The authors outline the latest discoveries in the biology of myelofibrosis (MF), discuss current clinical management of patients with MF, and summarize the ongoing clinical trials that hope to change the landscape of MF treatment.
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.
Since the discovery of JAK2V617F mutations in MPNs over 10 years ago, significant advancements have been made in understanding the biology of MF. Although activated JAK-STAT signaling is a hallmark abnormality in MF, even in cases of triple-negative MF, JAK2, MPL, and CALR mutations are often accumulated within already abnormal HSC clones. This is one possible reason why JAK inhibition with ruxolitinib is not sufficient in producing long-term disease remissions and reversal of bone marrow fibrosis. Therefore, efforts are underway to better understand the initiating events in MF to identify novel targets that alone and in combination with JAK inhibition have disease-modifying properties. As the knowledge of the molecular abnormalities in MF expands, there will be improvements in MF risk models as well, integrating both clinical and genetic information that impact prognosis. Intriguing molecularly based therapies include the use of IDH inhibitors, spliceosome inhibitors, and immunotherapeutic approaches particularly for patients with CALR-mutated MPNs.