{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T08:07:10Z","timestamp":1780560430895,"version":"3.54.1"},"reference-count":35,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T00:00:00Z","timestamp":1780531200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Relapse remains the leading cause of treatment failure following hematopoietic cell transplantation (HCT) for hematologic malignancies. Circulating tumor DNA (ctDNA) has emerged as a promising minimally invasive biomarker for measurable residual disease (MRD) assessment and early relapse detection; however, the prognostic significance of ctDNA in the post-transplant setting has not been comprehensively synthesized. We conducted a systematic review and meta-analysis in accordance with PRISMA guidelines and registered the protocol in PROSPERO (CRD420261392100). PubMed, Embase, Web of Science, EBSCO, Cochrane CENTRAL, and supplementary sources were searched through November 2025. Eligible studies evaluated tumor-specific ctDNA or tumor-informed\/tumor-associated cfDNA in patients undergoing allogeneic or autologous HCT for hematologic malignancies. Random-effects meta-analyses were performed for relapse\/progression, overall survival (OS), and relapse-free\/progression-free survival (RFS\/PFS). Studies evaluating total cfDNA quantity, methylation-based cfDNA profiling, cfRNA, or chimerism-only monitoring were synthesized narratively. Ten observational cohort studies comprising 883 patients met inclusion criteria. Across acute leukemias, lymphomas, multiple myeloma, and myelodysplastic syndromes, ctDNA\/cfDNA positivity was consistently associated with adverse outcomes. The pooled hazard ratio (HR) for relapse or disease progression was 12.57 (95% CI: 4.59\u201334.46; p &lt; 0.001), while pooled HRs were 7.45 (95% CI: 4.11\u201313.48; p &lt; 0.001) for OS and 4.46 (95% CI: 2.22\u20138.97; p &lt; 0.001) for RFS\/PFS. Although statistical heterogeneity was low, interpretation was limited by the relatively small number of studies contributing to each pooled endpoint. Narrative evidence additionally suggested that broader circulating nucleic acid approaches may provide complementary information regarding graft-versus-host disease, infection, and other post-transplant complications. Tumor-specific ctDNA positivity is consistently associated with increased relapse risk and inferior survival outcomes following HCT. These findings support further investigation of ctDNA-based MRD monitoring as a promising non-invasive biomarker for post-transplant molecular surveillance and risk stratification. However, prospective multicenter validation studies, assay standardization, and ctDNA-guided interventional trials remain necessary before routine clinical implementation can be recommended.<\/jats:p>","DOI":"10.3390\/ijms27115076","type":"journal-article","created":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T07:36:28Z","timestamp":1780558588000},"page":"5076","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Prognostic Value of Circulating Tumor DNA for Clinical Outcomes in Patients Undergoing Hematopoietic Cell Transplantation: A Systematic Review and Meta-Analysis"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-3007-2596","authenticated-orcid":false,"given":"Do Tung","family":"Dac","sequence":"first","affiliation":[{"name":"Faculty of Health Sciences, Kanazawa University, Kanazawa 9200942, Ishikawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7192-525X","authenticated-orcid":false,"given":"Hirokazu","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Hematology, Faculty of Medicine, Kindai University, Osaka-Sayama 5898511, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1822-9976","authenticated-orcid":false,"given":"Akiyoshi","family":"Takami","sequence":"additional","affiliation":[{"name":"Department of Hematology, Faculty of Medicine, Aichi Medical University, Nagakute 4801195, Aichi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1794-6666","authenticated-orcid":false,"given":"Jorge Luis","family":"Espinoza","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences, Kanazawa University, Kanazawa 9200942, Ishikawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1499","DOI":"10.1038\/s41409-025-02701-3","article-title":"Indications for haematopoietic cell transplantation and CAR-T for haematological diseases, solid tumours and immune disorders: 2025 EBMT practice recommendations","volume":"60","author":"Greco","year":"2025","journal-title":"Bone Marrow Transplant."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1038\/s41409-023-02042-z","article-title":"Haploidentical transplant with posttransplant cyclophosphamide vs matched related and unrelated donor transplant in acute myeloid leukemia and myelodysplastic neoplasm","volume":"58","author":"Rieger","year":"2023","journal-title":"Bone Marrow Transplant."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"101229","DOI":"10.1016\/j.blre.2024.101229","article-title":"Addressing the surge of infections by multidrug-resistant Enterobacterales in hematopoietic cell transplantation","volume":"68","author":"Akhmedov","year":"2024","journal-title":"Blood Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1186\/s12943-023-01889-6","article-title":"Relapse of acute myeloid leukemia after allogeneic stem cell transplantation: Immune escape mechanisms and current implications for therapy","volume":"22","author":"Sauerer","year":"2023","journal-title":"Mol. Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2753","DOI":"10.1182\/blood.2021013626","article-title":"2021 Update on MRD in acute myeloid leukemia: A consensus document from the European LeukemiaNet MRD Working Party","volume":"138","author":"Heuser","year":"2021","journal-title":"Blood"},{"key":"ref_6","first-page":"2173","article-title":"The use of prognostic models in allogeneic transplants: A perspective guide for clinicians and investigators","volume":"141","author":"Sorror","year":"2023","journal-title":"Blood"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1038\/nrc.2017.7","article-title":"Liquid biopsies come of age: Towards implementation of circulating tumour DNA","volume":"17","author":"Wan","year":"2017","journal-title":"Nat. Rev. Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.annonc.2024.12.006","article-title":"Minimal residual disease in colorectal cancer. Tumor-informed versus tumor-agnostic approaches: Unraveling the optimal strategy","volume":"36","author":"Camblor","year":"2025","journal-title":"Ann. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Sorbini, M., Carradori, T., Togliatto, G.M., Vaisitti, T., and Deaglio, S. (2024). Technical Advances in Circulating Cell-Free DNA Detection and Analysis for Personalized Medicine in Patients\u2019 Care. Biomolecules, 14.","DOI":"10.20944\/preprints202403.1530.v1"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1016\/j.cell.2019.06.011","article-title":"Dynamic Risk Profiling Using Serial Tumor Biomarkers for Personalized Outcome Prediction","volume":"178","author":"Kurtz","year":"2019","journal-title":"Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1038\/s41408-024-01185-6","article-title":"High level of circulating cell-free tumor DNA at diagnosis correlates with disease spreading and defines multiple myeloma patients with poor prognosis","volume":"14","author":"Martello","year":"2024","journal-title":"Blood Cancer J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e008450","DOI":"10.1136\/jitc-2023-008450","article-title":"Dynamic monitoring of circulating tumor DNA reveals outcomes and genomic alterations in patients with relapsed or refractory large B-cell lymphoma undergoing CAR T-cell therapy","volume":"12","author":"Zou","year":"2024","journal-title":"J. Immunother. Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3034","DOI":"10.1200\/JCO.21.00377","article-title":"Monitoring of Circulating Tumor DNA Improves Early Relapse Detection After Axicabtagene Ciloleucel Infusion in Large B-Cell Lymphoma: Results of a Prospective Multi-Institutional Trial","volume":"39","author":"Frank","year":"2021","journal-title":"J. Clin. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e1349","DOI":"10.1002\/ctm2.1349","article-title":"Serial monitoring of circulating tumour DNA on clinical outcome in myelodysplastic syndromes and acute myeloid leukaemia","volume":"13","author":"Zhou","year":"2023","journal-title":"Clin. Transl. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1007\/s40259-025-00735-z","article-title":"Bispecific Antibodies in Hematologic Malignancies: Attacking the Frontline","volume":"39","author":"Shastri","year":"2025","journal-title":"BioDrugs"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Tan, X., Yan, H., Chen, L., Zhang, Y., and Sun, C. (2021). Clinical Value of ctDNA in Hematological Malignancies (Lymphomas, Multiple Myeloma, Myelodysplastic Syndrome, and Leukemia): A Meta-Analysis. Front. Oncol., 11.","DOI":"10.3389\/fonc.2021.632910"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"195","DOI":"10.3343\/alm.2023.0389","article-title":"Clinical Practice Guideline for Blood-based Circulating Tumor DNA Assays","volume":"44","author":"Lee","year":"2024","journal-title":"Ann. Lab. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/1745-6215-8-16","article-title":"Practical methods for incorporating summary time-to-event data into meta-analysis","volume":"8","author":"Tierney","year":"2007","journal-title":"Trials"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"280","DOI":"10.7326\/0003-4819-158-4-201302190-00009","article-title":"Assessing bias in studies of prognostic factors","volume":"158","author":"Hayden","year":"2013","journal-title":"Ann. Intern. Med."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Dhakal, B., Sharma, S., Balcioglu, M., Shchegrova, S., Malhotra, M., Zimmermann, B., Billings, P.R., Harrington, A., Sethi, H., and Aleshin, A. (2022). Assessment of Molecular Residual Disease Using Circulating Tumor DNA to Identify Multiple Myeloma Patients at High Risk of Relapse. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.786451"},{"key":"ref_21","first-page":"1010","article-title":"Peripheral Blood Tumor Associated Cell-Free DNA Testing as a Predictor for Relapse Postallogeneic Stem Cell Transplant for Acute Myelogenous Leukemia","volume":"31","author":"Patel","year":"2025","journal-title":"Transpl. Cell Ther."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1111\/bjh.14311","article-title":"Next-generation sequencing-based detection of circulating tumour DNA After allogeneic stem cell transplantation for lymphoma","volume":"175","author":"Herrera","year":"2016","journal-title":"Br. J. Haematol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e2113476118","DOI":"10.1073\/pnas.2113476118","article-title":"Cell-free DNA profiling informs all major complications of hematopoietic cell transplantation","volume":"119","author":"Cheng","year":"2022","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4660","DOI":"10.1182\/bloodadvances.2023010416","article-title":"Cell-free DNA measurable residual disease as a predictor of postallogeneic hematopoietic cell transplant outcomes","volume":"7","author":"Pasca","year":"2023","journal-title":"Blood Adv."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2682","DOI":"10.1182\/blood-2018-10-880690","article-title":"Prognostic impact of circulating tumor DNA status post-allogeneic hematopoietic stem cell transplantation in AML and MDS","volume":"133","author":"Nakamura","year":"2019","journal-title":"Blood"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e13549","DOI":"10.1111\/petr.13549","article-title":"Highly sensitive chimerism detection in blood is associated with increased risk of relapse after allogeneic hematopoietic cell transplantation in childhood leukemia","volume":"23","author":"Haugaard","year":"2019","journal-title":"Pediatr. Transpl."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"138","DOI":"10.4274\/balkanmedj.galenos.2020.2019.8.25","article-title":"The Impact of Pre-transplant Cell-free DNA Levels on Leukemia Relapse and Transplant-related Complications in Allogeneic Hematopoietic Stem Cell Transplant Recipients","volume":"37","author":"Yegin","year":"2020","journal-title":"Balk. Med. J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"372","DOI":"10.21873\/invivo.13448","article-title":"Circulating-tumor DNA Assessment in Diffuse Large B-cell Lymphoma to Determine Up-front Stem Cell Transplantation: A Pilot Study","volume":"38","author":"Kim","year":"2024","journal-title":"In Vivo"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Waterhouse, M., Pennisi, S., Pfeifer, D., Scherer, F., Zeiser, R., Duyster, J., Bertz, H., Finke, J., and Duque-Afonso, J. (2022). Monitoring of Measurable Residual Disease Using Circulating DNA after Allogeneic Hematopoietic Cell Transplantation. Cancers, 14.","DOI":"10.3390\/cancers14143307"},{"key":"ref_30","first-page":"1044","article-title":"Liquid biopsies in myeloid malignancies","volume":"2","author":"Abdulmawjood","year":"2019","journal-title":"Cancer Drug Resist."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4371","DOI":"10.1182\/blood-2008-03-077974","article-title":"Graft-versus-leukemia effects of transplantation and donor lymphocytes","volume":"112","author":"Kolb","year":"2008","journal-title":"Blood"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3395","DOI":"10.1182\/bloodadvances.2023009856","article-title":"Next-generation sequencing\u2013based MRD in adults with ALL undergoing hematopoietic cell transplantation","volume":"7","author":"Liang","year":"2023","journal-title":"Blood Adv."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1182\/blood.2023023699","article-title":"How I use next-generation sequencing\u2013MRD to plan approach and prevent relapse after HCT for children and adults with ALL","volume":"144","author":"Muffly","year":"2024","journal-title":"Blood"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1038\/s41408-020-00377-0","article-title":"Comparison of next-generation sequencing (NGS) and next-generation flow (NGF) for minimal residual disease (MRD) assessment in multiple myeloma","volume":"10","author":"Medina","year":"2020","journal-title":"Blood Cancer J."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Maffini, E., Ursi, M., Barbato, F., Dicataldo, M., Roberto, M., Campanini, E., Dan, E., De Felice, F., De Matteis, S., and Storci, G. (2022). The prevention of disease relapse after allogeneic hematopoietic cell transplantation in acute myeloid leukemia. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.1066285"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/11\/5076\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T07:37:38Z","timestamp":1780558658000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/11\/5076"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,4]]},"references-count":35,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["ijms27115076"],"URL":"https:\/\/doi.org\/10.3390\/ijms27115076","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,4]]}}}