Seven years after the approval of the
Janus kinase 1/2 (JAK1/2) inhibitor
ruxolitinib, it remains the only
drug licensed for the treatment of
myelofibrosis. Patients who discontinue
ruxolitinib have a dismal outcome, and this is, therefore, an area of significant unmet need. Given the central role that JAK-signal transducer and activator of transcription (STAT) activation plays in disease pathogenesis, there have been many other
JAK inhibitors tested, but most have been abandoned, for a variety of reasons. The JAK2-selective inhibitor
fedratinib has recently been resurrected, and there has been a resurgence of interest in the failed JAK1/2 inhibitor
momelotinib, which possibly improves
anemia.
Pacritinib, a non-myelosuppressive JAK2-selective inhibitor, is currently in a dose-ranging study mandated by regulatory authorities. A plethora of other targeted agents, most backed by preclinical data, are in various stages of investigation. These include epigenetic and immune
therapies, agents targeting cellular survival, metabolic and apoptotic pathways, the cell cycle, DNA repair, and protein folding and degradation, among others. However, at this time, none of these is close to registration or even in a pivotal trial, illustrating the difficulties in recapitulating the clinical disease in preclinical models. Most current clinical trials are testing the addition of a novel agent to
ruxolitinib, either in the frontline setting or in the context of an insufficient response to
ruxolitinib, or attempting to study new drugs in the second-line, "
ruxolitinib failure" setting. Emerging data supports the addition of
azacitidine to
ruxolitinib in some patients. Other strategies have focused on improving
cytopenias, through amelioration of
bone marrow fibrosis or other mechanisms. This is important, because
cytopenias are the commonest reason for
ruxolitinib interruption and/or
dose reduction, and dose optimization of
ruxolitinib is tied to its survival benefit. The
activin receptor ligand trap,
sotatercept, and the anti-fibrotic agent,
PRM-151, have shown promise in this regard.