Advances in pharmacotherapy for myelofibrosis: what is the current state of play?

The introduction of the first JAK inhibitor (JAKi) ruxolitinib 10 years ago represented a pivotal advancement in myelofibrosis (MF) treatment, mostly in terms of spleen and symptoms response. Nowadays three more JAKi, fedratinib, pacritinib, and momelotinib, are available for both ruxolitinib-resistant and naïve patients. Moreover, many drugs are currently being investigated, both alone and in combination with JAKi.

In this review we discuss the long-term data of ruxolitinib and more recent evidence coming from clinical trials of fedratinib, pacritinib, and momelotinib, used as first- or second-line MF therapy. More, focus is set on data from non-JAKi drugs, such as the quite extensively studied BET-inhibitors (pelabresib) and BCL-inhibitors (navitoclax), novel target therapies, and drugs aimed to improve anemia, still representing a major determinant of reduced survival in MF.

It's now evident that JAKi monotherapy, though clinically effective, is rarely able to change MF natural history; novel drugs are promising but long-term data are inevitably lacking. We feel that soon MF treatment will require clinicians to select the most appropriate JAKi inhibitor, based on patient characteristics, associating either front-line or in case of early suboptimal response, non-JAKi drugs with the aim to pursue disease modification.