Myelofibrosis belongs to the group of Philadelphia chromosome negative myeloproliferative neoplasms along with polycythemia vera and essential thrombocythemia. Myelofibrosis is either de novo (primary or idiopathic) or secondary to polycythemia vera and essential thrombocythemia. There is proliferation of clonal hematopoietic stem cells leading to abnormal myeloid stem cell lineage with subsequent release of cytokines and growth factors in the bone marrow. This causes changes in stroma, bone marrow fibrosis and extramedullary hematopoiesis in organs, such as spleen and liver leading to clinical manifestations of the disease. It is a disease of older individuals with 67 years as the median age of diagnosis.
The symptoms of myelofibrosis are associated with cytopenias or thrombocytosis, splenomegaly and constitutional symptoms. These include, fatigue, weakness, fever, weight loss, itching, dyspnea, night sweats, tachycardia, bone pain, cachexia, early satiety, abdominal pain, diarrhea, splenic infarction, and easy bruising. These may worsen the quality of life of the patients suffering from myelofibrosis. About 20% patients transition to acute myeloid leukemia, which is the most frequent cause of death. The median survival of patients with myelofibrosis is 3.5-5.5 years. JAK2 mutation is seen in about 50-60% of the patients, CALR gene mutation is seen in about 15-20% cases, MPL mutation is seen in 5-10% cases and in 10% cases no known mutation are noted; hence, they are referred by triple negative myelofibrosis. (1)
What Is The Best Treatment For Myelofibrosis?
There is no single treatment for myelofibrosis. Since the disease is heterogeneous with many presenting symptoms and different clinical manifestations in different patients. The requirement for each patient is different from the other. The treatment varies from monitoring for low risk patients to aggressive treatment and stem cell transplantation for higher risk patients. Anemia is managed mostly with blood transfusions for symptomatic patients. Other treatment options for anemia include erythropoiesis stimulating agents (darbepoetin alfa) in non-transfusion dependent anemia, corticosteroids, androgens (danazol), immunomodulatory agents (thalidomide, lenalidomide, pomalidomide). Iron overload due to repeated transfusions is managed with deferasirox and deferoxamine.
Splenomegaly is managed with cytoreductive agents such as hydroxyurea, interferon alpha, oral alkylating agents (melphalan), methotrexate and ruxolitinib. Cladribine can also be used in refractory cases of splenomegaly. Splenectomy is another management option for refractory splenomegaly, portal hypertension (varices), transfusion dependent anemia, and cachexia. Splenic radiotherapy is another option for splenomegaly; however, it is effective only transiently. Ruxolitinib is a newly FDA approved drug for the management of splenomegaly and has been proved effective in reducing enlarged spleen. It has also been found to be effective in managing the constitutional symptoms associated with the disease and improving the quality of life of patients along with enhancing the survival of myelofibrosis patients. However, anemia and thrombocytopenia is worsened with ruxolitinib along with greater chances of infection. Currently, another JAK2 inhibitor, momelotinib is being clinically tested and has proved effective in the reduction of anemia, constitutional symptoms and splenomegaly. It’s in its Phase III of clinical trial. (1)
Currently, allogeneic stem cell transplantation is the only curative treatment of myelofibrosis that improves the survival of higher risk patients. It is associated with 40-50% 3 year progression free survival rate, according to recent data. However, patient selection, donor selection, conditioning regimen, pre and post transplant management, along with prevention and management of post transplant relapses are important factors to be taken into consideration. It is more effective in younger patients than elderly patients with additional comorbidities; therefore, it is recommended for younger patients with no other comorbidities. In older and patients with significant comorbidities are being treated with reduced intensity or nonmyeloablative allogeneic stem cell transplantation in which reduced doses of chemotherapy is delivered in preparatory phase of transplantation.
Therefore, there is no one treatment that is best for myelofibrosis. The best treatment is decided by the doctors depending on the age, symptoms, risk, comorbidities and therapeutic needs of the patient, in addition to complications and risk of transformation of myelofibrosis to acute myeloid leukemia. (2)