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Myeloproliferative Disorders and Myelofibrosis

Marjorie P. Zimmerman, MS, BSPharm, RPh; and Stanton R. Mehr
Myeloproliferative disorders are associated with bone marrow malfunction. The bone marrow contains stem cells that develop into red blood cells, white blood cells, and platelets in appropriate proportion. A change in the DNA of a single stem cell causes a growth advantage for one of the cell types, which leads to an abnormal under- or over-production of the respective cell types.1

Polycythemia vera, essential thrombocythemia, and primary myelofibrosis together comprise the myeloproliferative neoplasms, which are considered Philadelphia- chromosome–negative chronic myeloproliferative neoplasms.1-4

Polycythemia vera is characterized by an excessive amount of red blood cells being formed by the bone marrow. There may also be an increased number of leukocytes (white blood cells) and platelets and an enlarged spleen. Essential thrombocythemia is the result of the overproduction of platelets. As either of these 2 disorders progresses, bone marrow scarring may occur, which leads to myelofibrosis. Polycythemia vera progresses to myelofibrosis in about 15% of the cases, while only a small number of patients with essential thrombocythemia progress to myelofibrosis.3 Myelofibrosis can also arise without pre-existing conditions. Primary myelofibrosis and myelofibrosis secondary to polycythemia vera and essential thrombocythemia have a common mutant allele— JAK2.5 About 50% of patients with essential thrombocythemia have this same gene mutation as well as 95% of patients with polycythemia vera.3

Each of these diseases typically occurs in the fifth or sixth decade of life. Patients with essential thrombocythemia can lead a normal life with an unaffected life expectancy. The median survival for polycythemia vera is more than 10 years with treatment. Myelofibrosis has the worst prognosis of the 3 diseases, as it has a median survival of less than 3 years but younger patients (<55 years) have survivals of more than 10 years.5 Patients are stratified by risk (low risk, intermediate-1, intermediate- 2, or high risk) based on patients’ number of risk factors, which is predictive for survival.2,6 Approximately 10% to 20% of patients with myelofibrosis progress to acute myelogenous leukemia.7

Treatment is guided by addressing the presenting risk factors, with the goal of extending survival.2 Based on few effective treatments (and the relative rarity of these cancers), evidence for the economic value of treatment has not yet been quantified.

Polycythemia, essential thrombocythemia, and myelofibrosis are classified as orphan diseases, as they affect fewer than 200,000 people in the United States at any given time. Currently, these diseases are not measured by the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute. Market research has estimated that all 3 diseases have an annual incidence of fewer than 3 patients per 100,000 population.3,4,8 In 2003, the prevalence of polycythemia vera was 22 per 100,000 (65,243 patients total), and the prevalence of essential thrombocythemia was 24 per 100,000 (71,078 patients).9 Researchers investigating myelofibrosis in 1999 reported an incidence of 1.46 per 100,000, with a total prevalence of 30,000 patients.10

It is therefore understandable that for most health plans, these myeloproliferative neoplasms do not merit intense scrutiny. However, the available treatments for these disorders vary quite dramatically, and the therapeutic options for myelofibrosis in particular have changed dramatically in the past year.

Current Treatment Options
Patients without symptoms or with minimal symptoms are usually managed with a watch-and-wait strategy, until the patient’s risk score worsens or hematological abnormalities necessitate intervention.2

Therapies for polycythemia vera and essential thrombocythemia are similar, including phlebotomy to reduce the number of circulating red blood cells, low-dose aspirin to reduce the chance for blood clots (and to alleviate vasomotor symptoms experienced by some patients), hydroxyurea and anagrelide for those at high risk for blood clots, and interferon. Hydroxyurea is also used to treat splenomegaly, a complication of these disorders.4,11,12

Until late 2011, there were no approved therapies for myelofibrosis. Off-label therapies employed included hydroxyurea, androgens, corticosteroids, erythropoiesis- stimulating agents, danazol, thalidomide, lenalidomide, busulfan, melphalan, cladribine, and interferon. Blood transfusions, radiation, and removal of the spleen have been tried as well. However, these therapies have not prolonged survival.7 The only known cure for myelofibrosis has been allogeneic hemopoietic stem-cell transplantation, which is itself associated with high morbidity and mortality as well as high costs.2,7,13

Ruxolitinib (Jakafi), an oral JAK1 and JAK2 kinase inhibitor, was approved in November 2011 for the treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis, and post–essential thrombocythemia myelofibrosis.14 Two phase III trials demonstrated significant improvement compared with best available therapy for spleen size, symptoms, and burden reduction, as well as for quality of life.14-16 However, the reduced spleen size was not shown to be consistently durable in a phase I/II study and neither phase III study reported a significant survival benefit.17,18 This agent is commonly associated with hematologic side effects; anemia was reported in 96% of patients taking ruxolitinib (grade 3/4, 45%), and thrombocytopenia was reported in 70% (grade 3/4, 13%).14 This first JAK inhibitor therapy for myelofibrosis has been long anticipated; yet, the value of this treatment is not truly known. The treatment of adverse events and its overall effect in avoidance of other therapies will need to be included in the value equation. It is likely that it will be covered by health plans because of the low incidence of the disorder and the lack of other effective treatments.

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