Liquid Biopsy to Enable Diagnostics and Monitoring for Immune-mediated Lymphoproliferative Disorders

Study Overview
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Brief Summary
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Immune-mediated lymphoproliferative disorders (ILD), as per World Health Organization (WHO HAEM 5) classification, are rare conditions associated with a poor outcome. Current management of ILD is focusing on prevention (e.g.) early detection of ILD with preemptive Epstein Barr virus (EBV) Deoxyribonucleic acid (DNA) levels monitoring, however, this approach is useless for the early detection of EBV-negative ILD. Therapeutic management consists of a reduction in immunosuppressive therapy (RIS), allowing mostly partial and transient responses. Rituximab, an anti-CD20 (cluster differentiation 20) antibody, provides roughly 20-25% of complete and durable responses, thus the majority of ILD patients will require immunochemotherapy, burden with significant toxicity in this challenging population. Implementation of liquid biopsy, also called circulating tumor DNA (ctDNA) in plasma or serum is an area of investigation that is becoming increasingly relevant for clinical practice, allowing for non-invasive monitoring of disease status. Early detection and monitoring of ILD using ctDNA may allow for preemptive therapy, improved risk-stratification and ultimately, lead to outcome improvement. This multicenter Swiss project will allow a better understanding of ILD mutational landscape and pathogenesis, which could lead to the development of new screening and monitoring approaches for patients suffering from ILD.

Detailed Description
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In this observational prospective study, the investigators will collect clinical data from subjects' charts through a dedicated multicenter electronic case report form (eCRF). Whenever available, PET-CT will be transferred through a Web-based Imaging and Diagnosis Exchange Network (WIDEN) to perform a blinded independent review of staging and response. Biological samples included 20 ml of blood collected at each of the following planned clinical points in time: i) at ILD diagnosis, ii) after first cycle of therapy, iii) at interim response assessment, iv) at the end-of-treatment, v) at 3 months follow-up, vi) at 12 months follow-up, vii) at disease progression, if applicable. Additional samples could be collected if clinically relevant. Additionally, the investigators will request formalin-fixed and paraffin-embedded tissue (FFPET) or fresh-frozen (FF) tissue slices/blocks at ILD diagnosis from Pathology Departments of participating Centers for retrospective ILD subjects.

Official Title
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Liquid Biopsy-based Genomic Assay to Enable Non-invasive Precision Diagnostics and Monitoring for Immune-mediated Lymphoproliferative Disorders (ILD)

Conditions
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Lymphoproliferative Disorders, Lymphoproliferative Disorder Following Transplantation

Intervention / Treatment
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* Diagnostic Test: Liquid biopsy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Any patient with a diagnosis of ILD defined by the World Health Organization (WHO HAEM 5)(e.g. post-transplant setting, X-link, concomitant auto-immune disorders) Exclusion Criteria: Lymphoproliferative disorders non immune-mediated Lymphoproliferative disorders occurring in the context of a concomitant human immunodeficiency virus (HIV) infection
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 |
| --- | --- |
| ILD group<br>All patients newly diagnosed or relapsing from an ILD could be enrolled in this observational study | Diagnostic Test: Liquid biopsy<br>* ctDNA measured in the plasma and analyse by next generation sequencing (NGS) for minimal residual disease (MRD)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Predictive value of ctDNA to monitor response in ILD (MRD) using NGS | Molecular response (minimal residual disease, MRD) during therapy in ILD diagnosed patients will be monitored using regular liquid biopsy (ctDNA) and assessing the presence or not of genomic aberrations present at baseline if any. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Characterisation of ILD tumour microenvironment and genetic / epigenetic landscape | Tumour microenvironment and genetic / epigenetic landscape will be explored using various techniques such as NGS, multiplex immunohistochemistry, digital droplet Polymerase Chain Reaction (ddPCR) and methyloma assays. | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immune-related Lymphoproliferative Disorders