Characterization and Clinical Impact of the Gut Microbiota in Lymphoma

Characterization and Clinical Impact of the Gut Microbiota in Diffuse Large B-cell Lymphoma Patients

The study is a prospective observational single-center cohort study which compare the gut microbiome of newly diagnosed Diffuse Large B-cell Lymphoma patients with the gut microbiome of healthy controls. Furthermore the impact of lymphoma treatment, immune phenotypes, cytokine profiles, metabolomics, inflammation, driver mutations, comorbidity, body composition and lifestyle on the microbiome is also investigated

Study Overview

• Status: Recruiting
• Conditions: Diffuse Large B Cell Lymphoma
• Intervention / Treatment: Diagnostic test: Stool samples

Detailed Description

Microbiota refers to an ecological community of commensal, symbiotic and pathogenic microorganisms that colonize the various compartments within the human body including the gastrointestinal tract. The composition has been shown to play an important role in the pathophysiology of many diseases as well as influence host homeostatic processes such as regulation of metabolic processes, defense against pathogens, immune system development, regulation of the immune response and inflammation. However, the connection between the gut microbiota and lymphoma remain poorly understood.

The purpose of this study is to evaluate the composition and diversity of the gut microbiome in a large homogeneous group of patients with newly diagnosed and treatment-naive Diffuse Large B-cell Lymphoma (DLBCL). The investigators aim to identify the relationship between the intestinal microbiota, clinical and molecular subtypes of DLBCL and outcome of the disease. The association between nutrition, physical activity, body composition, toxicity to the antineoplastic therapy, infections, use of antibiotics, comorbidity and tumor genetics versus gut microbiota composition and diversity is also explored.

The project is carried out in collaboration between clinical departments, institutes and laboratories with expertise in microbiology, hematology, pathology, nutrition, molecular biology, immunology and bioinformatics.

Hypothesis of the study are:

1. Patients with DLBCL have distinct baseline microbiota signatures that differ from healthy subjects.
2. Significant changes in the microbiota composition and diversity can be identified during and after treatment (immunochemotherapy) of DLBCL.
3. Lymphoma response and outcome is affected by the composition and diversity of the DLBCL microbiota.
4. The intestinal microbiota changes towards a microbiota more like the microbiota of healthy controls in patients who remain in lymphoma remission one year after completion of therapy.
5. Distinct DLBCL microbiota profiles are associated with treatment-related toxicity.
6. The intestinal microbiota affects the risk of infections (clinically and/or microbiologically documented).
7. The intestinal microbiota is affected using antibiotics both as prophylaxis and treatment of infections.
8. The DLBCL microbiota depends on the dietary intake, smoking, physical activity and the body composition.
9. Distinct intestinal microbiota signatures can be associated with molecular subtypes of DLBCL (or vice versa)
10. The JAK2V617F, TET2, DNMT3A and ASXL1 mutations affect the intestinal microbiota signature and are associated with comorbidity and outcome in DLBCL
11. There is a vicious circle between intestinal dysbiosis and lymphoma with the crosstalk between the gut microbiota and the cancer being expressed as alterations in the profile of cytokines, chemokines and growth factors; an immune response reflected by immunophenotypic profiles of peripheral blood mononuclear cells; and characteristic metabolite signatures in the blood.

• Study Type: Observational
• Enrollment (Estimated): 200

Contacts and Locations

• Study Contact: Name: Christiane Sophie Staxen, MSc; Phone Number: +45 22618798; Email: cstax@regionsjaelland.dk
• Study Contact Backup: Name: Lars Møller Pedersen, MD, PhD; Phone Number: +45 47324803; Email: lmpn@regionsjaelland.dk

Study Locations

• Denmark
  • Zealand
    • Roskilde, Zealand, Denmark, 4000
      • Recruiting
      • Zealand University Hospital, Department of Hematology
      • Contact: Lars Møller Pedersen, MD; Phone Number: +45 47324803; Email: lmpn@regionsjaelland.dk
      • Contact: Christiane Sophie Staxen, MSc; Email: cstax@regionsjaelland.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

The study will include two different cohorts:

A: Newly diagnosed and treatment-naïve DLBCL patients

B: A healthy control cohort

Description

Inclusion Criteria for the DLBCL cohort:

• WHO 2022 classified newly diagnosed and treatment-naïve large B-cell lymphoma (DLBCL) belonging to one of the following entities:
• Diffuse large B-cell lymphoma, including transformation from an indolent lymphoma
• Follicular lymphoma grade 3B
• T-cell/histiocyte-rich LBCL
• Primary cutaneous DLBCL, leg type
• EBV-positive DLBCL, NOS
• Primary mediastinal LBCL
• High grade B-cell lymphoma with MYC/BCL2 rearrangement
• The patient is a candidate for R-CHOP-like first-line treatment
• Staging by PET available before treatment initiation
• Age ≥18 years
• Written informed consent

Exclusion Criteria for the DLBCL cohort:

• Pregnancy
• Psychiatric illness or condition which could interfere with their ability to understand the requirements of the study
• Clinical signs of uncontrolled serious infection
• Clinical gastrointestinal lymphoma involvement
• Other significant gastrointestinal comorbidities
• Any other prior malignancy than non-melanoma skin cancer or stage 0 (in situ), cervical carcinoma, unless treated with curative intent, and without relapse for 2 years, or low-grade prostate cancer, not in need of treatment
• Ileostomy
• CNS involvement at diagnosis
• Severe cardiac disease: NYHA grade 3-4
• Impaired liver (transaminases > 3 x normal upper limit or bilirubin > 1.5 x normal upper limit, unless due to Gilbert´s syndrome) or renal (GFR<30ml/min) function not caused by lymphoma

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
DLBCL cohort; Interventions for the DLBCL cohort are: Fecal samples; Blood samples; Bioelectrical impedance analyses; Filling in questionnaires All other procedures will be in accordance with local and national guidelines corresponding to clinical standard care.	Diagnostic test: Stool samples; Analysis of microbiome, mutations, alterations in body composition and lifestyle; Other Names: Questionnaires; Blood samples; Bioelectrical impedance analysis
Healthy control cohort; The control group applied in the current study is based on the Danish General Suburban Population Study (GESUS). The control subjects are selected from the GESUS cohort and matched according to age and gender. Serial stool samples are planned in a subset of the control cohort with sampling time points corresponding to the DLBCL cohort. The sample material is handled and stored the same way as for the DLBCL cohort.	Diagnostic test: Stool samples; Analysis of microbiome, mutations, alterations in body composition and lifestyle; Other Names: Questionnaires; Blood samples; Bioelectrical impedance analysis

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intestinal microbiota baseline characterization	Assessment using amplicon-based sequencing of ribosomal (r)RNA genes	1.5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intestinal microbiota characterization at mid-, post-treatment and at follow up	Assessment using amplicon-based sequencing of ribosomal (r)RNA genes	2.5 years
Assessment of habitual diet	Food frequency questionnaire (FFQ)	2.5 years
Assessment of energy and macronutrient intake	24h dietary recalls	2.5 years
Assessment of physical activity	International physical activity questionnaire (IPAQ)	2.5 years
Body composition	Body composition according to bioelectrical impedance analysis (BIA) using BioScan touch i8 - IVF version	2.5 years
Smoking	Packages (baseline lifestyle questionnaire)	2.5 years
Alcohol intake	Units (baseline lifestyle questionnaire)	2.5 years
Treatment-related toxicity	Treatment-related toxicity (CTCAE criteria)	1.5 years
Antibiotics	Use of any type of prophylactic and therapeutic antibiotics during treatment (baseline lifestyle questionnaire)	1.5 years
Statins	Use of any type of statins during treatment registered in the Shared Medication Record (FMK)	1.5 years
Medication	Use of any type of medication registered in the Shared Medication Record (FMK)	1.5 years
Infections	Clinical infections during treatment	1.5 years
Lymphoma response	Lymphoma response after completion of first line treatment (Lugano criteria)	1.5 years
Molecular signatures	Molecular signatures in standard clinical practice according to Hans classification (cell of origin (COO))	1.5 years
Chromosome abnormalities	Molecular signatures in standard clinical practice (fluorescent in situ hybridization (FISH))	1.5 years
Mutations	JAK2V617F, TET2, DNMT3A and ASXL1 mutation analyses (%VAF)	1.5 years
Cytokine profiles	Magnetic bead-based assays	1.5 years
Metabolite signatures	Metabolomic profiling by a combination of GC and LC coupled with MS	1.5 years
Peripheral blood mononuclear cell (PBMC) profiles	PBMC profiles according to flow cytometry	1.5 years

Collaborators and Investigators

• Sponsor: Lars Møller Pedersen
• Collaborators: Zealand University Hospital; Weill Medical College of Cornell University; Herlev Hospital; Statens Serum Institut
• Investigators: Principal Investigator: Christiane Sophie Staxen, MSc, Zealand University Hospital - Roskilde

Study record dates

Study Major Dates

• Study Start (Actual): May 6, 2024
• Primary Completion (Estimated): July 1, 2025
• Study Completion (Estimated): July 1, 2026

Study Registration Dates

• First Submitted: November 15, 2023
• First Submitted That Met QC Criteria: November 30, 2023
• First Posted (Actual): December 8, 2023

Study Record Updates

• Last Update Posted (Actual): August 9, 2024
• Last Update Submitted That Met QC Criteria: August 7, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse
• Other Study ID Numbers: MiCheLin

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: There is not a plan to make IPD available.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No