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

Myeloproliferative Neoplasm Clinical Trial

— EpiC  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06022328
• Other study ID #: CHUBX 2023/15
• Status: Recruiting
• Start date: December 15, 2023
• Est. completion date: December 2024

Study information

• Verified date: March 2024
• Source: University Hospital, Bordeaux
• Contact: Olivier MANSIER
• Email: olivier.mansier[@]chu-bordeaux.fr
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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 information / eligibility

• Status: Recruiting
• Enrollment: 120
• Est. completion date: December 2024
• Est. primary completion date: December 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Myeloproliferative Disorders
• Myeloproliferative Neoplasm
• Neoplasms

Intervention

Biological:
• Assessment of the epigenetic age
Retrospective assessment of the epigenetic age on DNA samples obtained at diagnosis

Locations

Country	Name	City	State
France	CHU de Bordeaux, service Hématologie Biologique	Bordeaux

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Bordeaux

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Accelerated ageing of patients	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	At inclusion, up to 1 year after diagnosis
Secondary	Type of MPN (ET, PV or PMF) at diagnosis	We will study patients with a diagnosis of ET, PV or PMF as defined by the WHO classification of hematological malignancies	At inclusion, up to 1 year after diagnosis
Secondary	Transformation into secondary myelofibrosis or acute leukemia	Evolution toward secondary myelofibrosis or acute leukemia will be defined according to the WHO classification of hematological malignancies	From date of inclusion until documentation of the event, assessed up to 5 years
Secondary	Occurrence of thrombosis prior to diagnosis or during follow-up of the disease	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	Between 1 year before and 2 years after MPN diagnosis
Secondary	Leukocytes	Leukocytes level on blood count in G/L	At inclusion, up to 1 year after diagnosis
Secondary	Platelets	Platelet level on blood count in G/L	At inclusion, up to 1 year after diagnosis
Secondary	Granulocytes	Granulocytes level on blood count in G/L	At inclusion, up to 1 year after diagnosis
Secondary	Monocytes	Monocytes level on blood count in G/L	At inclusion, up to 1 year after diagnosis
Secondary	Hemoglobin	Hemoglobin level on blood count in g/dL	At inclusion, up to 1 year after diagnosis
Secondary	Hematocrit	Hematocrit level on blood count in %	At inclusion, up to 1 year after diagnosis
Secondary	Additional somatic mutation	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	At inclusion, up to 1 year after diagnosis