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New Concepts of Treatment for Patients with Myelofibrosis

  • Prithviraj BoseEmail author
  • Mansour Alfayez
  • Srdan Verstovsek
Leukemia (PH Wiernik, Section Editor)
  • 137 Downloads
Part of the following topical collections:
  1. Topical Collection on Leukemia

Opinion statement

Seven years after the approval of the Janus kinase 1/2 (JAK1/2) inhibitor ruxolitinib, it remains the only drug licensed for the treatment of myelofibrosis. Patients who discontinue ruxolitinib have a dismal outcome, and this is, therefore, an area of significant unmet need. Given the central role that JAK-signal transducer and activator of transcription (STAT) activation plays in disease pathogenesis, there have been many other JAK inhibitors tested, but most have been abandoned, for a variety of reasons. The JAK2-selective inhibitor fedratinib has recently been resurrected, and there has been a resurgence of interest in the failed JAK1/2 inhibitor momelotinib, which possibly improves anemia. Pacritinib, a non-myelosuppressive JAK2-selective inhibitor, is currently in a dose-ranging study mandated by regulatory authorities. A plethora of other targeted agents, most backed by preclinical data, are in various stages of investigation. These include epigenetic and immune therapies, agents targeting cellular survival, metabolic and apoptotic pathways, the cell cycle, DNA repair, and protein folding and degradation, among others. However, at this time, none of these is close to registration or even in a pivotal trial, illustrating the difficulties in recapitulating the clinical disease in preclinical models. Most current clinical trials are testing the addition of a novel agent to ruxolitinib, either in the frontline setting or in the context of an insufficient response to ruxolitinib, or attempting to study new drugs in the second-line, “ruxolitinib failure” setting. Emerging data supports the addition of azacitidine to ruxolitinib in some patients. Other strategies have focused on improving cytopenias, through amelioration of bone marrow fibrosis or other mechanisms. This is important, because cytopenias are the commonest reason for ruxolitinib interruption and/or dose reduction, and dose optimization of ruxolitinib is tied to its survival benefit. The activin receptor ligand trap, sotatercept, and the anti-fibrotic agent, PRM-151, have shown promise in this regard.

Keywords

Myelofibrosis Treatment JAK inhibitors Anemia Bone marrow fibrosis Targeted therapies 

Notes

Funding

This work was supported, in part, by the MD Anderson Cancer Center support grant, P30 CA016672, from the National Institutes of Health (National Cancer Institute).

Compliance with Ethical Standards

Conflict of Interest

Prithviraj Bose has received research funding from Incyte Corporation, Celgene, Blueprint Medicines, Constellation Pharmaceuticals, Kartos Therapeutics, CTI BioPharma, Astellas, and Pfizer, and has received compensation from Incyte Corporation, Celgene, and Blueprint Medicines for service as a consultant.

Mansour Alfayez declares that he has no conflict of interest.

Srdan Verstovsek has received research support for the conduct of clinical studies from Incyte Corporation, Roche, NS Pharma, Celgene, Gilead, Promedior, CTI BioPharma, Genentech, Blueprint Medicines, and Novartis, and has received compensation from Constellation Pharmaceuticals, Pragmatist, Sierra, Incyte Corporation, Novartis, and Celgene for service as a consultant.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Prithviraj Bose
    • 1
    Email author
  • Mansour Alfayez
    • 1
  • Srdan Verstovsek
    • 1
  1. 1.Department of LeukemiaUniversity of Texas MD Anderson Cancer CenterHoustonUSA

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