Liquid Biopsy in Diffuse Large B-Cell Lymphoma

STUDY TITLE: Feasibility and Clinical Utility of Cell-free DNA (cfDNA) in Identifying Actionable Alterations and Minimal Residual Disease for Lymphoma Patients Across Community Centers in Texas

CLINICALTRIALS.GOV IDENTIFIER: NCT05676450

PARTICIPATING CENTERS: MD Anderson Cancer Center (Houston, TX) and Cancer Therapy and Research Center at UT Health Science Center (San Antonio, TX)

SPONSOR: MD Anderson Cancer Center

ACCRUAL GOAL: 517 patients (estimate)

STUDY DESIGN: This is a single-group assignment, open-label interventional study of a diagnostic test with three blood draws (by vein) to collect cell-free DNA (cfDNA) samples. Participants are adults aged 18 and older with histologically documented diffuse large B-cell lymphoma (DLBCL) requiring therapy. Excluded are pregnant individuals and cognitively impaired adults. The cfDNA samples are collected from participants before and after treatment. The study’s primary objective is to determine the feasibility and clinical utility of cfDNA in identifying actionable alterations and minimal residual disease for lymphoma patients across community centers in Texas. Secondary objectives are to provide prognostic information before treatment, assess molecular response at interim time points, assess residual disease at the end of therapy, and identify tumor-specific mutations, as well as to assess levels of cfDNA and its association with event-free survival (EFS) and overall survival (OS) in patients receiving therapy. The primary outcome measure is OS.

RATIONALE: The cfDNA from a peripheral blood draw can contain circulating tumor DNA (ctDNA), originating from cancer cells. In patients with lymphoma, the concentration of cfDNA ranges from 5-100 ng/mL, with ctDNA accounting for 5% of plasma-derived cfDNA in diagnostic samples.¹  This small fraction of ctDNA, in conjunction with the short half-life of plasma cfDNA, necessitates optimization of sampling techniques, collection tubes, post-collection sample processing, and storage.²  In addition to these pre-analytical considerations, methodological considerations include the ctDNA analysis assay, with polymer chain reaction-based techniques and a variety of next-generation sequencing-based techniques available,³  as well as the approach to ctDNA genomic profiling data (e.g., incorporation of paired tumor DNA from tissue biopsy with ctDNA or simultaneous sequencing of matched leukocyte-derived DNA).

Key studies on ctDNA in DLBCL were recently summarized by Esraa Jamal, MSCS, and colleagues.¹  Baseline ctDNA levels have been shown to correlate with tumor burden and predict clinical outcome.⁴  In addition, baseline ctDNA mutational profile has the potential to classify the DLBCL into molecular genetic subgroups, with just under 50% classified using the LymphGen algorithm in one study.⁵  Circulating tumor DNA may be more representative than lymphoma tissue biopsy due to tumor heterogeneity.⁶  Interim and end-of-treatment ctDNA levels may predict clinical outcomes and provide treatment guidance. For example, in a recently published study with an NGS approach, combining interim metabolic imaging (positron emission tomography combined with computed tomography) with a 2.5-log drop in ctDNA after two cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) resulted in improved patient prognosis stratification.⁷  Interim/end-of-treatment ctDNA study after CAR-T therapy is an area of ongoing research.⁸ 

COMMENT: Incorporation of ctDNA assessment in the clinical care of patients with DLBCL is on the horizon, with more ctDNA assays becoming commercially available for routine use. This clinical trial with a robust number of participants has the potential to add valuable data to the literature on the feasibility and clinical utility of ctDNA in patients with DLBCL, which is of particular importance given the pre-analytic and methodological variables inherent in this assessment.