"5","author":"M Lv","year":"2012","unstructured":"Lv M, Huang XJ. Allogeneic hematopoietic stem cell transplantation in China: where we are and where to go. J Hematol Oncol. 2012;5:10.","journal-title":"J Hematol Oncol"},{"issue":"4","key":"3348_CR5","doi-asserted-by":"publisher","first-page":"606","DOI":"10.1182\/blood-2014-08-551994","volume":"125","author":"ME Flowers","year":"2015","unstructured":"Flowers ME, Martin PJ. How we treat chronic graft-versus-host disease. Blood. 2015;125(4):606\u201315.","journal-title":"Blood"},{"issue":"437","key":"3348_CR6","doi-asserted-by":"publisher","first-page":"ra73","DOI":"10.1126\/scisignal.aad8953","volume":"9","author":"JM Weiss","year":"2016","unstructured":"Weiss JM, Chen W, Nyuydzefe MS, Trzeciak A, Flynn R, Tonra JR, et al. ROCK2 signaling is required to induce a subset of T follicular helper cells through opposing effects on STATs in autoimmune settings. Sci Signal. 2016;9(437):ra73.","journal-title":"Sci Signal"},{"issue":"47","key":"3348_CR7","doi-asserted-by":"publisher","first-page":"16814","DOI":"10.1073\/pnas.1414189111","volume":"111","author":"A Zanin-Zhorov","year":"2014","unstructured":"Zanin-Zhorov A, Weiss JM, Nyuydzefe MS, Chen W, Scher JU, Mo R, et al. Selective oral ROCK2 inhibitor down-regulates IL-21 and IL-17 secretion in human T cells via STAT3-dependent mechanism. Proc Natl Acad Sci U S A. 2014;111(47):16814\u20139.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"3348_CR8","doi-asserted-by":"publisher","first-page":"108823","DOI":"10.1016\/j.clim.2021.108823","volume":"230","author":"A Zanin-Zhorov","year":"2021","unstructured":"Zanin-Zhorov A, Blazar BR. ROCK2, a critical regulator of immune modulation and fibrosis has emerged as a therapeutic target in chronic graft-versus-host disease. Clin Immunol. 2021;230:108823.","journal-title":"Clin Immunol"},{"issue":"17","key":"3348_CR9","doi-asserted-by":"publisher","first-page":"2144","DOI":"10.1182\/blood-2015-10-678706","volume":"127","author":"R Flynn","year":"2016","unstructured":"Flynn R, Paz K, Du J, Reichenbach DK, Taylor PA, Panoskaltsis-Mortari A, et al. Targeted Rho-associated kinase 2 inhibition suppresses murine and human chronic GVHD through a Stat3-dependent mechanism. Blood. 2016;127(17):2144\u201354.","journal-title":"Blood"},{"issue":"22","key":"3348_CR10","doi-asserted-by":"publisher","first-page":"2278","DOI":"10.1182\/blood.2021012021","volume":"138","author":"C Cutler","year":"2021","unstructured":"Cutler C, Lee SJ, Arai S, Rotta M, Zoghi B, Lazaryan A, et al. Belumosudil for chronic graft-versus-host disease after 2 or more prior lines of therapy: the ROCKstar study. Blood. 2021;138(22):2278\u201389.","journal-title":"Blood"},{"issue":"12","key":"3348_CR11","doi-asserted-by":"publisher","first-page":"2488","DOI":"10.1158\/1078-0432.CCR-21-4176","volume":"28","author":"D Przepiorka","year":"2022","unstructured":"Przepiorka D, Le RQ, Ionan A, Li RJ, Wang YH, Gudi R, et al. FDA Approval Summary: Belumosudil for adult and pediatric patients 12 years and older with chronic GvHD after two or more prior lines of systemic therapy. Clin Cancer Res. 2022;28(12):2488\u201392.","journal-title":"Clin Cancer Res"},{"issue":"6","key":"3348_CR12","doi-asserted-by":"publisher","first-page":"984","DOI":"10.1016\/j.bbmt.2015.02.025","volume":"21","author":"SJ Lee","year":"2015","unstructured":"Lee SJ, Wolff D, Kitko C, Koreth J, Inamoto Y, Jagasia M, et al. Measuring therapeutic response in chronic graft-versus-host disease. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: IV. The 2014 Response Criteria Working Group report. Biol Blood Marrow Transplant. 2015;21(6):984\u201399.","journal-title":"Biol Blood Marrow Transplant"},{"issue":"4","key":"3348_CR13","doi-asserted-by":"publisher","first-page":"752","DOI":"10.1016\/j.bbmt.2015.12.026","volume":"22","author":"EC Merkel","year":"2016","unstructured":"Merkel EC, Mitchell SA, Lee SJ. Content validity of the Lee Chronic Graft-versus-host disease symptom scale as assessed by cognitive interviews. Biol Blood Marrow Transplant. 2016;22(4):752\u20138.","journal-title":"Biol Blood Marrow Transplant"},{"issue":"3","key":"3348_CR14","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1056\/NEJMoa2033122","volume":"385","author":"R Zeiser","year":"2021","unstructured":"Zeiser R, Polverelli N, Ram R, Hashmi SK, Chakraverty R, Middeke JM, et al. Ruxolitinib for glucocorticoid-refractory chronic graft-versus-host disease. N Engl J Med. 2021;385(3):228\u201338.","journal-title":"N Engl J Med"},{"issue":"17","key":"3348_CR15","doi-asserted-by":"publisher","first-page":"1888","DOI":"10.1200\/JCO.20.02754","volume":"39","author":"M Jagasia","year":"2021","unstructured":"Jagasia M, Lazaryan A, Bachier CR, Salhotra A, Weisdorf DJ, Zoghi B, et al. ROCK2 inhibition with belumosudil (KD025) for the treatment of chronic graft-versus-host disease. J Clin Oncol. 2021;39(17):1888\u201398.","journal-title":"J Clin Oncol"},{"issue":"1","key":"3348_CR16","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1016\/j.jtct.2021.10.002","volume":"28","author":"VR Bhatt","year":"2022","unstructured":"Bhatt VR, Wang T, Chen K, Kitko CL, MacMillan ML, Pidala JA, et al. Chronic graft-versus-host disease, nonrelapse mortality, and disease relapse in older versus younger adults undergoing matched allogeneic peripheral blood hematopoietic cell transplantation: A center for international blood and marrow transplant research analysis. Transplant Cell Ther. 2022;28(1):34\u201342.","journal-title":"Transplant Cell Ther"},{"issue":"9","key":"3348_CR17","doi-asserted-by":"publisher","first-page":"1341","DOI":"10.1016\/j.bbmt.2014.05.001","volume":"20","author":"A El-Jawahri","year":"2014","unstructured":"El-Jawahri A, Pidala J, Inamoto Y, Chai X, Khera N, Wood WA, et al. Impact of age on quality of life, functional status, and survival in patients with chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2014;20(9):1341\u20138.","journal-title":"Biol Blood Marrow Transplant"},{"issue":"10","key":"3348_CR18","doi-asserted-by":"publisher","first-page":"2002","DOI":"10.1016\/j.bbmt.2019.06.023","volume":"25","author":"EK Waller","year":"2019","unstructured":"Waller EK, Miklos D, Cutler C, Arora M, Jagasia MH, Pusic I, et al. Ibrutinib for chronic graft-versus-host disease after failure of prior therapy: 1-year update of a Phase 1b\/2 study. Biol Blood Marrow Transplant. 2019;25(10):2002\u20137.","journal-title":"Biol Blood Marrow Transplant"},{"issue":"21","key":"3348_CR19","doi-asserted-by":"publisher","first-page":"2243","DOI":"10.1182\/blood-2017-07-793786","volume":"130","author":"D Miklos","year":"2017","unstructured":"Miklos D, Cutler CS, Arora M, Waller EK, Jagasia M, Pusic I, et al. Ibrutinib for chronic graft-versus-host disease after failure of prior therapy. Blood. 2017;130(21):2243\u201350.","journal-title":"Blood"},{"issue":"10","key":"3348_CR20","doi-asserted-by":"publisher","first-page":"1876","DOI":"10.1200\/JCO.22.00509","volume":"41","author":"DB Miklos","year":"2023","unstructured":"Miklos DB, Abu Zaid M, Cooney JP, Albring JC, Flowers M, Skarbnik AP, et al. Ibrutinib for first-line treatment of chronic graft-versus-host disease: results from the randomized phase III iNTEGRATE study. J Clin Oncol. 2023;41(10):1876\u201387.","journal-title":"J Clin Oncol"},{"issue":"Supplement 1","key":"3348_CR21","doi-asserted-by":"publisher","first-page":"4788","DOI":"10.1182\/blood-2022-165547","volume":"140","author":"M Chin","year":"2022","unstructured":"Chin M, Shizuru JA, Muffly L, Shiraz P, Johnston LJ, Lowsky R, et al. Belumosudil combination therapy in refractory chronic graft-versus-host disease. Blood. 2022;140(Supplement 1):4788\u20139.","journal-title":"Blood"}],"container-title":["BMC Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12916-024-03348-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12916-024-03348-5\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12916-024-03348-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,26]],"date-time":"2024-03-26T08:07:24Z","timestamp":1711440444000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcmedicine.biomedcentral.com\/articles\/10.1186\/s12916-024-03348-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,26]]},"references-count":21,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["3348"],"URL":"https:\/\/doi.org\/10.1186\/s12916-024-03348-5","relation":{},"ISSN":["1741-7015"],"issn-type":[{"value":"1741-7015","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,26]]},"assertion":[{"value":"11 October 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 March 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 March 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The study was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice guidelines from the International Conference on Harmonisation, and local applicable regulatory requirements. All procedures were approved by the institutional review boards\/independent ethics committee at the leading site (First Affiliated Hospital of Soochow University) and participating institutions. The approval number for each ethics committee is listed below. All patients provided written informed consent prior to screening.The First Affiliated Hospital of Soochow University: (2020) Ethics approval No. 098Peking University People\u2019s Hospital: 2021PHA025-001Xinqiao Hospital of Army Medical University: 2021-Medical number 003-01The Affiliated Hospital of Xuzhou Medical University: XYFY2021-YL030-01Nanfang Hospital: NFEC-2021-113Zhujiang Hospital, Southern Medical University: 2021-YW-017\u201301Guangzhou First People\u2019s Hospital: A-2021\u2013023-01","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"YH, YW, and YZ are employees of BioNova Pharmaceuticals (Shanghai) Limited. YH holds BioNova Pharmaceuticals (Shanghai) Limited stocks and options. All other authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"142"}}