## Protocol Section
### Identification Module
**NCT ID:** NCT06424379

**Acronym:** BCL6-RINHL

**Brief Title:** BCL6-rearrangements Implications in Non-Hodgkin Lymphomas.

**Official Title:** Study of Clinical, Histological, Immunohistochemical and Molecular Impact of BCL6 Gene Rearrangement in Most Prevalent Non-Hodgkin Lymphomas

#### Organization Study ID Info
**ID:** 69HCL24_0515
#### Organization
**Class:** OTHER
**Full Name:** Hospices Civils de Lyon
### Status Module
#### Completion Date
**Date:** 2025-06-30

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2024-05-23

**Type:** ACTUAL

**Last Update Submit Date:** 2024-05-22

**Overall Status:** ACTIVE_NOT_RECRUITING

#### Primary Completion Date
**Date:** 2024-06-01

**Type:** ESTIMATED

#### Start Date
**Date:** 2024-01-01

**Type:** ACTUAL

**Status Verified Date:** 2024-05

#### Study First Post Date
**Date:** 2024-05-22
**Type:** ACTUAL
**Study First Submit Date:** 2024-05-16
**Study First Submit QC Date:** 2024-05-16
### Sponsor Collaborators Module

#### Lead Sponsor

**Class:** OTHER

**Name:** Hospices Civils de Lyon

#### Responsible Party

**Type:** SPONSOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** False

**Oversight Has DMC:** False

### Description Module

**Brief Summary:** Non-Hodgkin lymphomas (NHLs) constitute a heterogeneous group of malignant neoplasms, with diverse clinical behaviors and distinct pathologic and molecular characteristics. Among these lymphomas, follicular lymphomas (FLs), marginal zone lymphomas (MZLs) and diffuse large B-cell lymphomas (DLBCLs) emerge as the most prevalent entities. While FL and MZL are representative of indolent B-cell lymphomas, characterized by a slow progression of the disease and favorable clinical outcomes, DLBCL stands out as an aggressive lymphoma, often occuring from the transformation of a pre-existing indolent lymphoma.

Chromosome translocations are a hallmark of some NHL subtypes, offering insights into their molecular pathogenesis. For instance, the conventional FL is genetically characterized by the t(14;18) chromosomal translocation, found in 85-90% of cases, resulting in sustained elevation of the antiapoptotic protein B-cell lymphoma 2 (BCL2). However, certain FL cases lack BCL2 translocations and exhibit distinct clinical, morphological and phenotypical features with genetic heterogeneity.

A subset of BCL2-negative FLs displays rearrangements within chromosomal region 3q27, inducing abnormal modulation of B-cell lymphoma 6 (BCL6) expression. The BCL6 gene plays a critical role in germinal center development and B-cell differentiation. Previous investigations indicate that BCL6 rearrangements (BCL6-R) manifest distinct pathological and genetic features, diverging from classical FL presentations.

FLs carrying BCL6-R commonly share a specific CD10- Bcl-2- Bcl-6+ phenotype, often accompanied by a monocytoid component and increased frequency of diffuse architectural patterns. Patients with BCL6-R tend to exhibit advanced clinical stages and complex genetic profiles.

MZLs present differential diagnostic challenges due to shared monocytoid components, phenotypes traits, and common genetic features. The similarities observed between BCL6-R FL and MZL suggest a convergence in both morphological and genetic aspects, leading to intricate differentiation. Traditionally, these indolent NHLs with BCL6-R were categorized as FL and incorporated into the FL category in the WHO classification. However, few studies highlight the occurrence of BCL6-R in MZLs. This observation gives rise to the hypothesis that indolent NHLs exhibiting BCL6-R might correspond to a continuum comprising both FL and MZL.

Additionally, BCL6-R has been frequently documented in DLBCL cases with residual MZL component. These DLBCL cases might display a mutational profile reminiscent of MZL. This suggests a plausible origin of BCL6-R DLBCL from indolent BCL6-R MZLs or BCL6-R FLs cases.

### Conditions Module

**Conditions:**

- Non Hodgkin Lymphoma

- Follicular Lymphoma

- Marginal Zone Lymphoma

- Diffuse Large B Cell Lymphoma

**Keywords:**

- Non Hodgkin Lymphoma

- BCL6 gene rearrangement

- Next generation sequencing

### Design Module

#### Bio Spec

**Description:** The samples analyzed will have been collected as part of routine medical care for each patient before inclusion in the study.

These are formalin-fixed, paraffin-embedded (FFPE) tissue samples. They will be packaged and stored in the Biological Resources Center of the Hospices Civils de Lyon.

**Retention:** SAMPLES_WITH_DNA

#### Design Info

**Observational Model:** COHORT

**Time Perspective:** RETROSPECTIVE

#### Enrollment Info

**Count:** 135

**Type:** ESTIMATED

**Study Type:** OBSERVATIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** Diagnoses of follicular lymphomas based on the last World Health Organization (WHO) classification of haematolymphoid tumours at the time of occurrence of the disease. Fluorescence in situ hybridization (FISH) utilizes Vysis' Dual-Color Break-Apart Rearrangement Probes to detect BCL6 gene alterations. FISH patterns have been interpreted following established protocols.

**Intervention Names:**

- Other: Histopathological analysis

- Genetic: Molecular analysis

**Label:** Follicular lymphomas with BCL6 gene rearrangement

#### Arm Group 2

**Description:** Diagnoses of marginal zone lymphomas based on the last WHO classification of haematolymphoid tumours at the time of occurrence of the disease. FISH utilizes Vysis' Dual-Color Break-Apart Rearrangement Probes to detect BCL6 gene alterations. FISH patterns have been interpreted following established protocols.

**Intervention Names:**

- Other: Histopathological analysis

- Genetic: Molecular analysis

**Label:** Marginal zone lymphomas with BCL6 gene rearrangement

#### Arm Group 3

**Description:** Diagnoses of diffuse large B-cells lymphomas based on the last WHO classification of haematolymphoid tumours at the time of occurrence of the disease. FISH utilizes Vysis' Dual-Color Break-Apart Rearrangement Probes to detect BCL6 gene alterations. FISH patterns have been interpreted following established protocols.

**Intervention Names:**

- Other: Histopathological analysis

- Genetic: Molecular analysis

**Label:** Diffuse large B-cells lymphomas with BCL6 gene rearrangement

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Diffuse large B-cells lymphomas with BCL6 gene rearrangement

- Follicular lymphomas with BCL6 gene rearrangement

- Marginal zone lymphomas with BCL6 gene rearrangement

**Description:** Morphological analysis will include the description of architectural patterns and cytological features on formalin-fixed and paraffin-embedded (FFPE) tissue samples retrieved from the routine diagnostic archives of the Pathology Department of the University Hospital Lyon Sud.

A panel of immunohistochemical staining will be analyzed including CD20, CD3, CD10, Bcl-6, Bcl-2, CD5, CD23, CD38, MUM1, Ig kappa, Ig lambda, MEF2B, LMO2, MNDA, IRTA1, P53, CMYC and Ki67 . /MIB1. Diffuse large B-cells lymphomas will be classified into two distinct subgroups: centro-germinative (GC) and non-centro-germinative (nGC), using the Hans algorithm.

**Name:** Histopathological analysis

**Type:** OTHER

#### Intervention 2

**Arm Group Labels:**

- Diffuse large B-cells lymphomas with BCL6 gene rearrangement

- Follicular lymphomas with BCL6 gene rearrangement

- Marginal zone lymphomas with BCL6 gene rearrangement

**Description:** Next-generation sequencing (NGS) analysis will be performed on FFPE tissue samples retrieved from the routine diagnostic archives of the Pathology Department of the University Hospital Lyon Sud. A panel of 73 genes dedicated to lymphoma diagnosis determined by a consensus of French Lysa experts will be used. The identification of genetic variants will be followed by the attribution of pathogenicity class in accordance with the guidelines for validation of NGS-based oncology panels.

RNA extraction will classify DLBCLs into two distinct subgroups: germinal-centre B-cell-like (GCB-DLBCL) and activated B-cell-like (ABC-DLBCL).

**Name:** Molecular analysis

**Type:** GENETIC

### Outcomes Module

#### Primary Outcomes

**Description:** An examination of morphological attributes, including tissue architecture and cellular patterns will be performed on LF and MZL with BCL6-R. An extended immunohistochemical staining panel employing incorporated novel centro-germinative markers (LMO2 and MEF2B) and recently identified MZL-specific markers (IRTA1 and MNDA) is planned.

**Measure:** Comparison of LF and MZL with BCL6-R.

**Time Frame:** The primary outcome will be analyzed retrospectively, or through study completion, an average of 1 year

**Description:** Fluorescence in situ hybridization (FISH) will be employed for cytogenetic evaluation to detect BCL2 and BCL6 gene rearrangements. In parallel, targeted next-generation sequencing (NGS) analysis will enable genetic variant detection.

**Measure:** Comparison of LF and MZL with BCL6-R.

**Time Frame:** The primary outcome will be analyzed retrospectively, or through study completion, an average of 1 year

### Eligibility Module

**Eligibility Criteria:** Inclusion Criteria:

* Diagnostic of non-Hodgkin's lymphoma at anatomy and cytology department of Lyon Sud hospital
* Rearrangement of the BCL6 gene detected by FISH analysis
* Diagnostic of the disease between january 2016 and december 2023

Exclusion Criteria:

* Patients diagnosed with primary cutaneous centrofollicular B lymphoma, composite lymphoma, anaplastic B lymphoma or primary B lymphoma of the mediastinum.
* Presence of a rearrangement of the BLC2 gene or the CMYC gene in FISH
* Presence of a non-significant BCL6 gene rearrangement (\<5% of rearranged cells)

**Maximum Age:** 100 Years

**Minimum Age:** 25 Years

**Sampling Method:** NON_PROBABILITY_SAMPLE

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

**Study Population:** All patients diagnosed with non-Hodgkin lymphoma from the routine diagnostic archives of the pathology department of CHU Lyon Sud between January 2016 and August 2023 and with BCL6-R detected by FISH analysis will be included in the study. A cohort of 135 cases will be assembled and subjected to the analysis.

This dataset will be reviewed by two haematopathologists to ensure the inclusion of the most relevant cases. Selection will favor cases with substantial histological material and available clinical, immunophenotypic and cytogenetic data. Comparative assessments will be conducted between distinct subtypes of NHL exhibiting BCL6-R, including FLs, MZLs, and DLBCLs.

### Contacts Locations Module

#### Locations

**Location 1:**

**City:** Pierre-Bénite

**Country:** France

**Facility:** Hopital Lyon Sud - HCL

**Zip:** 69495

### IPD Sharing Statement Module

**IPD Sharing:** NO

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000009370

- Term: Neoplasms by Histologic Type

- ID: D000009369

- Term: Neoplasms

- ID: D000008232

- Term: Lymphoproliferative Disorders

- ID: D000008206

- Term: Lymphatic Diseases

- ID: D000007160

- Term: Immunoproliferative Disorders

- ID: D000007154

- Term: Immune System Diseases

- ID: D000016393

- Term: Lymphoma, B-Cell

### Condition Browse Module - Browse Branches

- Abbrev: BC04

- Name: Neoplasms

- Abbrev: BC15

- Name: Blood and Lymph Conditions

- Abbrev: BC20

- Name: Immune System Diseases

- Abbrev: All

- Name: All Conditions

- Abbrev: Rare

- Name: Rare Diseases

### Condition Browse Module - Browse Leaves

- ID: M11220

- Name: Lymphoma

- Relevance: HIGH

- As Found: Lymphoma

- ID: M11221

- Name: Lymphoma, Follicular

- Relevance: LOW

- As Found: Unknown

- ID: M20554

- Name: Lymphoma, B-Cell, Marginal Zone

- Relevance: HIGH

- As Found: Marginal zone lymphoma

- ID: M18831

- Name: Lymphoma, Large B-Cell, Diffuse

- Relevance: HIGH

- As Found: Diffuse Large B-Cell Lymphoma

- ID: M18828

- Name: Lymphoma, B-Cell

- Relevance: LOW

- As Found: Unknown

- ID: M11222

- Name: Lymphoma, Non-Hodgkin

- Relevance: HIGH

- As Found: Non-Hodgkin Lymphoma

- ID: M12315

- Name: Neoplasms by Histologic Type

- Relevance: LOW

- As Found: Unknown

- ID: M11225

- Name: Lymphoproliferative Disorders

- Relevance: LOW

- As Found: Unknown

- ID: M11203

- Name: Lymphatic Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M10206

- Name: Immunoproliferative Disorders

- Relevance: LOW

- As Found: Unknown

- ID: M10200

- Name: Immune System Diseases

- Relevance: LOW

- As Found: Unknown

- ID: T3543

- Name: Lymphosarcoma

- Relevance: HIGH

- As Found: Lymphoma

- ID: T2361

- Name: Follicular Lymphoma

- Relevance: HIGH

- As Found: Follicular lymphoma

- ID: T640

- Name: B-cell Lymphoma

- Relevance: HIGH

- As Found: B-cell Lymphoma

- ID: T3612

- Name: Marginal Zone Lymphoma

- Relevance: HIGH

- As Found: Marginal zone lymphoma

- ID: T1866

- Name: Diffuse Large B-Cell Lymphoma

- Relevance: HIGH

- As Found: Diffuse Large B-Cell Lymphoma

### Condition Browse Module - Meshes

- ID: D000008223

- Term: Lymphoma

- ID: D000008228

- Term: Lymphoma, Non-Hodgkin

- ID: D000018442

- Term: Lymphoma, B-Cell, Marginal Zone

- ID: D000016403

- Term: Lymphoma, Large B-Cell, Diffuse

### Intervention Browse Module - Browse Branches

- Abbrev: Infe

- Name: Anti-Infective Agents

- Abbrev: All

- Name: All Drugs and Chemicals

- Abbrev: HB

- Name: Herbal and Botanical

### Intervention Browse Module - Browse Leaves

- ID: M8681

- Name: Formaldehyde

- Relevance: LOW

- As Found: Unknown

- ID: T114

- Name: Chrysanthemum

- Relevance: LOW

- As Found: Unknown

### Misc Info Module

- Version Holder: 2024-05-31
