Novel and emerging therapies for the treatment of polycythemia vera

Abstract

Polycythemia vera (PV) is a chronic myeloproliferative neoplasm defined by erythrocytosis and often accompanied by leukocytosis and thrombocytosis. Current treatment options, including IFN-α and hydroxyurea, effectively manage PV in many patients. However, some high-risk patients, particularly those who become hydroxyurea-intolerant/resistant, may benefit from IFN-α or new treatment options. A better understanding of PV pathophysiology, including the role of the JAK/STAT pathway, has inspired the development of new therapies. Several JAK inhibitors directly target JAK/STAT pathway activation and have been evaluated in Phase II/III trials with promising results. Pegylated variants of IFN-α, which reduce dosing frequency and toxicity associated with recombinant IFN-α, have yielded favorable efficacy results in Phase II trials. Finally, histone deacetylase inhibitors have been developed to manage PV at the level of chromatin-regulated gene expression. The earliest Phase III results from these next-generation therapies are expected in 2014.

Keywords:

• IFN-α
• interferon-α
• JAK2
• MPN
• myeloproliferative neoplasms
• polycythemia vera
• ruxolitinib

Acknowledgements

We thank Elizabeth Hexner (University of Pennsylvania) for her review of the manuscript.

Financial & competing interests disclosure

S Verstovsek and RS Komrokji have received clinical research funding and served on advisory boards for Incyte Corporation. 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.

Writing assistance was provided by Cory Pfeiffenberger, PhD (Complete Healthcare Communications, Inc.,) whose work was funded by Incyte Corporation.

Key issues

• PV is a chronic MPN that is associated with excessive proliferation of erythrocytes, leukocytes, and platelets, as well as splenomegaly.

• Patients with PV have increased risk of thrombosis, as well as a broad symptom burden that includes fatigue and pruritus. Taken together, these can meaningfully detract from a patient’s quality of life.

• Current treatment guidelines are based on expert opinion and need to be validated with randomized clinical trials in patients with PV.

• Currently available treatment options provide clinical benefit for some patients; however, for other patients, PV is not adequately managed by current treatment options, including up to one quarter of patients who become resistant to or intolerant of HU.

• Several new therapy options are in the clinical trial phase of development, including JAK inhibitors, pegylated variants of IFN-α (as opposed to recombinant IFN-α), and HDAC inhibitors.

• The JAK1/JAK2 inhibitor ruxolitinib, PEG–IFN-α2a, and PEG–IFN-α2b have exhibited promising efficacy and safety results in Phase II clinical trials and are currently in Phase III development.

Notes

^†Spleen extending ≥10 cm from the costal margin.

^‡Per ELN 2009 criteria [41].

Adapted with permission from [51].