{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T05:16:21Z","timestamp":1788498981741,"version":"build-2803163510"},"reference-count":27,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T00:00:00Z","timestamp":1788480000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100014882","name":"Department of Finance of Hebei","doi-asserted-by":"publisher","award":["ZF2023205"],"award-info":[{"award-number":["ZF2023205"]}],"id":[{"id":"10.13039\/501100014882","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"\n Background<\/jats:title>\n Severe aplastic anemia (SAA) is a life-threatening bone marrow failure disorder. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an established curative treatment for pediatric patients with SAA. Busulfan, a key component of conditioning regimens, has a narrow therapeutic index and marked interindividual pharmacokinetic variability. However, the impact of different first-dose busulfan exposure levels on long-term outcomes, particularly immune reconstitution, remains unclear in pediatric patients receiving a 2-day conditioning regimen. We evaluated the clinical significance of busulfan exposure stratification in pediatric patients with SAA undergoing allo-HSCT.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n This retrospective study included 40 pediatric patients with SAA who underwent allo-HSCT. Patients were stratified into a low-exposure group (first-dose area under the concentration-time curve [AUC\n 0-t<\/jats:sub>\n ] &lt;900\u00a0\u03bcmol\u00a0min\/L, n = 24, 1\u00a0mg\u00a0h\/L \u2248 243.6\u00a0\u03bcmol\u00a0min\/L) and a standard-exposure group (AUC\n 0-t<\/jats:sub>\n \u2265900\u00a0\u03bcmol\u00a0min\/L, n = 16). Engraftment kinetics, transplant-related complications, and survival outcomes were compared between the groups. Longitudinal immune reconstitution (T-cell, NK-cell, B-cell counts, and immunoglobulin levels) was analyzed using linear mixed-effects models with Holm adjustment for multiple testing.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n No significant differences were observed between the groups in neutrophil or platelet engraftment, incidence of graft-versus-host disease, hemorrhagic cystitis, engraftment syndrome, or short-term survival outcomes. All nine immune outcomes changed significantly over the first 12 months after transplantation, documenting pronounced temporal immune reconstitution (All adjusted\n P<\/jats:italic>\n &lt; 0.001 except IgM:\n P<\/jats:italic>\n = 0.002). However, exposure-related differences in these trajectories were not confirmed after Holm adjustment (all adjusted\n P<\/jats:italic>\n &gt; 0.05).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n First-dose busulfan AUC\n 0-t<\/jats:sub>\n &lt; 900\u00a0\u03bcmol\u00a0min\/L (3.7\u00a0mg\u00a0h\/L) was not associated with impaired engraftment or increased early toxicity in pediatric patients with SAA undergoing allo-HSCT. The predominant longitudinal immune finding was time-dependent immune reconstitution, without confirmatory evidence that the two exposure groups followed different trajectories. These findings are limited by the modest sample size and retrospective design; therefore, prospective validation is needed to inform dosing strategies.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fphar.2026.1897156","type":"journal-article","created":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T04:27:02Z","timestamp":1788496022000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Impact of busulfan exposure stratification on transplant outcomes and immune reconstitution in children with severe aplastic anemia"],"prefix":"10.3389","volume":"17","author":[{"given":"Yanxiao","family":"Li","sequence":"first","affiliation":[{"name":"Department of Hematology and Oncology, Hebei Children\u2019s Hospital (Hebei Provincial Clinical Research Center for Child Health and Disease)","place":["Shijiazhuang, Hebei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoying","family":"Zhai","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Hebei Children\u2019s Hospital (Hebei Provincial Clinical Research Center for Child Health and Disease)","place":["Shijiazhuang, Hebei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianqian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Shijiazhuang Hospital of Traditional Chinese Medicine","place":["Shijiazhuang, Hebei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yile","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Hebei Children\u2019s Hospital (Hebei Provincial Clinical Research Center for Child Health and Disease)","place":["Shijiazhuang, Hebei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenhong","family":"Jia","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Hebei Children\u2019s Hospital (Hebei Provincial Clinical Research Center for Child Health and Disease)","place":["Shijiazhuang, Hebei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e526","DOI":"10.1016\/S2352-3026(16)30114-4","article-title":"Association of busulfan exposure with survival and toxicity after haemopoietic cell transplantation in children and young adults: a multicentre, retrospective cohort analysis","volume":"3","author":"Bartelink","year":"2016","journal-title":"Lancet Haematol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1988","DOI":"10.3389\/fimmu.2020.01988","article-title":"Immune reconstitution in pediatric patients following hematopoietic cell transplant for non-malignant disorders","volume":"11","author":"Bhatt","year":"2020","journal-title":"Front. Immunol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"762","DOI":"10.1038\/s41409-023-01971-z","article-title":"Busulfan target exposure attainment in children undergoing allogeneic hematopoietic cell transplantation: a single day versus a multiday therapeutic drug monitoring regimen","volume":"58","author":"Bogn\u00e0r","year":"2023","journal-title":"Bone Marrow Transpl."},{"key":"B4","doi-asserted-by":"publisher","first-page":"5137","DOI":"10.1182\/bloodadvances.2024013275","article-title":"Association of busulfan exposure and outcomes after HCT for patients with an inborn error of immunity","volume":"8","author":"Bogn\u00e0r","year":"2024","journal-title":"Blood Adv."},{"key":"B5","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1046\/j.1365-2125.2002.01555.x","article-title":"Pharmacokinetics of intravenous busulfan in children prior to stem cell transplantation","volume":"53","author":"Cremers","year":"2002","journal-title":"Br. J. Clin. Pharmacol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1641","DOI":"10.1038\/s41409-024-02413-0","article-title":"A practical guide to therapeutic drug monitoring in busulfan: recommendations from the Pharmacist Committee of the European Society for Blood and Marrow Transplantation (EBMT)","volume":"59","author":"Domingos","year":"2024","journal-title":"Bone Marrow Transpl."},{"key":"B7","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1186\/s12887-020-02028-6","article-title":"Busulfan systemic exposure and its relationship with efficacy and safety in hematopoietic stem cell transplantation in children: a meta-analysis","volume":"20","author":"Feng","year":"2020","journal-title":"BMC Pediatr."},{"key":"B8","doi-asserted-by":"publisher","first-page":"102860","DOI":"10.1016\/j.bcmd.2024.102860","article-title":"Diagnosis and management of acquired aplastic anemia in childhood. Guidelines from the Marrow Failure Study Group of the Pediatric Haemato-Oncology Italian Association (AIEOP)","volume":"108","author":"Guarina","year":"2024","journal-title":"Blood Cells Mol. Dis."},{"key":"B9","doi-asserted-by":"publisher","first-page":"436","DOI":"10.1016\/S0140-6736(13)62069-3","article-title":"Reduced-intensity conditioning and HLA-matched haemopoietic stem-cell transplantation in patients with chronic granulomatous disease: a prospective multicentre study","volume":"383","author":"G\u00fcng\u00f6r","year":"2014","journal-title":"Lancet"},{"key":"B10","doi-asserted-by":"publisher","first-page":"e14266","DOI":"10.1111\/petr.14266","article-title":"Role of therapeutic drug monitoring of intravenous busulfan for prevention of sinusoidal obstructive syndrome in children","volume":"26","author":"Gurlek Gokcebay","year":"2022","journal-title":"Pediatr. Transpl."},{"key":"B11","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1016\/j.bbmt.2015.09.001","article-title":"International, multicenter standardization of acute graft-versus-host disease clinical data collection: a report from the Mount Sinai acute GVHD international consortium","volume":"22","author":"Harris","year":"2016","journal-title":"Biol. Blood Marrow Transpl."},{"key":"B12","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1016\/j.bbmt.2014.12.001","article-title":"National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. The 2014 Diagnosis and Staging Working Group report","volume":"21","author":"Jagasia","year":"2015","journal-title":"Biol. Blood Marrow Transpl."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1540139","DOI":"10.3389\/fphar.2025.1540139","article-title":"A limited sampling strategy for estimating busulfan exposure in pediatric hematopoietic stem cell transplantation","volume":"16","author":"Jia","year":"2025","journal-title":"Front. Pharmacol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1049","DOI":"10.1007\/s40262-020-00877-z","article-title":"Intra-individual pharmacokinetic variability of intravenous busulfan in hematopoietic stem cell-transplanted children","volume":"59","author":"Marsit","year":"2020","journal-title":"Clin. Pharmacokinet."},{"key":"B15","doi-asserted-by":"publisher","first-page":"2045","DOI":"10.1016\/j.bbmt.2019.06.018","article-title":"Use of multivariate immune reconstitution patterns to describe immune reconstitution after allogeneic stem cell transplantation in children","volume":"25","author":"Mellgren","year":"2019","journal-title":"Biol. Blood Marrow Transpl."},{"key":"B16","doi-asserted-by":"publisher","first-page":"e151","DOI":"10.3346\/jkms.2021.36.e151","article-title":"Incidence, management, and prognosis of graft failure and autologous reconstitution after allogeneic hematopoietic stem cell transplantation","volume":"36","author":"Park","year":"2021","journal-title":"J. Korean Med. Sci."},{"key":"B17","volume-title":"Busulfex (Busulfan) for Injection. Prescribing Information","year":"2023"},{"key":"B18","first-page":"825","article-title":"1994 Consensus conference on Acute GVHD grading","volume":"15","author":"Przepiorka","year":"1995","journal-title":"Bone Marrow Transpl."},{"key":"B19","doi-asserted-by":"publisher","first-page":"778","DOI":"10.1097\/FTD.0000000000001225","article-title":"Model-informed precision dosing of intravenous busulfan in Thai pediatrics undergoing hematopoietic stem cell transplantation","volume":"46","author":"Puangpetch","year":"2024","journal-title":"Ther. Drug Monit."},{"key":"B20","first-page":"881","volume-title":"Guidelines for the Diagnosis and Management of Aplastic Anemia in China (2022)","year":"2022"},{"key":"B21","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1038\/sj.bmt.1705923","article-title":"Reduced intensity conditioning and allogeneic stem cell transplantation in childhood malignant and nonmalignant diseases","volume":"41","author":"Satwani","year":"2008","journal-title":"Bone Marrow Transpl."},{"key":"B22","doi-asserted-by":"publisher","first-page":"13","DOI":"10.3390\/pharmaceutics16010013","article-title":"Population pharmacokinetic modeling for twice-daily intravenous busulfan in a large cohort of pediatric patients undergoing hematopoietic stem cell transplantation\u2014a 10-year single-center experience","volume":"16","author":"Schreib","year":"2023","journal-title":"Pharmaceutics"},{"key":"B23","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1038\/s41409-021-01545-x","article-title":"Clinical outcomes of individualized busulfan-dosing in hematopoietic stem cell transplantation in Chinese children undergoing with therapeutic drug monitoring","volume":"57","author":"Shao","year":"2022","journal-title":"Bone Marrow Transpl."},{"key":"B24","doi-asserted-by":"publisher","first-page":"e31075","DOI":"10.1002\/pbc.31075","article-title":"Treatment of relapsed\/refractory severe aplastic anemia in children: evidence-based recommendations","volume":"71","author":"Shimano","year":"2024","journal-title":"Pediatr. Blood Cancer"},{"key":"B25","doi-asserted-by":"publisher","first-page":"821","DOI":"10.7150\/ijms.70146","article-title":"Immune reconstitution in pediatric aplastic anemia after allogeneic hematopoietic stem-cell transplantation","volume":"19","author":"Wang","year":"2022","journal-title":"Int. J. Med. Sci."},{"key":"B26","doi-asserted-by":"publisher","first-page":"61","DOI":"10.14740\/jh1264","article-title":"Acquired aplastic anemia therapies: immunosuppressive therapy versus alternative donor hematopoietic cell transplantation","volume":"13","author":"Wirk","year":"2024","journal-title":"J. Hematol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1692881","DOI":"10.3389\/fmed.2025.1692881","article-title":"Immunoglobulin levels of children with bronchiolitis obliterans syndrome after hematopoietic cell transplantation","volume":"12","author":"Yue","year":"2026","journal-title":"Front. Med."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1897156\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T04:27:03Z","timestamp":1788496023000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1897156\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,4]]},"references-count":27,"alternative-id":["10.3389\/fphar.2026.1897156"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1897156","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,4]]},"article-number":"1897156"}}