Characterization and Clinical Impact of the Gut Microbiota in Lymphoma

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:

• Patients with DLBCL have distinct baseline microbiota signatures that differ from healthy subjects.
• Significant changes in the microbiota composition and diversity can be identified during and after treatment (immunochemotherapy) of DLBCL.
• Lymphoma response and outcome is affected by the composition and diversity of the DLBCL microbiota.
• 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.
• Distinct DLBCL microbiota profiles are associated with treatment-related toxicity.
• The intestinal microbiota affects the risk of infections (clinically and/or microbiologically documented).
• The intestinal microbiota is affected using antibiotics both as prophylaxis and treatment of infections.
• The DLBCL microbiota depends on the dietary intake, smoking, physical activity and the body composition.
• Distinct intestinal microbiota signatures can be associated with molecular subtypes of DLBCL (or vice versa)
• The JAK2V617F, TET2, DNMT3A and ASXL1 mutations affect the intestinal microbiota signature and are associated with comorbidity and outcome in DLBCL
• 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.

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