MITHRIDATE: Ruxolitinib Versus Hydroxycarbamide or Interferon as First Line Therapy in High Risk Polycythemia Vera

Population: High risk PV defined as WBC \>11 x 10\^9/l\* AND at least ONE of the following * Age \>60 years * Prior thrombosis or haemorrhage * Platelet count \>1000 x 10\^9/l\* * Hypertension or diabetes requiring pharmacological therapy (\*At any time since diagnosis) Inclusion Criteria: 1. Patient ≥18 years of age 2. Diagnosis of PV meeting the WHO criteria within the past 15 years 3. Meets criteria of high risk\* PV (see above for specific population) 4. Patients must have a screening haemoglobin of \>8g/dl 5. Patients may have received antiplatelet agents and venesection 6. Patients may have received ONE cytoreductive therapy for PV less than 10 years (BUT they should not be resistant or intolerant to that therapy) 7. Able to provide written informed consent Exclusion Criteria: 1. Diagnosis of PV \> 15 years previously 2. Absence of JAK-2 mutation 3. Patients with any contraindications to any of the investigational medical products 4. Treatment with \>1 cytoreductive therapy OR a cytoreductive treatment duration exceeding 10 years OR resistance/intolerance to that therapy 5. Active infection including Human Immunodeficiency Virus (HIV), hepatitis B, hepatitis C, autoimmune hepatitis, Tuberculosis 6. Pregnant or lactating patients (Women of childbearing potential must have a negative urine or blood Human Chorionic Gonadotropin pregnancy test prior to trial entry) 7. Patients with lactose allergies, hypersensitivities, or rare hereditary problems, of galactose intolerance, total lactase deficiency or glucose- galactose malabsorption 8. Patients with uncontrolled neuropsychiatric disorders 9. Patients with uncontrolled cutaneous cancers 10. Patients and partners not prepared to adopt highly effective contraception measures (if sexually active) whilst on treatment and for at least 6 months after completion of study medication 11. ECOG Performance Status Score ≥ 3 12. Uncontrolled rapid or paroxysmal atrial fibrillation, uncontrolled or unstable angina, recent (within the last 6 months) myocardial infarction or acute coronary syndrome or any clinically significant cardiac disease \> NYHA ( New York Heart Association) Class II 13. Patients who have transformed to myelofibrosis 14. Previous treatment with ruxolitinib 15. Previous (within the last 12 months) or current platelet count \<100 x 109/L or neutrophil count \< 1 x 109/L not due to therapy 16. Inadequate liver function as defined by ALT/AST \>2.0 x ULN 17. Inadequate renal function as defined by eGFR \< 30 mls/min 18. Unable to give informed consent Additional Exclusion Criteria for France Only 19. All women of childbearing potential (as per Appendix 8 definition) 20. No affiliation with the French healthcare system 21. Persons under psychiatric care that would impede understanding of informed consent and optimal treatment and follow-up 22. Adults subject to a legal protection measure (guardianship, curatorship and safeguard of justice) 23. Patients deprived of their liberty by a judicial or administrative decision