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ABSTRACT & COMMENTARY
Synopsis: Essential thrombocythemia is a chronic myeloproliferative disorder that, left untreated, is associated with hemorrhagic or thrombotic complications. Several drugs have been shown to lower platelet counts and reduce the occurrence of these complications over the short term. This report is the first concerning long-term treatment with anagrelide in young patients. The common side effects of this drug diminished with time—some patients developed anemia—but in general it was well tolerated and effective for the 10 plus years of treatment.
Source: Storen EC, Tefferi A. Blood. 2001;97:863-866.
Of the chronic myeloproliferative disorders, essential thrombocythemia (ET) has the most favorable prognosis.1 This is, in part, because it carries the least potential to transform into acute leukemia. Thrombotic or hemorrhagic complications are known to occur, particularly in those patients for whom the platelet count is not maintained below 600 ´ 109/L. Various treatments have been used to reduce platelet counts in this disorder, including hydroxyurea, busulfan, alpha interferon, and, more recently, anagrelide, and these have been successful in reducing thrombotic and hemorrhagic complications over the short course. However, experience with long-term therapy has been tempered by the risk of acute leukemia development, at least for those receiving busulfan and hydroxyurea. Anagrelide (Agrylin—Shireus), an oral imidazo-quinazoline derivative, was licensed in 1997 for treatment of ET, and it holds the theoretical advantage of not being leukemogenic.2 Short-term toxicity has been manageable for most, and toxicities include headache, fluid retention, and nausea.3 Anagrelide is effective in reducing platelet counts in the great majority of ET patients, and this has been shown to reduce thrombotic and hemorrhagic complications for those with the disorder.3,4
In the study recently published from the Mayo Clinic, 35 patients who received anagrelide before 1992 were evaluated. All patients were younger than 50 years of age at the time of treatment initiation (older patients were deliberately excluded from this analysis). Anagrelide treatments were adjusted on an individual basis, but the average starting dose was 2 mg/d (range, 1-10 mg/d), and the average maintenance dose was 2.5 mg/d (range, 1-5 mg/d). Three-quarters of the patients were symptomatic with ET (thrombosis in 20%, hemorrhage in 26%, and vasomotor symptoms in 51%). The median platelet count at the beginning of treatment was 1075 ´ 109/L (range, 690-2525 ´ 109/L).
Of the initially treated 35 patients, 26 (74%) achieved a completed remission and 7 (20%) a partial remission, for an overall response rate of 94%. Over the period of study, 27 of the 33 responding patients had remained on the drug for a median of 10.8 years (range, 7-15.5 years). Two of the initial responders had died (1 from a basilar artery hemorrhage and 1 in a motor vehicle accident) and the other 4 withdrew, primarily because of side effects.
With regard to the long-term toxicity, the following observations were described. Whereas the appearance of initial toxicity (headache, tachycardia, edema, and diarrhea) was common, the occurrence waned with the length of time on the drug. Over the long term, anemia was the only new side effect that emerged, with the average drop in hemoglobin, when compared to pretreatment levels, being 1.2 g/dL. However, 8 patients (24%) had a more than 3 g/dL drop. Only 3 patients discontinued therapy because of side effects, but dose reductions were documented in an additional 3 patients.
Anagrelide remained effective throughout the treatment period. Seven patients (20%) experienced a total of 10 episodes of thrombosis, and these were found to occur only in those whose platelet count was more than 400 ´ 109/L. In fact, in 8 of the 10, the platelet count was greater that 600 ´ 109/L at the time of the thrombotic event. Similarly, there were 4 reported bleeding events, and these occurred only when the platelet count was more than 400 ´ 109/L.
COMMENT by William B. Ershler, MD
This report indicates that the majority of young patients with ET can be effectively and safely treated long term with anagrelide. This is good news because ET is a chronic disease, but with high risk for thrombotic or hemorrhagic events when platelet counts are not reduced. It is gratifying to see that the initial adverse symptom complex (particularly headache and fluid retention) diminish with time. The anemia that develops is of some concern but, at least in this series, was not sufficient to require termination of treatment. (It is a curious note that the cause of the anemia remains unexplained but that it does not appear to be a direct inhibition of erythroid precursors by the drug).
The data cannot be generalized to all ET patients, inasmuch as only those younger than the age of 50 at diagnosis were included. Perhaps older patients on long-term anagrelide will have more substantial side effects or other evidence of toxicity. The older group, however, is also more likely to have catastrophic consequences of thrombocytosis, and continued effective therapy is required.
Anagrelide is, no doubt, a welcome advance for the management of essential thrombocythemia. It is effective in reducing platelet counts and most patients are able to get back in the normal range. More importantly, thrombotic and hemorrhagic complications are greatly lessened in treated patients. Now, it is apparent that long-term therapy is both safe and effective, at least for those patients younger than 50 years. There remain, however, no data that such therapy, or any specific drug therapy for this disorder, improves overall survival. It would take a randomized clinical trial to establish that, but it is unlikely that such will occur any time in the near future. Also needed are data about long-term management in older patients. Perhaps we will see an additional report from the Mayo Clinic group on this topic.
1. Rozman C, et al. Cancer. 1991;67:2658-2663.
2. Silverstein MN, et al. N Engl J Med. 1988;318: 1292-1294.
3. Mazur EM, et al. Blood. 1992;79:1931-1937.
4. Tefferi A, et al. Semin Thromb Hemost. 1997;23: 379-383.