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

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ClinicalTrials.gov Identifier: NCT05924074
Recruitment Status : Not yet recruiting
First Posted : June 29, 2023
Last Update Posted : June 29, 2023
Sponsor:
Information provided by (Responsible Party):
University Hospital, Bordeaux

Study Description
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Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Myelodysplastic Syndromes Ferroptosis Biological: Biological sampling Not Applicable

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 Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: Ferroptosis Study in SF3B1-mutant Myelodysplastic Syndromes (FerMDS)
Estimated Study Start Date : July 2023
Estimated Primary Completion Date : July 2025
Estimated Study Completion Date : July 2025

Resource links provided by the National Library of Medicine


Arms and Interventions
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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


Outcome Measures
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Primary Outcome Measures :
  1. 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)


Secondary Outcome Measures :
  1. 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)

  2. 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

  3. 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


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05924074


Contacts
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Contact: Victor-Emmanuel BRETT 0556774357 victor.brett@chu-bordeaux.fr
Contact: Charles DUSSIAU charles.dussiau@chu-bordeaux.fr

Locations
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France
CHU de Bordeaux, Laboratoire d'Hématologie
Pessac, France
Contact: Victor-Emmanuel BRETT       victor.brett@chu-bordeaux.fr   
CHU de Bordeaux, Service de Médecine Interne
Pessac, France
Contact: Estibaliz LAZARO       estibaliz.lazaro@chu-bordeaux.fr   
CHU de Bordeaux, Service Hématologie Clinique et Thérapie Cellulaire
Pessac, France
Contact: Sophie DIMICOLI-SALAZAR       sophie.dimicoli-salazar@chu-bordeaux.fr   
Sponsors and Collaborators
University Hospital, Bordeaux
More Information
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Responsible Party: University Hospital, Bordeaux
ClinicalTrials.gov Identifier: NCT05924074    
Other Study ID Numbers: CHUBX 2022/43
First Posted: June 29, 2023    Key Record Dates
Last Update Posted: June 29, 2023
Last Verified: June 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Preleukemia
Myelodysplastic Syndromes
Syndrome
Disease
Pathologic Processes
 Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Neoplasms