{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:54:19Z","timestamp":1786978459718,"version":"build-2736575974"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"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>Krabbe disease is a rare, rapidly progressive leukodystrophy with high early mortality. Hematopoietic stem cell transplantation (HSCT) is the main disease-modifying intervention used in clinical practice and may act through donor-derived myeloid and immune-cell replacement, enzymatic cross-correction, and immunomodulation. However, its benefits and immune-related toxicities remain incompletely quantified.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We conducted a systematic review and meta-analysis of studies reporting HSCT outcomes in genetically or enzymatically confirmed Krabbe disease. The primary outcome was overall survival (OS). Secondary outcomes included 5-year OS, transplant-related mortality (TRM), acute and chronic graft-versus-host disease (aGVHD and cGVHD), neurological stability, and MRI stability. For OS, publication bias or small-study effects were assessed using funnel-plot inspection and Egger\u2019s regression test. Exploratory univariable meta-regression examined total study sample size, publication year, and Newcastle\u2013Ottawa Scale (NOS) score, and robustness was assessed using leave-one-out sensitivity analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Fifteen studies involving 141 patients were included. Pooled OS after HSCT was 84% (95% CI, 75%\u201393%), 5-year OS was 80% (69%\u201392%), and TRM was 7% (1%\u201313%). The pooled incidences of aGVHD and cGVHD were 53% (16%\u201390%) and 25% (0%\u201353%), respectively. Neurological stability was reported in only four studies including 15 patients (77%; 31%\u2013100%), and MRI stability in four studies including 32 patients (49%; 7%\u201390%); both estimates showed substantial heterogeneity and wide confidence intervals. Subgroup analyses by disease-onset age, pre-transplant symptom status, and age at HSCT showed no statistically significant OS differences. Egger\u2019s test detected no significant funnel-plot asymmetry (P\u00a0=\u00a00.569). Leave-one-out estimates ranged from 82% to 86%. Meta-regression showed inverse associations of reported OS with total study sample size and NOS score (both P &amp;lt; 0.001), whereas publication year was not significant (P\u00a0=\u00a00.118).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>HSCT is associated with favorable survival and relatively low pooled TRM in selected patients with Krabbe disease. However, survival should not be interpreted as preservation of neurological function, because neurological, MRI, and GVHD outcomes were reported in few studies and patients and remained heterogeneous and imprecisely estimated. These findings require cautious interpretation but provide clinically useful benchmark data for counseling and comparison with emerging cellular and gene-based therapies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Systematic review registration<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link>https:\/\/www.crd.york.ac.uk\/PROSPERO\/<\/jats:ext-link>\n                      , identifier CRD420261285624.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1924827","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T05:32:46Z","timestamp":1786599166000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Survival benefit and immune-related toxicities after hematopoietic stem cell transplantation in Krabbe disease: a systematic review and meta-analysis"],"prefix":"10.3389","volume":"17","author":[{"given":"Jie","family":"Zhang","sequence":"first","affiliation":[{"name":"Children\u2019s Medical Center, Department of Pediatric Neurology, Peking University First Hospital","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quanzhen","family":"Tan","sequence":"additional","affiliation":[{"name":"Children\u2019s Medical Center, Department of Pediatric Neurology, Peking University First Hospital","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiyi","family":"Zhu","sequence":"additional","affiliation":[{"name":"Children\u2019s Medical Center, Department of Pediatric Neurology, Peking University First Hospital","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan","family":"Yi","sequence":"additional","affiliation":[{"name":"Children\u2019s Medical Center, Department of Pediatric Neurology, Peking University First Hospital","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Wu","sequence":"additional","affiliation":[{"name":"Children\u2019s Medical Center, Department of Pediatric Neurology, Peking University First Hospital","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1006\/mgme.2000.2990","article-title":"Krabbe disease: Genetic aspects and progress toward therapy","volume":"70","author":"Wenger","year":"2000","journal-title":"Mol Genet Metab"},{"key":"B2","article-title":"Krabbe Disease","author":"Orsini","year":"2000"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1002\/humu.21367","article-title":"Identification and characterization of 15 novel GALC gene mutations causing Krabbe disease","volume":"31","author":"Tappino","year":"2010","journal-title":"Hum Mutat"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1177\/08830738211027717","article-title":"Hospitalization burden and incidence of Krabbe disease","volume":"37","author":"Ghabash","year":"2022","journal-title":"J Child Neurol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.35624","article-title":"Death rates in the U.S. due to Krabbe disease and related leukodystrophy and lysosomal storage diseases","author":"Barczykowski","year":"2012","journal-title":"Am J Med Genet Pt A"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-018-0766-x","article-title":"Consensus guidelines for newborn screening, diagnosis and treatment of infantile Krabbe disease","volume":"13","author":"Kwon","year":"2018","journal-title":"Orphanet J Rare Dis"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2021006094","article-title":"Benefits of newborn screening and hematopoietic cell transplant in infantile Krabbe disease","volume":"6","author":"Page","year":"2022","journal-title":"Blood Adv"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1056\/nejm199804163381605","article-title":"Hematopoietic stem-cell transplantation in globoid-cell leukodystrophy","volume":"338","author":"Krivit","year":"1998","journal-title":"N Engl J Med"},{"key":"B9","doi-asserted-by":"publisher","first-page":"65","DOI":"10.2139\/ssrn.3464653","article-title":"Macrophages expressing GALC improve peripheral Krabbe disease by a mechanism independent of cross-correction","volume":"107","author":"Weinstock","year":"2020","journal-title":"Neuron"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1523\/jneurosci.1802-11.2011","article-title":"Bone marrow transplantation augments the effect of brain- and spinal cord-directed adeno-associated virus 2\/5 gene therapy by altering inflammation in the murine model of globoid-cell leukodystrophy","volume":"31","author":"Reddy","year":"2011","journal-title":"J Neurosci"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2006.01.006","article-title":"Gene therapy for lysosomal storage diseases","volume":"13","author":"Sands","year":"2006","journal-title":"Mol Ther"},{"key":"B12","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1089\/hum.2021.245","article-title":"Efficacy and safety of a Krabbe disease gene therapy","volume":"33","author":"Hordeaux","year":"2022","journal-title":"Hum Gene Ther"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2025.149949","article-title":"Gene therapy for Krabbe disease: Evidence from mouse and canine models","volume":"980","author":"Li","year":"2026","journal-title":"Gene"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1172\/jci133953","article-title":"Krabbe disease successfully treated via monotherapy of intrathecal gene therapy","volume":"130","author":"Bradbury","year":"2020","journal-title":"J Clin Invest"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1002\/pst.2068","article-title":"Assessing the quality of studies in meta\u2010research: Review\/guidelines on the most important quality assessment tools","volume":"20","author":"Luchini","year":"2021","journal-title":"Pharm Stat"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bmt.1704024","article-title":"Allogeneic bone marrow stem cell transplantation following CD34+ immunomagnetic enrichment in patients with inherited metabolic storage diseases","volume":"31","author":"Gaipa","year":"2003","journal-title":"Bone Marrow Transplant"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2018.12.405","article-title":"Long-term neurodevelopmental outcomes of hematopoietic stem cell transplantation for late-infantile Krabbe disease","volume":"137","author":"Yoon","year":"2021","journal-title":"Blood"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbmt.2018.06.020","article-title":"Long-term functional outcomes after hematopoietic stem cell transplant for early infantile Krabbe disease","volume":"24","author":"Allewelt","year":"2018","journal-title":"Biol Blood Marrow Transplant"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.23787","article-title":"Evidence for improved survival in postsymptomatic stem cell\u2010transplanted patients with K rabbe\u2019s disease","volume":"94","author":"Langan","year":"2016","journal-title":"J Neurosci Res"},{"key":"B20","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1016\/j.pediatrneurol.2012.02.023","article-title":"Later onset phenotypes of Krabbe disease: Results of the world-wide registry","volume":"46","author":"Duffner","year":"2012","journal-title":"Pediatr Neurol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1148\/radiol.2353040716","article-title":"Krabbe disease treated with hematopoietic stem cell transplantation: Serial assessment of anisotropy measurements\u2014initial experience","volume":"236","author":"McGraw","year":"2005","journal-title":"Radiology"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1111\/jns.70040","article-title":"Peripheral neuropathy as an early marker in newborn\u2010screened Krabbe disease: The value of pre\u2010confirmatory neurophysiological testing","volume":"30","author":"Gnanakumar","year":"2025","journal-title":"J Peripheral Nervous Sys"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.2005.05585.x","article-title":"Reconstitution of lymphocyte subpopulations in children with inherited metabolic storage diseases after haematopoietic cell transplantation","volume":"130","author":"Corti","year":"2005","journal-title":"Br J Haematol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2016.35","article-title":"Clinical outcomes of children with abnormal newborn screening results for Krabbe disease in New York State","volume":"18","author":"Wasserstein","year":"2016","journal-title":"Genet Med"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgmr.2025.101242","article-title":"Outcome of two siblings with late-onset Krabbe disease following allogeneic hematopoietic stem cell transplantation: And review of literature","volume":"44","author":"Almudhry","year":"2025","journal-title":"Mol Genet Metab Rep"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2021.764626","article-title":"National U.S. patient and transplant data for Krabbe disease","volume":"9","author":"Ghabash","year":"2021","journal-title":"Front Pediatr"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1212\/wnl.0000000000004418","article-title":"Developmental outcomes of cord blood transplantation for Krabbe disease: A 15-year study","volume":"89","author":"Wright","year":"2017","journal-title":"Neurology"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3969\/j.issn.1673-5323.2025.03.005","article-title":"A single-center clinical study of haploidentical hematopoietic stem cell transplantation in the treatment of hereditary metabolic diseases in children","volume":"30","author":"Tang","year":"2025","journal-title":"J China Pediatr Blood Cancer"},{"key":"B29","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1186\/s13023-019-1018-4","article-title":"Early progression of Krabbe disease in patients with symptom onset between 0 and 5 months","volume":"14","author":"Beltran-Quintero","year":"2019","journal-title":"Orphanet J Rare Dis"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2024-069152","article-title":"Evidence and recommendation for infantile Krabbe disease newborn screening","volume":"155","author":"Ream","year":"2025","journal-title":"Pediatrics"},{"key":"B31","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1186\/s13023-020-01489-3","article-title":"Natural history of Krabbe disease \u2013 a nationwide study in Germany using clinical and MRI data","volume":"15","author":"Krieg","year":"2020","journal-title":"Orphanet J Rare Dis"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2021.135841","article-title":"Krabbe disease: New hope for an old disease","volume":"752","author":"Bradbury","year":"2021","journal-title":"Neurosci Lett"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.spen.2021.100876","article-title":"Recent advancements in the diagnosis and treatment of leukodystrophies","volume":"37","author":"Bradbury","year":"2021","journal-title":"Semin Pediatr Neurol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1205858109","article-title":"Brain conditioning is instrumental for successful microglia reconstitution following hematopoietic stem cell transplantation","volume":"109","author":"Capotondo","year":"2012","journal-title":"Proc Natl Acad Sci USA"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2022.895511","article-title":"Hematopoietic stem cell transplantation for neurological disorders: A focus on inborn errors of metabolism","volume":"16","author":"De Vasconcelos","year":"2022","journal-title":"Front Cell Neurosci"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.23804","article-title":"Neuroimmune mechanisms in K rabbe\u2019s disease","volume":"94","author":"Potter","year":"2016","journal-title":"J Neurosci Res"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1353\/hcr.2007.0088","article-title":"Hematopoietic stem cell transplantation to treat leukodystrophies: Clinical practice guidelines from the Hunter\u2019s Hope Leukodystrophy Care Network","volume":"25","author":"Page","year":"2019","journal-title":"Biol Blood Marrow Transplant"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2006-0747","article-title":"A staging system for infantile Krabbe disease to predict outcome after unrelated umbilical cord blood transplantation","volume":"118","author":"Escolar","year":"2006","journal-title":"Pediatrics"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1080\/08880010802243524","article-title":"Safety of hematopoietic stem cell transplantation in children less than three years of age","volume":"25","author":"Dvorak","year":"2008","journal-title":"Pediatr Hematol Oncol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1111\/petr.13944","article-title":"Mortality among pediatric hematopoietic stem cell transplantation patients: Report from a single center in southern Brazil","volume":"25","author":"Jardim","year":"2021","journal-title":"Pediatr Transplant"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1111\/petr.13158","article-title":"Transplant\u2010related mortality and survival in children with Malignancies treated with allogeneic hematopoietic stem cell transplantation. A multicenter analysis","volume":"22","author":"Zaucha\u2010Prazmo","year":"2018","journal-title":"Pediatr Transplant"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2023022751","article-title":"Outcomes of hematopoietic stem cell transplantation in 813 pediatric patients with Fanconi anemia","volume":"144","author":"Lum","year":"2024","journal-title":"Blood"},{"key":"B43","doi-asserted-by":"publisher","first-page":"e1","DOI":"10.1111\/bjh.19122.","article-title":"Busulfan\u2013fludarabine\u2010 or treosulfan\u2013fludarabine\u2010based conditioning before allogeneic HSCT from matched sibling donors in paediatric patients with sickle cell disease: A study on behalf of the EBMT Paediatric Diseases and Inborn Errors Working Parties","volume":"204","author":"Cseh","year":"2024","journal-title":"Br J Haematol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2021.760236","article-title":"Krabbe disease: Prospects of finding a cure using AAV gene therapy","volume":"8","author":"Nasir","year":"2021","journal-title":"Front Med"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1924827\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T13:50:55Z","timestamp":1786974655000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1924827\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,13]]},"references-count":44,"alternative-id":["10.3389\/fimmu.2026.1924827"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1924827","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,13]]},"article-number":"1924827"}}