The proposed revised World Health Organization (WHO) criteria for the diagnosis of essential thrombocythemia requires the following criteria:
- Sustained platelet count of at least 450 × 109/L.
- Bone marrow biopsy showing predominant proliferation of enlarged mature megakaryocytes; no significant increase of granulocytic or erythroid precursors. This finding distinguishes essential thrombocythemia from another entity with thrombocytosis, namely prefibrotic primary myelofibrosis, which is identified by increased granulocytic or erythroid precursors, atypical megakaryocytes, and increased bone marrow cellularity.
Patients with prefibrotic primary myelofibrosis have a worse survival than patients with essential thrombocythemia because of an increased progression to myelofibrosis and increased progression to acute myelogenous leukemia.[2,3] Patients with prefibrotic primary myelofibrosis may also have a higher tendency to bleed, which can be exacerbated by low-dose aspirin.
- Not meeting criteria for polycythemia vera (p. vera), primary myelofibrosis, chronic myelogenous leukemia, myelodysplastic syndrome, or other myeloid neoplasm.
- Demonstration of JAK2 V617F mutation or myeloproliferative leukemia (MPL) exon 10 mutation. In the absence of a clonal marker, there must be no evidence for reactive thrombocytosis. In particular, with a decreased serum ferritin, there must be no increase in hemoglobin level to p. vera range with iron replacement therapy. In the presence of a JAK2 or MPL mutation and exclusion of other myeloproliferative or myelodysplastic features, a bone marrow aspirate/biopsy may not be mandatory for a diagnosis. About 60% of patients with essential thrombocythemia carry a JAK2 mutation, and about 5% to 10% of the patients have activating mutations in the thrombopoietin receptor gene, MPL. About 70% of the patients without JAK2 or MPL carry a somatic mutation of the calreticulin gene, which is associated with a more indolent clinical course than is seen with JAK2 or MPL mutations.[7,8]
Patients older than 60 years or those with a prior thrombotic episode or with leukocytosis have as much as a 25% chance of developing cerebral, cardiac, or peripheral arterial thromboses and, less often, a chance of developing a pulmonary embolism or deep venous thrombosis.[2,9,10] Similar to the other myeloproliferative syndromes, conversion to acute leukemia is found in a small percentage of patients (<10%) with long-term follow-up.
There is no staging system for this disease.
Untreated essential thrombocythemia means that a patient is newly diagnosed and has had no prior treatment except supportive care.Treatment Overview
Controversy is considerable regarding whether asymptomatic patients with essential thrombocythemia require treatment. In a case-controlled, observational study of 65 low-risk patients (<60 years of age, platelet count <1,500 × 109/L, and no history of thrombosis or hemorrhage) with a median follow-up of 4.1 years, the thrombotic risk of 1.91 cases per 100 patient years and hemorrhagic risk of 1.12 cases per 100 patient years was not increased any more than in the normal controls.
- A randomized trial of patients with essential thrombocythemia and a high risk of thrombosis compared treatment with hydroxyurea titrated to attain a platelet count below 600,000/mm3 with a control group that received no therapy. Hydroxyurea was found to be effective in preventing thrombotic episodes (4% vs. 24%).[Level of evidence: 1iiDiv] A retrospective analysis of this trial found that antiplatelet drugs had no significant influence on the outcome. Resistance to hydroxyurea is defined as a platelet count of greater than 600,000/mcL after 3 months of at least 2 g per day of hydroxyurea or a platelet count greater than 400,000/µL and a white blood count of less than 2,500/µL or a hemoglobin less than 10 g/dL at any dose of hydroxyurea.
- A prospective, randomized trial in the United Kingdom (UK) of 809 patients compared hydroxyurea plus aspirin with anagrelide plus aspirin. Although the platelet-lowering effect was equivalent, the anagrelide group had significantly more thrombotic and hemorrhagic events (hazard ratio [HR], 1.57; P = .03) and more myelofibrosis (HR, 2.92; P = .01). No differences were seen for subsequent myelodysplasia or acute leukemia in this trial.[Level of evidence: 1iiD]
- Another prospective, randomized trial also compared hydroxyurea and anagrelide in 259 previously untreated and high-risk patients. In this central European trial, the diagnosis of essential thrombocythemia was made by the WHO recommendations, not by the Polycythemia Vera Study Group criteria as in the UK study. This means that patients with leukocytosis and a diagnosis of early prefibrotic myelofibrosis (both groups with much higher rates of thrombosis) were excluded from the central European trial. In this analysis, there were no differences in outcome for thrombotic or hemorrhagic events.[Level of evidence: 1iiD]
These three randomized, prospective trials establish the efficacy and safety for the use of hydroxyurea for patients with high-risk essential thrombocythemia (age >60 years + platelet count >1,000 × 109/L or >1,500 × 109/L). For patients diagnosed by WHO standards (excluding patients with leukocytosis and prefibrotic myelofibrosis by bone marrow biopsy), anagrelide represents a reasonable alternative therapy. The addition of aspirin to cytoreductive therapies like hydroxyurea or anagrelide remains controversial, but a retrospective anecdotal report suggested reduction in thrombosis for patients older than 60 years.
Many clinicians use hydroxyurea or platelet apheresis prior to elective surgery to reduce the platelet count and to prevent postoperative thromboembolism. No prospective or randomized trials document the value of this approach.
Among low-risk patients (defined as age ≤60 years with no prior thrombotic episodes), a retrospective review of 300 patients showed benefit for antiplatelet agents in reducing venous thrombosis in JAK2-positive cases and in reducing arterial thrombosis in patients with cardiovascular risk factors. Balancing the risks and benefits of aspirin for low-risk patients can be difficult. In an extrapolation of the data from trials of p. vera, low-dose aspirin to prevent vascular events has been suggested, but there are no data from clinical trials to address this issue.
- No treatment, unless complications develop, if patients are asymptomatic, younger than 60 years, and have a platelet count of less than 1,500 × 109/L.
- Interferon-alpha [20,21] or pegylated interferon-alpha.[22,23]
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with essential thrombocythemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.References
- Tefferi A, Thiele J, Vardiman JW: The 2008 World Health Organization classification system for myeloproliferative neoplasms: order out of chaos. Cancer 115 (17): 3842-7, 2009. [PUBMED Abstract]
- Passamonti F, Thiele J, Girodon F, et al.: A prognostic model to predict survival in 867 World Health Organization-defined essential thrombocythemia at diagnosis: a study by the International Working Group on Myelofibrosis Research and Treatment. Blood 120 (6): 1197-201, 2012. [PUBMED Abstract]
- Barbui T, Thiele J, Carobbio A, et al.: Disease characteristics and clinical outcome in young adults with essential thrombocythemia versus early/prefibrotic primary myelofibrosis. Blood 120 (3): 569-71, 2012. [PUBMED Abstract]
- Finazzi G, Carobbio A, Thiele J, et al.: Incidence and risk factors for bleeding in 1104 patients with essential thrombocythemia or prefibrotic myelofibrosis diagnosed according to the 2008 WHO criteria. Leukemia 26 (4): 716-9, 2012. [PUBMED Abstract]
- Campbell PJ, Green AR: The myeloproliferative disorders. N Engl J Med 355 (23): 2452-66, 2006. [PUBMED Abstract]
- Harrison CN, Bareford D, Butt N, et al.: Guideline for investigation and management of adults and children presenting with a thrombocytosis. Br J Haematol 149 (3): 352-75, 2010. [PUBMED Abstract]
- Klampfl T, Gisslinger H, Harutyunyan AS, et al.: Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med 369 (25): 2379-90, 2013. [PUBMED Abstract]
- Nangalia J, Massie CE, Baxter EJ, et al.: Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med 369 (25): 2391-405, 2013. [PUBMED Abstract]
- Cortelazzo S, Finazzi G, Ruggeri M, et al.: Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis. N Engl J Med 332 (17): 1132-6, 1995. [PUBMED Abstract]
- Harrison C, Kiladjian JJ, Al-Ali HK, et al.: JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med 366 (9): 787-98, 2012. [PUBMED Abstract]
- Ruggeri M, Finazzi G, Tosetto A, et al.: No treatment for low-risk thrombocythaemia: results from a prospective study. Br J Haematol 103 (3): 772-7, 1998. [PUBMED Abstract]
- Barosi G, Besses C, Birgegard G, et al.: A unified definition of clinical resistance/intolerance to hydroxyurea in essential thrombocythemia: results of a consensus process by an international working group. Leukemia 21 (2): 277-80, 2007. [PUBMED Abstract]
- Harrison CN, Campbell PJ, Buck G, et al.: Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N Engl J Med 353 (1): 33-45, 2005. [PUBMED Abstract]
- Green A, Campbell P, Buck G: The Medical Research Council PT1 trial in essential thrombocythemia. [Abstract] Blood 104 (11): A-6, 2004.
- Gisslinger H, Gotic M, Holowiecki J, et al.: Anagrelide compared with hydroxyurea in WHO-classified essential thrombocythemia: the ANAHYDRET Study, a randomized controlled trial. Blood 121 (10): 1720-8, 2013. [PUBMED Abstract]
- Alvarez-Larrán A, Pereira A, Arellano-Rodrigo E, et al.: Cytoreduction plus low-dose aspirin versus cytoreduction alone as primary prophylaxis of thrombosis in patients with high-risk essential thrombocythaemia: an observational study. Br J Haematol 161 (6): 865-71, 2013. [PUBMED Abstract]
- Alvarez-Larrán A, Cervantes F, Pereira A, et al.: Observation versus antiplatelet therapy as primary prophylaxis for thrombosis in low-risk essential thrombocythemia. Blood 116 (8): 1205-10; quiz 1387, 2010. [PUBMED Abstract]
- Harrison C, Barbui T: Aspirin in low-risk essential thrombocythemia, not so simple after all? Leuk Res 35 (3): 286-9, 2011. [PUBMED Abstract]
- Finazzi G: How to manage essential thrombocythemia. Leukemia 26 (5): 875-82, 2012. [PUBMED Abstract]
- Sacchi S: The role of alpha-interferon in essential thrombocythaemia, polycythaemia vera and myelofibrosis with myeloid metaplasia (MMM): a concise update. Leuk Lymphoma 19 (1-2): 13-20, 1995. [PUBMED Abstract]
- Gilbert HS: Long term treatment of myeloproliferative disease with interferon-alpha-2b: feasibility and efficacy. Cancer 83 (6): 1205-13, 1998. [PUBMED Abstract]
- Quintás-Cardama A, Kantarjian H, Manshouri T, et al.: Pegylated interferon alfa-2a yields high rates of hematologic and molecular response in patients with advanced essential thrombocythemia and polycythemia vera. J Clin Oncol 27 (32): 5418-24, 2009. [PUBMED Abstract]
- Quintás-Cardama A, Abdel-Wahab O, Manshouri T, et al.: Molecular analysis of patients with polycythemia vera or essential thrombocythemia receiving pegylated interferon α-2a. Blood 122 (6): 893-901, 2013. [PUBMED Abstract]
- Anagrelide, a therapy for thrombocythemic states: experience in 577 patients. Anagrelide Study Group. Am J Med 92 (1): 69-76, 1992. [PUBMED Abstract]