Myeloproliferative Disorders and Myelofibrosis

May 24, 2012
Marjorie P. Zimmerman, MS, BSPharm, RPh

Stanton R. Mehr

Evidence-Based Oncology, May, Volume 18, Issue SP3

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.


Until recently, very little information was available about the costs of myeloproliferative neoplasms. A study presented at the American Society of Hematology meeting in December 2011 showed that annual medical and drug costs for patients with myelofibrosis neoplasms were 2 to 6 times that of patients with ailments other than cancer.19 This study tracked the costs of 25,145 patients with these disorders, based on claims from a database of about 100 payers across the country.

For patients with myelofibrosis, mean total annual costs were $34,690, with outpatient costs accounting for 53% of the total (mean, $18,395). Inpatient visits (23%, $8106), drug costs (22%, $7803), and emergency department visits (1%, $386) accounted for the remaining costs. Patients with myelofibrosis incurred the greatest costs, followed by patients with essential thrombocythemia (mean annual total, $19,672) and polycythemia vera (mean annual total, $11,927).19

Drivers of Cost

Drugs, laboratory costs, phlebotomy, radiation, surgery (including splenectomy), and allogeneic hemopoietic stem-cell transplantation all contribute to the costs of treating and managing myeloproliferative disorders. It is likely that the approval of ruxolitinib will have a significant effect on the proportion of total costs associated with pharmaceutical treatment (depending on its coverage by payers and anticipated utilization). Like some other oral oncology treatments, ruxolitinib is intended to be taken chronically, as long as spleen size is reduced and symptoms are improved. All the therapies except for allogeneic hemopoietic stem-cell transplantation are palliative in nature, with no impact on overall survival.

It remains to be seen whether JAK inhibitors in development can cure the disease. However, drug therapies that reduce the burden of the disease have the potential to reduce the costs currently associated with managing the disease, principally by delaying the need for the most costly treatments, like allogeneic hemopoietic stem-cell transplantation.

Payer PerspectiveInterview with Neil Minkoff, MD

EBO: How do you define value in patients being treated for myelofibrosis?

Dr Minkoff: In general, value here is related to the difficulties with available chronic therapy. These patients will require transfusions and many get chemotherapy. A significant number get a marrow transplant. A significant number of patients will require splenectomy. Average survival is 5 years as the disease progresses. So, value will be defined in a number of ways: increased survival, reduction in transfusion, reduction in the need for splenectomy, or slowed progression of the disease.

EBO: In rare diseases like myelofibrosis, how does the value equation change compared with more common cancers, such as chronic myelogenous leukemia?

Dr Minkoff: I don’t think it does. The budget impact is different and the impact on trend is different, but a good evaluation of value should be the same for any product.

EBO: From the health plan perspective, what is the top objective when managing a patient with myelofibrosis: preventing/delaying transformation to acute myelogeneous leukemia? Avoiding the need for allogeneic stem cell transplants?

Dr Minkoff: In myelofibrosis, we are still at a stage where any clinical improvement or delay in disease progression will lead to value. I don’t limit my concern in a disease state like this to a single outcome.

EBO: How are payers like you managing the utilization of the targeted JAKinhibitor drug ruxolitinib for these diseases?

Dr Minkoff: As in many orphan conditions, management of new treatments is difficult. In this case, the drug is limited to patients with moderate-to-severe myelofibrosis and is often distributed through the specialty pharmaceutical channel in an effort to manage costs.

EBO: Are patients with myelofibrosis typically managed through case or care management in your plan?

Dr Minkoff: They will have care managers to make sure their care is integrated. The care managers will also ensure that all follow-up appointments are booked, and that the patient is stable between visits. However, the actual management of the disease (stem-cell transplant, chemotherapy, etc) is generally done by the hematologist.

EBO: Do you emphasize the use of clinical practice guidelines or care pathways to ensure value in the treatment of rare cancers like myelofibrosis?

Dr Minkoff: In general, the answer is no. For disease states like myelofibrosis, we depend more on the clinical acumen of the hematologists in the network.

Dr Minkoff is the founder of FountainHead HealthCare and former medical director, Harvard Pilgrim Health Plan, Wellesley, MA.

Additional Suggested Reading

Tefferi A, Lasho TL, Jimma T, et al. One thousand patients with primary myelofibrosis: the Mayo Clinic experience. Mayo Clin Proc. 2012;87(1):25-33.

A description of the experience of the Mayo Clinic’s 1000 consecutive patients with primary myelofibrosis, from 1977 to the present.

Kundranda MN, Tibes R, Mesa RA. Transformation of a chronic myeloproliferative neoplasm to acute myelogenous leukemia: does anything work [published online ahead of print December 15, 2011]? Curr Hematol Malig Rep.

Over the natural course of Bcr/Abl-negative myeloproliferative neoplasms of essential thrombocythemia, polycythemia vera, and primary myelofibrosis, transformation to acute myelogenous leukemia is more likely; although a rare event, the molecular events leading to transformation are poorly defined. The authors describe the latest advances in our understanding of the biology of leukemic transformation and current clinical therapies that are available for this patient population.

Vakil E, Tefferi A. BCR-ABL1--negative myeloproliferative neoplasms: a review of molecular biology, diagnosis, and treatment. Clin Lymphoma Myeloma Leuk. 2011;11(suppl 1):S37-S45.

The mutation JAK2V617F is the best characterized of the BCR-ABL1-negative neoplasm mutations, with an estimated prevalence of more than half of patients with primary myelofibrosis, according to researchers from Ireland. Current diagnostic strategies rely on molecular markers, and their prognostic value continues to be investigated. There have been promising results from clinical trials that involve the JAK tyrosine kinase inhibitors TG101384 and INCB018424, but their role in future therapy is yet to be established.

Santos FP, Verstovsek S. JAK2 inhibitors: are they the solution? Clin Lymphoma Myeloma Leuk. 2011;11(suppl 1):S28-S36.

The discovery of the JAK2V617F mutation in patients with Philadelphia chromosome— negative myeloproliferative neoplasms started the era of targeted therapy for these diseases. The authors review recent data on JAK2 inhibitors for the management of patients with Philadelphia chromosome–negative myeloproliferative neoplasms.

Passamonti F. Prognostic factors and models in polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Clin Lymphoma Myeloma Leuk. 2011;11(suppl 1):S25-S27.

Prognosis in primary myelofibrosis is predicted at diagnosis by a combination of different risk factors, such as advanced age (>60 years), anemia, leukocytosis (white blood cell count >25 x 109/L), the presence of blast cells (≥1%), and the presence of constitutional symptoms. This model may also predict survival when applied during follow-up.

Stein BL, Crispino JD, Moliterno AR. Janus kinase inhibitors: an update on the progress and promise of targeted therapy in the myeloproliferative neoplasms. Curr Opin Oncol. 2011;23(6):609-616.

The discovery of the JAK2 V617F mutation in the classical myeloproliferative neoplasms has ushered in a new era of scientific discovery in these diseases, resulting in a molecular classification and an improved understanding of disease pathogenesis. The initial enthusiasm for these agents has been tempered by recognition that JAK2 V617F may represent only 1 component of lesions driving the heterogeneity of the MPN. It might be rational to give these inhibitors along with other agents that target alternate mechanisms of the disease pathogenesis.

Myeloproliferative Disorders Research Consortium. Chronic idiopathic myelofibrosis. Published September 6, 2006. Accessed January 4, 2012.

A fact sheet on myelofibrosis from an international consortium of nearly 40 institutions. Ostojic A, Vrhovac R, Verstovsek S. Ruxolitinib: a new JAK1/2 inhibitor that offers promising options for treatment of myelofibrosis. Future Oncol. 2011;7(9):1035-1043. A review of the clinical trial benefits of ruxolitinib.Funding Source: None.

Author Disclosures: Mr Mehr reports receiving payment for involvement in the preparation of this article. Ms Zimmerman reports no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Authorship Information: Concept and design (MPZ); acquisition of data (SRM, MPZ); analysis and interpretation of data (SRM, MPZ); drafting of the manuscript (SRM, MPZ); critical revision of the manuscript for important intellectual content (SRM, MPZ); and sidebar development (SRM).1. Myeloproliferative Disorders Research Consortium. What are myeloproliferative disorders. Published September 8, 2006. Accessed January 4, 2012.

2. Vannucchi AM. Management of myelofibrosis. Hematology Am Soc Hematol Educ Program. 2011;2011:222-230.

3. Myeloproliferative neoplasms (MPNs) Research Foundation. Primary myelofibrosis. Accessed January 4, 2012.

4. Advani A, Theil K. Chronic myeloproliferative disorders. Cleveland Clinic Center for Continuing Education website. http://www.clevelandclinicmeded. com/medicalpubs/diseasemanagement/hematology-oncology/chronic-myeloproliferativedisorders/.Accessed January 3, 2012.

5. Tefferi A, Barosi G, Mesa RA, et al. International Working Group (IWG) consensus criteria for treatment response in myelofibrosis with myeloid metaplasia. Blood. 2006;108(5):1497-1503.

6. Tefferi A. Primary myelofibrosis: 2012 update on diagnosis, risk stratification, and management. Am J Hematol. 2011:86(12):1017-1026.

7. Cervantes F, Pereira A. Prognosticating in primary myelofibrosis [published online ahead of print November 10, 2011]. Curr Hematol Malig Rep.

8. JAK inhibitor provides rapid, durable relief for myelofibrosis patients. Published September 15, 2010. Accessed January 5, 2012.

9. Ma X, Vanasse G, Cartmel B, et al. Prevalence of polycythemia vera and essential thrombocythemia. Am J Hematol. 2008;83(5):359-362.

10. Mesa RA, Silverstein MN, Jacobson SJ, Wollan PC, Tefferi A. Population-based incidence and survival figures in essential thrombocythemia and agnogenic myeloid metaplasia: an Olmsted county study, 1976-1995. Am J Hematol. 1999;61(1):10-15.

11. Tefferi A, Spivak JL. Polycythemia vera: scientific advances and current practice. Semin Hematol. 2005;42(4):206-220.

12. Tefferi A, Solberg LA, Silverstein MN. A clinical update on polycythemia vera and essential thrombocythema. Am J Med. 2000;109(2):141-149.

13. Barbui T, Barosi G, Birgegard G, et al. Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. J Clin Oncol. 2011;29(6):761-770.

14. Jakafi package insert. Incyte Pharmaceuticals; November 2011. uspi_jakafi.pdf. Accessed January 4, 2012.

15. Harrison CN, Kiladijan JJ, Al-Ali HK, et al. Results of a randomized study of the JAK inhibitor INC424 compared with best available therapy (BAT) in primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF) or post-essential thrombocythemia-myelofibrosis (PETMF) (abstract). J Clin Oncol. 2011;29:LBA6501A.

16. Verstovsek S, Mes R, Gotlib JR, et al. Results of COMFORT-I, a randomized double-blind phase III trial of JAK 1/2 inhibitor INCB18424 (424) versus placebo (PB) for patients with myelofibrosis (MF) (abstract). J Clin Oncol. 2011;29:6500.

17. Tefferi A, Litzow MR, Pardanani A. Long-term outcome of treatment with ruxolitinib in myelofibrosis. N Engl J Med. 2011;365(15):1455-1457.

18. JAK inhibitor ruxolitinib demonstrates significant clinical benefit in myelofibrosis. ASCO Daily News. comfort.aspx. Published June 2011. Accessed January 6, 2012.

19. Price GL, Pohl GM, Xie J, et al. A retrospective observational study of annual healthcare costs for patients with forms of myeloproliferative neoplasms (MPN). ASCO abstract 2060. December 10, 2011.