MDS04: Prospective Study of Molecular Predictors of Survival in Myelodysplastic Syndromes

Sponsor

Assistance Publique - Hôpitaux de Paris (Other)

Overall Status

Completed

CT.gov ID

NCT02619565

Collaborator

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

349

Enrollment

Location

Arm

Actual Duration (Months)

4.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Myelodysplastic Syndromes	Other: blood samples	N/A

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 Design

Study Type:

Interventional

Actual Enrollment :

349 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Diagnostic

Official Title:

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

Actual Study Start Date :

Apr 12, 2010

Actual Primary Completion Date :

Jun 12, 2017

Actual Study Completion Date :

Jun 12, 2017

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Number of patients who survived event-free [5 years]
Number of surviving patients [5 years]

Secondary Outcome Measures

Number of mutations on event-free survival in myelodysplastic syndromes [5 years]
prevalence of TET2 mutation and other karyotypic abnormalities
Number of medullary blast and Hemoglobin, platelet and neutrophil polynuclear [5 years]
to evaluate response to treatment

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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