The British Society for Haematology recommends a variety of first-, second- and third-line treatments for patients with PV.1 Click here to see the BSH guideline recommendations.

Patients can become intolerant or resistant to conventional therapies2

HU is often used as a first-line cytoreductive treatment in high-risk patients.2 For patients under the age of 60, interferon* can be recommended instead.1,3,4

Switching to a second-line treatment may need to be considered, depending on individual patient factors.4 Up to 20.7% of patients with PV may become intolerant or resistant to HU treatment, which may lead to increased mortality.†5–7

Use the modified ELN recommendations to identify intolerance and resistance.4

*Not all forms of interferon therapies are licensed for the treatment of PV. Please refer to individual summary of product characteristics prior to prescribing.


Modified ELN criteria to help identify HU resistance and intolerance:4


 Icon of a pill bottle representing intolerance.


  • Haematologic toxicities
    • Absolute neutrophil count <1.0 × 109/L
    • Platelet count <100 × 109/L
    • Haemoglobin <10 g/dL
  • Non-haematological toxicities
    • Fever
    • Manifestations of the mucous membrane
    • Gastrointestinal symptoms
    • Pneumonitis
    • Leg ulcers

Icon of pill and a tick representing resistance.


  • Thrombosis or bleeding
  • Unacceptable number of phlebotomies to keep HCT <45%
  • Persisting disease-related symptoms
  • Platelet count >400 × 109/L and/or white blood cell count >10 × 109/L
  • No reduction of splenomegaly or a reduction <50%

HU intolerance or resistance is associated with reduced survival, increased risk of thrombosis and reduced quality of life5,6,8–10

HU resistance decreases median OS5

The development of HU resistance, as defined by the ELN criteria, was assessed in patients with PV that were treated with HU for a median time of 4.4 years (n=261). Patients that developed HU resistance, compared to those that did not, experienced a:5

The text '5.6x'

increase in the risk of death5

HR: 5.6; (95% CI: 2.7–11.9); p<0.001


Icon of a pill and a no entry sign representing treatment resistance.

A failure to keep HCT levels below 45% is associated with an increase in CV-related mortality or thrombotic events8

The CYTO-PV study was a large-scale, multicentre, prospective, randomised clinical trial comparing the efficacy of phlebotomy, HU or both for maintaining a HCT target of less than 45%, as compared with maintaining a target of 45–50%, for the prevention of thrombotic events in patients with polycythaemia vera (n=365). The protocol dictated that the HCT target to which patients were randomly assigned in a 1:1 ratio had to be maintained during the course of the study. The primary composite endpoint was the time until death from cardiovascular causes or major thrombotic events.§8

Adapted from Marchioli, et al. 2013.8

 Image representing elevated HCT level.


Skin toxicities linked with HU intolerance can lead to treatment discontinuation9

In a prospective, non-interventional study of skin alterations in 151 patients with MPNs (n=55 with PV) who gave informed consent:9

The text '43%'

of patients on HU developed skin toxicities9

The text '13%'

of patients discontinued HU treatment due to skin ulcers, phototoxicity/erythroderma, actinic keratoses and dry skin/xerostomia9


Patients with PV are recommended to switch to a second-line cytoreductive therapy if they meet the criteria for intolerance or resistance.3 The 2021 ELN recommendations for treatment suggest that treatment choice should be based on individual clinical features:3

  • Age
  • Spleen size
  • Symptoms
  • History of skin cancers
  • Patient preference



Download the Hydroxyurea Resistance and Intolerance Guide for further information on signs and treatment



Hydroxyurea is synonymous with/refers to hydroxycarbamide throughout.


HU resistance or intolerance was defined using the 2010 ELN criteria.7,11 In a retrospective analysis of 106 patients with PV in Belgium, when using the original and modified ELN criteria, 20.7% and 39.6% of patients were resistant or intolerant to HU, respectively.4,7,11
After 3 months of at least 2 g per day of HU or the maximum tolerated dose.5
§Event is defined as death from cardiovascular causes or thrombotic events (stroke, acute coronary syndrome, transient ischaemic attack, pulmonary embolism, abdominal thrombosis, deep-vein thrombosis, or peripheral arterial thrombosis).8

BSH, British Society for Haematology; CI, confidence interval; CV, cardiovascular; ELN, European LeukemiaNet; HCT, haematocrit; HR, hazard ratio; HU, hydroxyurea; IFN-alpha, interferon-alpha; MPN, myeloproliferative neoplasms; OS, overall survival; PV, polycythaemia vera; QoL, quality of life.


  1. McMullin F, et al. Br J Haematol. 2019;184:176–191.
  2. Raman I, et al. Leuk Lymphoma. 2021;62:2310–2319.
  3. Marchetti M, et al. Lancet Haematol. 2022;9:e301–e311.
  4. McMullin F, et al. Br J Haematol. 2016;172:337–349.
  5. Alvarez-Larrán A, et al. Blood. 2012;119:1363–1369.
  6. Alvarez-Larrán A, et al. Br J Haematol. 2016;172:786–793.
  7. Demuynck T, et al. Ann Hematol. 2019;98:1421–1426.
  8. Marchioli R, et al. N Engl J Med. 2013;368:22–33.
  9. Stegelmann FA, et al. EHA Congress 2017, 22–25 June; Madrid, Spain. Abstract E1335.
  10. Harrison CN, et al. Ann Hematol. 2017;96:1653–1655.
  11. Barosi G, et al. Br J Haematol. 2010;148:961–963. 
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UK | July 2023 | 253139

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 via [email protected] or online through the pharmacovigilance intake (PVI) tool at www.novartis.com/report
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