Givinostat: an emerging treatment for polycythemia vera.

Abstract

INTRODUCTION:

Polycythemia vera (PV), a Philadelphia chromosome-negative myeloproliferative neoplasm, is characterized by panmyelosis, pancytosis, and a JAK2 mutation. Patients are at increased risk of thrombohemorrhagic events, and progression to myelofibrosis or acute leukemia. Current treatments include aspirin, phlebotomy, and cytoreductive drugs (most commonly hydroxyurea). Givinostat is a potent, class I/II histone deacetylase (HDAC) inhibitor that is in phase I/II clinical trials in PV. Givinostat was well tolerated and yielded promising clinico-hematological responses. A phase III study of givinostat versus hydroxyurea in high-risk PV patients is planned.

AREAS COVERED:

We present an overview of PV, current treatment guidelines, and the putative mechanism(s) of action of givinostat. We discuss the preclinical and clinical studies of givinostat in PV and briefly review approved and investigational competitor compounds.

EXPERT OPINION:

HDAC inhibitors have long been known to be active in PV, but chronic toxicities can be challenging. Givinostat, however, is active and well tolerated, and is entering a pivotal Phase III randomized trial. Givinostat offers the possibility of replacing hydroxyurea as the standard first-line cytoreductive choice for PV patients. This would completely change the current therapeutic paradigm and guidelines for PV management. Although surrogate clinical study endpoints may suffice for regulatory purposes, thrombosis reduction and prevention of disease progression remain most important to patients and clinicians.

• Authors: Helen T Chifotides, Prithviraj Bose, Srdan Verstovsek
• Journal: Expert opinion on investigational drugs (Expert Opin Investig Drugs) Vol. 29 Issue 6 Pg. 525-536 (Jun 2020) ISSN: 1744-7658 [Electronic] England
• PMID: 32693648 (Publication Type: Comparative Study, Journal Article, Review)

Chemical References

• Carbamates
• Histone Deacetylase Inhibitors
• givinostat
• JAK2 protein, human
• Janus Kinase 2
• Hydroxyurea

Topics

• Animals
• Carbamates (administration & dosage, adverse effects, pharmacology)
• Disease Progression
• Histone Deacetylase Inhibitors (administration & dosage, adverse effects, pharmacology)
• Humans
• Hydroxyurea (administration & dosage, adverse effects, pharmacology)
• Janus Kinase 2 (genetics)
• Mutation
• Polycythemia Vera (drug therapy, genetics, physiopathology)