TY - JOUR
T1 - Short Diagnosis-to-Treatment Interval Is Associated With Higher Circulating Tumor DNA Levels in Diffuse Large B-Cell Lymphoma
AU - Alig, Stefan
AU - Macaulay, Charles W.
AU - Kurtz, David M.
AU - Dührsen, Ulrich
AU - Hüttmann, Andreas
AU - Schmitz, Christine
AU - Jin, Michael C.
AU - Sworder, Brian J.
AU - Garofalo, Andrea
AU - Esfahani, Mohammad Shahrokh
AU - Nabet, Barzin Y.
AU - Soo, Joanne
AU - Scherer, Florian
AU - Craig, Alexander F.M.
AU - Casasnovas, Olivier
AU - Westin, Jason R.
AU - Gaidano, Gianluca
AU - Rossi, Davide
AU - Roschewski, Mark
AU - Wilson, Wyndham H.
AU - Meignan, Michel
AU - Diehn, Maximilian
AU - Alizadeh, Ash A.
N1 - Funding Information:
Supported by the National Cancer Institute (R01CA188298 and R01CA233975 to M.D. and A.A.A., 1-K08-CA241076-01 to D.M.K.), the US National Institutes of Health Director’s New Innovator Award Program (1-DP2-CA186569 to M.D.), the US National Institutes of Health, the Virginia and D.K. Ludwig Fund for Cancer Research (M.D. and A.A.A.), the CRK Faculty Scholar Fund (M.D.), the Bakewell Foundation (M.D. and A.A.A.), the Damon Runyon Cancer Research Foundation (PST#09-16 to D.M.K.), the SDW/DT and Shanahan Family Foundations (A.A.A.), and Stand Up To Cancer (M.D. and A.A.A.). The PETAL trial was supported by grants from the Deutsche Krebshilfe (107592, 110515). S.A. was funded by a Dr Mildred Scheel postdoctoral fellowship of the Deutsche Krebshilfe (57406718). A.A.A. is a Scholar of The Leukemia & Lymphoma Society.
Publisher Copyright:
© 2021 by American Society of Clinical Oncology.
PY - 2021/8/10
Y1 - 2021/8/10
N2 - PURPOSE Patients with Diffuse Large B-cell Lymphoma (DLBCL) in need of immediate therapy are largely underrepresented 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 (RS = 20.37; 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.
AB - PURPOSE Patients with Diffuse Large B-cell Lymphoma (DLBCL) in need of immediate therapy are largely underrepresented 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 (RS = 20.37; 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.
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U2 - 10.1200/JCO.20.02573
DO - 10.1200/JCO.20.02573
M3 - Article
C2 - 33909455
AN - SCOPUS:85114074021
SN - 0732-183X
VL - 39
SP - 2605
EP - 2616
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 23
ER -