Myelofibrosis is a clonal stem cell neoplasm that progressively causes fibrosis of the bone marrow. Basically, myelofibrosis is of two types, namely, primary myelofibrosis and secondary myelofibrosis. In 2008, WHO classified primary myelofibrosis under Ph chromosome negative myeloproliferative neoplasms along with polycythemia vera, essential thrombocytosis, chronic eosinophilic leukemia, chronic neutrophil leukemia, mastocytosis, unclassifiable myeloproliferative neoplasm and neoplasms associated with eosinophilia and PDGFR abnormalities.
Polycythemia vera is associated with increased in erythroid, megakaryocytic and granulocytic production in bone marrow. However, after 10-12 years of diagnosis of polycythemia vera, in about 20-30% of the patients it can transform to secondary myelofibrosis and fibrosis maybe evident in the bone marrow of these patients. At this stage, it is quite difficult to differentiate between polycythemia vera and primary myelofibrosis.
Essential thrombocytosis is associated with increased proliferation of megakaryocytes in the bone marrow with subsequent elevation of platelets in peripheral blood. The other stem cell lineages of granulocytes and erythrocytes are not affected. It also has a tendency to transform into secondary myelofibrosis; however, its transformation to it is less common accounting in only <1% patients at 10 years and <10% at 15 years.
Primary myelofibrosis is a heterogeneous disease with bone marrow changes associated with proliferation of megakaryocytes and reticulin and/or collagen fibrosis. Although, bone marrow fibrosis is a characteristic feature of primary myelofibrosis, in some cases and early phases it may be devoid of fibrosis known as prefibrotic primary myelofibrosis. In these cases, megakaryocytes proliferation is accompanied by little or no fibrosis along with granulocytic proliferation mostly associated with erythropoiesis alleviation. (1)
Stages Of Progression In Myelofibrosis
Although, prefibrotic phase of primary myelofibrosis is accepted by WHO, there is still doubt regarding the progression of myelofibrosis due to few conflicting studies that have studied sequential biopsy specimens. A retrospective study with a cohort of 109 individuals classified myelofibrosis into 4 stages, namely, MF0 (absence of reticulin fibrosis), MF1 (mild reticulin fibrosis), MF2 (overt collagen myelofibrosis) and MF4 (osteomyelosclerotic stage). The results were consistent with disease progression in about 71% patients in MF0 phase and in these 32% showed step wise disease progression to fully developed primary myelofibrosis. About 60.6% cases in MFI phase evolved to MF2 and 36.4% cases in MF2 evolved to MF3 phase, whereas, MF3 phase remained consistent without any further evolution. This indicates progression of disease from the time of diagnosis form mild to moderate and moderate to severe primary myelofibrosis. However, in some patients, there was steady decline in myelofibrosis, although the percentage was quite small than the cases that progressed to more severe form.
The progressive worsening of primary myelofibrosis is seen clinically as overt splenomegaly, in addition to progressive systemic symptoms. The initial phase of primary myelofibrosis may resemble essential thrombocytosis, due to the presence of thrombocytosis. In addition, systemic symptoms maybe present including, fatigue, weakness, weight loss, night sweats, fever, dyspnea, bleeding and early satiety due to splenomegaly. In some patients, renal stones and gouty arthritis may also be present secondary to hyperuricemia.
No curative treatment exists for primary myelofibrosis with the exception for allogeneic stem cell transplantation. However, the treatment cannot be available to most of the patients due to increased mortality and morbidity of the procedure. Treatment is aimed at reducing the constitutional symptoms along with anemia, splenomegaly, thrombocytsis, leucocytosis and resulting complications. Allogeneic stem cell transplantation is reserved for intermediate and high risk patients only. Low risk patients are managed with drug therapy (interferon, hydrea). Intermediate risk and high risk patients are managed with a combination of drug therapy, blood transfusions, splenectomy, radiotherapy and allogeneic stem cell transplantation. Some chemotherapeutic drugs include erythropoiesis stimulating agents, androgens, cladribine, thalidomide, lenalidomide, danazol and prednisone.
Mutation of JAK2 is seen in about 70% of the patients of myelofibrosis; therefore, JAK2 inhibitors have been able to improve symptomatic splenomegaly and systemic symptoms of the disease. However, more clinical trials need to be done to prove their safety due to their adverse effects of cytopenias and bone marrow suppression.
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