PT-1

Primary Thrombocythaemia 1 Trial

Research summary

The myeloproliferative disease primary thrombocythaemia (PT), also known as essential thrombocythaemia, 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.

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. 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%/year3. 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.

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. 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. 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. This group has now closed to recruitment and was randomised to receive 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.

This is a NCRI collaborative study in primary thrombocythaemia in adults. By dividing the patients into 3 risk groups this allows the patient population as a whole to be studied during their long term care. This is a non-commercial, open label phase III study with three patient groups. The groups are assigned on age and risk factors associated with the PT diseases for forming blood clots. The low risk group are aged 18 to ≤ 39 years with no high risk features. The intermediate group are aged 40 to ≤ 59 years with no high risk features and the high risk group have either high risk features or are aged > 60 years. Centres are based in Australia, France, New Zealand and UK & NI. Due to the frequency of low and intermediate risk patients, the aim is to recruit approximately 280 centres. Centres were opened in Ireland but following introduction of the EU Directive these centres were no longer able to continue as a coordinating investigator for the country was not available.

clinicaltrials.gov

isrctn.com

Main inclusion criteria

To be included in the study the patient must have:

  • Given written informed consent

  • Aged > 18 years

Patients with PT are eligible assuming they meet the diagnostic criteria as specified below. This includes previously diagnosed patients whether or not they have received treatment and newly diagnosed patients.

  • The diagnostic criteria for primary thrombocythaemia for the purposes of this study are:-

  1. Platelet count >600x109/l. *

  2. No evidence of overt polycythaemia (confirmed by RCM if necessary) or of polycythaemia masked by co-existent iron deficiency. †

  3. No Philadelphia chromosome. =

  4. Absence of peripheral blood and/or marrow appearances of myelodysplasia, or myelofibrosis.

  5. No known cause of reactive thrombocytosis. Particular care should be taken to exclude iron deficiency in pre-menopausal women $

Notes:

* In asymptomatic patients, the platelet count should be observed for a period of at least 2 months to confirm >600x109/l, and to allow any cause of reactive thrombocytosis to become overt.

† If the PCV is above normal upper limit (that is, males >0.51, females >0.48) or in high normal range in a patient with palpable splenomegaly measure RCM. Iron deficient primary polycythaemia (polycythaemia vera) is strongly suggested if Hb/PCV is normal in the presence of iron deficient red cell changes. In this situation, iron therapy is potentially dangerous.

= Exceeding rarely, bcr-abl positive, Philadelphia chromosome negative patients present with high platelet counts and little or no elevation in WBC counts. The features that suggest it is necessary to examine for bcr-abl, are: - basophilia, left-shift in WBC, granulocyte count >16x109/l, difficulty in controlling platelet count, megakaryocytes of low ploidy (NAP is usually unhelpful).

$ A normal ESR, CRP or plasma viscosity is useful in excluding a reactive thrombocytosis.

It should be noted that patients with impaired hepatic / renal function are not excluded although the respective biochemical tests should be monitored during therapy and reduced doses of cytoreductive agent should be used, particularly in the case of hydroxyurea and renal dysfunction.

In instances where the Investigator is unsure of diagnosis the investigator is encouraged to discuss the criteria on a patient by patient basis with the Chief Investigator.

Main exclusion criteria

The presence of any of the following will preclude patient inclusion from trial entry:

  • Medical or psychiatric conditions which may affect the patient’s ability to give consent.

  • Any medical or psychiatric condition which in the opinion of the investigator may make it undesirable for the patient to enter the study.

Closure of the intermediate and high risk groups to further recruitment therefore excludes patients with the following features

  • High risk features (any of the following)
    • Age > 40 years

- Platelet count > 1500x109/l (current or previous) a
- History of ischaemia, thrombosis or embolic events (including erythromelalgia) b
- Haemorrhage considered to be related to PT b
- Presence of hypertension c or diabetes d

Notes on the definition of high risk
a. In patients with borderline counts the allocation of a patient to a high risk group based on platelet count alone should rely on at least three samples taken on separate occasions over at least 2 months.
b. Documentation of previous thrombo-embolic, ischaemic and haemorrhagic events should be given on the patient’s entry proforma.
c. Hypertension is defined as those patients requiring anti hypertensive therapy.
d. Diabetes is defined as those patients requiring therapy with a hypoglycaemic agent.

Chief investigator

Prof Anthony Green

Contact details

Clinical Trials Manager: Dr Paula Kareclas

Telephone: 01223 596473 | Email: [email protected]