{"doi":"10.1136/jitc-2023-008450","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","abstract":"<jats:sec>\n                  <jats:title>Background</jats:title>\n                  <jats:p>Over 50% of patients with relapsed or refractory large B-cell lymphoma (r/r LBCL) receiving CD19-targeted chimeric antigen receptor (CAR19) T-cell therapy fail to achieve durable remission. Early identification of relapse or progression remains a significant challenge. In this study, we prospectively investigate the prognostic value of dynamic circulating tumor DNA (ctDNA) and track genetic evolution non-invasively, for the first time in an Asian population of r/r patients undergoing CAR19 T-cell therapy.</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>Methods</jats:title>\n                  <jats:p>Longitudinal plasma samples were prospectively collected both before lymphodepletion and at multiple timepoints after CAR19 T-cell infusion. ctDNA was detected using a capture-based next-generation sequencing which has been validated in untreated LBCL.</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>Results</jats:title>\n                  <jats:p>The study enrolled 23 patients with r/r LBCL and collected a total of 101 ctDNA samples. Higher pretreatment ctDNA levels were associated with inferior progression-free survival (PFS) (p=0.031) and overall survival (OS) (p=0.023). Patients with undetectable ctDNA negative (ctDNA–) at day 14 (D14) achieved an impressive 3-month complete response rate of 77.8% vs 22.2% (p=0.015) in patients with detectable ctDNA positive (ctDNA+), similar results observed for D28. CtDNA– at D28 predicted significantly longer 1-year PFS (90.9% vs 27.3%; p=0.004) and OS (90.9% vs 49.1%; p=0.003) compared with patients who remained ctDNA+. Notably, it is the first time to report that shorter ctDNA fragments (&lt;170 base pairs) were significantly associated with poorer PFS (p=0.031 for D14; p=0.002 for D28) and OS (p=0.013 for D14; p=0.008 for D28) in patients with LBCL receiving CAR T-cell therapy. Multiple mutated genes exhibited an elevated prevalence among patients with progressive disease, including <jats:italic>TP53</jats:italic>, <jats:italic>IGLL5</jats:italic>, <jats:italic>PIM1</jats:italic>, <jats:italic>BTG1</jats:italic>, <jats:italic>CD79B</jats:italic>, <jats:italic>GNA13</jats:italic>, and <jats:italic>P2RY8</jats:italic>. Notably, we observed a significant correlation between <jats:italic>IGLL5</jats:italic> mutation and inferior PFS (p=0.008) and OS (p=0.014).</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions</jats:title>\n                  <jats:p>Our study highlights that dynamic ctDNA monitoring during CAR T-cell therapy can be a promising non-invasive method for early predicting treatment response and survival outcomes. Additionally, the ctDNA mutational profile provides novel insights into the mechanisms of tumor-intrinsic resistance to CAR19 T-cell therapy.</jats:p>\n               </jats:sec>","journal":"Journal for ImmunoTherapy of Cancer","year":2024,"id":645873,"datarank":0.4566783656585135,"base_score":3.044522437723423,"endowment":3.044522437723423,"self_citation_contribution":0.4566783656585135,"citation_network_contribution":0.0,"self_endowment_contribution":0.4566783656585135,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":20,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":645930,"name":"Wei Liu","orcid":"0000-0002-0448-7210","position":1,"is_corresponding":false},{"id":1439043,"name":"Xiaojuan Wang","orcid":"0000-0002-5617-9180","position":2,"is_corresponding":false},{"id":710398,"name":"Yi Wang","orcid":"0000-0001-8043-4869","position":3,"is_corresponding":false},{"id":160847,"name":"Chunyang Wang","orcid":"0000-0001-9694-5831","position":4,"is_corresponding":false},{"id":1474845,"name":"Chen Qiu","orcid":"0000-0003-0825-450X","position":5,"is_corresponding":false},{"id":471411,"name":"Huimin Liu","orcid":"0000-0003-4823-3420","position":6,"is_corresponding":false},{"id":563121,"name":"Dandan Shan","orcid":"0000-0003-4761-7385","position":7,"is_corresponding":false},{"id":449737,"name":"Ting Xie","orcid":"0000-0002-6648-7697","position":8,"is_corresponding":false},{"id":647029,"name":"Wenyang Huang","orcid":null,"position":9,"is_corresponding":false},{"id":647028,"name":"Weiwei Sui","orcid":"0000-0002-6982-8258","position":10,"is_corresponding":false},{"id":647022,"name":"Shuhua Yi","orcid":"0000-0002-6291-812X","position":11,"is_corresponding":false},{"id":459878,"name":"Gang An","orcid":"0000-0003-4922-4614","position":12,"is_corresponding":false},{"id":530628,"name":"Yan Xu","orcid":"0000-0002-4758-1100","position":13,"is_corresponding":false},{"id":1518342,"name":"Tonghui Ma","orcid":"0000-0002-5414-0522","position":14,"is_corresponding":false},{"id":647032,"name":"Jianxiang Wang","orcid":"0000-0001-9437-9151","position":15,"is_corresponding":false},{"id":1297099,"name":"Lugui Qiu","orcid":"0000-0002-7438-8277","position":16,"is_corresponding":false},{"id":453058,"name":"Dehui Zou","orcid":"0000-0002-8135-4913","position":17,"is_corresponding":false},{"id":1681919,"name":"Hesong Zou","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"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","abstract":"<jats:sec>\n                  <jats:title>Background</jats:title>\n                  <jats:p>Over 50% of patients with relapsed or refractory large B-cell lymphoma (r/r LBCL) receiving CD19-targeted chimeric antigen receptor (CAR19) T-cell therapy fail to achieve durable remission. Early identification of relapse or progression remains a significant challenge. In this study, we prospectively investigate the prognostic value of dynamic circulating tumor DNA (ctDNA) and track genetic evolution non-invasively, for the first time in an Asian population of r/r patients undergoing CAR19 T-cell therapy.</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>Methods</jats:title>\n                  <jats:p>Longitudinal plasma samples were prospectively collected both before lymphodepletion and at multiple timepoints after CAR19 T-cell infusion. ctDNA was detected using a capture-based next-generation sequencing which has been validated in untreated LBCL.</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>Results</jats:title>\n                  <jats:p>The study enrolled 23 patients with r/r LBCL and collected a total of 101 ctDNA samples. Higher pretreatment ctDNA levels were associated with inferior progression-free survival (PFS) (p=0.031) and overall survival (OS) (p=0.023). Patients with undetectable ctDNA negative (ctDNA–) at day 14 (D14) achieved an impressive 3-month complete response rate of 77.8% vs 22.2% (p=0.015) in patients with detectable ctDNA positive (ctDNA+), similar results observed for D28. CtDNA– at D28 predicted significantly longer 1-year PFS (90.9% vs 27.3%; p=0.004) and OS (90.9% vs 49.1%; p=0.003) compared with patients who remained ctDNA+. Notably, it is the first time to report that shorter ctDNA fragments (&lt;170 base pairs) were significantly associated with poorer PFS (p=0.031 for D14; p=0.002 for D28) and OS (p=0.013 for D14; p=0.008 for D28) in patients with LBCL receiving CAR T-cell therapy. Multiple mutated genes exhibited an elevated prevalence among patients with progressive disease, including <jats:italic>TP53</jats:italic>, <jats:italic>IGLL5</jats:italic>, <jats:italic>PIM1</jats:italic>, <jats:italic>BTG1</jats:italic>, <jats:italic>CD79B</jats:italic>, <jats:italic>GNA13</jats:italic>, and <jats:italic>P2RY8</jats:italic>. Notably, we observed a significant correlation between <jats:italic>IGLL5</jats:italic> mutation and inferior PFS (p=0.008) and OS (p=0.014).</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions</jats:title>\n                  <jats:p>Our study highlights that dynamic ctDNA monitoring during CAR T-cell therapy can be a promising non-invasive method for early predicting treatment response and survival outcomes. Additionally, the ctDNA mutational profile provides novel insights into the mechanisms of tumor-intrinsic resistance to CAR19 T-cell therapy.</jats:p>\n               </jats:sec>","is_dataset_classified":null,"base_score":3.044522437723423,"endowment":3.044522437723423,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"38443094","pmcid":"PMC11146396","openalex_id":"https://openalex.org/W4392469028","authors":[],"funders":[{"funder_name":"CAMS Innovation Fund for Medical Sciences","grant_id":"CIFMS 2020-I2M-C&T-B-085","title":null},{"funder_name":"CAMS Innovation Fund for Medical Sciences","grant_id":"CIFMS 2021-I2M-1-041","title":null},{"funder_name":"CAMS Innovation Fund for Medical Sciences","grant_id":"CIFMS 2022-I2M-1-022","title":null},{"funder_name":"CAMS Innovation Fund for Medical Sciences","grant_id":"CIFMS 2020-I2M-C&amp;T-B-085","title":null}],"total_grants":4,"fwci":3.6013,"citation_percentile":0.94777098,"influential_citations":0,"citation_trend":[{"year":2024,"count":3},{"year":2025,"count":10},{"year":2026,"count":7}],"oa_status":"gold","license":"cc-by-nc","oa_locations":[{"url":"https://jitc.bmj.com/content/jitc/12/3/e008450.full.pdf","host_type":"journal"},{"url":"https://jitc.bmj.com/content/jitc/12/3/e008450.full.pdf","host_type":"publisher"},{"url":"https://syndication.highwire.org/content/doi/10.1136/jitc-2023-008450","host_type":"publisher"},{"url":"https://doi.org/10.1136/jitc-2023-008450","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/38443094","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/11146396","host_type":"repository"},{"url":"https://doaj.org/article/001c258fa8f143cf974c3eaa69999765","host_type":"repository"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11146396/pdf/jitc-2023-008450.pdf","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC11146396","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC11146396?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["CAR-T cell therapy research","Cancer Genomics and Diagnostics","Lymphoma Diagnosis and Treatment","Humans","Circulating Tumor DNA","Immunotherapy, Adoptive","Neoplasm Recurrence, Local","Genomics","Lymphoma, Large B-Cell, Diffuse"],"mesh_terms":["Circulating Tumor DNA","Humans","Neoplasm Recurrence, Local","Immunotherapy, Adoptive","Lymphoma, Large B-Cell, Diffuse","Genomics"],"keywords":["Medicine","Refractory (planetary science)","Internal medicine","Population","Lymphoma","Oncology","Gastroenterology","Biology","Immunotherapy","Chimeric Antigen Receptor - Car"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"No poverty"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"nct"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-09T10:28:48.636168Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}