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 sincediagnosis)

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 (BUTthey 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 durationexceeding 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 negativeurine or blood Human Chorionic Gonadotropin pregnancy test prior to trial entry)

7. Patients with lactose allergies, hypersensitivities, or rare hereditary problems, ofgalactose 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 completionof study medication

11. ECOG Performance Status Score ≥ 3

12. Uncontrolled rapid or paroxysmal atrial fibrillation, uncontrolled or unstableangina, recent (within the last 6 months) myocardial infarction or acute coronarysyndrome or any clinically significant cardiac disease > NYHA ( New York HeartAssociation) 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 orneutrophil 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 consentand optimal treatment and follow-up

22. Adults subject to a legal protection measure (guardianship, curatorship andsafeguard of justice)

23. Patients deprived of their liberty by a judicial or administrative decision