TY - JOUR
T1 - Circulating tumor DNA measurements as early outcome predictors in diffuse large B-cell lymphoma
AU - Kurtz, David M.
AU - Scherer, Florian
AU - Jin, Michael C.
AU - Soo, Joanne
AU - Craig, Alexander F.M.
AU - Esfahani, Mohammad Shahrokh
AU - Chabon, Jacob J.
AU - Stehr, Henning
AU - Liu, Chih Long
AU - Tibshirani, Robert
AU - Maeda, Lauren S.
AU - Gupta, Neel K.
AU - Khodadoust, Michael S.
AU - Advani, Ranjana H.
AU - Levy, Ronald
AU - Newman, Aaron M.
AU - Dührsen, Ulrich
AU - Hüttmann, Andreas
AU - Meignan, Michel
AU - Casasnovas, René Olivier
AU - Westin, Jason R.
AU - Roschewski, Mark
AU - Wilson, Wyndham H.
AU - Gaidano, Gianluca
AU - Rossi, Davide
AU - Diehn, Maximilian
AU - Alizadeh, Ash A.
N1 - Publisher Copyright:
© 2018 by American Society of Clinical Oncology.
PY - 2018/10/1
Y1 - 2018/10/1
N2 - Purpose 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. Patients and Methods 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. Results 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. Conclusion 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.
AB - Purpose 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. Patients and Methods 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. Results 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. Conclusion 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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U2 - 10.1200/JCO.2018.78.5246
DO - 10.1200/JCO.2018.78.5246
M3 - Article
C2 - 30125215
AN - SCOPUS:85053318139
SN - 0732-183X
VL - 36
SP - 2845
EP - 2853
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 28
ER -