Jakafi Gives New Hope in Myelofibrosis

This issue of the Heme-O-Gram reviews clinical trials of oral Jakafi (ruxolitinib), the first FDA-approved medication indicated for treatment of intermediate and high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis. Myelofibrosis Myelofibrosis, a myeloproliferative malignancy, can be a primary disease or can develop from polycythemia vera or essential thrombocythemia.Pathogenic features of myelofibrosis include marrow fibrosis, progressive anemia, thrombocytosis or thrombocytopenia, leukocytosis or leucopenia, and splenomegaly. Patients with myelofibrosis commonly experience debilitating symptoms, such as weakness, fatigue, weight loss, cachexia, bone pain, night sweats, and pruritis. Although allogenic stem cell transplantation may be curative, few patients are candidates. Other treatments are not disease-modifying and are palliative in nature. Survival of myelofibrosis patients ranges from 2 to 11 years. Molecular Dysregulation in Myelofibrosis Dysregulation of Janus kinase (JAK), signal tranducer and activator of transcription (STAT) pathways and pro-inflammatory cytokines and growth factors that signal through JAK 1 and 2 play important roles in the pathogenesis of myelofibrosis.A JAK 2 mutation occurs in half of patients with primary myelofibrosis. About one-third of patients with myelofibrosis, however, do not have JAK-STAT-related mutations.3 Jakafi selectively inhibits JAK 1 and 2 and selectively blocks cell proliferation. Placebo-Controlled Trial of Jakafi In a double-blind, multi-center Phase 3 trial (COMFORT-I), patients with intermediate and high-risk myelofibrosis were randomized to receive either twice-daily Jakafi or placebo. Treatment resulted in reduction in size of spleen, decrease in debilitating disease-related symptoms, and improvement in overall survival. During the early part of the treatment period, patients in the Jakafi-treated group experienced more frequent anemia and thrombocytopenia. Trial of Jakafi vs Best Available Therapy In a multi-center Phase 3 trial (COMFORT-II), 219 patients with intermediate or high-risk primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocytopenia myelofibrosis were randomized to receive either continuous oral Jakafi or the best available therapy. Jakafi treatment caused significant, rapid and durable reduction in splenomegaly; and other disease-related symptoms and rapidly and durably improved patients’ quality of life. In both arms of the trial, common hematological adverse events were thrombocytopenia and anemia. These were managed with reduction in dose of study drug, interruption of therapy, or transfusion. Jakafi as an Addition to the Armamentarium of Palliative Therapeutics As palliative treatment for myelofibrosis, Jakafi therapy results in a partial response in splenomegaly and reduces constitutional symptoms. An estimated 30% of patients with myelofibrosis have symptoms that are sensitive to Jakafi therapy. However, patients in the Phase 3 trials did not experience histopathologic, cytogenetic, or molecular remission of their disease. Thus, the effects of Jakafi appear to be primarily anti-cytokine in nature, rather than as a disease-modifying therapeutic. Nevertheless, oncologists view Jakafi as an important addition to choices for palliation of myelofibrosis. Jakafi should be considered as an option for myelofibrosis patients who are not candidates for potentially curative allogeneic stem cell transplantation or clinical trials of investigative drugs. For more discussion, please visit the following URLs and links: 1 www.nejm.org/doi/full/10.1056/NEJMoa1110556 2 www.nejm.org/doi/full/10.1056/NEJMoa1110557 3 www.nejm.org/doi/full/10.1056/NEJMe1115119