Advances in potential treatment options for myeloproliferative neoplasm associated myelofibrosis

The Janus kinase (JAK)1/2 inhibitor ruxolitinib provides rapid, sustained and often dramatic benefits to patients with myelofibrosis, inducing spleen shrinkage and ameliorating symptoms, and improves survival. However, the drug has little effect on the underlying bone marrow fibrosis or on mutant allele burden, and clinical resistance eventually develops. Furthermore, ruxolitinib-induced cytopenias can be challenging in everyday practice.

The developmental therapeutics landscape in MF is discussed. This includes potential partners for ruxolitinib being developed with an aim to improve cytopenias, or to enhance its disease-modifying effects. The development of other JAK inhibitors with efficacy post-ruxolitinib or other unique attributes is being pursued in earnest. Agents with novel mechanisms of action are being studied in patients whose disease responds sub-optimally to, is refractory to or progresses after ruxolitinib.

The JAK inhibitors fedratinib, pacritinib and momelotinib are clearly active, and it is expected that one or more of these will become licensed in the future. The activin receptor ligand traps are promising as treatments for anemia. Imetelstat has shown interesting activity post-ruxolitinib, and azactidine may be a useful partner for ruxolitinib in some patients. Appropriately, multiple pre-clinical and clinical leads are being pursued in this difficult therapeutic area.