The evolving landscape of polycythemia vera therapies

ABSTRACT

Introduction

The treatment landscape of polycythemia vera (PV) has seen major advancements within the last decade including approval of ruxolitinib in the second line setting after hydroxyurea, ropegylated interferon-α2b, and advanced clinical development of a novel class of agents called hepcidin mimetics.

Areas covered

We provide a comprehensive review of the evidence discussing the risk stratification, treatment indications, role and limitations of phlebotomy only approach and pivotal trials covering nuances related to the use of interferon-α (IFN-α), ruxolitinib, hepcidin mimetics and upcoming investigational agents including HDAC and LSD1 inhibitors.

Expert opinion

The research paradigm in PV is slowly shifting from the sole focus on hematocrit control and moving toward disease modification. The discovery of hepcidin mimetics has come as a breakthrough in restoring iron homeostasis, achieving phlebotomy-independence and may lead to improved thrombosis-free survival with stricter hematocrit control. On the other hand, emerging data with IFN- α and ruxolitinib as well as combination of the two agents suggests the potential for achieving molecular remission in a subset of PV patients and long-term follow-up is awaited to validate the correlation of molecular responses with clinically relevant outcomes of progression-free and thrombosis-free survival.

KEYWORDS:

• Polycythemia vera
• myeloproliferative neoplasm
• interferon-α
• ruxolitinib
• hepcidin mimetics
• rusfertide

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Article Highlights

1. Hepcidin mimetics act by restoring dysregulated iron metabolism in PV and are the latest class of drugs being evaluated in PV, with promising results from the phase 2 REVIVE trial of first-in-class hepcidin mimetic- rusfertide in controlling hematocrit while eliminating the need for phlebotomy.

2. Ongoing trials are evaluating combinations of ruxolitinib and IFN as well as alternative dosing schedule (250/350/500) of ropeg-IFN with rapid uptitration with the goals of achieving improved complete hematologic and molecular responses.

3. JAK2V617 allele burden is being extensively evaluated as a much needed surrogate endpoint; with higher VAFs of >50% being independent prognostic factors for thrombosis and decrease in VAF correlating with improved event-free and overall survival as per recent results from the MAJIC-PV study.

4. Emerging longer term data with IFN-α use suggests the possibility of durable molecular remission in a subset of patients (~20%) where treatment discontinuation maybe feasible.

5. Two novel epigenetic targets, LSD1 inhibitor Bomedemstat and HDAC inhibitor Givinostat, are being investigated in clinical trials. Bomedemstat is being tested in a phase 2 trial for patients who are intolerant or resistant to hydroxyurea (HU). Givinostat, on the other hand, is being compared to HU as a first-line treatment in a phase 3 trial.

Declaration of interests

M Kremyanskaya receives consulting fees from Protagonist Therapeutics, Incyte, Silence Therapeutics, Abbvie, Morphosys and Agios. The other authors have no relevant conflicts to disclose. 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.

Reviewer disclosures

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

Acknowledgement

the figures were created using BioRender.com.

Additional information

Funding

This paper was not funded.