Cytoreductive Agents

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The value of platelet count reduction in ET depends on the estimated risk of major thrombotic or hemorrhagic complications in the untreated patient. The parameters that separate patients into different risk categories are still somewhat uncertain, but there is widespread agreement that older patients with higher platelet counts (rather arbitrary values of 60 years and above 1,000 or 1,500 X 109/L may be taken), or other thrombotic risk factors as above (particularly a previous ischemic event or thrombosis) would benefit from a cytoreductive agent.17 Disagreement mainly occurs in the management of young and middle-aged patients, in whom the need for prospective trials is particularly strong. The risk of thrombotic problems in young untreated patients is uncertain, although there is growing recognition that it may not be negligible.

Hydroxyurea Hydroxyurea slows DNA synthesis and repair by inhibiting ribonucleotide reductase, which results in reduction of red cells and white cells as well as platelets. It is the most extensively used myelosuppressive agent in the treatment of ET as well as other myeloproliferative disorders. It has to be taken regularly by mouth, and there is a risk of rebound rise of the platelet count if it is stopped suddenly. It can be difficult to maintain a platelet count steadily below the usual target of 400 X 109/L in some patients, and there is sometimes an unacceptable degree of macrocytic anemia or neutropenia. Mild gastrointestinal and cutaneous side effects are not usually a problem, although troublesome leg ulceration can occur and is a contraindication to hydroxyurea use. It is still uncertain whether hydroxyurea increases the background risk of transformation to acute leukemia, a feature of particular relevance in young patients with potentially prolonged exposure. Sterkers et al.18 in a retrospective study found an incidence of 3.5 percent of acute leukemia or myelodysplasia in patients with ET treated with hydroxyurea alone at a mean follow-up time of 98 months. A decreased risk of myelofibrotic transformation in patients taking hydroxyurea has not yet been established in ET but is a possibility, particularly in those who have histological changes of the so-called prefibrotic myelofibrosis group. Cortelazzo et al.19 have demonstrated a significant decrease of thrombotic episodes in "high-risk" patients treated with hydroxyurea and compared these patients prospectively with a randomized control group who had no myelosuppression. They observed a 3.6 percent incidence of thrombotic episodes in treated versus 24 percent in untreated patients over a median follow-up period of 27 months. The ability of other platelet-lowering agents (discussed below) to achieve clinical benefit is presumed but has not yet been demonstrated. The use of an untreated "high-risk" control group of patients would now be difficult to justify in prospective trials.

Alpha-interferon The attraction of a presumed nonleuke-mogenic agent with the potential to eradicate an abnormal hemopoietic clone has led to the use of a-interferon especially in the young. It can successfully reduce the platelet count, and a maintenance dose of approximately 9 milliunits/week is required.20 Very occasionally, short remissions occur without the requirement for a-interferon therapy. However, the persistence of nonspecific side effects, rather than the inconvenience of subcutaneous injections, means that more than half of the patients cannot sustain treatment in the long term, thus delaying knowledge of any crucial effects on the progression of ET.

Anagrelide The oral agent anagrelide was unexpectedly found to specifically reduce platelet counts by inhibiting megakary-ocyte platelet budding and is active in 95 percent of patients. It is not expected to have neoplastic potential. Its convenience and probable long-term advantages are now becoming attractive, especially for younger patients. Its use in older patients with ischemic heart disease or cardiac failure is discouraged. Other side effects caused by the drug's vasodilatory action (headaches, diarrhea) and positive inotropic action (palpitations) are usu ally transient.21 However, some 20 percent of patients do not tolerate the drug. The results of prospective randomized studies comparing anagrelide with hydroxyurea in terms of thrombotic risk and marrow transformation are awaited.

Busulfan Suspicion of the potential long-term side effects of all alkylating agents, as well as the risk of prolonged bone marrow suppression, means that busulfan is no longer favored for the treatment of ET, although it has some specific effect on proliferating megakaryocytes. However, it has been successfully and conveniently used in surprisingly small intermittent doses by some centers.22 Its use is now mainly confined to elderly patients. A recent study suggesting an increased risk of second malignancies after sequential use of busulfan and hydroxyurea strikes a further warning note.23

Future Directions

Important future aims in the management of ET are to identify further parameters (e.g., clonality and histological evidence of prefibrotic myelofibrosis) that may predict vascular and disease transformation risks. This would help direct appropriate treatment with the lowest cost/benefit ratio in what is clearly a het-erogenous disease.1 The potential of bone marrow transplantation in ET has not yet been assessed. In any event it would only be considered in the few younger patients who have thrombotic events in spite of optimal traditional treatment.

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