Risk Assessment With Low-Pass Whole-Genome Sequencing of Cell-Free DNA Before CD19 Car T-cell Therapy for Large B-cell Lymphoma

Authors

Hua-Jay J Cherng
Ryan Sun
Bryant Sugg
Russell Irwin
Haopeng Yang
Cao Cuong Le
Qing Deng
Luis Fayad
Nathan H Fowler
Simrit Parmar
Raphael Steiner
Fredrick Hagemeister
Ranjit Nair
Hun Ju Lee
Maria Rodriguez
Felipe Samaniego
Swaminathan P Iyer
Christopher R Flowers
Linghua Wang
Loretta J Nastoupil
Sattva S Neelapu
Sairah Ahmed
Paolo Strati
Michael R Green
Jason Westin

Publication Date

8-4-2022

Journal

Blood

Abstract

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.

Keywords

Antigens, CD19, Cell-Free Nucleic Acids, Humans, Immunotherapy, Adoptive, Lymphoma, Large B-Cell, Diffuse, Risk Assessment

DOI

10.1182/blood.2022015601

PMID

35512184

PMCID

PMC9353148

PubMedCentral® Posted Date

8-4-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes