Mixed Molecular Clinical Index (MMCI) in Diffuse Large B-cell Lymphoma (DLBCL) (MMCI)

February 25, 2021 updated by: Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori

This is a prospective observational study. The primary objective is to identify new prognostic biomarkers for DLBCL patients in terms of progression-free survival (PFS) and able to add predictive capacity to recognized important clinical factors.

The secondary objectives are:

  • to identify new biomarkers associated with overall survival (OS) and objective response rate (ORR)
  • to characterize tissue and circulating immune microenvironment of DLBCL patients by bulk and single cell transcriptomics;
  • to assess the correlation between the expression of immune checkpoint genes and mRNA signature;
  • to describe the mutational status of a panel of genes relevant to DLBCL pathogenesis;.
  • to assess the correlation between protein expression, mutational status and the messenger RNA (mRNA) signature.

For each enrolled patient, immunohistochemical determinations will be performed: Cell of origin (COO) (Germinal Cell -GC- or activated B-cell - ABC- type according with Hans algorithm ), evaluation of cluster of differentiation antigen 20 (CD20), cluster of differentiation antigen 5 (CD5), cluster of differentiation antigen 10 (CD10), Bcl6, Bcl2 (cut off>50%), Multiple Myeloma 1 / Interferon Regulatory Factor 4 protein (MUM1/IRF4), c-myc (cut off>40%) and Ki67, fluorescence in situ hybridization (FISH) for c-myc and if rearranged, for Bcl2 e Bcl6 ). Moreover, paraffin embedded (FFPE) tumor specimens will be collected for RNA extraction and mRNA expression analysis and sent to Bioscience Laboratory of Istituto Scientifico Romagnolo per lo studio e la cura dei tumori (IRST-IRCCS).

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Diffuse large B-cell lymphoma (DLBCL) is an heterogeneous group of cancers classified together on the basis of morphology, immunophenotype, genetic alterations and clinical behavior. The distinction of DLBCL into cell-of origin (COO) categories, based on patterns of gene expression reminiscent ( germinal center B-cell- the GC group and activated B-cell- the ABC group-), as defined and characterized by the Lymphoma & Leukemia Molecular Profiling Project (LLMPP), has profound biological, prognostic and potential therapeutic implications and in addiction, the negative prognostic effect of myelocytomatosis oncogene (MYC), B-cell lymphoma 2 (BCL2) and B-cell lymphoma-6 (BCL6) alterations in DLBCL has been showed largely dependent on COO subtypes . Furthermore, the combination of BCL2, MYC and BCL6 alterations with IPI (International Prognostic Index), identifies markedly worse prognostic groups within individual COO subtypes. The original methods used to define these entities, performed gene expression profiling (GEP) using microarrays on RNA derived from frozen tissue (FT). Subsequently, in an attempt to determine COO in standard practice using commonly available formalin-fixed paraffin-embedded tissue (FFPE) less precise but relatively inexpensive binary immunohistochemical (IHC) methods has been used . However in particular in non GC, the rate of concordance was unsatisfactory. A high degree of agreement has been demonstrated instead in COO determining, with a signature of 20 genes from formalin-fixed paraffin embedded (FFPE) tumor specimens, with Lymph2Cx kit (nCounter® Technology, NanoString Technologies), becoming the gold standard suggested in World Health Organization (WHO) classification . However recently, was demonstrated that the COO and BCL2, MYC, BCL6 status are not enough to describe the molecular risk of these patients, suggesting a genetic substructure that still to be discovered . Moreover, the tumor microenvironment and in particular the ratio of immune effectors and checkpoint molecules also have a prognostic role in DLBCL. Besides, elevated frequency of myofibroblasts, dendritic cells, and cluster of differentiation 4 (CD4) positive T cells correlated with better outcomes.

In conclusion, a comprehensive genomic analysis of these patients and a deep characterization of the immune compartment and immune checkpoints (Nanostring, immunohistochemistry for BCL2, MYC, BCL6, mutation analysis, proteomic analysis etc.) joined with IPI score, will allow the creation of a mixed, molecular, clinical, index (MMCI) to identify extremely poor prognostic groups, within each COO subtype, to consider a risk-adapted treatments in future.

It is a prospective observational study with a total duration of 36 months. The primary objective is the identification of new prognostic biomarkers for DLBCL patients in terms of progression-free survival (PFS) and able to add predictive capacity to recognized important clinical factors.

The secondary objectives are:

  • to identify new biomarkers associated with overall survival (OS) and objective response rate (ORR);
  • to characterize tissue and circulating immune microenvironment of DLBCL patients by bulk and single cell transcriptomics;
  • to assess the correlation between the expression of immune - checkpoint genes and mRNA signature;
  • to describe the mutational status of a panel of genes relevant to DLBCL pathogenesis;.
  • to assess the correlation between protein expression, mutational status and the mRNA signature.

For each enrolled patient, immunohistochemical determinations will be performed by each Pathology Unit: COO (GC o ABC type according with Hans algorithm ), evaluation of CD20, CD5, CD10, Bcl6, Bcl2 (cut off>50%), MUM1/IRF4, c-myc (cut off>40%) and Ki67, FISH for c-myc and if rearranged, for Bcl2 e Bcl6). Moreover, paraffin embedded (FFPE) tumor specimens will be collected for RNA extraction and mRNA expression analysis and centralised at IRST-IRCCS.

Study Type

Observational

Enrollment (Anticipated)

100

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Italy
      • Bologna, Italy
        • Recruiting
        • L'Azienda Ospedaliero-Universitaria Di Bologna Policlinico S. Orsola-Malpighi
        • Contact:
          • Elena Sabbatini, MD
      • Rimini, Italy, 47924
    • FC
      • Meldola, FC, Italy, 47014
    • RA
      • Ravenna, RA, Italy, 48121

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Patients with a new diagnosis of High grade Diffuse large B cell Lymphoma

Description

Inclusion Criteria:

  • New diagnosis of High grade Diffuse large B cell Lymphoma
  • Signed written informed consent.

Exclusion Criteria:

  • Any other malignancy within 5 years (except for adequately treated carcinoma in situ of the cervix or basal or squamous cell skin cancer or surgically resected prostate cancer with normal PSA).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
DLBCL patients
All patients with diagnosis of DLBCL
Other: molecular characterization

immunohistochemical determinations: Cell of Origin (COO) (according with Hans algorithm), evaluation of Cluster of Differentiation (CD) (CD20, CD5, CD10), Bcl6, Bcl2 (cut off>50%), MUM1/IRF4, c-myc (cut off>40%) and Ki67, FISH for c-myc and if rearranged for Bcl2 e Bcl6.

mRNA expression by Nanostring Single cell analysis Immune checkpoint expression Proteomic analysis Metabolic analysis

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
identification of new prognostic biomarkers
Time Frame: 3 years
To identify new prognostic biomarkers for DLBCL patients that combined to clinical factors (IPI) are able to create a MMCI, predictive in terms of progression-free survival (PFS) of DLBCL patients.
3 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
identification of molecular and clinical parameters
Time Frame: 3 years
to identify molecular and clinical parameters associated with overall survival (OS) and objective response rate (ORR)
3 years
characterization of tissue and circulating immune microenvironment
Time Frame: 3 years
to characterize tissue and circulating immune microenvironment by bulk and single cell transcriptomics
3 years
immune checkpoint genes analysis
Time Frame: 3 years
to assess the correlation between the expression of immune checkpoint genes and mRNA signatures
3 years
mutational status
Time Frame: 3 years
describe the mutational status of a panel of genes relevant to DLBCL pathogenesis
3 years
Correlation of protein expression, mutational status and the mRNA signatures
Time Frame: 3 years
assess the correlation between protein expression, mutational status and the mRNA signatures.
3 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori

Investigators

  • Principal Investigator: Gerardo Musuraca, MD, Irst Irccs

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 14, 2020

Primary Completion (Anticipated)

March 1, 2023

Study Completion (Anticipated)

March 1, 2023

Study Registration Dates

First Submitted

March 5, 2020

First Submitted That Met QC Criteria

March 5, 2020

First Posted (Actual)

March 9, 2020

Study Record Updates

Last Update Posted (Actual)

February 26, 2021

Last Update Submitted That Met QC Criteria

February 25, 2021

Last Verified

February 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IRSTB094

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Diffuse Large B Cell Lymphoma

Clinical Trials on molecular characterization

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Kosovo

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe