The Role of Navitoclax in Myelofibrosis

Primary myelofibrosis (PMF) is the most aggressive type of chronic myeloproliferative neoplasm, characterized by a disarray of hematopoietic stem cells and bone marrow fibrosis. The estimated incidence is 1.5 per 100,000 individuals per year with a median survival of less than six years. This statistic can vary by risk category, primarily based on clinical and cytogenetic features. Death can result from many causes, including leukemic transformation, cachexia, vascular events, and infection. Currently, allogeneic hematopoietic cell transplant is the only curative method for those at high risk. Unfortunately, only about 10% are eligible for this therapy. JAK2 kinase inhibitors are commonly used for high-risk patients with symptomatic splenomegaly or systemic symptoms from PMF. In clinical trials, the major endpoint is a reduction of spleen size by 35%. Secondary endpoints have included amelioration of symptomatic PMF and overall survival, which can be difficult to determine because of frequent co-morbid conditions. Current Food and Drug Administration (FDA)-approved JAK2 inhibitors have not shown increased survival or reduced risk of leukemic transformation. In relapsed or refractory disease, there is currently no standard of care. In this paper, we discuss the role of a new anti-apoptotic B cell leukemia 2 (Bcl-2) inhibitor, Navitoclax, for the treatment of myelofibrosis. The clinical data thus far for Navitoclax, especially in synergistic combination with traditional JAK2 inhibitors, have been promising for those with a refractory or relapsing disease on prior therapies. Following the encouraging results of phase II trials, ongoing phase III trials will primarily evaluate splenic size reduction versus the standard of care and evaluate secondary endpoints such as symptom reduction and overall survival. These studies may establish a new standard of care for refractory or relapsed myelofibrosis.