Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Kurtz DM

PROVIDER: S-EPMC6161832 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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

Kurtz David M DM Scherer Florian F Jin Michael C MC Soo Joanne J Craig Alexander F M AFM Esfahani Mohammad Shahrokh MS Chabon Jacob J JJ Stehr Henning H Liu Chih Long CL Tibshirani Robert R Maeda Lauren S LS Gupta Neel K NK Khodadoust Michael S MS Advani Ranjana H RH Levy Ronald R Newman Aaron M AM Dührsen Ulrich U Hüttmann Andreas A Meignan Michel M Casasnovas René-Olivier RO Westin Jason R JR Roschewski Mark M Wilson Wyndham H WH Gaidano Gianluca G Rossi Davide D Diehn Maximilian M Alizadeh Ash A AA

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20180820 28

<h4>Purpose</h4>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.<h4>Patients and methods</h4>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 duri ...[more]

PMID: 30125215

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Project description:PURPOSE:This pilot study aimed to determine interobserver reliability and ease of use of three workflows for measuring metabolic tumor volume (MTV) and total lesion glycolysis (TLG) in diffuse large B cell lymphoma (DLBCL). PROCEDURES:Twelve baseline [18F]FDG PET/CT scans from DLBCL patients with wide variation in number and size of involved organs and lymph nodes were selected from the international PETRA consortium database. Three observers analyzed scans using three workflows. Workflow A: user-defined selection of individual lesions followed by four automated segmentations (41%SUVmax, A50%SUVpeak, SUV?2.5, SUV?4.0). For each lesion, observers indicated their "preferred segmentation." Individually selected lesions were summed to yield total MTV and TLG. Workflow B: fully automated preselection of [18F]FDG-avid structures (SUV?4.0 and volume?3ml), followed by removing non-tumor regions with single mouse clicks. Workflow C: preselected volumes based on Workflow B modified by manually adding lesions or removing physiological uptake, subsequently checked by experienced nuclear medicine physicians. Workflow C was performed 3 months later to avoid recall bias from the initial Workflow B analysis. Interobserver reliability was expressed as intraclass correlation coefficients (ICC). RESULTS:Highest interobserver reliability in Workflow A was found for SUV?2.5 and SUV?4.0 methods (ICCs for MTV 0.96 and 0.94, respectively). SUV?4.0 and A50%Peak were most and SUV?2.5 was the least preferred segmentation method. Workflow B had an excellent interobserver reliability (ICC?=?1.00) for MTV and TLG. Workflow C reduced the ICC for MTV and TLG to 0.92 and 0.97, respectively. Mean workflow analysis time per scan was 29, 7, and 22 min for A, B, and C, respectively. CONCLUSIONS:Improved interobserver reliability and ease of use occurred using fully automated preselection (using SUV?4.0 and volume?3ml, Workflow B) compared with individual lesion selection by observers (Workflow A). Subsequent manual modification was necessary for some patients but reduced interobserver reliability which may need to be balanced against potential improvement on prognostic accuracy.

Dataset Information

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

Publications

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

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