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Impact of Epigenetic Age on Clinic-biological Presentation and Prognosis in Myeloproliferative Neoplasms Epigenetic Age in Myeloproliferative Neoplasms (EpiC)

Recruiting
Conditions
Myeloproliferative Neoplasm
Interventions
Biological: Assessment of the epigenetic age
Registration Number
NCT06022328
Lead Sponsor
University Hospital, Bordeaux
Brief Summary

Myeloproliferative Neoplasms (MPN) are hematological malignancies characterized by the excessive production of myeloid cells. MPN can be complicated by thrombosis and evolution into more aggressive diseases (myelofibrosis and acute leukemia). Aging remains the principal factor determining patients' survival in MPN. In recent years, DNA methylation has appeared as a mean to measure aging via the development of epigenetic clocks that have also been associated with the occurrence of thrombosis and cancer. The epiC project aims at determining epigenetic age of MPN patients and search for an association between this parameter and thrombotic/hematological complications.

Detailed Description

Myeloproliferative Neoplasia (MPN) are hematological malignancies characterized by the excessive production of myeloid cells. They include Essential Thrombocythemia (ET), Polycythemia Vera (VP) and Primary Myelofibrosis (PMF). Thrombosis are the most frequent complications and are largely responsible for the morbidity and mortality observed in ET and PV patients. The most feared complications are hematological transformations (into myelofibrosis for PV and ET, into acute myeloid leukemia for PV, ET and PMF). The prognostic assessment of MPN patients is mainly based on clinical data. Although recent studies have shown that certain mutations are associated with a poorer prognosis, age remains the main risk factor affecting survival in MPN patients. Recent studies have shown that DNA methylation can be used to determine an "epigenetic age". Interestingly, this epigenetic age is associated with the development of cardiovascular disease and cancer.

In this project, the epigenetic age of MPN patients will be determined by studying the DNA methylation at diagnosis using the Infinium Human MethylationEPIC kit (Illumina). Epigenetic age will be determined with the most commonly used epigenetic clocks (DNAmAge, DNAmHannum, DNAmPhenoAge, DNAmSkinClock, DNAmGrimAge, intrinsic epigenetic age acceleration, extrinsic epigenetic age acceleration). It will be searched for an association between accelerated epigenetic aging (as assessed by the difference between epigenetic age and chronological age) and the type of MPN, the clinical and biological presentation at diagnosis (including the mutational profile of patients) and the occurrence of thrombosis and hematological evolution into myelofibrosis and/or acute leukemia.

Recruitment & Eligibility

Status
RECRUITING
Sex
All
Target Recruitment
120
Inclusion Criteria

For the 110 patients with MPN:

  • Patients with PV, ET or PMF
  • DNA extracted from purified granulocytes at time of diagnosis
  • No treatment likely to impact DNA methylation (chemotherapy, immunosuppressants in particular)

For the 10 subjects without MPN:

  • Absence of hematological malignancy
  • Search for JAK2V617F mutation in the context of reactive thrombocytosis or secondary polycythemia
  • Absence of treatment likely to impact DNA methylation (chemotherapy, immunosuppressants in particular)
Exclusion Criteria

For the 110 patients with MPN:

  • Patients without PV, ET or PMF
  • Patients without purified granulocytes DNA available at time of diagnosis
  • Patients treated by cytoreductive drug, demethylating agent, chemotherapy or immunosuppressive therapy at the time of DNA sampling
  • Patients with less than 2 years' follow-up

For the 10 subjects in NMP :

  • Patients with hematological malignancy and/or solid cancer
  • Patients treated by cytoreductive drug, demethylating agent, chemotherapy or immunosuppressive therapy at the time of DNA sampling

Study & Design

Study Type
OBSERVATIONAL
Study Design
Not specified
Arm && Interventions
GroupInterventionDescription
Patients with ETAssessment of the epigenetic age45 patients with ET: * 15 without thrombotic event (neither at diagnosis nor during follow-up) * 15 with thrombotic events (thrombosis at diagnosis or within 2 years of diagnosis) * 15 who progressed to myelofibrosis or AML during follow-up
Patients with PMFAssessment of the epigenetic age20 patients with PMF: * 10 without transformation into AML * 10 patients who progressed to AML
Patients with PVAssessment of the epigenetic age45 patients with PV * 15 without thrombotic event (neither at diagnosis nor during follow-up) * 15 with thrombotic event (thrombosis at diagnosis or within 2 years of diagnosis) * 15 who progressed to myelofibrosis or AML during follow-up
Patients without MPNAssessment of the epigenetic age10 patients without MPN
Primary Outcome Measures
NameTimeMethod
Accelerated ageing of patientsAt inclusion, up to 1 year after diagnosis

Accelerated ageing will be defined as an increased difference between the epigenetic age (calculated from DNA methylation data with the different molecular clocks described: DNAmAge, DNAmHannum, DNAmPhenoAge, DNAmSkinClock, DNAmGrimAge, intrinsic epigenetic age acceleration, extrinsic epigenetic age acceleration) and the chronological age

Secondary Outcome Measures
NameTimeMethod
Additional somatic mutationAt inclusion, up to 1 year after diagnosis

In up to 50% of MPN patients, genetic variants can be detected in genes such as DNMT3A, TET2, ASXL1, SRSF2, SF3B1, U2AF1, EZH2 or TP53. We will determine which somatic genetic variant is detected by high throughput sequencing

Type of MPN (ET, PV or PMF) at diagnosisAt inclusion, up to 1 year after diagnosis

We will study patients with a diagnosis of ET, PV or PMF as defined by the WHO classification of hematological malignancies

Transformation into secondary myelofibrosis or acute leukemiaFrom date of inclusion until documentation of the event, assessed up to 5 years

Evolution toward secondary myelofibrosis or acute leukemia will be defined according to the WHO classification of hematological malignancies

Occurrence of thrombosis prior to diagnosis or during follow-up of the diseaseBetween 1 year before and 2 years after MPN diagnosis

Occurrence of myocardial infarction, ischemic stroke, deep vein thrombosis, pulmonary embolism, splanchnic thrombosis or any other significant thrombosis. Tinnitus, vertigo, headaches, erythromelalgia as well as superficial vein thrombosis will not be considered as thrombotic events

LeukocytesAt inclusion, up to 1 year after diagnosis

Leukocytes level on blood count in G/L

PlateletsAt inclusion, up to 1 year after diagnosis

Platelet level on blood count in G/L

HemoglobinAt inclusion, up to 1 year after diagnosis

Hemoglobin level on blood count in g/dL

GranulocytesAt inclusion, up to 1 year after diagnosis

Granulocytes level on blood count in G/L

MonocytesAt inclusion, up to 1 year after diagnosis

Monocytes level on blood count in G/L

HematocritAt inclusion, up to 1 year after diagnosis

Hematocrit level on blood count in %

Trial Locations

Locations (1)

CHU de Bordeaux, service Hématologie Biologique

🇫🇷

Bordeaux, France

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