Novel strategies for challenging scenarios encountered in managing myelofibrosis

Given its rarity, multi-faceted clinical presentation and the relative paucity of approved therapies, the management of myeloproliferative neoplasm (MPN)-associated myelofibrosis (MF) can be challenging. Janus kinase (JAK) inhibitors, the only approved agents at present, have brought many clinical benefits to patients, with prolongation of survival also demonstrated for ruxolitinib. However, these agents have clear limitations. Optimal management of anemia in MF remains a major unmet need. Neither ruxolitinib nor fedratinib is recommended for use in patients with severe thrombocytopenia, i.e. platelets <50 × 10⁹/L, who have a particularly poor prognosis. The search for the optimal partner for JAK inhibitors to address some of the shortcomings of these agents (e.g. limited ability to improve bone marrow fibrosis, cytopenias and induce molecular responses) and achieve meaningful ‘disease modification’ continues. This has led to the development of a number of rational, preclinically synergistic combinations for use either upfront or in the setting of sub-optimal response to JAK inhibition. Finally, the outlook for patients whose disease progresses on JAK inhibitor therapy continues to be grim, and agents with alternative mechanisms of action may be needed in this setting. In this article, we use a case-based approach to illustrate challenges commonly encountered in clinical practice and our management of the same. Fortunately, there has been enormous growth in drug development efforts in the MF space in the last few years, some of which appear poised to bear fruit in the very near future.