Myelofibrosis

Overview

Myelofibrosis (MF) is characterized by bone marrow fibrosis, symptom burden, splenomegaly, and cytopenias

MF is a Philadelphia chromosome–negative myeloproliferative neoplasm (MPN)1 characterized by bone marrow fibrosis, symptom burden, splenomegaly, and cytopenias.2 MF is a disease with significant heterogeneity in natural history and symptom burden. Patients with MF fall along a spectrum that ranges from those who are essentially asymptomatic to those who have severe symptoms that affect daily functioning and quality of life.3-5 MF can be a primary disease or it can be secondary to other conditions, including malignancies and other hematologic diseases.6

Although the precise etiology of myelofibrosis remains unknown, overactive Janus-associated kinase (JAK) pathway signaling is present in all patients with the disease.7,8 Multiple mechanisms, including genetic mutations,9-11 excessive production of cytokines,12 increased JAK1 signaling,13 and damaged intracellular signaling14 may play a role in overactive JAK pathway signaling.

Because MF has a heterogeneous presentation, determining a patient’s prognosis can be difficult.15 However, progress in understanding the clinical variables associated with myelofibrosis has led to the development of prognostic scoring systems, including the International Prognostic Scoring System (IPSS). The IPSS estimates prognosis based on risk factors present at diagnosis.16

Prevalence and demographics

MF is a rare disease, with a prevalence of 16,000 to 18,500 patients in the United States.17 Although MF can occur at any age, the median age at diagnosis ranges from 60 to 67 years.2,3 The disease affects both men and women.18

image of myelofibrosis patient Eleanor

Eleanor is a retired elementary school teacher who presents with fatigue and night sweats.

FOLLOW HER CASE HERE

MF Is Characterized by Bone Marrow and Blood Cell Abnormalities

MF is a progressive hematopoietic stem cell disorder19,20 characterized by bone marrow1,17,21 and blood cell abnormalities.17

Both marrow fibrosis and insufficient hematopoiesis drive extramedullary hematopoiesis, particularly in the spleen.22 Blood cell abnormalities in myelofibrosis include a reduction in the number of red blood cells and a variable or increased white blood cell count.17

MF is a complex disease characterized by multiple genetic, epigenetic, and cellular alterations. The primary driver of myelofibrosis, however, is overactive JAK signaling, including overactivation of both normal (wild-type) and mutated JAK1 and JAK2 expression.23

No Single Hallmark Mutation Has Been Identified for MF

Although numerous JAK pathway mutations have been identified in patients with MF, no single hallmark mutation has been identified for the disease.24-26 Approximately 50% to 60% of affected patients have a mutation of the JAK2 gene.26 Several other mutations have been observed, including the CALR mutation which is found in approximately 25% of patients with myelofibrosis.27

Patients with MF also have high levels of circulating inflammatory cytokines, such as interleukin-6, which likely contribute to a hypermetabolic state and cytokine-mediated systemic symptoms.7

Examining Bone Marrow
image of normal bone marrow vs bone marrow presenting with myelofibrosis disease
Adapted from Arber DA et al. Blood. 2016;127(20):2391-2405.28

MF is a progressive disease

MF is associated with progressive constitutional symptoms, increasing splenomegaly, and worsening cytopenias. PV or ET may progress to a myelofibrotic stage29 and MF itself can transform to secondary acute myelogenous leukemia.30 Leukemic transformation occurs in 8% to 23% of patients with MF during the first decade after diagnosis.30

Transformation Rates to MF
image of chart that shows transformation rates of PV and ET to myelofibrosis
AML, acute myelogenous leukemia; EMH, extramedullary hematopoiesis; ET, essential thrombocythemia; PMF, primary myelofibrosis; PET-MF, post–essential thrombocythemia myelofibrosis; PPV-MF, post–polycythemia vera myelofibrosis; PV, polycythemia vera.
References

1. Vannucchi AM, Guglielmelli P, Tefferi A. CA Cancer J Clin. 2009;59(3):171-191. 2. Abdel-Wahab OI, Levine RL. Annu Rev Med. 2009;60:233-245. 3. Mesa RA, Niblack J, Wadleigh M, et al. Cancer. 2007;109(1):68-76. 4. Emanuel RM, Dueck AC, Geyer HL, et al. J Clin Oncol. 2012;30(33):4098-4104. 5. Geyer HL, Scherber RM, Dueck AC, et al. Blood. 2014;123(24):3803-3810. 6. The Merck Manual for Health Care Professionals. Available at: http://www.merckmanuals.com/professional/hematology_and_oncology/myeloproliferative_disorders/primary_myelofibrosis.html. Accessed March 3, 2013. 7. Verstovsek S. Clin Cancer Res. 2010;16(7):1988-1996. 8. Jones AV, Campbell PJ, Beer PA, et al. Blood. 2010;115(22):4517-4523. 9. Pikman Y, Lee BH, Mercher T, et al. PLoS Med. 2006;3(7):1140-1151. 10. Kralovics R, Passamonti F, Buser AS, et al. N Engl J Med. 2005;352(17):1779-1790. 11. Kralovics R. Leukemia. 2008;22(10):1841-1848. 12. Tefferi A, Vaidya R, Caramazza D, Finke C, Lasho T, Pardanani A. J Clin Oncol. 2011;29(10):1356-1363. 13. Quintás-Cardama A, Vaddi K, Liu P, et al. Blood. 2010;115(15):3109-3117. 14. Fourouclas N, Li J, Gilby DC, et al. Haematologica. 2008;93(11):1635-1644. 15. Passamonti F, Cervantes F, Vannucchi AM, et al. Blood. 2010;115(9):1703-1708. 16. Cervantes F, Dupriez B, Pereira A, et al. Blood. 2009;113(13):2895-2901. 17. Data on file. Incyte Corporation. 18. The Leukemia & Lymphoma Society. White Plains, NY; 2012. Number 14. 19. Campbell PJ, Green AR. N Engl J Med. 2006;355(23):2452-2466. 20. Rambaldi A, Barbui T, Barosi G. Hematology Am Soc Hematol Educ Program. 2008;2008:83-91. 21. Abdel-Wahab O, Manshouri T, Patel J, et al. Cancer Res. 2010;70(2):447-452. 22. Holden C, Hennessy O, Lee WK. AJR Am J Roentgenol. 2006;186(2):507-510. 23. Verstovsek S. Hematology Am Soc Hematol Educ Program. 2009:636-642. 24. Levine RL, Pardanani A, Tefferi A, Gilliland DG. Nat Rev Cancer. 2007;7(9):673-683. 25. Verstovsek S, Kiladjian J-J, Sandor VA, et al. Poster presented at the 48th annual meeting of the American Society of Clinical Oncology; June 1-5, 2012; Chicago, IL. 26. Cross NC. Hematology Am Soc Hematol Educ Program. 2011;2011:208-214. 27. Rumi E, Pietra D, Pascutto C, et al. Blood. 2014;124(7):1062-1069. 28. Arber DA, Orazi A, Hasserjian R, et al. Blood. 2016;127(20):2391-2405. 29. Tefferi A. Am J Hematol. 2008;83(6):491-497. 30. Mesa RA, Li CY, Ketterling RP, Schroeder GS, Knudson RA, Tefferi A. Blood. 2005;105(3):973-977. 31. Mesa RA. Blood. 2009;113(22):5394-5400.

 
Resources
By: World Health Organization (WHO)
A diagnostic worksheet from the WHO for primary MF, PV, and ET.
By: International Working Group for Myeloproliferative Neoplasms Research and Treatment (IWG-MRT)
Diagnostic criteria from the IWG-MRT.