Myelofibrosis in 2019: moving beyond JAK2 inhibition

Abstract

Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by ineffective clonal hematopoiesis, splenomegaly, bone marrow fibrosis, and the propensity for transformation to acute myeloid leukemia. The discovery of mutations in JAK2, CALR, and MPL have uncovered activated JAK-STAT signaling as a primary driver of MF, supporting a rationale for JAK inhibition. However, JAK inhibition alone is insufficient for long-term remission and offers modest, if any, disease-modifying effects. Given this, there is great interest in identifying mechanisms that cooperate with JAK-STAT signaling to predict disease progression and rationally guide the development of novel therapies. This review outlines the latest discoveries in the biology of MF, discusses current clinical management of patients with MF, and summarizes the ongoing clinical trials that hope to change the landscape of MF treatment.

Fig. 1. Activated JAK-STAT signaling drives myelofibrosis.

In normal physiology (top), binding of erythropoietin (EPO) or thrombopoietin (TPO) to their respective receptors (EPO-R, MPL) leads to phosphorylation and activation of JAK2 resulting in STAT-dependent transcription of target genes. The JAK^V617F (left), MPL^W515L (right), and CALR exon 9 (CALR^ex9, bottom) mutations result in constitutive JAK-STAT activation

Fig. 2. Therapeutic strategies for disease-modifying therapy myelofibrosis.

These are classified as inhibitors of proliferative signaling, epigenetic regulators, agents involved in HSC maintenance, survival, and differentiation, immune therapies, and antifibrotic agents. Classes in red depict areas with FDA-approved agents (see Table 2). Signaling pathways cooperating with JAK-STAT activation include the tyrosine kinase receptor FLT3, the PI3K/mTOR axis, and Hedgehog signaling mediated by GLI1