Canterbury DHB

Context

PV Refractory or Intolerant Hydroxyurea

Patients are considered refractory to hydroxyurea if:

Up to 20% of patients may be refractory or intolerant.

See Barbui T, et al. (2011),7 table 4, page 4 for the European LeukemiaNet definition of resistance/intolerance to hydroxyurea in patients with polycythemia vera and essential thrombocythemia.

Resistance to hydroxyurea was an adverse prognostic factor in the same European LeukemiaNet study. The optimal second-line therapy is unclear, and there is a lack of large-scale controlled clinical trials. The situation in New Zealand is further complicated by the lack of funding for treatments commonly recommended by overseas experts.

Cytoreductive agents

The European LeukemiaNet recommends cytoreductive agents as second-line agents for patients ≥60 years after failure of hydroxyurea. However, due to the potential leukemogenicity of some of these agents, the low rate of progression of PV and ET to malignant neoplasms, and relatively long life expectancy for patients with PV and ET, other experts recommend reserving agents such as pipobroman, busulphan, or radiophosphorous for elderly patients or those with advanced disease.

Pegylated interferon-2-alpha

Pegylated interferon-2-alpha has shown high response rates in PV, and data8 indicates that JAK2 mutation burden is reduced in patients who use this medication (molecular response). However, as yet, most experts still do not recommend it over hydroxyurea as first-line therapy (except possibly in patients <40 years old), and it is not funded for MPN in New Zealand.

It is generally started at 45 mcg/week subcutaneously for the first 2 weeks, and increased (as tolerated) to a maximal dose of 180 mcg/week.

As of July 2018, the outcome of a prospective, randomized evaluation of pegylated IFN alfa versus hydroxyurea in PV and essential thrombocythemia (NCT01259856) is awaited.

Short-acting IFN

Short-acting IFN can be considered, but is poorly tolerated. More than half of patients discontinue treatment due to adverse effects and reduced quality of life.

JAK2 inhibitors

JAK2 inhibitors, e.g. ruxolitinib, have been shown to be effective in PV patients who have failed other treatments, especially in patients with significant constitutional symptoms, splenomegaly, or puritus. They have not been shown to induce molecular response or alter the natural history. They are expensive and, as of July 2018, not funded in New Zealand.

Pipobroman

Pipobroman is a commonly used drug for PV and ET in Europe, and has similar efficacy to hydroxyurea. The median dose is 25-50mg daily. As of July 2018, it is only available through NPPA.

Anagrelide

Anagrelide is associated with an increased risk of vascular complications compared to hydroxyurea in the MRC PT-1 trial in ET, therefore exercise caution in its use in PV. Low-dose hydroxyurea and anagrelide may be a suitable option for a minority of patients.

Phosphorus-32 ( 32 P) therapy

Phosphorus-32 ( 32 P) therapy should be reserved for patients aged older than 80 years, or patients with comorbid conditions whose life expectancy is less than 5–10 years, where the convenience of 32 P dosing outweighs the substantial risks of developing acute leukaemia 5–15 years after 32 P administration.

Busulfan

Busulfan is usually reserved for older patients (≥60 years) who require myelosuppression, but have failed treatment with other agents. A reasonable starting dose is 2–4 mg/day, adjusted based on weekly monitoring of complete blood counts.

About this Canterbury DHB document (6232):

Document Owner:

Sean Macpherson (see Who's Who)

Issue Date:

August 2018

Next Review:

April 2021

Keywords:

Note: Only the electronic version is controlled. Once printed, this is no longer a controlled document. Disclaimer

Topic Code: 6232