After receiving CD19 chimeric antigen receptor T-cell therapy (CART19), patients with relapsed or refractory large B-cell lymphomas (rrLBCL) can have long-term remission. But more than 50% of patients do not respond to therapy. In order to identify high-risk patients who could benefit from alternative or consolidative therapy, methods were required.
Prior to CART19, researchers assessed low-pass whole-genome sequencing (lpWGS) of cell-free DNA (cfDNA) as a fresh method for risk categorization. In order to identify DNA copy number alterations (CNAs), they conducted lpWGS on pretreatment plasma samples from 122 patients at the time of leukapheresis who received standard-of-care CART19 for rrLBCL. High focal CNA scores (FCS), which indicated genomic instability, were the most important pretreatment factor in the multivariable selection and were negatively correlated with 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).
In 108 (89%) patients, they found 34 distinct focal CNAs; the deletion of 10q23.3, which results in the loss of the FAS death receptor, was most strongly related to poor outcomes, resulting in worse PFS (P<.0001; hazard ratio, 3.49) and OS (P=.0027; hazard ratio, 2.68) in both patients. They developed a straightforward risk model that could accurately risk stratifying patients by integrating FCS with conventional indicators of increasing tumor mass (elevated lactate dehydrogenase and >1 extranodal site).
As a result, lpWGS of cfDNA was a minimally invasive assay that might quickly identify high-risk patients and help determine which patients to choose from and which targeted medicines to test in upcoming clinical trials.