Prescribing information (hosted externally)

The treatment landscape
for polycythaemia vera

First-line treatment options for polycythaemia vera1

Antithrombotics
Antiplatelet therapy with
low‑dose aspirin1,2

Phlebotomy
(venesection)1,2

HIGH-RISK PATIENTS1-4

Cytoreductive therapies:1-4*

  • Hydroxyurea (HU)†
  • IFN‑alfa
  • PegIFN‑alfa
  • RopegIFN alfa-2b

Symptom-directed therapies as needed1,5,6

Therapies for splenomegaly:2

  • Splenectomy
  • Splenic irradiation

Therapies for pruritus:1,5,6

  • Antihistamines
  • Skin lubrication
  • Topical agents

*Cytoreductive therapies may be considered for low-risk patients with progressively increasing splenomegaly or leucocyte and platelet counts, and those who do not tolerate phlebotomy.7
†HU should be used with caution in younger patients (aged <40 years).2

Antiplatelet therapy: aspirin

All eligible patients with PV should be managed with low‑dose aspirin2

  • Aspirin reduces the rate of platelet formation in artery walls1
  • The ECLAP study (N=518) showed that aspirin significantly lowered the risk of the primary composite endpoint of CV death, non-fatal MI, non-fatal stroke and major VTE versus placebo8‡
  • Adverse events include bleeding, gastric intolerance and heartburn1,9

Anticoagulant medications

  • A 2015 study demonstrated that anticoagulant (VKA) treatment reduced risk of thrombotic recurrence without a significant effect on major bleeding, compared with no VKA10
  • Nevertheless, major bleeding remains a possible adverse event and a clinical risk that must be factored into decision‑making11

‡European Collaboration on Low-Dose Aspirin in Polycythemia Vera (ECLAP) was a double‑blind, placebo‑controlled, randomised clinical study evaluating the efficacy and safety of prophylactic low‑dose aspirin in patients with PV. Patients without a clear indication or contraindications to aspirin were enrolled (N=518); the median age was 61 years and the mean duration of follow‑up was about 3 years. Aspirin significantly lowered the risk of a primary composite endpoint, including CV death, non‑fatal MI, non‑fatal stroke and major VTE, versus placebo (3.2% vs 7.9%; relative risk: 0.40; 95% CI: 0.18‑0.91; p=0.03). The rate of major bleeding events was not significantly different for aspirin versus placebo (1.2% vs 0.8%; relative risk: 1.62; 95% CI: 0.27‑9.71). Low‑dose aspirin remains standard therapy for all patients with PV.8

All eligible patients with PV should be managed with phlebotomy together with daily low dose aspirin2,12

  • Targeting HCT <45% reduces thrombosis risk and is recommended by the ELN and BSH guidelines4,12
  • A volume of blood is drawn at regular intervals - initially every other day or twice per week, until the haematocrit target is reached9,13

 

Advantages

Can reduce HCT concentration to normal within weeks or months1

Can ease PV-related symptoms, such as headaches, ringing in the ears and dizziness1

Disadvantages

Phlebotomy is generally unsuitable for long-term treatment; a ≥15‑year follow‑up analysis found it increases the risk of early progression to myelofibrosis with myeloid splenomegaly14

Iron deficiency can develop in patients who receive phlebotomies over a long period of time1

Phlebotomy dependence is one of the independent risk factors for thrombosis.15 See more 

Phlebotomy can result in abnormal RBC morphology and cause reactive thrombocytosis symptoms9

Cytoreductive therapies

Cytoreductive therapies should be considered for high-risk patients with PV (aged ≥60 years and/or history of PV‑related thrombosis) and may also be considered for low‑risk patients (any age):12,16

  • with progressively increasing splenomegaly
  • with progressively increasing leucocyte and platelet counts
  • who do not tolerate phlebotomy

About hydroxyurea (HU)

  • Targets multiple areas of haematologic overproduction by inhibiting ribonucleotide reductase, which prevents DNA synthesis4,9
  • Can reduce HCT concentration and platelet count1
  • Is the most commonly used first‑line cytoreductive therapy in patients with PV17
    • In the PVSG study (N=51), HU was compared retrospectively with phlebotomy alone in 194 patients. HU led to a reduction in thrombotic events (9.8% vs 32.8% in the phlebotomy group; p=0.009)17
  • Hydroxyurea should be used with caution in younger patients12

Adverse events

Adverse events include, but are not limited to, macrocytosis, myelosuppression, ulceration in perimalleolar areas, oral aphthous ulceration, actinic keratosis, squamous cell cancer and other skin lesions, as well as gastrointestinal side effects.4

Intolerance and resistance

  • Although HU is generally well tolerated,4 intolerance may affect 1 in 8 people18
  • 1 in 9 patients develop resistance to HU18
    • Resistance to HU is associated with an approximately 5.6-fold increase in risk of death (95% CI: 2.7-11.9; p<0.001)18
  • Monitoring resistance and intolerance criteria is important to inform when a change of therapy is needed18,19
Visit module 2 of this series to learn more about HU resistance and intolerance 

About IFN‑alfa

  • Not licensed for PV20
  • Directly inhibits fibroblast progenitor cells and suppresses proliferation of haematopoietic progenitors20
  • Has demonstrated efficacy in normalising blood counts, treating splenomegaly, preventing thrombosis and treating pruritus in patients with PV4

Adverse events and tolerability

  • Adverse events include flu-like symptoms, fatigue, depression, musculoskeletal pain, changes in mood, anxiety, injection site reaction, gastrointestinal toxicity (nausea, vomiting, diarrhoea) and weight loss20

About pegIFN‑alfa

  • Modified IFN with PEG chain attached, with a longer half-life than IFN‑alfa21
  • Less frequent administration and better tolerability versus IFN‑alfa (latter applies to pegIFN‑alfa-2a)4,22
  • Has demonstrated efficacy in normalising myeloproliferation and preventing thrombosis2
  • Off-label in patients with PV that are intolerant or resistant to hydroxyurea21

Adverse events and tolerability

  • The most frequent grade 3 or 4 toxicity with pegIFN‑alfa-2a is neutropenia. Other adverse events reported include infection, diarrhoea, depression and elevated liver function tests22
  • PegIFN‑alfa-2b shares similarities with unmodified IFN‑alfa;20 side effects include fatigue, injection site reaction, flu-like symptoms, headache, myalgia, depression, insomnia, alopecia and weight loss23

About ropegIFN alfa‑2b

  • Indicated as monotherapy in adults with PV without symptomatic splenomegaly25
  • May be considered more frequently for younger patients26
  • Has demonstrated complete haematological responses in 71% of patients with PV and sustained reductions in mutation burden of JAK2 V617F from baseline4,25
    • An open-label, phase IIIb extension study (CONTINUATION-PV) enrolled 171 adult patients with PV who previously completed the PROUD-PV study to evaluate the long-term efficacy and safety of ropegIFN alfa-2b. 95 patients continued to receive ropegIFN alfa-2b (from 50-500 mcg administered subcutaneously every 2, 3 or 4 weeks). The mean dose after 36 months of treatment (12-month treatment duration in the PROUD-PV study and 24-month treatment duration in the extension study) was 363 (±149) mcg for ropegIFN alfa-2b4

Adverse events and tolerability

  • The most common adverse reactions include leukopenia, thrombocytopenia, arthralgia, fatigue, increased gamma-glutamyltransferase, flu-like illness, myalgia, pyrexia, pruritus, increased alanine aminotransferase, anaemia, pain in extremity, alopecia, neutropenia, increased aspartate aminotransferase, headache, diarrhoea, chills, dizziness and injection site reaction25

Symptom-directed therapies

Pruritus

Patients with PV can suffer from aquagenic pruritus, a debilitating condition characterised by strong itching, stinging, tingling or burning sensations upon contact with water without visible changes to the skin:27

  • Antihistamines can be used but are largely ineffective9
  • Topical agents such as cooling cream, lidocaine cream, capsaicin or corticosteroids may be helpful6
  • Patients can try to reduce discomfort by lubricating the skin and minimising bathing6

Splenomegaly

Splenectomy

  • Indications for splenectomy include symptomatic portal hypertension, drug‑refractory painful splenomegaly and frequent RBC transfusions2
  • Adverse events include portal vein thrombosis, deep venous thrombosis and pulmonary emboli28

Splenic irradiation

  • Splenic irradiation is a palliative treatment for symptoms resulting from splenomegaly, especially discomfort and mechanical symptoms2,28
  • The procedure is typically reserved for patients who are unable to undergo splenectomy28
  • Adverse events include increased haemoglobin levels and decreased WBC counts29
NEXT: About second-line+ treatment options 

BSH: British Society for Haematology; CI: confidence interval; CV: cardiovascular; ELN: European LeukemiaNet; HCT: haematocrit; HR: hazard ratio; IFN: interferon; MI: myocardial infarction; PV: polycythaemia vera; PVSG: Polycythemia Vera Study Group; RBC: red blood cell; ropegIFN: ropeginterferon; VKA: vitamin K antagonist; VTE: venous thromboembolism; WBC: white blood cell

JAKAVI® (ruxolitinib) is indicated for the treatment of adult patients with polycythaemia vera who are resistant to or intolerant of hydroxyurea.30

Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard. Adverse events should also be reported to Novartis online through the pharmacovigilance intake (PVI) tool at www.novartis.com/report or alternatively email medinfo.uk@novartis.com or call 01276 698370.

References
  1. Leukemia and Lymphoma Society. Polycythemia vera facts. Available at: lls.org. Accessed November 2024
  2. Barbui T, Barosi G et al. Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. J Clin Oncol 2011;29(6):761-770
  3. Gisslinger H, Klade C et al. Evidence for superior efficacy and disease modification after three years of prospective randomized controlled treatment of polycythemia vera patients with ropeginterferon alfa-2b vs HU/BAT. Blood 2018;132:579
  4. McMullin M F, Harrison C N et al. A guideline for the diagnosis and management of polycythaemia vera. A British Society for Haematology Guideline. Br J Haematol 2019;184(2):176-191
  5. NHS. Itchy skin. Available at: nhs.uk. Accessed November 2024
  6. Seccareccia D, Gebara N. Pruritus in palliative care: getting up to scratch. Can Fam Physician 2011;57(9):1010-1013, e1316-1019
  7. Arya Y, Syal A et al. Advances in the treatment of polycythemia vera: trends in disease management. Cureus 2021;13(3):e14193
  8. Landolfi R, Marchioli R et al. Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med 2004;350(2):114-124
  9. Passamonti F. How I treat polycythemia vera. Blood 2012;120(2):275-284
  10. Hernandez-Boluda J C, Arellano-Rodrigo E et al. Oral anticoagulation to prevent thrombosis recurrence in polycythemia vera and essential thrombocythemia. Ann Hematol 2015;94(6):911-918
  11. Kaifie A, Kirschner M et al. Bleeding, thrombosis, and anticoagulation in myeloproliferative neoplasms (MPN): analysis from the German SAL‑MPN-registry. J Hematol Oncol 2016;9:18
  12. Barbui T, Tefferi A et al. Philadelphia chromosome-negative classical myeloproliferative neoplasms: revised management recommendations from European LeukemiaNet. Leukemia 2018;32(5):1057-1069
  13. Marchioli R, Finazzi G et al. Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med 2013;368(1):22-33
  14. Najean Y, Dresch C, Rain J D. The very-long-term course of polycythaemia: a complement to the previously published data of the Polycythaemia Vera Study Group. Br J Haematol 1994;86(1):233-235
  15. Alvarez-Larran A, Perez-Encinas M et al. Risk of thrombosis according to need of phlebotomies in patients with polycythemia vera treated with hydroxyurea. Haematologica 2017;102(1):103-109
  16. Marchetti M, Vannucchi A M et al. Appropriate management of polycythaemia vera with cytoreductive drug therapy: European LeukemiaNet 2021 recommendations. Lancet Haematol 2022;9(4):e301-e311
  17. Griesshammer M, Kiladjian J J, Besses C. Thromboembolic events in polycythemia vera. Ann Hematol 2019;98(5):1071-1082
  18. Alvarez-Larran A, Pereira A et al. Assessment and prognostic value of the European LeukemiaNet criteria for clinicohematologic response, resistance, and intolerance to hydroxyurea in polycythemia vera. Blood 2012;119(6):1363-1369
  19. Barosi G, Birgegard G et al. A unified definition of clinical resistance and intolerance to hydroxycarbamide in polycythaemia vera and primary myelofibrosis: results of a European LeukemiaNet (ELN) consensus process. Br J Haematol 2010;148(6):961-963
  20. Nazha A, Gerds A T. Where to turn for second-line cytoreduction after hydroxyurea in polycythemia vera? Oncologist 2016;21(4):475-480
  21. PegIFN‑alfa Summary of Product Characteristics
  22. Quintas-Cardama A, Kantarjian H et al. Pegylated interferon alfa-2a yields high rates of hematologic and molecular response in patients with advanced essential thrombocythemia and polycythemia vera. J Clin Oncol 2009;27(32):5418-5424
  23. Samuelsson J, Hasselbalch H et al. A phase II trial of pegylated interferon alpha-2b therapy for polycythemia vera and essential thrombocythemia: feasibility, clinical and biologic effects, and impact on quality of life. Cancer 2006;106(11):2397-2405
  24. Mascarenhas J, Mesa R et al. Optimal therapy for polycythemia vera and essential thrombocythemia can only be determined by the completion of randomized clinical trials. Haematologica 2014;99(6):945-949
  25. Ropeginterferon alfa-2b Summary of Product Characteristics
  26. Benevolo G, Vassallo F et al. Polycythemia vera (PV): update on emerging treatment options. Ther Clin Risk Manag 2021;17:209-221
  27. Siegel F P, Tauscher J, Petrides P E. Aquagenic pruritus in polycythemia vera: characteristics and influence on quality of life in 441 patients. Am J Hematol 2013;88(8):665-669
  28. Logan M S, Watson C M, Nottingham J M. Symptomatic splenomegaly in polycythemia vera: a review of the indications for splenectomy and perioperative considerations. Am Surg 2009;75(5):363-368
  29. Nazmy M S, Radwan A, Mokhtar M. Palliative spleen irradiation: can we standardize its technique? J Egypt Natl Canc Inst 2008;20(1):31-35
  30. JAKAVI® Summary of Product Characteristics. Available at: www.medicines.org.uk (for GB) or www.emcmedicines.com (for NI). Accessed November 2024