Myelofibrosis: an update on drug therapy in 2016

ABSTRACT

Introduction: Primary myelofibrosis (PMF) is the least common but the most aggressive of the classic Philadelphia chromosome-negative myeloproliferative neoplasms. Survival is much shorter in PMF than in polycythemia vera (PV) or essential thrombocythemia (ET). Post-PV/ET myelofibrosis (MF) is clinically indistinguishable from PMF and approached similarly.

Areas covered: Current pharmacologic therapy of MF revolves around the Janus kinase 1/2 (JAK1/2) inhibitor ruxolitinib, which dramatically improves constitutional symptoms and splenomegaly in the majority of patients, and improves overall survival (OS). However, allogeneic stem cell transplantation remains the only potential cure. Other JAK inhibitors continue to be developed for MF, and momelotinib and pacritinib are in phase III clinical trials. Anemia is common in MF, and initially worsened by ruxolitinib. Momelotinib and pacritinib may prove advantageous in this regard. Current strategies for managing anemia of MF include danazol, immunomodulatory drugs and erythroid stimulating agents, either alone or in combination with ruxolitinib.

Expert opinion: A number of other agents, representing diverse drug classes, are in various stages of development for MF. These include newer JAK inhibitors, other signaling inhibitors, epigenetic modifiers, anti-fibrotic agents, telomerase inhibitors, and activin receptor ligand traps (for anemia). Hopefully, these novel therapies will further extend the clinical benefits of ruxolitinib.

KEYWORDS:

• Myelofibrosis
• JAK inhibitors
• ruxolitinib
• momelotinib
• pacritinib
• danazol
• Imids
• erythroid stimulating agents
• hydroxyurea
• hypomethylating agents

Article highlights

• The JAK1/2 inhibitor ruxolitinib is the cornerstone of drug therapy for myelofibrosis.

• Ruxolitinib markedly improves symptoms and splenomegaly in the majority of patients with myelofibrosis, as well as overall survival in higher risk patients.

• Anemia is not improved and often initially worsened by ruxolitinib; therapies commonly used for anemia of myelofibrosis include steroids, androgens, erythroid stimulating agents and immunomodulatory drugs.

• Newer JAK2 inhibitors in phase 3 trials include momelotinib and pacritinib; momelotinib improves anemia in a substantial proportion of patients with myelofibrosis and pacritinib is a relatively non-myelosuppressive JAK2 inhibitor.

• Novel agents in earlier phases of clinical development include the anti-fibrotic agent PRM-151 and the telomerase inhibitor imetelstat; a number of rational ruxolitinib-based combinations are are also being pursued in clinical trials.

This box summarizes key points contained in the article.

Acknowledgments

The authors gratefully acknowledge Kate J. Newberry, Ph.D. for her assistance in preparing the tables.

Declaration of interest

P Bose discloses an honorarium from Incyte Corporation for advisory board participation. S Verstovsek reports research funding from Incyte Corporation, Roche, AstraZeneca, Lilly Oncology, Geron Corporation, NS Pharma, Inc., Bristol-Myers Squibb, Celgene Corporation, Gilead, Seattle Genetics, Promedior, CTI BioPharma Corporation, Galena BioPharma, Pfizer, Genentech and Blueprint Pharmaceuticals. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was supported in part by the University of Texas MD Anderson Cancer Center Support Grant P30 CA016672 from the National Cancer institute.