Non-invasive Tumor Immunoglobulin Gene Next Generation Sequencing (IgNGS) in Diffuse Large B Cell Lymphoma (DLBCL): Prognostic Implications and Assessment of Tumor Response

In B-cell malignancies, every lymphocyte clone expresses a unique antigen receptor structure, therefore immunoglobulin gene rearrangements (the sequence of nucleotides at the V(D)J recombination site) serves as a specific marker for each clone. Methods of analysis have changed over time to improve the sensitivity and to allow its application in clinical settings.

Diffuse Large B-cell lymphoma (DLBCL) displays molecular heterogeneity. In this context, IgNGS allows for detection of tumor clonotype from plasma (ctDNA) (Liquid Biopsy-LB) of DLBCL patients with high sensitivity and specificity. ctDNA can be tracked with this methodology in the vast majority (>90%) of patients, in contrast to NGS-methods based on genotyping for specific DLBCL mutations, which have overall low frequency. Furthermore, most newly discovered neoantigens in lymphoma derive from immunoglobulin variable sequences, supporting the relevance of the analysis of this particular region in contrast to the use of specific B-cell mutations. Importantly, preliminary studies on clonotype detection by IgNGS at the end of treatment correlate with outcome (poorer progression-free survival) and the persistence or reemergence of the tumor clonotype by ctDNA studies may anticipate the clinical relapse. We propose to evaluate IgNGS at different time points in newly diagnosed DLBCL patients treated with RCHOP to address its correlation with conventional techniques (i.e., PET/CT imaging) and outcome.