ABSTRACT
Platelet-lowering therapy in myeloproliferative disorders includes cytostatic drugs, mainly hydroxyurea, interferon α, and anagrelide. Anagrelide is the latest addition to the therapeutic arsenal, and the basis for its use is reviewed. The platelet-lowering efficacy is 70 to 80% in essential thrombocythemia, and the response is rapid; most of the patients reach the treatment goal within a few weeks. Side effects are common, mainly caused by the vascular effects, and include palpitation, headache, loose stools/diarrhea, and edema. Some side effects are time-limited, but late dropout from therapy is not uncommon. The total dropout rate in prospective studies is 30 to 50%. Pharmacologic treatment of side effects is often helpful. Cardiac insufficiency may be worsened in patients with previous heart failure, and special caution is warranted in such patients. Anagrelide has recently been registered in Europe as a second-line therapy in ET but is often used as first-line therapy in the United States, especially in younger patients, due to the concern about increased leukemia risk with cytostatic treatment. The first randomized anagrelide study, with its limitations, gives support for the second-line registration. Given that dose escalation is a problem in some patients with all therapeutic agents used, combination of two drugs in lower doses is a practical option already used by many clinicians without basis in any published study.
KEYWORDS
Myeloproliferative disease - platelet reduction - thrombocytosis - essential thrombocythemia - anagrelide
REFERENCES
-
1
Finazzi G, Barbui T.
Treatment of essential thrombocythemia with special emphasis on leukemogenic risk.
Ann Hematol.
1999;
78
389-392
-
2
Sastre J L, Bravo A, Tembras S, Gomez R, Ulibarrena C.
Leg ulcers associated with hydroxyurea therapy.
Haematologica.
2003;
88
EIM01
-
3
Lengfelder E, Griesshammer M, Hehlmann R.
Interferon-alpha in the treatment of essential thrombocythemia.
Leuk Lymphoma.
1996;
22(suppl 1)
135-142
-
4
Langer C, Lengfelder E, Thiele J et al..
Pegylated interferon for the treatment of high risk essential thrombocythemia: results of a phase II study.
Haematologica.
2005;
90
1333-1338
-
5
Samuelsson J, Hasselbalch H, Bruserud O et al..
A phase II trial of pegylated interferon a-2b therapy in polycythemia vera and essential thrombocythemia. Feasibility, clinical and biological effects and impact on quality of life.
Cancer.
2006;
, In press
-
6
Thiele J, Kvasnicka H M, Diehl V, Fischer R, Michiels J.
Clinicopathological diagnosis and differential criteria of thrombocythemias in various myeloproliferative disorders by histopathology, histochemistry and immunostaining from bone marrow biopsies.
Leuk Lymphoma.
1999;
33
207-218
-
7
James C, Ugo V, Le Couedic J P et al..
A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera.
Nature.
2005;
434
1144-1148
-
8
Gillespie E.
Anagrelide: a potent and selective inhibitor of platelet cyclic AMP phosphodiesterase enzyme activity.
Biochem Pharmacol.
1988;
37
2866-2868
-
9
Hong Y, Erusalimsky J D.
Comparison of the pharmacological mechanisms involved in the platelet lowering actions of anagrelide and hydroxyurea: a review.
Platelets.
2002;
13
381-386
-
10
Thiele J, Ollig S, Schmitt-Graff A.
Anagrelide does not exert a myelodysplastic effect on megakaryopoiesis: a comparative immunohistochemical and morphometric study with hydroxyurea.
Histol Histopathol.
2005;
20
1071-1076
-
11
Hong Y, Wang G, Gutierrez del Arroyo A, Hernandez J, Skene C, Erusalimsky J.
Comparison between anagrelide and hydroxycarbamide in their activites against haematopoietic progenitor cell growth and differentiation: Selectivity of anagrelide for the megakaryocytic lineage.
Leukemia.
2006;
, In press
-
12
Abe Andes W, Noveck R J, Fleming J S.
Inhibition of platelet production induced by an antiplatelet drug, anagrelide, in normal volunteers.
Thromb Haemost.
1984;
52
325-328
-
13
Anagrelide Study Group .
Anagrelide, a therapy for thrombocythemic states: experience in 577 patients.
Am J Med.
1992;
92
69-76
-
14
Petitt R M, Silverstein M N, Petrone M E.
Anagrelide for control of thrombocythemia in polycythemia and other myeloproliferative disorders.
Semin Hematol.
1997;
34
51-54
-
15
Petrides P E, Beykirch M K, Trapp O M.
Anagrelide, a novel platelet lowering option in essential thrombocythaemia: treatment experience in 48 patients in Germany.
Eur J Haematol.
1998;
61
71-76
-
16
Balduini C L, Bertolino G, Noris P, Ascari E.
Effect of anagrelide on platelet count and function in patients with thrombocytosis and myeloproliferative disorders.
Haematologica.
1992;
77
40-43
-
17
Mills A K, Taylor K M, Wright S J et al..
Efficacy, safety and tolerability of anagrelide in the treatment of essential thrombocythaemia.
Aust NZ J Med.
1999;
29
29-35
-
18
Knutsen H, Hysing J.
Anagrelide in primary thrombocythemia [In Norwegian].
Tidsskr For Laegeforen.
2001;
121
1478-1482
-
19
Silverstein M N, Petitt R M, Solberg Jr L A, Fleming J S, Knight R C, Schacter L P.
Anagrelide: a new drug for treating thrombocytosis.
N Engl J Med.
1988;
318
1292-1294
-
20
Mazzucconi M G, De Sanctis V, Chistolini A, Dragoni F, Mandelli F.
Therapy with anagrelide in patients affected by essential thrombocythemia: preliminary results.
Haematologica.
1992;
77
315-317
-
21
Storen E C, Tefferi A.
Long-term use of anagrelide in young patients with essential thrombocythemia.
Blood.
2001;
97
863-866
-
22
Birgegard G, Bjorkholm M, Kutti J et al..
Adverse effects and benefits of two years of anagrelide treatment for thrombocythemia in chronic myeloproliferative disorders.
Haematologica.
2004;
89
520-527
-
23
Steurer M, Gastl G, Jedrzejczak W W et al..
Anagrelide for thrombocytosis in myeloproliferative disorders: a prospective study to assess efficacy and adverse event profile.
Cancer.
2004;
101
2239-2246
-
24
Penninga E, Jensen B A, Hansen P B et al..
Anagrelide treatment in 52 patients with chronic myeloproliferative diseases.
Clin Lab Haematol.
2004;
26
335-340
-
25
Fruchtman S M, Petitt R M, Gilbert H S, Fiddler G, Lyne A.
Anagrelide: analysis of long-term efficacy, safety and leukemogenic potential in myeloproliferative disorders.
Leuk Res.
2005;
29
481-491
-
26
Trapp O M, Beykirch M K, Petrides P E.
Anagrelide for treatment of patients with chronic myelogenous leukemia and a high platelet count.
Blood Cells Mol Dis.
1998;
24
9-13
-
27
Laguna M S, Kornblihtt L I, Marta R F, Michiels J J, Molinas F C.
Effectiveness of anagrelide in the treatment of symptomatic patients with essential thrombocythemia.
Clin Appl Thromb Hemost.
2000;
6
157-161
-
28
Harrison C N, Campbell P J, Buck G et al..
Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia.
N Engl J Med.
2005;
353
33-45
-
29
Tefferi A, Silverstein M N, Petitt R M, Mesa R A, Solberg Jr L A.
Anagrelide as a new platelet-lowering agent in essential thrombocythemia: mechanism of actin, efficacy, toxicity, current indications.
Semin Thromb Hemost.
1997;
23
379-383
-
30
James C W.
Anagrelide-induced cardiomyopathy.
Pharmacotherapy.
2000;
20
1224-1227
-
31
Harrison C N.
Management of essential thrombocythemia Implications of the Medical Research Council Primary Thrombocythemia 1 Trial.
Semin Thromb Hemost.
2006;
32
283-288
Gunnar BrigegardM.D. Ph.D.
Professor, OTM-Division, University Hospital
S-751-85 Uppsala, Sweden
eMail: gunnar.birgegard@medsci.uu.se
