When and How to Treat Essential Thrombocythemia
http://www.100md.com
《新英格兰医药杂志》
Essential thrombocythemia is one of the chronic myeloproliferative disorders, a heterogeneous group of diseases involving clonal hematopoietic stem cells that also includes polycythemia vera, idiopathic myelofibrosis, and chronic myelogenous leukemia.1 Among these disorders, essential thrombocythemia has the most favorable outcome: patients with this disease have a life span that nearly rivals that of a healthy population matched by age and sex.2 The principal causes of death in patients with essential thrombocythemia are thrombosis, hemorrhage, and progression to myelofibrosis or acute myelogenous leukemia. The myelosuppressive therapy that prevents vascular events in essential thrombocythemia may itself increase the risk of transformation to myelofibrosis or acute myelogenous leukemia. The challenge in treating essential thrombocythemia is to prevent bleeding and thrombosis without increasing this risk.
A risk-adapted treatment strategy can help physicians to meet this challenge. The important risk factors for thrombotic events in patients with essential thrombocythemia are an age of 60 years or more and previous vascular episodes,3 whereas hemorrhagic complications are paradoxically associated with extreme thrombocythemia. Young, asymptomatic patients with a platelet count of less than 1.5 million per cubic millimeter should be considered at low risk for thrombosis and hemorrhagic events, and do not require myelosuppressive treatment. By contrast, patients who are at least 60 years of age or who have a history of serious bleeding or thrombosis or a platelet count of 1.5 million per cubic millimeter or more should receive cytoreductive treatment. Hypertension, dyslipidemia, diabetes, and smoking can also increase the risk of thrombosis; patients with these coexisting conditions may constitute an "intermediate risk" category, but the assignment of patients to this subgroup is not universally accepted.
The myelosuppressive agent of choice in patients who have essential thrombocythemia and a high risk of thrombosis is hydroxyurea. This drug was found to be effective in reducing the incidence of thrombosis in a trial that randomly assigned 114 high-risk patients to receive either hydroxyurea or no cytoreductive therapy. After a median follow-up of 27 months, thrombosis developed in 3.6 percent of the treated patients, whereas 24 percent of the untreated patients had one or more thrombotic events.4
The major concern regarding hydroxyurea is whether it is leukemogenic. However, to date, no randomized studies with sufficient statistical power have been conducted to determine whether the risk of leukemia in patients treated with hydroxyurea is higher than the inherent risk that essential thrombocythemia will evolve into acute myelogenous leukemia. Nevertheless, the putative risk of leukemia associated with hydroxyurea prompted investigators to test new drugs that lack this potential, such as anagrelide and interferon alfa.
Anagrelide is an imidazoquinazoline derivative that reduces the platelet count in essential thrombocythemia and other myeloproliferative diseases.5 It selectively inhibits maturation of megakaryocytes, with either minimal or no effect on the other blood-cell precursors. There is extensive experience with anagrelide, which is licensed in the United States as a first-line agent for the control of thrombocytosis associated with any myeloproliferative disorder. Clinical studies of anagrelide, however, have not been randomized, have lacked control groups, have enrolled relatively few patients, and have had limited follow-up.
In this issue of the Journal, Harrison and colleagues6 report the results of a randomized trial that compares hydroxyurea with anagrelide (plus low-dose aspirin in both groups) in 809 high-risk patients with essential thrombocythemia. After a median follow-up of 39 months, the trial was terminated early by the data-monitoring committee because of excess rates of vascular events and transformation to myelofibrosis in the anagrelide group. Control of the platelet count and the incidence of leukemia were similar in the two groups. The investigators concluded that hydroxyurea plus aspirin was superior to anagrelide plus aspirin for patients with essential thrombocythemia who are at high risk for vascular events.
Besides the outcome, this well-designed and well-conducted trial has important features. First, it shows that control of the platelet count alone should not be taken as an appropriate surrogate end point to judge the efficacy of a treatment for essential thrombocythemia, because there was an excess of vascular events in the anagrelide group despite a reduction in the platelet count that was similar to the reduction in the hydroxyurea group. A likely explanation for this finding is the broader myelosuppressive activity of hydroxyurea, which also affects leukocytes and red cells. There is growing evidence that these cells play an important role in the pathogenesis of thrombosis in essential thrombocythemia.7
Second, anagrelide and low-dose aspirin appear to act synergistically to increase the risk of bleeding complications. This effect was unexpected and may result from the inhibition of platelet function by the two drugs given simultaneously. In contrast, the combination of hydroxyurea and aspirin provided protection against thrombosis with only a small risk of bleeding. This finding is in agreement with recent data from a randomized trial involving patients with polycythemia vera (about 50 percent of whom received hydroxyurea), in which aspirin reduced the risk of serious thrombosis and overall mortality without increasing the risk of serious bleeding.8
Third, the study by Harrison et al. showed that progression to myelofibrosis was about three times as frequent in the anagrelide group as it was in the hydroxyurea group. Evolution into myelofibrosis is part of the natural history of essential thrombocythemia and occurs in about 3 percent of patients after 5 years, 8 percent after 10 years, and 15 percent after 15 years.9 However, the risk of myelofibrosis differs according to the baseline characteristics of the bone marrow10: it is very low in so-called true essential thrombocythemia, in which the marrow has none of the histopathological features of myelofibrosis, and is higher when the marrow shows prefibrotic stages of myelofibrosis. For this reason, a limitation of the trial by Harrison et al. is the lack of a baseline examination of bone marrow. A trial comparing hydroxyurea with anagrelide in true essential thrombocythemia alone is ongoing in Europe.
Last but not least, transformation into acute myelogenous leukemia was found in similar numbers of patients in the hydroxyurea and anagrelide groups. This finding reassures us about the low leukemogenic potential of hydroxyurea and confirms the recently reported results of a large prospective study of polycythemia vera, in which there was no increase in acute myelogenous leukemia among patients treated with hydroxyurea, as compared with patients treated with phlebotomy alone.11
In summary, for now, hydroxyurea plus aspirin should be the standard of treatment for patients with essential thrombocythemia who are at high risk for thrombosis. A new avenue for the treatment of essential thrombocythemia and other myeloproliferative diseases was opened by the recent identification of an acquired mutation of the JAK2 gene in most patients with polycythemia vera and about one half the patients with essential thrombocythemia or myelofibrosis.12,13,14,15 The predicted consequence of this mutation is constitutive tyrosine kinase activity of Janus kinase 2 (JAK2), resulting in proliferative and survival advantages of hematopoietic progenitor cells. New tyrosine kinase inhibitors are being developed with the aim of discovering targeted therapy for these diseases. We foresee clinical trials comparing tyrosine kinase inhibitors with standard therapy in the near future.
Source Information
From the Division of Hematology, Ospedali Riuniti, Bergamo, Italy.
References
Schafer AI. Thrombocytosis. N Engl J Med 2004;350:1211-1219.
Barbui T, Barosi G, Grossi A, et al. Practice guidelines for the therapy of essential thrombocythemia: a statement from the Italian Society of Hematology, the Italian Society of Experimental Hematology and the Italian Group for Bone Marrow Transplantation. Haematologica 2004;89:215-232.
Cortelazzo S, Viero P, Finazzi G, D'Emilio A, Rodeghiero F, Barbui T. Incidence and risk factors for thrombotic complications in a historical cohort of 100 patients with essential thrombocythemia. J Clin Oncol 1990;8:556-562.
Cortelazzo S, Finazzi G, Ruggeri M, et al. Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis. N Engl J Med 1995;332:1132-1136.
Anagrelide Study Group. Anagrelide, a therapy for thrombocythemic states: experience in 577 patients. Am J Med 1992;92:69-76.
Harrison CN, Campbell PJ, Buck G, et al. A randomized comparison of hydroxyurea with anagrelide in high-risk essential thrombocythemia. N Engl J Med 2005;353:33-45. [Free Full Text]
Falanga A, Marchetti M, Evangelista V, et al. Polymorphonuclear leukocyte activation and hemostasis in patients with essential thrombocythemia and polycythemia vera. Blood 2000;96:4261-4266.
Landolfi R, Marchioli R, Kutti J, et al. Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med 2004;350:114-124.
Cervantes F, Alvarez-Larran A, Talarn C, Gomez M, Montserrat E. Myelofibrosis with myeloid metaplasia following essential thrombocythaemia: actuarial probability, presenting characteristics and evolution in a series of 195 patients. Br J Haematol 2002;118:786-790.
Thiele J, Kvasnicka HM, Zankovich R, Diehl V. Relevance of bone marrow features in the differential diagnosis between essential thrombocythemia and early stage idiopathic myelofibrosis. Haematologica 2000;85:1126-1134.
Finazzi G, Caruso V, Marchioli R, et al. Acute leukemia in polycythemia vera: an analysis of 1638 patients enrolled in a prospective observational study. Blood 2005;105:2664-2670.
Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 2005;352:1779-1790.
James C, Ugo V, Le Couedic J-P, et al. A unique clonal JAK2 mutation leading to constitutive signaling causes polycythaemia vera. Nature 2005;434:1144-1148.
Levine RL, Wadleigh M, Cools J, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 2005;7:387-397.
Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005;365:1054-1061.(Tiziano Barbui, M.D., and)
A risk-adapted treatment strategy can help physicians to meet this challenge. The important risk factors for thrombotic events in patients with essential thrombocythemia are an age of 60 years or more and previous vascular episodes,3 whereas hemorrhagic complications are paradoxically associated with extreme thrombocythemia. Young, asymptomatic patients with a platelet count of less than 1.5 million per cubic millimeter should be considered at low risk for thrombosis and hemorrhagic events, and do not require myelosuppressive treatment. By contrast, patients who are at least 60 years of age or who have a history of serious bleeding or thrombosis or a platelet count of 1.5 million per cubic millimeter or more should receive cytoreductive treatment. Hypertension, dyslipidemia, diabetes, and smoking can also increase the risk of thrombosis; patients with these coexisting conditions may constitute an "intermediate risk" category, but the assignment of patients to this subgroup is not universally accepted.
The myelosuppressive agent of choice in patients who have essential thrombocythemia and a high risk of thrombosis is hydroxyurea. This drug was found to be effective in reducing the incidence of thrombosis in a trial that randomly assigned 114 high-risk patients to receive either hydroxyurea or no cytoreductive therapy. After a median follow-up of 27 months, thrombosis developed in 3.6 percent of the treated patients, whereas 24 percent of the untreated patients had one or more thrombotic events.4
The major concern regarding hydroxyurea is whether it is leukemogenic. However, to date, no randomized studies with sufficient statistical power have been conducted to determine whether the risk of leukemia in patients treated with hydroxyurea is higher than the inherent risk that essential thrombocythemia will evolve into acute myelogenous leukemia. Nevertheless, the putative risk of leukemia associated with hydroxyurea prompted investigators to test new drugs that lack this potential, such as anagrelide and interferon alfa.
Anagrelide is an imidazoquinazoline derivative that reduces the platelet count in essential thrombocythemia and other myeloproliferative diseases.5 It selectively inhibits maturation of megakaryocytes, with either minimal or no effect on the other blood-cell precursors. There is extensive experience with anagrelide, which is licensed in the United States as a first-line agent for the control of thrombocytosis associated with any myeloproliferative disorder. Clinical studies of anagrelide, however, have not been randomized, have lacked control groups, have enrolled relatively few patients, and have had limited follow-up.
In this issue of the Journal, Harrison and colleagues6 report the results of a randomized trial that compares hydroxyurea with anagrelide (plus low-dose aspirin in both groups) in 809 high-risk patients with essential thrombocythemia. After a median follow-up of 39 months, the trial was terminated early by the data-monitoring committee because of excess rates of vascular events and transformation to myelofibrosis in the anagrelide group. Control of the platelet count and the incidence of leukemia were similar in the two groups. The investigators concluded that hydroxyurea plus aspirin was superior to anagrelide plus aspirin for patients with essential thrombocythemia who are at high risk for vascular events.
Besides the outcome, this well-designed and well-conducted trial has important features. First, it shows that control of the platelet count alone should not be taken as an appropriate surrogate end point to judge the efficacy of a treatment for essential thrombocythemia, because there was an excess of vascular events in the anagrelide group despite a reduction in the platelet count that was similar to the reduction in the hydroxyurea group. A likely explanation for this finding is the broader myelosuppressive activity of hydroxyurea, which also affects leukocytes and red cells. There is growing evidence that these cells play an important role in the pathogenesis of thrombosis in essential thrombocythemia.7
Second, anagrelide and low-dose aspirin appear to act synergistically to increase the risk of bleeding complications. This effect was unexpected and may result from the inhibition of platelet function by the two drugs given simultaneously. In contrast, the combination of hydroxyurea and aspirin provided protection against thrombosis with only a small risk of bleeding. This finding is in agreement with recent data from a randomized trial involving patients with polycythemia vera (about 50 percent of whom received hydroxyurea), in which aspirin reduced the risk of serious thrombosis and overall mortality without increasing the risk of serious bleeding.8
Third, the study by Harrison et al. showed that progression to myelofibrosis was about three times as frequent in the anagrelide group as it was in the hydroxyurea group. Evolution into myelofibrosis is part of the natural history of essential thrombocythemia and occurs in about 3 percent of patients after 5 years, 8 percent after 10 years, and 15 percent after 15 years.9 However, the risk of myelofibrosis differs according to the baseline characteristics of the bone marrow10: it is very low in so-called true essential thrombocythemia, in which the marrow has none of the histopathological features of myelofibrosis, and is higher when the marrow shows prefibrotic stages of myelofibrosis. For this reason, a limitation of the trial by Harrison et al. is the lack of a baseline examination of bone marrow. A trial comparing hydroxyurea with anagrelide in true essential thrombocythemia alone is ongoing in Europe.
Last but not least, transformation into acute myelogenous leukemia was found in similar numbers of patients in the hydroxyurea and anagrelide groups. This finding reassures us about the low leukemogenic potential of hydroxyurea and confirms the recently reported results of a large prospective study of polycythemia vera, in which there was no increase in acute myelogenous leukemia among patients treated with hydroxyurea, as compared with patients treated with phlebotomy alone.11
In summary, for now, hydroxyurea plus aspirin should be the standard of treatment for patients with essential thrombocythemia who are at high risk for thrombosis. A new avenue for the treatment of essential thrombocythemia and other myeloproliferative diseases was opened by the recent identification of an acquired mutation of the JAK2 gene in most patients with polycythemia vera and about one half the patients with essential thrombocythemia or myelofibrosis.12,13,14,15 The predicted consequence of this mutation is constitutive tyrosine kinase activity of Janus kinase 2 (JAK2), resulting in proliferative and survival advantages of hematopoietic progenitor cells. New tyrosine kinase inhibitors are being developed with the aim of discovering targeted therapy for these diseases. We foresee clinical trials comparing tyrosine kinase inhibitors with standard therapy in the near future.
Source Information
From the Division of Hematology, Ospedali Riuniti, Bergamo, Italy.
References
Schafer AI. Thrombocytosis. N Engl J Med 2004;350:1211-1219.
Barbui T, Barosi G, Grossi A, et al. Practice guidelines for the therapy of essential thrombocythemia: a statement from the Italian Society of Hematology, the Italian Society of Experimental Hematology and the Italian Group for Bone Marrow Transplantation. Haematologica 2004;89:215-232.
Cortelazzo S, Viero P, Finazzi G, D'Emilio A, Rodeghiero F, Barbui T. Incidence and risk factors for thrombotic complications in a historical cohort of 100 patients with essential thrombocythemia. J Clin Oncol 1990;8:556-562.
Cortelazzo S, Finazzi G, Ruggeri M, et al. Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis. N Engl J Med 1995;332:1132-1136.
Anagrelide Study Group. Anagrelide, a therapy for thrombocythemic states: experience in 577 patients. Am J Med 1992;92:69-76.
Harrison CN, Campbell PJ, Buck G, et al. A randomized comparison of hydroxyurea with anagrelide in high-risk essential thrombocythemia. N Engl J Med 2005;353:33-45. [Free Full Text]
Falanga A, Marchetti M, Evangelista V, et al. Polymorphonuclear leukocyte activation and hemostasis in patients with essential thrombocythemia and polycythemia vera. Blood 2000;96:4261-4266.
Landolfi R, Marchioli R, Kutti J, et al. Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med 2004;350:114-124.
Cervantes F, Alvarez-Larran A, Talarn C, Gomez M, Montserrat E. Myelofibrosis with myeloid metaplasia following essential thrombocythaemia: actuarial probability, presenting characteristics and evolution in a series of 195 patients. Br J Haematol 2002;118:786-790.
Thiele J, Kvasnicka HM, Zankovich R, Diehl V. Relevance of bone marrow features in the differential diagnosis between essential thrombocythemia and early stage idiopathic myelofibrosis. Haematologica 2000;85:1126-1134.
Finazzi G, Caruso V, Marchioli R, et al. Acute leukemia in polycythemia vera: an analysis of 1638 patients enrolled in a prospective observational study. Blood 2005;105:2664-2670.
Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 2005;352:1779-1790.
James C, Ugo V, Le Couedic J-P, et al. A unique clonal JAK2 mutation leading to constitutive signaling causes polycythaemia vera. Nature 2005;434:1144-1148.
Levine RL, Wadleigh M, Cools J, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 2005;7:387-397.
Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005;365:1054-1061.(Tiziano Barbui, M.D., and)