Advances in potential treatment options for myeloproliferative neoplasm associated myelofibrosis

ABSTRACT

Introduction: 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.

Areas covered: 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.

Expert opinion: 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.

KEYWORDS:

• Fedratinib
• imetelstat
• luspatercept
• momelotinib
• myelofibrosis
• pacritinib
• PRM-151
• rational combinations
• ruxolitinib
• sotatercept

Article highlights

• Ruxolitinib remains the only approved therapy for patients with MPN-associated MF, although other Janus kinase (JAK) inhibitors, e.g. fedratinib, pacritinib and momelotinib, are being actively developed for this indication.

• Many rational ruxolitinib-based combinations are being pursued in clinical trials; some of these aim to counteract ruxolitinib-induced cytopenias, while many others are based on laboratory evidence of synergism and are being tested as ‘add on’ therapy in patients with ‘insufficient’ responses to ruxolitinib.

• Ruxolitinib ‘failure’, which has no uniformly accepted definition, nevertheless represents a major unmet need: a number of novel agents are being studied in this setting.

This box summarizes key points contained in the article.

Declaration of interest

P Bose reports research funding from Incyte Corporation, Celgene Corporation, Blueprint Medicines Corporation, CTI BioPharma Corporation, Kartos Therapeutics, Constellation Pharmaceuticals, Pfizer, Inc., Astellas Pharmaceuticals, NS Pharma and Promedior, and honoraria from Incyte Corporation, Celgene Corporation, and Blueprint Medicines Corporation.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by the NIH/NCI grant number: P30 CA016672.