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

• ClinicalTrials.gov Identifier: NCT06022328
• Recruitment Status: Recruiting
• First Posted: September 1, 2023
• Last Update Posted: March 7, 2024
• Sponsor: University Hospital, Bordeaux
• Information provided by (Responsible Party): University Hospital, Bordeaux

Tracking Information

• First Submitted Date: July 24, 2023
• First Posted Date: September 1, 2023
• Last Update Posted Date: March 7, 2024
• Actual Study Start Date: December 15, 2023
• Estimated Primary Completion Date: December 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 28, 2023)

Accelerated ageing of patients [ Time Frame: At 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

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: August 28, 2023)

• Type of MPN (ET, PV or PMF) at diagnosis [ Time Frame: At 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 leukemia [ Time Frame: From 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 disease [ Time Frame: Between 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
• Leukocytes [ Time Frame: At inclusion, up to 1 year after diagnosis ]
  Leukocytes level on blood count in G/L
• Platelets [ Time Frame: At inclusion, up to 1 year after diagnosis ]
  Platelet level on blood count in G/L
• Granulocytes [ Time Frame: At inclusion, up to 1 year after diagnosis ]
  Granulocytes level on blood count in G/L
• Monocytes [ Time Frame: At inclusion, up to 1 year after diagnosis ]
  Monocytes level on blood count in G/L
• Hemoglobin [ Time Frame: At inclusion, up to 1 year after diagnosis ]
  Hemoglobin level on blood count in g/dL
• Hematocrit [ Time Frame: At inclusion, up to 1 year after diagnosis ]
  Hematocrit level on blood count in %
• Additional somatic mutation [ Time Frame: At 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

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Impact of Epigenetic Age on Clinic-biological Presentation and Prognosis in Myeloproliferative Neoplasms Epigenetic Age in Myeloproliferative Neoplasms (EpiC)
• Official Title: Impact of Epigenetic Age on Clinic-biological Presentation and Prognosis in Myeloproliferative Neoplasms Epigenetic Age in Myeloproliferative Neoplasms (EpiC)
• 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.

• Study Type: Observational
• Study Design: Observational Model: Cohort; Time Perspective: Retrospective
• Target Follow-Up Duration: Not Provided
• Biospecimen: Not Provided
• Sampling Method: Probability Sample
• Study Population: Patients with Myeloproliferative Neoplasia (MPN) : Essential Thrombocythemia (ET), Polycythemia Vera (VP) or Primary Myelofibrosis (PMF)
• Condition: Myeloproliferative Neoplasm

Intervention

Biological: Assessment of the epigenetic age

Retrospective assessment of the epigenetic age on DNA samples obtained at diagnosis

Study Groups/Cohorts

• Patients with ET

  45 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
  Intervention: Biological: Assessment of the epigenetic age
• Patients with PV

  45 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
  Intervention: Biological: Assessment of the epigenetic age
• Patients with PMF

  20 patients with PMF:

  • 10 without transformation into AML
  • 10 patients who progressed to AML
  Intervention: Biological: Assessment of the epigenetic age
• Patients without MPN
  10 patients without MPN
  Intervention: Biological: Assessment of the epigenetic age

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: August 28, 2023): 120
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 2024
• Estimated Primary Completion Date: December 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Olivier MANSIER; olivier.mansier@chu-bordeaux.fr

• Listed Location Countries: France

Administrative Information

• NCT Number: NCT06022328
• Other Study ID Numbers: CHUBX 2023/15
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: University Hospital, Bordeaux
• Original Responsible Party: Same as current
• Current Study Sponsor: University Hospital, Bordeaux
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: University Hospital, Bordeaux
• Verification Date: March 2024