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J Clin Oncol. 2018 Oct 1;36(28):2845-2853. doi: 10.1200/JCO.2018.78.5246. Epub 2018 Aug 20.

Circulating Tumor DNA Measurements As Early Outcome Predictors in Diffuse Large B-Cell Lymphoma.

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David M. Kurtz, Florian Scherer, Michael C. Jin, Joanne Soo, Alexander F.M. Craig, Mohammad Shahrokh Esfahani, Jacob J. Chabon, Henning Stehr, Chih Long Liu, Robert Tibshirani, Lauren S. Maeda, Neel K. Gupta, Michael S. Khodadoust, Ranjana H. Advani, Ronald Levy, Aaron M. Newman, Maximilian Diehn, and Ash A. Alizadeh, Stanford University, Stanford, CA; Florian Scherer, University Medical Center Freiburg, Freiburg; Ulrich Dührsen and Andreas Hüttmann, University Hospital Essen, Essen, Germany; Michel Meignan, Hôpitaux Universitaires Henri Mondor, Creteil; René-Olivier Casasnovas, Hôpital Le Bocage, Centre Hospitalier Universitaire, Dijon, France; Jason R. Westin, University of Texas MD Anderson Cancer Center, Houston, TX; Mark Roschewski and Wyndham H. Wilson, National Cancer Institute, National Institutes of Health, Bethesda, MD; Gianluca Gaidano and Davide Rossi, University of Eastern Piedmont, Novara, Italy; and Davide Rossi, Oncology Institute of Southern Switzerland and Institute of Oncology Research, Bellinzona, Switzerland.



Outcomes for patients with diffuse large B-cell lymphoma remain heterogeneous, with existing methods failing to consistently predict treatment failure. We examined the additional prognostic value of circulating tumor DNA (ctDNA) before and during therapy for predicting patient outcomes.


We studied the dynamics of ctDNA from 217 patients treated at six centers, using a training and validation framework. We densely characterized early ctDNA dynamics during therapy using cancer personalized profiling by deep sequencing to define response-associated thresholds within a discovery set. These thresholds were assessed in two independent validation sets. Finally, we assessed the prognostic value of ctDNA in the context of established risk factors, including the International Prognostic Index and interim positron emission tomography/computed tomography scans.


Before therapy, ctDNA was detectable in 98% of patients; pretreatment levels were prognostic in both front-line and salvage settings. In the discovery set, ctDNA levels changed rapidly, with a 2-log decrease after one cycle (early molecular response [EMR]) and a 2.5-log decrease after two cycles (major molecular response [MMR]) stratifying outcomes. In the first validation set, patients receiving front-line therapy achieving EMR or MMR had superior outcomes at 24 months (EMR: EFS, 83% v 50%; P = .0015; MMR: EFS, 82% v 46%; P < .001). EMR also predicted superior 24-month outcomes in patients receiving salvage therapy in the first validation set (EFS, 100% v 13%; P = .011). The prognostic value of EMR and MMR was further confirmed in the second validation set. In multivariable analyses including International Prognostic Index and interim positron emission tomography/computed tomography scans across both cohorts, molecular response was independently prognostic of outcomes, including event-free and overall survival.


Pretreatment ctDNA levels and molecular responses are independently prognostic of outcomes in aggressive lymphomas. These risk factors could potentially guide future personalized risk-directed approaches.

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[Available on 2019-10-01]

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