Myelofibrosis is a clonal myeloid stem cell malignancy that affects production of erythrocytes, thrombocytes, neutrophils and leads to fibrosis of bone marrow due to abnormal expression of proinflammatory cytokines. The abnormality in myeloid cell lineage hematopoiesis leads to extramedullary hematopoiesis, more so in spleen and liver causing their pathology. Primary myelofibrosis along with polycythemia vera and essential thrombocythemia are grouped under Philadelphia chromosome negative myeloproliferative neoplasms. Myelofibrosis is either primary or secondary arising from polycythemia vera or essential thrombocythemia. Mutation in JAK/STAT (Janus kinase/signal transducer and activator of transcription) signaling pathway is implicated in the pathogenesis of myelofibrosis. In later stages, myelofibrosis may transform into acute myeloid leukemia.
Alternative Treatment For Myelofibrosis
Ruxolitinib (Jakafi) is the only FDA approved (in 2011) JAK 1&2 inhibitor for treatment of myelofibrosis. It is known to improve the symptoms related to the disease progression along with reduction in spleen size and decreased mortality in higher risk patients who fail the criteria of allogeneic stem cell transplantation. However, anemia, thrombocytopenia and myelosuppression are a major concern for myelofibrosis patients. This led to alternative treatment options and alternative JAK inhibitors, which have less toxic effects, that ruxolitinib.
Pacritinib is other JAK2 inhibitor that was given fast track designation by FDA for management of higher risk myelofibrosis and it is currently in Phase III trial. Phase II trials have shown encouraging results with reduction in splenomegaly and constitutional symptoms. However, due to its potential adverse effects related to intracranial hemorrhage and cardiac events, its trial is under hold. However, no infection or myelosuppression adverse effects were seen in patients as were noted with ruxolitinib use. Clinical trials of XL019, fedratinib and lestaurtinib have also been put on hold due to higher toxicities.
Momelotinib is the only JAK inhibitor for which clinical trials are underway in the treatment of myelofibrosis. It has also shown positive results for constitutional symptoms, anemia and splenomegaly. It is currently in Phase III trial against ruxolitinib for the management of myelofibrosis in JAK inhibitor naive patients. (1)
Other pathways apart from JAK/STAT dysregulation have been implicated in the pathogenesis of myelofibrosis, since only 40-60% patients are positive for JAK2 mutation. Therefore, other drugs that might inhibit other pathways are under investigation. These drugs include everolimus (mammalian target of rapamycin inhibitor), longer acting interferon alpha (pegylated IFN alpha), givinostat (histone deacetylase inhibitor). Other JAK inhibitors, hypomethylating agents, Hedgehog inhibitors, proteasome inhibitors, PI3K inhibitors and different other pathway inhibitors are being studied for the evolutionary alternate management of myelofibrosis.
Conventional Treatment For Myelofibrosis
Allogeneic stem cell transplantation is the only curative treatment for myelofibrosis till date. Bone marrow transplantation is quite effective for younger patients. However, myelofibrosis is a disease of the elderly, therefore, only few patients become possible candidates for bone marrow transplantation. This is due to greater mortality associated with post-transplant complications leading to graft failure, graft versus host disease and infection. Patients with higher risk myelofibrosis and younger age with no significant co-morbidities are the best candidates for allogeneic stem cell transplantation.
Non-candidates for bone marrow transplantation are managed with other chemotherapeutics for controlling leucocytosis, anemia, thrombocytosis and hepatosplenomegaly. Anemia is controlled with erythropoietin stimulating agents, blood transfusions, immunomodulating agents and androgens (danazol). Immunomodulating agents (with/without corticosteroids), such as thalidomide, lenalidomide and pomalidomide are used for the management of cytopenias, systemic symptoms and cytopenias. Hydroxyurea, and alpha interferon can be used to manage organomegaly and constitutional symptoms along with myelosuppression. However, all these chemotherapeutics do not modulate the natural course of treatment or improve overall survival of the patient.
Splenectomy is also a possible alternative; however, it is associated with high mortality (9%) and morbidity (31%) due to perioperative bleeding, infections and thrombosis. It is reserved for patients with splenomegaly refractory to hydroxyurea, progressive anemia and portal hypertension. Splenic irradiation can be used for splenic infarction and symptomatic splenomegaly; however, the results are usually temporary lasting only about 6 months. (1)
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