{"doi":"10.1002/hon.70096_854","title":"854 | SEQUENCING‐GUIDED CHEMOTHERAPY OPTIMIZATION USING REAL‐TIME EVALUATION IN NEWLY DIAGNOSED DLBCL WITH CIRCULATING TUMOR DNA: SHORTEN‐ctDNA","abstract":"Introduction: Circulating tumor DNA (ctDNA) is a clinically valid tool for detection of measurable residual disease (MRD) in patients with diffuse large B-cell lymphoma (DLBCL). Phased variant enrichment and detection sequencing (PhasED-seq), which uses multiple somatic mutations on individual DNA fragments, improves upon first-generation single nucleotide variant-based MRD tests with improved sensitivity (Kurtz et al. Nat Biotech 2021). To utilize ctDNA-MRD testing in a clinical setting to guide treatment decisions, the ability to test and report in a real-time manner is required. However, the feasibility of real-time MRD testing using the PhasED-seq-based Foresight CLARITY platform to inform treatment decisions has yet to be established. Therapy de-escalation after 4 cycles of standard R-CHOP therapy was non-inferior and less toxic than 6 cycles for patients with DLBCL with no baseline risk factors (Poeschel et al. Lancet 2019). Identification of patients who are ideal candidates for de-escalation based instead on mid-treatment response remains a challenge as radiographic imaging has a high false-negative rate (Le Gouill & Casanovas, Blood 2017). ctDNA-MRD has a higher sensitivity and may be a better test to guide dose de-escalation decisions in patients with DLBCL. This feasibility study has two co-primary objectives: (1) to evaluate the feasibility of ctDNA sequencing for real-time guidance of clinical decision making during frontline therapy for DLBCL; and (2) to determine the outcomes of patients with newly diagnosed DLBCL who become undetectable for ctDNA and demonstrate a radiographic complete response (CR) during standard frontline therapy and discontinue chemotherapy early. Methods: This single-center investigator-initiated study (NCT06693830) opened in 11/2024 and is enrolling patients (n = 32) with newly diagnosed stage II-IV DLBCL with measurable disease. Patients will receive 4 cycles of standard therapy (R-CHOP or R-pola-CHP). Positron emission tomography/computed tomography (PET/CT) scans will be performed after cycle four (C4) and at the end of therapy (EOT). Additionally, whole blood samples will be drawn on C4 day 1 (C4D1) and shipped to Foresight Diagnostics, Inc. (Boulder, CO) for real-time MRD testing. Patients who experience a CR on iPET4 and have undetectable ctDNA on C4D1 will de-escalate therapy and receive rituximab alone for C5–6. Patients not meeting these response criteria or with unsuccessful real-time MRD testing for any reason will continue standard therapy for C5–6 (Figure). MRD will also be evaluated in a batched manner at other timepoints to evaluate the kinetics of ctDNA and correlation with clinical outcomes. The primary efficacy endpoint is the EOT CR rate on PET/CT performed 10–14 weeks after C6D1 in the patients who de-escalate treatment (estimated n = 13); their expected EOT CR rate is at least 94%. Patient reported outcomes and adverse events associated with abbreviated chemotherapy will be evaluated. Research funding declaration: NCI/NIH (R03CA286676); Conquer Cancer, the ASCO Foundation Career Development Award Encore Abstract: ASCO 2025 Keywords: minimal residual disease; aggressive B-cell non-Hodgkin lymphoma; ongoing trials Potential sources of conflict of interest: H. J. Cherng Honoraria: ADC Therapeutics S. Meek Employment or leadership position: Foresight Diagnostics, Inc. Stock ownership: Pfizer J. E. Amengual Consultant or advisory role: AstraZeneca Honoraria: Incyte, Ipsen, ADC Therapeutics B. Pro Honoraria: Bio Secura Educational grants: Takeda, Seagen D. M. Kurtz Employment or leadership position: Foresight Diagnostics, Inc. Stock ownership: Foresight Diagnostics, Inc.","journal":"Hematological Oncology","year":2025,"id":568494,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9543,"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":1473304,"name":"S. Meek","orcid":null,"position":1,"is_corresponding":false},{"id":297280,"name":"Costin Leu","orcid":"0000-0003-0598-3301","position":2,"is_corresponding":false},{"id":1473305,"name":"Beatriz Raposo Corradini","orcid":null,"position":3,"is_corresponding":false},{"id":366906,"name":"Seda S. Tolu","orcid":"0000-0003-2235-4902","position":4,"is_corresponding":false},{"id":977509,"name":"Jennifer E. Amengual","orcid":"0000-0003-4117-2469","position":5,"is_corresponding":false},{"id":265108,"name":"Barbara Pro","orcid":null,"position":6,"is_corresponding":false},{"id":252125,"name":"David M. Kurtz","orcid":"0000-0002-6382-4651","position":7,"is_corresponding":false},{"id":933073,"name":"Hua‐Jay J. Cherng","orcid":"0000-0002-8266-8447","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T02:56:52.212268Z","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":[]}