Clinical trial NCT01210274: Characterization of the Mechanisms of Resistance to Azacitidine
Official title: Characterization of the Mechanisms of Action of Resistance to Azacitidine in High-risk Myelodysplastic Syndromes and Acute Myeloid Leukemia With Multilineage Dysplasia
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Myelodysplastic Syndromes or Acute Myeloid Leukemia With Multilineage Dysplasia
Lead sponsor: Centre Hospitalier Universitaire de Nice
Sponsor class: OTHER
First posted: 2010-09-28
Enrollment: 250
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Patients with myelodysplastic syndromes or acute myeloid leukemia with multilineage dysplasia treated with Azacitidine

Brief summary: 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).


Eligibility criteria: 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

Primary outcomes:
measure: hematological response
timeFrame: at 3 months
measure: hematological response
timeFrame: at 6 months
Secondary outcomes:
measure: Overall survival
timeFrame: Day 1 of treatment
measure: Overall survival
timeFrame: at the death
Other outcomes:
Locations:
city: Antibes
country: France
facility: CH d'Antibes
city: Nice
country: France
facility: CHU de Nice - Hôpital de l'Archet
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: Monaco
country: Monaco
facility: CH Princesse Grace
Study officials:
References:
citation: 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.