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Purpose: Patients with Diffuse Large B-cell Lymphoma (DLBCL) in need of immediate therapy are largely under-represented in clinical trials. The diagnosis-to-treatment interval (DTI) has recently been described as a metric to quantify such patient selection bias, with short DTI being associated with adverse risk factors and inferior outcomes. Here, we characterized the relationships between DTI, circulating tumor DNA (ctDNA), conventional risk factors, and clinical outcomes, with the goal of defining objective disease metrics contributing to selection bias., Patients and Methods: We evaluated pretreatment ctDNA levels in 267 patients with DLBCL treated across multiple centers in Europe and the United States using Cancer Personalized Profiling by Deep Sequencing. Pretreatment ctDNA levels were correlated with DTI, total metabolic tumor volumes (TMTVs), the International Prognostic Index (IPI), and outcome., Results: Short DTI was associated with advanced-stage disease ( P < .001) and higher IPI ( P < .001). We also found an inverse correlation between DTI and TMTV ( R S = - 0.37; P < .001). Similarly, pretreatment ctDNA levels were significantly associated with stage, IPI, and TMTV (all P < .001), demonstrating that both DTI and ctDNA reflect disease burden. Notably, patients with shorter DTI had higher pretreatment ctDNA levels ( P < .001). Pretreatment ctDNA levels predicted short DTI independent of the IPI ( P < .001). Although each risk factor was significantly associated with event-free survival in univariable analysis, ctDNA level was prognostic of event-free survival independent of DTI and IPI in multivariable Cox regression (ctDNA: hazard ratio, 1.5; 95% CI [1.2 to 2.0]; IPI: 1.1 [0.9 to 1.3]; -DTI: 1.1 [1.0 to 1.2])., Conclusion: Short DTI largely reflects baseline tumor burden, which can be objectively measured using pretreatment ctDNA levels. Pretreatment ctDNA levels therefore have utility for quantifying and guarding against selection biases in prospective DLBCL clinical trials., Competing Interests: David M. KurtzStock and Other Ownership Interests: Foresight DiagnosticsConsulting or Advisory Role: Roche Molecular Diagnostics, GenentechPatents, Royalties, Other Intellectual Property: Patent filings on ctDNA detection and methods for treatment selection based on statistical frameworks, assigned to Stanford University Ulrich DührsenHonoraria: Roche Pharma AG, Janssen-Cilag, Novartis, Amgen, CPT Cellex Patient Treatment GmbHConsulting or Advisory Role: Takeda, Gilead Sciences, AbbvieResearch Funding: CelgeneTravel, Accommodations, Expenses: Abbvie, Janssen-Cilag Andreas HüttmannHonoraria: TakedaConsulting or Advisory Role: TakedaTravel, Accommodations, Expenses: Takeda, Roche Pharma AG Christine SchmitzResearch Funding: NovartisTravel, Accommodations, Expenses: Abbvie Brian J. SworderStock and Other Ownership Interests: Allogene TherapeuticsPatents, Royalties, Other Intellectual Property: Dr Sworder has patents related to methods of resistance to immunotherapy for lymphoma Barzin Y. NabetEmployment: Roche/GenentechStock and Other Ownership Interests: Roche/GenentechPatents, Royalties, Other Intellectual Property: Dr Nabet has a patent pending related to immunomodulatory nucleic acids, Provisional patent related to noninvasive means to predict immune checkpoint blockade outcomes Olivier CasasnovasHonoraria: Roche/Genentech, Takeda, Gilead Sciences, Bristol-Myers Squibb, Merck, Abbvie, Celgene, Janssen, AmgenConsulting or Advisory Role: Roche/Genentech, Takeda, Gilead Sciences, Bristol-Myers Squibb, Merck, Abbvie, Celgene, Janssen, IncyteResearch Funding: Roche/Genentech, Gilead Sciences, TakedaTravel, Accommodations, Expenses: Roche/Genentech, Takeda, Gilead Sciences, Janssen Jason R. WestinConsulting or Advisory Role: Novartis, Celgene, Genentech/Abbvie, Kite/Gilead, Janssen Scientific Affairs, Amgen, MorphoSys, Juno Therapeutics, CurisResearch Funding: Celgene, Janssen, Genentech, Novartis, Kite/Gilead, Bristol-Myers Squibb, Curis Gianluca GaidanoHonoraria: Janssen, Abbvie, Sunesis Pharmaceuticals, AstraZenecaConsulting or Advisory Role: Janssen, Abbvie, AstraZeneca, Sunesis PharmaceuticalsSpeakers' Bureau: Janssen, AbbvieTravel, Accommodations, Expenses: Janssen, Amgen Davide RossiHonoraria: Abbvie, Janssen, AstraZenecaResearch Funding: Abbvie, Janssen, AstraZeneca Michel MeignanHonoraria: RocheTravel, Accommodations, Expenses: Roche Maximilian DiehnStock and Other Ownership Interests: CiberMed, Foresight DiagnosticsConsulting or Advisory Role: Roche, AstraZeneca, Illumina, Reflexion Medical, Gritstone Oncology, BioNTech AG, Novartis, GenentechResearch Funding: Varian Medical Systems, IlluminaPatents, Royalties, Other Intellectual Property: Patent filings on ctDNA detection assigned to Stanford University, Patent filings on tumor treatment resistance mechanisms assigned to Stanford UniversityTravel, Accommodations, Expenses: Roche, Varian Medical Systems, AstraZeneca Ash A. AlizadehLeadership: Lymphoma Research FoundationStock and Other Ownership Interests: CiberMed, CAPP Medical, Forty Seven, Foresight DiagnosticsHonoraria: Roche, Janssen OncologyConsulting or Advisory Role: Celgene, Roche/Genentech, Gilead Sciences, Cibermed, Foresight DiagnosticsResearch Funding: CelgenePatents, Royalties, Other Intellectual Property: Patent filings on ctDNA detection, assigned to Stanford UniversityTravel, Accommodations, Expenses: Roche, Gilead SciencesNo other potential conflicts of interest were reported.