Prospective Study of Molecular Predictors of Survival in Myelodysplastic Syndromes (MDS04)

March 16, 2018 updated by: Assistance Publique - Hôpitaux de Paris

Prognostic Value of Recurrent Mutations in a Prospective Cohort of Myelodysplasia and Secondary Acute Myeloid Leukemias

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

349

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 Locations

  • France
      • Paris, France, 75014
        • Assistance publique-Hôpitaux de Paris, Hôpital Cochin

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

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

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: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: Blood samples if evolution of the disease
blood samples at Day 0 and also if there is an evolution of the disease
Other: blood samples
blood samples at Day 0 and also if there is an evolution of the disease

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Number of patients who survived event-free
Time Frame: 5 years
5 years
Number of surviving patients
Time Frame: 5 years
5 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of mutations on event-free survival in myelodysplastic syndromes
Time Frame: 5 years
prevalence of TET2 mutation and other karyotypic abnormalities
5 years
Number of medullary blast and Hemoglobin, platelet and neutrophil polynuclear
Time Frame: 5 years
to evaluate response to treatment
5 years

Collaborators and Investigators

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

Sponsor

Assistance Publique - Hôpitaux de Paris

Collaborators

Institut National de la Santé Et de la Recherche Médicale, France
Gustave Roussy, Cancer Campus, Grand Paris
Groupe Francophone des Myelodysplasies
Institut Cochin

Investigators

  • Study Chair: Michaela Fontenay, MD, PhD, Assistance publique-Hôpitaux de Paris and Paris Descartes University.

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

Helpful Links

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 (Actual)

April 12, 2010

Primary Completion (Actual)

June 12, 2017

Study Completion (Actual)

June 12, 2017

Study Registration Dates

First Submitted

April 20, 2015

First Submitted That Met QC Criteria

December 1, 2015

First Posted (Estimate)

December 2, 2015

Study Record Updates

Last Update Posted (Actual)

March 19, 2018

Last Update Submitted That Met QC Criteria

March 16, 2018

Last Verified

March 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • AOM09236 - P081246

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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