{"doi":"10.1002/hon.70093_21","title":"21 | PROGNOSTIC VALUE OF CIRCULATING TUMOR DNA IN PATIENTS WITH ADVANCED STAGE CLASSIC HODGKIN LYMPHOMA TREATED ON SWOG S1826","abstract":"J. Paczkowska, M. Kaszkowiak, M. LeBlanc, C. Stewart, A. F. Herrera, G. Getz, J. W. Friedberg, M. A. Shipp equally contributing author. Background: S1826 demonstrated that incorporation of nivolumab into initial chemotherapy (N-AVD) improved progression-free survival (PFS) compared with Bv-AVD. In this pre-planned analysis, we assessed the prognostic value of serial circulating tumor DNA (ctDNA) detection in S1826 using a newly developed assay. Methods: Pts were ≥ 12 years (y) with stage 3–4 cHL. Serial plasma samples from first 388 pts and paired germline DNAs were evaluated with a targeted sequencing panel that included recurrently mutated genes (single nucleotide variants and indels), somatic copy number alterations, and structural variants in cHL; and probes to detect sites of physiologic and aberrant somatic hypermutation and determine EBV status. Duplex read sequencing was employed to enhance error suppression and recurrent mutations, SCNAs and SVs were detected using computational algorithms optimized for ctDNA analysis. A newly developed computational pipeline, MTB-Tracker, was used to identify clustered SNVs and assess treatment-related changes in molecular tumor burden (MTB), reflected as log-fold changes in haploid genome equivalents per milliliter of plasma (hGE/mL) over time. Results: 375/388 (97%) had detectable clustered SNVs at baseline and were included in the MTB analysis. The baseline clinical characteristics of these pts mirrored the overall S1826 population: median age 25 years (range, 12–83 years), 28% < 18 years, 10% > 60 years, 37% with IPS 4–7; 191 pts received N-AVD (2 years PFS 91%);184 pts received BV-AVD (2 years PFS 81%). Baseline MTB correlated with clinical features including IPS score (0–3 vs. 4–7, p < 0.0001) and B symptoms (p < 0.0001) in all analyzed pts. MTB at C3D1 was prognostic for outcome in the full cohort; undetectable ctDNA at C3D1 was associated with 2 years PFS 91% versus 2 years PFS 64% in the ctDNA+ group, p < 0.0001. Similar results were observed within each treatment arm at C3D1 (N-AVD: ctDNA− 2 years PFS 95% versus ctDNA+, 74%; BV-AVD: ctDNA− 2 years PFS 88% versus ctDNA+ 53%, both p < 0.0001). Dynamic assessment of the changes in MTB between baseline and C3D1 allowed further discrimination of low and higher risk groups (Figure). In comparison to pts with undetectable ctDNA at C3D1, pts with a > median (3.64) log fold drop in MTB at C3D1 had slightly less favorable outcomes: 2 years PFS in all, N-AVD and BV-AVD pts of 87%, 88% and 86%, respectively. In contrast, pts with < median log-fold drop at C3D1 had significantly inferior outcomes: 2 years PFS in all, N-AVD and BV-AVD pts of 41%, 59% and 25%, all p < 0.0001. The presence versus absence of detectable ctDNA at EOT was also significantly associated with PFS (ctDNA−, 2 years PFS 92% vs. ctDNA+ 42%): N-AVD (ctDNA−, 2 years PFS 93% vs. ctDNA+ 47%) and BV-AVD (ctDNA− 2 years PFS 91% vs. ctDNA+ 39%), all p < 0.0001. Conclusion: MTB assessed via ctDNA was significantly associated with PFS in the entire cohort and within each study arm at C3D1 and EOT. These findings support the potential use of ctDNA as an integral biomarker in a ctDNA response-adapted clinical trial in advanced stage cHL. Research funding declaration: Funding provided by the National Cancer Institute U10CA180888, U10CA180819, U10CA180821, U10CA180820, U10CA180863, UG1CA189955 (all investigators), the Miller Family Fund (MS) and a Leukemia and Lymphoma Society Fellowship Award (JP). Funding and drug provided by Bristol-Myers Squibb, drug provided by SeaGen for pts enrolled in Canada. Keywords: diagnostic and prognostic biomarkers; Hodgkin lymphoma Potential sources of conflict of interest: B. Kahl Honoraria: BMS","journal":"Hematological Oncology","year":2025,"id":523634,"datarank":0.2540348820727893,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"self_citation_contribution":0.24141568686511508,"citation_network_contribution":0.01261919520767423,"self_endowment_contribution":0.24141568686511508,"citer_contribution":0.01261919520767423,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":3,"citers_with_citation_signal":1,"citers_with_endowment":1,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9518,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1396056,"name":"Marcin Kaszkowiak","orcid":"0000-0002-8691-1205","position":1,"is_corresponding":false},{"id":268627,"name":"Michael LeBlanc","orcid":"0000-0001-7192-2860","position":2,"is_corresponding":false},{"id":14089,"name":"Chip Stewart","orcid":"0000-0003-2245-9552","position":3,"is_corresponding":false},{"id":282395,"name":"Alex F. Herrera","orcid":"0000-0002-9665-7415","position":4,"is_corresponding":false},{"id":1396057,"name":"J Castillo","orcid":"0009-0007-1411-5991","position":5,"is_corresponding":false},{"id":282785,"name":"Sharon M. Castellino","orcid":"0000-0001-8367-2002","position":6,"is_corresponding":false},{"id":559298,"name":"Sarah C. Rutherford","orcid":"0000-0002-1064-7727","position":7,"is_corresponding":false},{"id":262607,"name":"Andrew M. Evens","orcid":"0000-0002-6900-1824","position":8,"is_corresponding":false},{"id":559300,"name":"Kelly Davison","orcid":"0000-0001-5159-3916","position":9,"is_corresponding":false},{"id":315159,"name":"Huilin Li","orcid":"0000-0002-8288-7068","position":10,"is_corresponding":false},{"id":3266,"name":"Donna Neuberg","orcid":"0000-0003-2566-3145","position":11,"is_corresponding":false},{"id":1396545,"name":"Motohiro Murakami","orcid":null,"position":12,"is_corresponding":false},{"id":1386076,"name":"Jitin Makker","orcid":"0000-0001-6197-8641","position":13,"is_corresponding":false},{"id":258333,"name":"Brad S. Kahl","orcid":"0000-0003-0459-6609","position":14,"is_corresponding":false},{"id":285253,"name":"John P. Leonard","orcid":"0000-0002-5083-1115","position":15,"is_corresponding":false},{"id":11098,"name":"Nancy L. Bartlett","orcid":"0000-0001-8470-394X","position":16,"is_corresponding":false},{"id":356246,"name":"Susan M. Smith","orcid":"0000-0001-6027-2727","position":17,"is_corresponding":false},{"id":423661,"name":"Joo Y. Song","orcid":"0000-0003-3497-2513","position":18,"is_corresponding":false},{"id":321130,"name":"Kara M. Kelly","orcid":"0000-0003-1473-3937","position":19,"is_corresponding":false},{"id":1212675,"name":"Gaddy Getz","orcid":null,"position":20,"is_corresponding":false},{"id":11108,"name":"Jonathan W. Friedberg","orcid":"0000-0002-1420-5563","position":21,"is_corresponding":false},{"id":322581,"name":"Margaret A. Shipp","orcid":"0000-0002-3949-6897","position":22,"is_corresponding":false},{"id":1330545,"name":"Julia Paczkowska","orcid":"0000-0002-3976-4353","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:50:03.004175Z","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":[]}