Disease Focus

Myelofibrosis (MF) is a rare blood cancer that progressively impairs red blood cell production. It is thought to be driven by dysregulation of the JAK-STAT pathway.1

Continual activation of this pathway results in local inflammation and progressive bone marrow fibrosis, reducing the hematopoietic capacity of the marrow (anemia) and triggering extramedullary hematopoiesis in the spleen (splenomegaly).2 The systemic pro-inflammatory cytokine profile (eg IL-6) induces a hyper-metabolic state and constitutional symptoms3 and drives production of hepcidin, the master regulator of iron homeostasis. Elevated hepcidin restricts iron availability for erythropoiesis, further reducing red blood cell.

MF is a rare disease, with a prevalence of 18,000 patients in the United States.4 Although MF can occur at any age, the median age at diagnosis ranges from 60 to 67 years.5,6 MF is a progressive disease7 that affects both men and women7 and can transform to secondary acute myelogenous leukemia.8 This leukemic transformation occurs in 8% to 23% of patients during the first decade after diagnosis.8 The median survival for all patients with MF is about 6 years, but it is considerably shorter for high-risk patients at just 2.25 years.9

The Unmet Need in Myelofibrosis

The current standard of care for MF is treatment with JAK inhibitors. However, currently approved JAK inhibitors can be myelosuppressive, leading to reduced hemoglobin and platelet production. Dose reductions due to cytopenia are common, which can compromise long-term efficacy of current therapies. Furthermore, some patients may never receive a JAK inhibitor due to presentation with severe anemia and/or thrombocytopenia at diagnosis. Severe anemia can lead to transfusion dependency and shortened overall survival. New treatments that address all three MF disease hallmarks, without long-term toxicity and increased cytopenias are needed.

1 Verstovsek S. Hematology Am Soc Hematol Educ Program. 2009:636-642.
2 Holden C, Hennessy O, Lee WK. AJR Am J Roentgenol. 2006;186(2):507-510
3 Verstovsek S. Clin Cancer Res. 2010;16(7):1988-1996.
4 Mehta J, Wang H, Iqbal SU, Mes R. Epidemiology of myeloproliferative neoplasns in the United States. Leukemia & Lymphoma. 2014;55(3):595-600
5 Abdel-Wahab OI, Levine RL. Annu Rev Med. 2009;60:233-245
6 Mesa RA, Niblack J, Wadleigh M, et al. Cancer. 2007;109(1):68-76.
7 Tefferi A. Am J Hematol. 2008;83(6):491-497
8 Mesa RA, Li CY, Ketterling RP, Schroeder GS, Knudson RA, Tefferi A. Blood. 2005;105(3):973-977.
9 Cervantes F, Dupriez B, Pereira A, et al. Blood. 2009;113(13):2895-2901.

Burden of Disease

Common disease manifestations include bone marrow failure, enlarged spleen due to extramedullary hematopoiesis (splenomegaly), debilitating symptoms including fatigue, night sweats, pruritus, early satiety, abdominal pain and discomfort, and marked decrement in patient’s quality of life (QoL). MF is a progressive disease, with splenomegaly, constitutional symptoms and reductions in blood cell production worsening over time. The most common cause of mortality in MF is transformation to acute leukemia.10

Anemia is among the cardinal features of MF. Approximately two thirds of patients with myelofibrosis (MF) are anemic, and nearly half are transfusion dependent within 1 year of diagnosis, with most progressing to transfusion dependency over time.11 Anemia has consistently been associated with inferior quality-of-life measures among MF patients and response to anemia-targeted therapies has been associated with improvement in quality of life.8,12 Importantly, transfusion dependency and moderate-to-severe anemia are strong negative prognostic factors in MF and are inversely correlated to overall survival.13 Elevated hepcidin, which reduces iron availability and erythropoiesis leading to anemia of chronic inflammation, has also been associated with reduced survival in MF patients.

10 Cervantes F, Dupriez B, Pereira A, et al. Blood. 2009;113(13):2895-2901.
11 Sierra Internal Data
12 Naymagon L & Mascarenhas, J. HemaSphere. 2017. 1(1): e1.
13 Pardanani A, Finke C, Ramy A, et al., American Journal of Hematology. 2013; 88(4): 312-316.
14 Scherber R & Mesa, R. Blood Reviews. 2020. 42.
Oh S, Talpaz M, Gerds A, et al. 2020. Blood Advances. 4(18):4282-4291.