Non-invasive Tumor Immunoglobulin Gene Next Generation Sequencing (IgNGS) in Diffuse Large B Cell Lymphoma (DLBCL)

Study Overview
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Brief Summary
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This study will evaluate IgNGS at different time points in newly diagnosed DLBCL patients homogeneously treated (RCHOP) to address its correlation with conventional techniques (i.e., positron emission tomography/computed tomography imaging (PET/CT) and outcome.

Detailed Description
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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.

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

Conditions
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Lymphoma, Large B-Cell, Diffuse

Intervention / Treatment
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* Diagnostic Test: IgNGS from circulating tumor DNA


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: patients diagnosed with de novo DLBCL, all ages, treated with R-CHOP. Patients with DLBCL not otherwise specified (NOS) according to World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues (WHO) 2016 would be included. In addition, those with high-grade B cell lymphoma (including both NOS and those with Myc and bcl2 and/or bcl6 alterations) will be also included. Exclusion Criteria: Primary mediastinal DLBCL. Transformed DLBCL Patients HIV+ Central Nervous System (CNS) DLBCL All other DLBCL not included under NOS classification, according to WHO 2016 (except those specifically indicated in inclusion criteria).
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| DLBCL patients<br>newly diagnosed DLBCL (de novo, all ages) patients treated with RCHOP (first-line treatment regimen) | Diagnostic Test: IgNGS from circulating tumor DNA<br>* 3 longitudinal plasma samples will be evaluated at three different time points per patient: 0 (pre-treatment), end of treatment, and at 6 months after treatment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Association between ctDNA level and clinical response at the end of treatment | Correlation between ctDNA level (in nanograms) and clinical response per PET/CT at the end of treatment (responses will be defined according to International Working Group consensus response evaluation criteria in lymphoma - IWGRECIL - 2017) will be assessed by means of Spearman correlation. | 12-18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlation between detection of tumor clonotype ctDNA and relapse | The relationship between detection of tumor clonotype ctDNA (detection: yes/no, using a frequency threshold of 5%) and relapse (disease status will be assessed by PET/CT) will be measured by means of a logistic regression model. These analyses are explorative and will be done if possible. | 18 months | 
| Impact of IgNGS at the end of treatment and 6 months after treatment on outcome (as measured by progression-free survival PFS) | The relationship between impact of IgNGS (ctDNA level in nanograms, detection of tumor clonotype: yes/no, relative frequency of index sequences in %) with PFS will be assessed by means of a Proportional-hazards (PH) Cox regression model. These analyses are explorative and will be done if possible. | 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diffuse large B cell lymphoma, immunoglobulin gene next generation sequencing, liquid biopsy