treatment

Last edited 11/2021 and last reviewed 10/2023

Risk stratification in PV

The principal aims of risk stratification in PV are:

a) to select patients at higher risk of thrombosis for consideration of cytoreductive therapy and

b) to provide the most accurate information to patients on the risks and implications of a diagnosis of PV

Recommendations: risk stratification

• Age and thrombotic history should be used to define risk groups for thrombosis in polycythaemia vera (PV)

• 'High risk': age >=65 years and/or prior PV-associated arterial or venous thrombosis
• 'Low risk': age <65 years and no PV-associated thrombotic history


• Some 'low risk patients' may be to be considered at higher risk in the presence of cardiovascular risk factors, elevated white blood cell (WBC) count, extreme thrombocytosis or haematocrit (Hct) uncontrolled with venesection

• A number of variables including age, prior thrombosis, the presence of splenomegaly, serum lactate dehydrogenase (LDH) level, degree of reticulin staining, presence of an abnormal karyotype and JAK2 mutant allele burden may be utilised when counselling the patient on longer term prognosis including overall survival and disease transformation risk.

• Deep sequencing for 'high risk mutations' e.g. ASXL1, SRSF2, IDH1/2 is not yet 'standard of care' but may be considered in selected cases where their presence may influence management.

Treatment goals:

o Reduce thrombosis and haemorrhage risk
o Minimise complications and symptomatology
o Minimise risk of transformation to myelofibrosis and acute leukaemia
o Manage specific situations such as pregnancy and surgery
o Achieve good haematocrit control to <0.45

Hydroxycarbamide

• Hydroxycarbamide (HC) is a cytoreductive agent, a non-alkylating antimetabolite which acts through inhibition of ribonucleotide reductase thereby regulating the rate of DNA synthesis.
• HC has a dose-dependent effect and needs to be individually titrated to achieve optimal count control
• Evidence suggests, in patients with PV, patients treated with HC experienced significantly fewer vascular complications (11%) than patients treated with venesection only, with a survival advantage for patients treated with HC when adjusted for variables supporting the use of this agent in first-line treatment

Side effects

• HC is generally well tolerated
• Macrocytosis is expected and myelosuppression is seen in some patients
• Mucocutaneous side effects occur, including ulceration in perimalleolar areas, oral aphthous ulceration, actinic keratosis, squamous cell cancer and other skin lesions
• Gastrointestinal side effects have been reported.

European LeukaemiaNet criteria for hydroxycarbamide intolerance and resistance

1. Need for phlebotomy to keep haematocrit <0.45 after 3 months of at least 2 g/day of hydroxycarbamide OR
2. Uncontrolled myeloproliferation, i.e. platelet count >400 x 10^9/l AND white blood cell count >10 x 10^9/l after 3 months of at least 2 g/day
of hydroxycarbamide OR
3. Failure to reduce massive* splenomegaly by more than 50% as measured by palpation OR failure to completely relieve symptoms related to
splenomegaly, after 3 months of at least 2 g/day of hydroxycarbamide OR
4. Absolute neutrophil count <1.0 x 10^9/l OR platelet count <100 x 10^9/l OR haemoglobin <100 g/l at the lowest dose of hydroxycarbamide
required to achieve a complete or partial clinico-haematological response OR
5. Presence of leg ulcers or other unacceptable hydroxycarbamide -related non-haematological toxicities, such as mucocutaneous manifestations,
gastrointestinal symptoms, pneumonitis or fever at any dose of hydroxycarbamide

Polycythaemia vera is a myeloproliferative neoplasm known to be associated with dysregulated signalling of the Janus associated kinases JAK1 and JAK2

• Ruxolitinib is a selective inhibitor of JAK1 and JAK2 and is the first in class for this indication

Recommendations: management options for ALL PV including low-risk patients

• Target haematocrit of <0.45 in all patients

• Low dose aspirin (75-100 mg) in all patients

• Targeted intervention to reduce cardiovascular risk factors

• Consider cytoreductive therapy in low-risk patients with:
• History of treated arterial hypertension, ischaemic heart disease or diabetes mellitus
• Persistent leucocytosis (e.g. WBC count >15 x 10^9/l)
• Uncontrolled haematocrit (or poor tolerability of venesection)
• Extreme/progressive thrombocytosis (e.g. >= 1500 x 10^9/ l) and/or haemorrhagic symptoms
• Progressive/symptomatic splenomegaly
• Uncontrolled or progressive disease-related symptoms, e.g. weight loss, sweats
  

Recommendations: Management options in high-risk patients

• First Line: hydroxycarbamide (HC) or interferon (preferably pegylated interferon)

• consensus guidelines recommend interferon as an option for first-line cytoreduction, and in particular in younger or pregnant patients (3)

• Second line: in patients treated with HC as first line, interferonas second line treatment, or, where treated with interferon as first line, recommend HC as second line treatment

• consider pegylated interferon as second line in those patients who have had non-pegylated interferon first line and could not tolerate it
• Ruxolitinib second/third line in HC resistant or intolerant patients

Third-line or further treatment options

• Busulfan or 32P or pipobroman in those with limited life expectancy
• Anagrelide in combination with HC may be helpful in those where platelet control is difficult

Reference:

1. McMullin MF et al. Guidelines for the diagnosis, investigation and management of polycythaemia/erythrocytosis. Br J Haematol. 2005 Jul;130(2):174-95
2. McMullin MF et al. A guideline for the diagnosis and management of polycythaemia vera. A British Society for Haematology Guideline.British Journal of Haematology, 2019, 184, 176-191
3. How J, Hobbs G. Use of Interferon Alfa in the Treatment of Myeloproliferative Neoplasms: Perspectives and Review of the Literature. Cancers (Basel). 2020;12(7):1954. Published 2020 Jul 18. doi:10.3390/cancers12071954