Characterization of the Mechanisms of Resistance to Azacitidine

March 17, 2025 updated by: Centre Hospitalier Universitaire de Nice

Characterization of the Mechanisms of Action of Resistance to Azacitidine in High-risk Myelodysplastic Syndromes and Acute Myeloid Leukemia with Multilineage Dysplasia

Myelodysplastic syndromes (MDS) are frequent diseases in elderly patients (median age: 71 years). IPSS classification defines low risk (Low and Intermediate 1), and high risk (Intermediate 2 and High) MDS. High-risk MDS (MDS-HR) have a high risk of transformation into acute leukemia with multilineage dysplasia (AML-DML). The success of Azacitidine has been mainly achieved through a rigorous empirical and clinical research, but the molecular mechanisms by which this molecule exerts its effects remain poorly characterized. The primary mode of action of Azacytidine is through DNA demethylation, and integration in to mRNA that favor traduction inhibition. The impact of this molecule on various cell death programs involved in the elimination of leukemic cells : apoptosis and autophagy is currently poorly known.

The research program and clinical studies we proposed focus on two major aspects:

- Main objective: Molecular mechanism of action and resistance to Azacitidine: Role of apoptosis versus autophagy.

- Secondary Objective: Reversion of Azacytidine resistance using different drugs targeting apoptosis and/or autophagy. Our laboratory has identified new molecules to selectively induce different types of cell death (apoptosis or autophagy).

Study Overview

Status

Recruiting

Conditions

Myelodysplastic Syndromes or Acute Myeloid Leukemia with Multilineage Dysplasia

Study Type

Observational

Enrollment (Estimated)

250

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
- - Antibes, France
    - Recruiting
    - CH d'Antibes
    - Contact:
      
      Vanina OLIVERI, Project Manaer
      
      Email: oliveri.v@chu-nice.fr
    - Contact:
      
      Daniel RE, PH
  - Nice, France
    - Recruiting
    - Centre Antoine Lacassagne
    - Contact:
      
      Vanina OLIVERI, Project Manager
      
      Email: oliveri.v@chhu-nice.fr
    - Contact:
      
      Antoine THYSS, PU-PH
    - Contact:
      
      Frederic PEYRADE, PH
    - Contact:
      
      Lauris GASTAUD, PH
  - Nice, France, 06200
    - Recruiting
    - CHU de Nice - Hopital De L'Archet
    - Contact:
      
      Vanina OLIVERI, Project Manager
      
      Email: oliveri.v@chu-nice.fr
    - Contact:
      
      Thomas CLUZEAU, PH
Monaco
- - Monaco, Monaco
    - Recruiting
    - CH Princesse Grace
    - Contact:
      
      Vanina OLIVERI, Project Manager
      
      Email: oliveri.v@chu-nice.fr
    - Contact:
      
      Georges GARNIER, PH
    - Contact:
      
      Philippe HEUDIER, PH

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

14 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

Sampling Method

Probability Sample

Study Population

Patients with myelodysplastic syndromes or acute myeloid leukemia with multilineage dysplasia treated with Azacitidine

Description

Inclusion Criteria:

Age ≥ 18 years
High Risk or Intermediate 2 MDS (IPSS)
AML-MD (WHO classification)
Treatment with minimum three to six cycles of Azacitidine
Informed consent form signed

Exclusion Criteria:

Treatment with others chemotherapies alone or in association

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: Case-Only
Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
hematological response Time Frame: at 3 months	Hematological response evaluated by the International Working Group (IWG) response of Cheson	at 3 months
hematological response Time Frame: at 6 months	Hematological response evaluated by the International Working Group (IWG) response of Cheson	at 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival Time Frame: Day 1 of treatment	Overall survival (OS) defined as the time from start of treatment	Day 1 of treatment
Overall survival Time Frame: at the death	Overall survival (OS) defined as the time from start of treatment	at the death

Collaborators and Investigators

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

Sponsor

Centre Hospitalier Universitaire de Nice

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Cluzeau T, Robert G, Mounier N, Karsenti JM, Dufies M, Puissant A, Jacquel A, Renneville A, Preudhomme C, Cassuto JP, Raynaud S, Luciano F, Auberger P. BCL2L10 is a predictive factor for resistance to azacitidine in MDS and AML patients. Oncotarget. 2012 Apr;3(4):490-501. doi: 10.18632/oncotarget.481.

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

September 1, 2010

Primary Completion (Actual)

September 1, 2014

Study Completion (Estimated)

September 1, 2025

Study Registration Dates

First Submitted

September 27, 2010

First Submitted That Met QC Criteria