Myelofibrosis is a stem cell-derived clonal myeloproliferative disease frequently associated with a mutation in the JAK2 gene (JAK2V617F). Inhibition of JAK1/ JAK2 has recently been shown to lead to clinical benefit in patients with advanced MF and platelet counts of 100,000 or higher at study entry, resulting in the first JAK1/JAK2 inhibitor to be approved for patients with advanced MF. The approved JAK inhibitor is not selective for JAK2 but inhibits both JAK1 and JAK2. While effective in reducing patients symptoms associated with MF, JAK1/JAK2 inhibitors frequently cause suppression of platelets and red blood cells, often leading to a need for red blood cell transfusions. Pacritinib may offer an advantage over other JAK inhibitors by having less bone marrow suppression. Such agents may also lead to a modification of the underlying disease process by selectively affecting the malignant clone expressing JAK2V617F.
About Myeloproliferative Neoplasms (MPN)
MPN comprise several diseases all characterized by stem cell derived clonal myeloproliferation, including primary and secondary myelofibrosis, polycythemia vera (PV) and essential thrombocythemia (ET).
Myelofibrosis (MF), the most common MPN, is a progressive and life threatening neoplasm that affects the blood-forming tissues in the body. According to the MPN Research Foundation, in 2011 there were an estimated 30,000 patients in the United States with MF approximately 30-40% of whom are thrombocytopenic with platelet counts below 150,000/uL.Myelofibrosis is caused by the accumulation of malignant bone marrow cells that triggers an inflammatory response, scarring the bone marrow and limiting its ability to produce red blood cells prompting the spleen and liver to take over this function resulting in enlargement of the spleen and related debilitating symptoms including anemia, extreme fatigue and pain. Myelofibrosis patients have a range of cellular mutations associated with the disease, of which a mutation in the JAK2gene (the JAK2V617F mutation) is the most common, occurring in more than half of patients with primary myelofibrosis. Normally in the body, JAK2 is turned on by various natural growth factors to make new blood cells as needed. The JAK2 mutation leaves the JAK2 enzyme permanently turned on, which causes the overgrowth of bone marrow stromal cells at the heart of myelofibrosis. Blood tests have now been developed that can specifically identify patients with this mutation.