Clinical Trial: Hydroxyurea Versus Aspirin and Hydroxyurea in Essential Thrombocythemia

Study Status: Not yet recruiting
Recruit Status: Not yet recruiting
Study Type: Interventional

Official Title: French Aspirin Study in Essential Thrombocythemia: an Open and Randomized Study

Brief Summary:

The hypothesis is that efficient prevention of thrombosis with aspirin at diagnosis becomes less useful once patients have achieved a complete hematologic response (CHR) and/or that this benefit is hampered by an increased hemorrhagic risk especially in elderly patients.

Hence, investigator propose a prospective randomized study to assess the benefit / risk ratio of aspirin maintenance in high risk Essential thrombocythemia (ET) patients, in complete hematological response on Hydroxyurea.


Detailed Summary:

ET is a myeloproliferative neoplasm (MPN) characterized by a high platelet level. Increased occurrence of thrombosis and hemorrhages are the main complications in ET. In this regard, the key factors defining high risk ET include age over 60 years, past history of thrombosis, platelet > 1500 109/L and to a lesser degree cardiovascular risk factors. These criteria currently serve as therapeutic guidelines for the use of cytoreductive therapy, with hydroxyurea (HU) being the treatment of choice in the first line setting.

The use of antiplatelet agent i.e. low-dose aspirin is also generally recommended. However, the benefit of aspirin has never been formally demonstrated in ET. Only indirect evidence come from the ECLAP study that enrolled patients with polycythemia vera (PV). Of note in the ECLAP study, the efficacy of aspirin was assessed only at diagnosis but not correlated thereafter with the hematological response on cytoreductive therapy.

In general non-MPN population studies, primary prophylaxis with aspirin has been associated with a risk reduction of major vascular events, but an increased risk of hemorrhage, especially considering age and prior gastrointestinal history. In a recent retrospective study, the combination of aspirin and cytoreduction was reported to prevent thrombosis but concomitantly increase the bleeding risk when compared to HU alone , especially in patients older than 60 years, thus questioning the benefits of long term use of aspirin therapy. These data raise the question of the actual benefit of aspirin maintenance, once patients have been efficiently treated with cytoreductive therapy.

Hence, investigator propose a prospective randomized study to assess the benefit / risk ratio of aspirin maintenance in high risk ET patients, in complete hemato
Sponsor: Assistance Publique - Hôpitaux de Paris

Current Primary Outcome: Cumulative incidence of death from vascular origin and other thrombotic and hemorrhagic events (combined endpoint) [ Time Frame: at 2-years follow-up ]

Definition of vascular events:

Thrombotic events: Myocardial infarction, unstable angina, stroke, transient ischemic attack, peripheral arterial thrombosis, splanchnic or limb deep vein thrombosis, pulmonary embolism, and erythromelalgia

Hemorrhagic events:

Intracranial or retroperitoneal bleed, overt hemorrhage associated with a decrease in hemoglobin ≥20 g/l or overt hemorrhage requiring a blood transfusion of two red blood cell (RBC) units or more, and hemorrhage of grade >=2 according to the NCI Common Toxicity criteria (CTC) V.4.0 scale.

Deaths will be included as a death from thrombosis or hemorrhage if they satisfied criteria for one of the above diagnoses immediately ANTE-MORTEM or if they had a POST-MORTEM examination confirming the diagnosis. Sudden death of presumed vascular origin without a POST-MORTEM examination will be included as a thrombotic death.



Original Primary Outcome: Same as current

Current Secondary Outcome:

  • Cumulative incidence and characteristics of vascular complications: thrombosis and hemorrhage, (grade, site, recurrence), assessed yearly over a 5-year follow-up period. [ Time Frame: at 5 years ]
  • Rate of hematological response to hydroxyurea every 6 months [ Time Frame: at 5 years ]
    Hematological response as assessed by European Leukemia Net (ELN) criteria, revised ELN International Working Group on Myeloproliferative Neoplasms Research and Treatment (ELN -IWG MRT).
  • Adverse event (AE) frequency and incidence, comparison in the two arms [ Time Frame: at 5 years ]
  • Number of HU-related nonhematologic toxicities [ Time Frame: at 5 years ]
  • Cumulative incidence of thrombosis [ Time Frame: at 5 years ]
  • Cumulative incidence of hemorrhagic complications [ Time Frame: at 5 years ]
  • Estimation of the progression-free survival [ Time Frame: at 5 years ]
  • Estimation of overall survival [ Time Frame: at 5 years ]
  • Short Form 36 (SF36) Health Survey [ Time Frame: through study completion, an average of 1 year ]
    Evaluation of quality of life by using SF36
  • Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) [ Time Frame: through study completion, an average of 1 year ]
    Evaluation of quality of life by using (MPN-SAF)
  • Number of mortality cause. [ Time Frame: at 5 years ]
  • Cumulative incidence of progression to polyglobulia [ Time Frame: at 5 years ]
  • Cumulative incidence of progression to myelofibrosis (MF) [ Time Frame: at 5 years ]
  • Cumulative incidence of progression to myelodysplastic syndrome (MDS) [ Time Frame: at 5 years ]
  • Cumulative incidence of progression AML [ Time Frame: at 5 years ]
  • Frequencies of mutations (JAK2V617F, MPLw515 and CALR) and JAK2V617F allele burden, MPLw515 allele burden and CALR mutation allele burden (in blood DNA) in patients presenting thrombosis or not . [ Time Frame: at 5 years ]
  • Frequencies of mutations (JAK2V617F, MPLw515 and CALR) and JAK2V617F allele burden, MPLw515 allele burden and CALR mutation allele burden in patients in persistent complete hematological response. [ Time Frame: at 5 years ]
    responses and intolerance define according to ELN criteria
  • Frequencies of mutations (JAK2V617F, MPLw515 and CALR) and JAK2V617F allele burden, MPLw515 allele burden and CALR mutation allele burden in patient who will lose their complete hematological response. [ Time Frame: at 5 years ]
    responses and intolerance define according to ELN criteria
  • Frequencies of mutations (JAK2V617F, MPLw515 and CALR) and JAK2V617F allele burden, MPLw515 allele burden and CALR mutation allele burden in patients presenting intolerance to treatment. [ Time Frame: at 5 years ]
    responses and intolerance define according to ELN criteria


Original Secondary Outcome: Same as current

Information By: Assistance Publique - Hôpitaux de Paris

Dates:
Date Received: October 13, 2015
Date Started: November 2015
Date Completion: November 2022
Last Updated: November 19, 2015
Last Verified: September 2015