Myelofibrosis (MF) is a chronic myeloproliferative neoplasm. It can either appear de nova (primary MF) or secondary following previous essential thrombocytosis (ET) or polycythemia Vera (PV). MF is characterized by the clonal proliferation of a pluripotent hematopoietic stem cell. These abnormal cells release various cytokines and growth factors resulting in marrow fibrosis and other stromal changes. Extramedullary hematopoiesis is common leading to hepatosplenomegaly. Approximately 60% of cases of primary MF or post-ET MF will harbor the V617F mutation in the JAK2 gene; 95% of post-PV MF will have the presence of the JAK2 mutation. Mutations in the thrombopoietin receptor gene (MPL) are found in 3-8% of primary MF and post-ET MF and up to 50% of cases of primary MF and post-ET MF without JAK2 or MPL mutations will harbor a mutation in the calreticulin gene (CALR).
The only known curative therapy for MF is allogeneic stem cell transplantation (HSCT). Unfortunately the number of patients eligible for such a procedure is limited by patient co morbidities, advancing age and donor availability. Therefore, the goals of therapy are largely centered on controlling disease symptoms and improving quality of life. Recently, the introduction of the JAK2 inhibitors has lead to improvements in the therapeutic approach of MF. JAK2 inhibitors are effective in both JAK2 negative and positive MF providing improvements in symptomatic splenomegaly and constitutional symptoms. However, there is no clear evidence of disease modifying effect.
The median survival of primary MF is approximately 7 years, but can be variable. A number of prognostic models have been developed in an attempt to predict the clinical course and overall survival of individual patients diagnosed with MF. The IPSS utilizes five variables at diagnosis (age, constitutional symptoms, hemoglobin, leukocyte count and peripheral blood blasts) to categorize patients as low risk, intermediate-1 risk, intermediate-2 risk and high risk, with median survivals of 11, 8, 4 and 2 years respectively. The DIPSS model is derived from the IPSS, but is designed to be utilized during the course of the disease and gives more prognostic weight to the development of anemia. Further refinement of the DIPSS model has lead to the DIPPS-plus model that includes thrombocytopenia, transfusion need and karyotype. Patients within the DIPPS low or intermediate-1 risk category are candidates for close observation or therapy with JAK2 inhibitors for symptomatic splenomegaly or constitutional symptoms. A trial of erythropoietin (if serum EPO<500) or danazol, thalidomide or prednisone may be considered for symptomatic anemia. Patients with DIPPS intermediate-2 or high risk disease should be considered for allogeneic HSCT as deemed appropriate. The potential morbidity and mortality of such a procedure will need careful consideration for each patient in this high risk category. Therapy with a JAK2 inhibitor prior to allogeneic HSCT may be helpful to reduce disease burden, decrease splenomegaly and improve symptom control. Please refer to the treatment algorithm below for further details.
Further refinement of the prognostic models is underway with the incorporation of molecular markers including mutations in ASXL1, EZH2, IDH1/2 and SRSF2 which are associated with a poor prognosis. Triple negative (no evidence of JAK2, MPL, CALR) MF patients also appear to have an inferior prognosis. In combination with clinical data from the DIPPS, these molecular markers can add further prognostic value to the scoring models and may help to further identify high-risk patients who should be evaluated for HSCT.
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