Prospective Study of Molecular Predictors of Survival in Myelodysplastic Syndromes

NCT ID: NCT02619565

Last Updated: 2025-09-08

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 349 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-04-12
• Study Completion Date: 2017-06-12

Brief Summary

This study aims at prospectively enrolling a cohort of 400 incident cases of myelodysplastic syndromes (MDS) at diagnosis, to evaluate the impact of recurrent mutations on overall survival and event-free survival, using next generation sequencing. Patients are affected by ineffective hematopoiesis and a propensity to leukemia in the elderly with a global incidence of 10/100,000/year.

Detailed Description

Myelodysplastic syndromes (MDS) are a heterogeneous group of stem cell disorders characterized by ineffective hematopoiesis with dysplasia and a propensity to acute myeloid leukemia. Patients are affected in the elderly with a global incidence of 10/100,000/year.

During the past 3 years, a significant progress has been made in the understanding of molecular pathogenesis through identification of mutations in epigenetic genes like TET2, ASXL1, EZH2, RUNX1, DNMT3A, IDH1/2, transcription factors, signalling molecules, cohesion and splicing regulators. Inactivating mutations targeting the hematopoietic stem cell may alter its gene expression pattern and could be an early mechanism of clonal selection. However, a single genetic alteration does not readily recapitulate the apoptotic and dysplastic phenotype. Several clones may co-exist, but their architecture is still unclear.

This study aims at prospectively enrolling a cohort of 350 incident cases at diagnosis, to identify evaluate the impact of recurrent mutations on overall survival and event-free survival, using next generation sequencing.

Considering the current knowledge, investigators propose to:

• perform whole exome sequencing to identify new mutations in a subset of 30 patients at diagnosis and in 10/30 samples at follow-up, and validate the recurrence of the new mutations in a training set.
• validate a high throughput technology for extensive genotyping to determine the mutational status of 54 target genes in the entire prospective cohort.
• analyze the frequency and impact on phenotype, OS and EFS of the most frequent mutations including SF3B1, SRSF2, ZRSR2, U2AF1, TET2, ASXL1, EZH2, IDH1/2, DNMT3A, NRAS, TP53, and RUNX1 and possibly of the newly discovered new mutations. Individual follow-up will be 36 months.

As ancillary studies, the evolution of mutation profiles after leukemic transformation in 10/30 MDS tested by WES, or after evaluation of the response to treatments in 100 MDS included in clinical trials of the "Groupe Francophone des Myélodysplasies" will be analyzed.

Understanding clonal architecture at diagnosis and after leukemic transformation is crucial for the knowledge of the pathophysiology of MDS. Better knowledge could help to adapt the therapeutic strategy. The study will help to delineate the pattern of genes which mutations with independent prognostic value modify the natural course of the disease. Then, investigators will apply for a grant to support a medico-economic evaluation of the molecular diagnosis in MDS.

Conditions

Myelodysplastic Syndromes

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: DIAGNOSTIC
• Blinding Strategy: NONE

Study Groups

Blood samples if evolution of the disease

blood samples at Day 0 and also if there is an evolution of the disease

Group Type: OTHER

blood samples

Intervention Type: OTHER

blood samples at Day 0 and also if there is an evolution of the disease

Interventions

blood samples

blood samples at Day 0 and also if there is an evolution of the disease

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

Myelodysplastic syndromes, mixed myelodysplastic/myeloproliferative disorders or secondary acute myeloid leukemia at diagnosis:

• De novo MDS subtype according to the WHO classification: RCMD and RA with or without ring sideroblasts, RAEB 1, or MDS-U, RAEB 2, therapy-related MDS or sAML, MDS/MPD.
• IPSS
• Documented chromosome 5 and 7 abnormality (del(5q) or -5, del(7q) or -7) by FISH analysis, if possible AND
• ECOG performance status ≤ 2
• Age ≥ 18 years
• Life expectancy ≥ 3 months
• Adequate renal and liver function (transaminases serum levels ≤ 3N; calculated creatinine clearance > 40 ml/min)
• Signed informed consent prior to start of any study-specific procedures
• Ability to participate to a clinical trial and adhere to study procedures

Exclusion Criteria

• Active serious infection not controlled by oral or intravenous antibiotics
• Treatment with any investigational antileukemic agent or chemotherapy at least 6 weeks prior to study entry and lack of full recovery from side effects due to prior therapy independent of when that therapy were given
• Rapidly progressive disease with compromised organ function judged to be life-threatening by the Investigator
• Pregnant or lactating female
• Known human immunodeficiency virus (HIV) infection
• Known active hepatitis B and/or C virus infection
• ECOG performance status > 2
• Age < 18 years

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Groupe Francophone des Myelodysplasies

OTHER

Sponsor Role: collaborator

Institut National de la Santé Et de la Recherche Médicale, France

OTHER_GOV

Sponsor Role: collaborator

Institut Cochin

OTHER

Sponsor Role: collaborator

Gustave Roussy, Cancer Campus, Grand Paris

OTHER

Sponsor Role: collaborator

URC-CIC Paris Descartes Necker Cochin

OTHER

Sponsor Role: collaborator

Assistance Publique - Hôpitaux de Paris

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Michaela Fontenay, MD, PhD

Role: STUDY_CHAIR

Assistance publique-Hôpitaux de Paris and Paris Descartes University.

Locations

Assistance publique-Hôpitaux de Paris, Hôpital Cochin

Paris, , France

Countries

France

References

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Related Links

http://www.carpem.fr

Cancer research for personalized medicine is a consortium dedicated to integrative research against cancer at the Assistance Publique-Hôpitaux de Paris

Other Identifiers

AOM09236 - P081246

Identifier Type: -

Identifier Source: org_study_id