Hydroxyurea Versus Aspirin and Hydroxyurea in Essential Thrombocythemia

Study Overview
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Brief Summary
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The hypothesis is that efficient prevention of thrombosis with aspirin at diagnosis becomes less useful once patients have achieved a hematologic response (HR) (modified by amendment 1/03/2017) 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 hematological response (modified by amendment 1/03/2017) on Hydroxyurea.

Detailed Description
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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 hematological response (modified by amendment 1/03/2017) on Hydroxyurea. Patients for which Aspirin interruption will not be possible because of extra-ET indications will be enrolled in the control observational arm.

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

Conditions
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MPN, Essential Thrombocythemia

Intervention / Treatment
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* Other: Aspirin therapy interruption
* Other: Usual treatment by aspirin 100 mg/d in the active comparator arm
* Other: No interruption of aspirin in the Observational arm
* Drug: Hydroxyurea treatment (HU)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: > 18 years and older (modified by amendment 01/03/2017) Contraception considered effective by the investigator: for women of childbearing and for men whose partner is likely to procreate (added by amendment 01/03/2017) Diagnosis of ET performed within the last 10 years (modified by amendment 01/03/2017) : with or without Janus kinase 2V617F (JAK2V617F) mutation according to the WHO 2008 criteria (TEFFERI,2007) ET patients currently treated with hydroxyurea in first line, who have achieved a complete or partial hematologic response according to the ELN 2009 (BAROSI, 2009) modified (at least three month apart and at inclusion) (modified by amendment 01/03/2017) Signed Written Informed Consent Health insurance coverage. Exclusion Criteria: Other myeloproliferative disorder than ET. Contra-indication to hydroxyurea. Other uncontrolled malignancies at the time of diagnosis or inclusion. History of haemostasis perturbation not related to ET, associated with a significant risk of hemorrhage or thrombosis (modified by amendment 01/03/2017) -.• Pregnancy or breastfeeding (added by amendment 01/03/2017) Inability to freely provide consent through judiciary or administrative condition.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HU without aspirin<br> | Other: Aspirin therapy interruption<br>* Stop the treatment by aspirin 100mg/d in the experimental arm.<br>Drug: Hydroxyurea treatment (HU)<br>* HU maintenance<br>|
| Active Comparator: HU + aspirin maintenance<br> | Other: Usual treatment by aspirin 100 mg/d in the active comparator arm<br>* HU+ aspirin maintenance<br>Drug: Hydroxyurea treatment (HU)<br>* HU maintenance<br>|
| Other: HU + AAG<br>Observational arm | Other: No interruption of aspirin in the Observational arm<br>* patient with Contre indication to aspirin or required antithrombotic therapy<br>Drug: Hydroxyurea treatment (HU)<br>* HU maintenance<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative incidence of death from vascular origin and other thrombotic and hemorrhagic events (combined endpoint) | 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. | at 2-years follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative incidence and characteristics of vascular complications: thrombosis and hemorrhage, (grade, site, recurrence), assessed yearly over a 5-year follow-up period. |  | at 5 years | 
| Rate of hematological response every 6 months | Hematological response as assessed by European Leukemia Net (ELN) criteria, revised ELN International Working Group on Myeloproliferative Neoplasms Research and Treatment (ELN -IWG MRT). | at 5 years | 
| Adverse event (AE) frequency and incidence, comparison in the two arms |  | at 5 years | 
| Number of HU-related nonhematologic toxicities |  | at 5 years | 
| Cumulative incidence of thrombosis |  | at 5 years | 
| Cumulative incidence of hemorrhagic complications |  | at 5 years | 
| Estimation of the progression-free survival |  | at 5 years | 
| Estimation of overall survival |  | at 5 years | 
| Short Form 36 (SF36) Health Survey | Evaluation of quality of life by using SF36 | through study completion, an average of 1 year | 
| Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) | Evaluation of quality of life by using (MPN-SAF) | through study completion, an average of 1 year | 
| Number of mortality cause. |  | at 5 years | 
| Cumulative incidence of progression to polyglobulia |  | at 5 years | 
| Cumulative incidence of progression to myelofibrosis (MF) |  | at 5 years | 
| Cumulative incidence of progression to myelodysplastic syndrome (MDS) |  | at 5 years | 
| Cumulative incidence of progression AML |  | 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 . |  | 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 hematological response (modified by amendment 1/03/2017). | responses and intolerance define according to ELN criteria | at 5 years | 
| 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 hematological response (modified by amendment 1/03/2017). | responses and intolerance define according to ELN criteria | at 5 years | 
| 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. | responses and intolerance define according to ELN criteria | at 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Essential Thrombocythemia, Aspirin