Primary Thrombocythaemia 1 Trial
Condition: Thrombocythemia; Myeloproliferative Disorder
MeSH terms: Thrombocytosis; Myeloproliferative Disorders; Thrombocythemia, Essential
Study type: Interventional

Summary: 
      The purpose of this trial is to see if Hydroxyurea + aspirin is a better treatment than
      aspirin alone for Intermediate Risk Primary Thrombocythemia (PT) patients.
    

Detailed description: 
      The myeloproliferative disease, primary thrombocythaemia (PT), has a median age of
      presentation of 60 years but is increasingly being recognised at an earlier age. The risks of
      the untreated condition are micro-vascular and major vessel occlusive events and haemorrhage.
      Older patients and those with a previous thrombosis are particularly prone to experience a
      significant vascular occlusive event. An anti-aggregating agent, such as aspirin, has been
      shown to reduce/alleviate minor ischaemic symptoms. Therefore, except in patients with
      haemorrhagic symptoms, peptic ulceration and known side-effects to aspirin, the use of
      low-dose aspirin is appropriate.

      Myelofibrotic and acute leukaemic transformations can be long-term complications of PT. The
      ability of therapeutic agents to delay myelofibrosis or reduce/increase the incidence of
      acute leukaemia in prospective studies is unknown. However, examination of retrospective data
      provides anxiety about the leukaemogenic risk of the commonly used cytoreductive agent,
      hydroxyurea. From an analysis of a few relatively small studies of primary thrombocythaemia,
      the incidence of acute leukaemic transformation in selected patients treated with hydroxyurea
      has been given as 5-10% over 4-11 years (1).

      Based on the risk factors for vascular occlusion, older patients with a thrombotic history
      and high platelet count can be separated into a 'high' risk group. There is evidence from a
      randomised prospective study of 'high-risk' patients that cytoreduction with hydroxyurea
      significantly reduces vascular occlusion (2). The observed reduction in this prospective
      study of 29 months median duration was from 24% for those not given cytoreductive treatment
      to 3.6% for those receiving hydroxyurea - approximately a six-fold reduction. In another
      prospective study where all patients received hydroxyurea, an incidence of major thrombotic
      events was 5.6%/year (3). In these high-risk patients, cytoreductive treatment should
      therefore be given. The high risk arm of the PT1 trial, which has now closed, assessed the
      cytoreductive treatment of choice for these high risk patients and the results suggest that
      hydroxyurea plus aspirin is superior to anagrelide plus aspirin (4).

      In the patients at lower risk of vascular occlusion the dilemma is that the risk of vascular
      occlusion in untreated patients is relatively low, but includes major life-threatening
      events. In two small prospective studies of these patients not receiving platelet lowering
      agents, the observed major complications were 3% and 4.1% per year and the total
      complications were 5.1% and 10.5% per year respectively (1). Cyto-reductive treatment should
      prevent such events and one could predict a similar reduction in complications as seen in the
      high-risk patients. However, there is evidence that in patients under the age of 40 years the
      complication rate is only one quarter of that seen in patients aged 40 - 59 years (5).
      Therefore it has been decided to divide these patients at lower risk of vascular occlusion
      into 'intermediate' and 'low risk' groups. Patients aged 40-59 years will fall into the
      'intermediate risk' group and will be randomised to cytoreduction or not, while all will
      receive aspirin. Patients under 40 years will form the 'low-risk' group and will receive
      aspirin alone. Cyto-reductive treatment might also delay myelofibrotic transformation as
      observed in primary polycythaemia. However, this benefit and the possible reduction in
      vaso-occlusive episodes need to be balanced against the potential long-term risk of
      increasing acute leukaemic transformation.
    

Intervention name(s): Hydroxyurea; Aspirin
Intervention type(s): Drug; Drug
Intervention description(s): Hydroxyurea (or hydroxycarbamide) is an antineoplastic drug commonly used to treat haematological malignancies.; Aspirin is an anti-aggregating agent, and has been shown to reduce/alleviate minor ischaemic symptoms.
Other intervention name(s): Hydroxycarbamide
Intervention MeSH terms: Aspirin; Hydroxyurea
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Primary Thrombocythmeia; Hydroxyurea; Randomised; Thrombosis; Haemorrhage