Impact of molecular profiling on the management of patients with myelofibrosis

Abstract

Myelofibrosis (MF) is a chronic myeloproliferative neoplasm (MPN) characterized by a highly heterogeneous clinical course, which can be complicated by severe constitutional symptoms, massive splenomegaly, progressive bone marrow failure, cardiovascular events, and development of acute leukemia. Constitutive signaling through the JAK-STAT pathway plays a fundamental role in its pathogenesis, generally due to activating mutations of JAK2, CALR and MPL genes (i.e., the MPN driver mutations), present in most MF patients. Next Generation Sequencing (NGS) panel testing has shown that additional somatic mutations can already be detected at the time of diagnosis in more than half of patients, and that they accumulate along the disease course. These mutations, mostly affecting epigenetic modifiers or spliceosome components, may cooperate with MPN drivers to favor clonal dominance or influence the clinical phenotype, and some, such as high molecular risk mutations, correlate with a more aggressive clinical course with poor treatment response. The current main role of molecular profiling in clinical practice is prognostication, principally for selecting high-risk patients who may be candidates for transplantation, the only curative treatment for MF to date. To this end, contemporary prognostic models incorporating molecular data are useful tools to discriminate different risk categories. Aside from certain clinical situations, decisions regarding medical treatment are not based on patient molecular profiling, yet this approach may become more relevant in novel treatment strategies, such as the use of vaccines against the mutant forms of JAK2 or CALR, or drugs directed against actionable molecular targets.

Keywords: Myelofibrosis; Prognostication; Somatic mutations; Survival; Treatment.