Identification of Molecular Defects in Idiopathic Cytopenia of Undetermined Significance

Study Overview
=================
Brief Summary
-----------------
The project's objective is to identify and characterize somatic mutations in cases of idiopathic cytopenia of undetermined significance (ICUS) on the basis of molecular defects found in myelodysplastic syndrome (MDS), in order to validate the hypothesis whereby ICUS may be a precursor of MDS

Detailed Description
-----------------
The project's objective is to identify and characterize somatic mutations in cases of idiopathic cytopenia of undetermined significance (ICUS) on the basis of molecular defects found in myelodysplastic syndrome (MDS), in order to validate the hypothesis whereby ICUS may be a precursor of MDS. To this end, high-throughput exon sequencing (using next-generation sequencing (NGS)) will be used to target the genes known to be mutated in MDS. This study is important for two reasons. Firstly, it will help to optimise the clinical monitoring of patients with molecular defects and considered to be at risk of progression. Secondly, it will provide a better understanding of the fundamental molecular mechanisms underlying the progression of ICUS to MDS.

Official Title
-----------------
Identification of Molecular Defects in Idiopathic Cytopenia of Undetermined Significance

Conditions
-----------------
Myelodysplastic Syndromes

Intervention / Treatment
-----------------
* Genetic: ICUS


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age 18 or over. Haemoglobin <11 g/dl and/or a polynuclear neutrophil count <1.5.109/L and/or a platelet count <100.109/L Full clinical biochemistry/haematological profiling: complete blood count, blood smear, reticulocyte count, iron status, folates, B12, TSH, creatinine, liver enzymes, ANAs, rheumatoid factor, anticardiolipin antibodies, Coombs test, EPO assay, serological tests for HIV, HVB and HVC. Availability of a bone marrow differential cell count and an evaluation of myelopoiesis disorders (number of lineages, percentage of cells affected, etc.) plus Perls staining. Availability of a cytogenetic analysis. Voluntary provision of written, informed consent Life expectancy >6 months Social security coverage Exclusion Criteria: An obvious cause of anaemia (if isolated): iron deficiency, chronic kidney failure (clearance <60 ml/min), regenerative anaemia (reticulocytes >150G/L) Vitamin B12 or B9 deficiency Hepatomegaly, or clinical and/or ultrasound signs of portal hypertension Clinical and/or ultrasound signs of splenomegaly Abnormal liver enzyme levels: total bilirubin, alkaline phosphatases or transaminases > 1.5N; gammaGT > 2N. A history of (or diagnostic criteria during screening) auto-immune diseases such as systemic erythematous lupus, antiphospholipid syndrome or Evans syndrome. An abnormal bone marrow differential cell count A bone marrow karyotype revealing MDS Medical, psychological or social conditions that prevent the participant from correctly understanding the study procedures. Legal guardianship and incarceration.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| ICUS<br>idiopathic cytopenia of undetermined significance (ICUS) | Genetic: ICUS<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| high-throughput sequencing | The presence or absence of one or several of the following molecular defects, as detected by high-throughput sequencing: DNMT3A, TET2, IDH1/2, ASXL1, EZH2, RUNX1, EVI1, GATA2, P53, JAK2, CBL, KRAS, SF3B1, SRSF2, U2AF1, and ZRSR2. | Day 0 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| phenotypic defects | Analysis of phenotypic defects detected by flow cytometry. | Day 0 | 
| growth of erythroid progenitors | Analysis of the growth of erythroid progenitors (BFU-E) and granulocyte-monocyte progenitors (CFU-GM). | Day 0 | 
| Appearance of MDS | Appearance of MDS during follow-up: a bone marrow differential cell count at 6 months and whenever cytopenia appears. | 6 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
idiopathic cytopenia of undetermined significance (ICUS), molecular defects