Toward Immune Biomarkers for Tolerance and GvHD in Humans (BioGvHD)

February 18, 2019 updated by: Assistance Publique - Hôpitaux de Paris

Graft-versus-Host Disease (GVHD), is the most frequent and severe complication of allogeneic hematopoietic stem cell transplantation (HSCT). Much of our knowledge on the pathophysiology of GVHD has been gained from experimental models but far less from the study of the disease in humans. Recent developments in basic biology open new avenues to the development of biomarker sets that could predict GVHD severity and prognosis that could be tested and validated through well-designed multicenter clinical trials.

The main goal of this project is to further our understanding of the pathogenic mechanisms of human GVHD on one hand, and of functional immune tolerance on the other. Furthermore, this study aims at setting up a clinically relevant biomarker set in human GVHD and immune tolerance in a discovery cohort.

The objectives of this project are:

1. To define phenotypic, functional and molecular correlates of acute GVHD early after HSCT/at its onset 2. To study thymic reconstitution and the T-cell repertoire after HSCT during period 2 3. To identify functional and molecular correlates of immune tolerance in long-term survivors of HSCT 4. Preparing for biomarker validation into a clinical trial We propose a prospective analysis of a cohort of 680 patients transplanted from an HLA-identical sibling donor at Saint Louis hospital. Analyses will be performed during 3 critical, clinically relevant, periods.

Period 1: Analysis at the onset of GVHD, or at the time of engraftment 30 days after HSCT in patients not developing GVHD. An additional blood sample will also be analyzed 90 days after HSCT.
Period 2: Thymic function analysis using measurements of T-cell receptor excision circles (TREC) will be performed at 6 and 12 months post-transplant for all patients. T-cell receptor analysis on sorted T-cell populations will be performed by NGS.
Period 3: In "tolerant" patients (patients more than 2 years after HSCT not requiring immunosuppressive treatment), or in patients still requiring immunosuppressive therapy after 2 years. We will also analyze the corresponding immune parameters for each donor.

The longitudinal design of this study will allow us to provide an integrated view of GVHD pathophysiology and mechanisms of immune tolerance in human.

Prospectively identified phenotypic, molecular or functional biomarkers will then be tested, in a subsequent study, from biological materials prospectively collected within the French wide CryoStem cohort. Thus, as the final task of this project, we will perform statistical analyses taking into account confounding clinical variables influencing the outcome (i.e. GVHD-related death or tolerance). Preparing for a clinical trial will need moving from classical Bioinformatics analyses into clinically relevant statistical analyses that include sequential biological measurement in the discovery set cohort. Main points that will be taken into accounts for this task are the followings;

Transplant-related mortality (TRM) can be estimated in the range of 20%; 2year post-allogeneic HSCT
TRM is mostly (even if totally) due to GVHD and its associated immune deficiency
GVHD cumulative incidence can be estimated in the range of 40%
80 patients will be prospectively studied and 30 patients will be analyzed (cross sectional study) for part 3 only.
Since GVHD-related mortality and tolerance are mutually exclusive situation the optimal calculation for the validation cohort can be expected
This calculation will be the basis for the proposal of an interventional clinical trial.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Other: Transplantation from an HLA-identical sibling donor

Study Type

Observational

Enrollment (Actual)

Contacts and Locations

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

Study Locations

France
- - Paris, France, 75019
    - Hopital Siant-louis

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

Child
Adult
Older Adult

Accepts Healthy Volunteers

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Adult patients transplanted from an HLA-identical sibling donor

Description

Inclusion Criteria:

Patients transplanted from an HLA-identical sibling donor

Exclusion Criteria:

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
acute Graft-versus-Host Disease (GVHD) early after allogeneic hematopoietic stem cell transplantation (HSCT) Time Frame: 30 days	30 days

Collaborators and Investigators

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

Sponsor

Assistance Publique - Hôpitaux de Paris

Collaborators

National Research Agency, France

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

May 1, 2014

Primary Completion (Actual)

February 1, 2019

Study Completion (Anticipated)

October 1, 2020

Study Registration Dates

First Submitted

December 13, 2014

First Submitted That Met QC Criteria