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Diagnosis-to-Treatment Interval and Circulating Tumor DNA Levels in Diffuse Large B-Cell Lymphoma


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In a study reported in the Journal of Clinical Oncology, Stefan Alig, MD, and colleagues found that a short diagnosis-to-treatment interval in patients with diffuse large B-cell lymphoma (DLBCL) was associated with higher baseline tumor burden, reflected in higher pretreatment circulating tumor DNA (ctDNA) levels.

As stated by the investigators, “Patients with DLBCL in need of immediate therapy are largely underrepresented in clinical trials. The diagnosis-to-treatment interval has recently been described as a metric to quantify such patient selection bias, with short diagnosis-to-treatment interval being associated with adverse risk factors and inferior outcomes. Here, we characterized the relationships between diagnosis-to-treatment interval, ctDNA, conventional risk factors, and clinical outcomes, with the goal of defining objective disease metrics contributing to selection bias.”


Short diagnosis-to-treatment interval 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.
— Stefan Alig, MD, and colleagues

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Study Details

The study included 267 patients with DLBCL treated in multiple centers in the United States and Europe. The associations between pretreatment ctDNA levels and diagnosis-to-treatment interval, total metabolic tumor volumes, International Prognostic Index (IPI) score, and outcome were evaluated. When used as dichotomized variables, short diagnosis-to-treatment interval was defined as an interval of 14 days or less, and ctDNA levels > 2.5 log hGE/mL were defined as high.

Key Findings

Short diagnosis-to-treatment interval was significantly associated with advanced-stage disease (P < .001) and higher IPI score (P < .001), with a significant inverse correlation observed between diagnosis-to-treatment interval and total metabolic tumor volume (RS = -0.37, P < .001).

Higher pretreatment ctDNA levels were significantly associated with advanced-stage disease (P < .001), higher IPI score (P < .001), and total metabolic tumor volume (RS  = 0.6, P < .001), indicating that both short diagnosis-to-treatment interval and higher ctDNA level reflect higher disease burden.

Shorter diagnosis-to-treatment interval was significantly associated with higher pretreatment ctDNA levels (P <.001), with pretreatment ctDNA levels being predictive of short diagnosis-to-treatment interval independent of IPI score (P <.001).

In analyses including ctDNA level (log space) and diagnosis-to-treatment interval (week increments) as continuous variables, ctDNA levels, IPI, and diagnosis-to-treatment interval were significantly associated with event-free survival on univariate analysis; on multivariate analysis, only ctDNA level remained significantly associated (hazard ratio [HR] = 1.5, P < .001). In analysis of overall survival, ctDNA, IPI, and diagnosis-to-treatment interval were prognostic factors in univariate analysis, with only ctDNA level remaining significant in multivariate analysis (HR = 1.4, P = .02).

The investigators concluded, “Short diagnosis-to-treatment interval 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.”

Ash A. Alizadeh, MD, PhD, of Stanford University School of Medicine, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by the National Cancer Institute, National Institutes of Health, Virginia and D.K. Ludwig Fund for Cancer Research, and others. For full disclosures of the study authors, visit ascopubs.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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