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

Does Anti-coagulation Improve Results in Cancer?

Should heparin be offered to patients with cancer who have no standard indication for anticoagulation therapy? Patients with advanced cancer, especially patients undergoing chemotherapy, commonly experience venous thromboembolism (VTE), such as deep venous thrombosis (DVT) and pulmonary embolism (PE). Consequences of venous thromboembolism include higher morbidity, hospitalization, interruption of chemotherapy, initiation of anticoagulant therapy or insertion of a vena cava filter, decreased quality of life, increased medical costs, and increased mortality.1,2 The current issue of Heme-O-Gram reviews a recent NEJM report and editorial on the potential improvement in outcomes that may be brought about by use of low molecular weight heparin (LMWH). Semuloparin Reduces Venous Thromboembolism in Cancer Patients In the SAVE-ONCO study, a multi-center double-blinded trial of 3,212 adult patients with locally advanced or metastatic cancer of various representative types who were undergoing chemotherapy patients were randomized to receive daily subcutaneous injections of either 20 mg of semuloparin, a semisynthetic, ultra-LMWH, or placebo for a median duration of 3.5 months. The treatment arm had significantly lowered incidence of venous thromboembolism (including DVT and fatal and non-fatal PE) without significantly increased major bleeding. However, the anticoagulant did not lower the mortality rate, as the rate of death in the semuloparin and placebo group was 43.4% and 44.5%, respectively.1 Pooled Analysis of Clinical Studies of Anticoagulation for Cancer Patients In the accompanying NEJM editorial on the SAVE-ONCO study, Aki and Schunemann analysed data pooled from the SAVE-ONCO study, their prior Cochrane systematic review of studies with LMWH, and another clinical trial. Using this pooled data approach of several studies they concluded that a year of treatment with LMWH in 1,000 patients with advanced cancer would result in no significant rise in major bleeding, 20 fewer thromboembolic events (and a decrease in related hospitalizations), and approximately 30 fewer deaths. The reduction in mortality was something that the SAVE-ONCO study was not strongly powered enough to demonstrate. Intriguing Mechanisms of Action of Heparins Heparins theoretically may have anti-tumor effects (including inhibiting cell to cell interactions, activity of extracellular matrix enzymes, and angiogenesis), in addition to direct anticoagulant effects.2 Antithrombotic drugs may counteract the prothrombotic effects of chemotherapy.1 Future Directions for Anticoagulant Use in Cancer Patients At the present time, guidelines recommend that cancer patients who have been hospitalized for medical illness or have undergone surgery for cancer should receive prophylaxis with anticoagulants. Given the results of the clinical studies of LMWH, stratification of risk for VTE among cancer patients, including ambulatory patients receiving chemotherapy, may be helpful.1 Ongoing and future trials may reveal whether patients with particular types and stages of solid tumors will obtain improved tumor response, quality-of-life benefits, and survival extension from adjuvant anticoagulant therapy.2 For more discussion, please visit the following URLs and links: 1 http://www.nejm.org/doi/full/10.1056/NEJMoa1108898 2 http://www.nejm.org/doi/full/10.1056/NEJMe1113672 E Thanks to everyone who has sent me feedback. Feel free to email me, or post your own comments. Stanford University