TY - JOUR
T1 - Risk assessment with low-pass whole-genome sequencing of cell-free DNA before CD19 CAR T-cell therapy for large B-cell lymphoma
AU - Cherng, Hua Jay J.
AU - Sun, Ryan
AU - Sugg, Bryant
AU - Irwin, Russell
AU - Yang, Haopeng
AU - Le, Cao Cuong
AU - Deng, Qing
AU - Fayad, Luis
AU - Fowler, Nathan H.
AU - Parmar, Simrit
AU - Steiner, Raphael
AU - Hagemeister, Fredrick
AU - Nair, Ranjit
AU - Lee, Hun Ju
AU - Rodriguez, Maria
AU - Samaniego, Felipe
AU - Iyer, Swaminathan P.
AU - Flowers, Christopher R.
AU - Wang, Linghua
AU - Nastoupil, Loretta J.
AU - Neelapu, Sattva S.
AU - Ahmed, Sairah
AU - Strati, Paolo
AU - Green, Michael R.
AU - Westin, Jason
N1 - Publisher Copyright:
© 2022 American Society of Hematology
PY - 2022/8/4
Y1 - 2022/8/4
N2 - Patients with relapsed or refractory large B-cell lymphomas (rrLBCL) can achieve long-term remission after CD19 chimeric antigen receptor T-cell therapy (CART19). However, more than half of recipients will experience treatment failure. Thus, approaches are needed to identify high-risk patients who may benefit from alternative or consolidative therapy. We evaluated low-pass whole-genome sequencing (lpWGS) of cell-free DNA (cfDNA) before CART19 as a new approach for risk stratification. We performed lpWGS on pretreatment plasma samples from 122 patients at time of leukapheresis who received standard-of-care CART19 for rrLBCL to define DNA copy number alterations (CNAs). In multivariable selection, high focal CNA score (FCS) denoting genomic instability was the most significant pretreatment variable associated with inferior 3-month complete response rates (28% vs 56%, P = .0029), progression-free survival (PFS; P = .0007; hazard ratio, 2.11), and overall survival (OS; P = .0026; hazard ratio, 2.10). We identified 34 unique focal CNAs in 108 (89%) patients; of these, deletion 10q23.3 leading to loss of FAS death receptor was the most highly associated with poor outcomes, leading to inferior PFS (P < .0001; hazard ratio, 3.49) and OS (P = .0027; hazard ratio, 2.68). By combining FCS with traditional markers of increased tumor bulk (elevated lactate dehydrogenase and >1 extranodal site), we built a simple risk model that could reliably risk stratify patients. Thus, lpWGS of cfDNA is a minimally invasive assay that could rapidly identify high-risk patients and may guide patient selection for and targeted therapies to evaluate in future clinical trials.
AB - Patients with relapsed or refractory large B-cell lymphomas (rrLBCL) can achieve long-term remission after CD19 chimeric antigen receptor T-cell therapy (CART19). However, more than half of recipients will experience treatment failure. Thus, approaches are needed to identify high-risk patients who may benefit from alternative or consolidative therapy. We evaluated low-pass whole-genome sequencing (lpWGS) of cell-free DNA (cfDNA) before CART19 as a new approach for risk stratification. We performed lpWGS on pretreatment plasma samples from 122 patients at time of leukapheresis who received standard-of-care CART19 for rrLBCL to define DNA copy number alterations (CNAs). In multivariable selection, high focal CNA score (FCS) denoting genomic instability was the most significant pretreatment variable associated with inferior 3-month complete response rates (28% vs 56%, P = .0029), progression-free survival (PFS; P = .0007; hazard ratio, 2.11), and overall survival (OS; P = .0026; hazard ratio, 2.10). We identified 34 unique focal CNAs in 108 (89%) patients; of these, deletion 10q23.3 leading to loss of FAS death receptor was the most highly associated with poor outcomes, leading to inferior PFS (P < .0001; hazard ratio, 3.49) and OS (P = .0027; hazard ratio, 2.68). By combining FCS with traditional markers of increased tumor bulk (elevated lactate dehydrogenase and >1 extranodal site), we built a simple risk model that could reliably risk stratify patients. Thus, lpWGS of cfDNA is a minimally invasive assay that could rapidly identify high-risk patients and may guide patient selection for and targeted therapies to evaluate in future clinical trials.
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U2 - 10.1182/blood.2022015601
DO - 10.1182/blood.2022015601
M3 - Article
C2 - 35512184
AN - SCOPUS:85135412129
SN - 0006-4971
VL - 140
SP - 504
EP - 515
JO - Blood
JF - Blood
IS - 5
ER -