Ferroptosis Study in SF3B1-mutant Myelodysplastic Syndromes (FerMDS) (FerMDS)

June 19, 2023 updated by: University Hospital, Bordeaux
Myelodysplastic syndromes (MDS) are clonal diseases of hematopoietic stem cells (HSC) characterized by dysplastic and inefficient hematopoiesis related to excessive progenitor cell death. Ferroptosis is a recently described cell death mechanism and we think that it could be a major player in the pathophysiology of MDS, involved in the cell death that characterizes these diseases and contributing to cytopenias. The study aims to demonstrate that there is a significant activation of this phenomenon in MDS patients compared to a population of subjects without MDS.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

Myelodysplastic syndromes (MDS) are hematological malignancies characterized by a defect in blood cells production. Their pathophysiology remains poorly understood, but an excessive death of progenitor cells is considered as a key mechanism contributing to the appearance of cytopenia. Furthermore, it is known that there are abnormalities of iron metabolism in MDS, especially in patients with ring sideroblasts and SF3B1 mutation. The classical therapeutic strategy in MDS relies on symptomatic management of cytopenias (transfusions, growth factors) associated with demethylating agents in high-risk forms. Unfortunately, these treatments only stabilize the disease and only allogeneic bone marrow transplantation (reserved to limited number of patients) can cure the patients. Therefore, there is a urgent need to identify new therapeutic targets in these diseases.

An excessive apoptosis activation has been shown in MDS for a long time. However, other cell death pathways could also contribute to their pathophysiology. Among them, ferroptosis, a cell death process triggered by the accumulation of free iron in the cell, seems to be a promising candidate.

The project is proposed to study ferroptosis in SF3B1-mutant MDS patients. An additionnal bone marrow sample will be aspirate at diagnosis. Ferroptosis will be analyzed using flow cytometry (labeling of peroxidized lipids with C11-BODIPY). The percentage of cells in ferroptosis will be compared between SF3B1-mutant MDS patients and control patients (patients evaluated for Monoclonal Gammapathy of Unknown Significance-MGUS). The presence of an excess of ferroptosis in SF3B1-mutant MDS patients will be correlated to clinico-biological parameters. No follow up will be be performed.

Study Type

Interventional

Enrollment (Estimated)

80

Phase

  • Not Applicable

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

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

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

For all :

  • Patients of legal age (age ≥ 18 years)
  • Subjects affiliated to or benefiting from a social security scheme
  • Free, written and informed consent signed by the participant and the investigator

For MDS patients :

  • Sampling at diagnosis for MDS patients (WHO 2016 criteria)
  • Presence of ring sideroblasts on bone marrow smear

For MGUS patients :

- Sampling as part of the exploration of monoclonal gammopathy of undetermined significance (MGUS) for controls (WHO 2016 criteria).

Exclusion Criteria:

For all

  • Patient transfused with red blood cells within 120 days prior to collection
  • Patients treated with haematopoietic growth factors (EPO, TPO, G-CSF) within 30 days prior to collection
  • Patients with conditions that affect systemic iron metabolism: hemochromatosis, Gaucher disease, ferroportin disease, porphyria cutanea tarda
  • Person under a legal protection measure (legal protection, guardianship or curatorship)
  • Person deprived of liberty by judicial or administrative decision
  • Person who is unable to give consent
  • Subject who is in an exclusion period after another study or who has participated in another interventional drug study within 30 days prior to entry into the protocol

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

  • Primary Purpose: Diagnostic
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: SF3B1 mutant Myelodysplastic syndromes patients (MDS)
Patients diagnosed with MDS carrying the SF3B1 somatic mutation associated myelodysplastic neoplasm with ring sideroblasts
Biological: Biological sampling
The procedure will consist of an additional bone marrow sample and blood sample
Active Comparator: Monoclonal Gammapathy of Unknown Significance patients (MGUS)
MGUS patients, referred to as normal bone marrow controls
Biological: Biological sampling
The procedure will consist of an additional bone marrow sample and blood sample

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Percentage of cells undergoing ferroptosis in SF3B1-mutant MDS patients compared to MGUS patients
Time Frame: At Baseline
Mean values for the proportion of ferroptose cells will be compared between arms, using comparative statistical methods (Student's t test, Student's test for unequal variances or Wilcoxon test)
At Baseline

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Percentage of cells undergoing ferroptosis in the different bone marrow subpopulations (stem cells, progenitors, and erythroid and myeloid precursors at different stages of differentiation) of SF3B1-mutant MDS patients
Time Frame: At Baseline
Mean values for the proportion of ferroptose cells among the different bone marrow subpopulations will be compared between arms, using comparative statistical methods (Student's t test, Student's test for unequal variances or Wilcoxon test)
At Baseline
Biological characteristics of SF3B1-mutant MDS patients with an excess of cells undergoing ferroptosis in the bone marrow compared to MGUS controls
Time Frame: At baseline
Biological differences in number (1 to 3) and type of cytopenias (anemia, thrombocytopenia, neutropenia) in SF3B1-mutated MDS patients will be studied and statistically compared with the MGUS control group, based on the number of ferroptosis cells observed by cytometry
At baseline
Clinical characteristics of SF3B1-mutant MDS patients with an excess of cells undergoing ferroptosis in the bone marrow compared to MGUS controls
Time Frame: Through study completion, up to 2 years
Overall survival after diagnosis, progression-free survival (evolution of MDS towards a higher-grade hemopathy or death) in SF3B1-mutated MDS patients will be studied and statistically compared with the MGUS control group, based on the number of ferroptosis cells observed by cytometry
Through study completion, up to 2 years

Collaborators and Investigators

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

Sponsor

University Hospital, Bordeaux

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 (Estimated)

July 1, 2023

Primary Completion (Estimated)

July 1, 2025

Study Completion (Estimated)

July 1, 2025

Study Registration Dates

First Submitted

June 7, 2023

First Submitted That Met QC Criteria

June 19, 2023

First Posted (Actual)

June 29, 2023

Study Record Updates

Last Update Posted (Actual)

June 29, 2023

Last Update Submitted That Met QC Criteria

June 19, 2023

Last Verified

June 1, 2023

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CHUBX 2022/43

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

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.

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