The safety of JAK kinase inhibitors for the treatment of myelofibrosis

Introduction: During the last decade, the development of small molecule inhibitors of Janus kinases (JAKi) contributed to revolutionize the therapeutic landscape of myelofibrosis (MF). JAKi proved to be effective in controlling disease-related symptoms and splenomegaly with remarkable inter-drug variability. However, in some cases the border between clinical efficacy of JAKi and dose-dependent toxicities is narrow leading to sub-optimal dose modifications and/or treatment discontinuation. Areas covered: In the current review, the authors aimed at providing a comprehensive review of the safety profile of JAKi that are currently approved or in advanced clinical development. Also, a short discussion of promising JAKi in early clinical evaluation and molecules ‘lost’ early in clinical development is provided. Finally, we discuss the possible strategies aimed at strengthening the safety of JAKi while improving the therapeutic efficacy. Expert opinion: Overall, JAKi display a satisfactory risk-benefit ratio, with main toxicities being gastrointestinal or related to the myelo/immunosuppressive effects, generally mild and easily manageable. However, JAKi may be associated with potentially life-threatening toxicities, such as neurological and infectious events. Thus, many efforts are needed in order to optimize JAKi-based therapeutic strategies without burdening patient safety. This could be attempted through drug combinations or the development of more selective molecules.