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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.
Article Highlights
Polycythemia vera (PV) is a chronic myeloproliferative neoplasm, characterized by trilineage myeloproliferation and JAK2 mutations in approximately 99% of patients. While considered an indolent malignancy, survival in PV is inferior to that of an age- and sex-matched population. The main clinical concerns in patients with PV are thrombo-hemorrhagic complications, troublesome symptoms, progression to myelofibrosis, and transformation to acute myeloid leukemia (AML).
There is a major unmet need for drugs that can prevent PV progression to myelofibrosis and AML.
Givinostat is a potent histone deacetylase inhibitor that is under clinical development for the treatment of patients with PV. Givinostat has been evaluated in several phase I/II clinical trials in patients with myeloproliferative neoplasms (MPNs), primarily PV, where it showed the highest efficacy.
Givinostat downregulated JAK2 and STAT5 phosphorylation, reduced JAK2/STAT5 signaling, and selectively induced apoptosis of JAK2V617F+ MPN cell lines at very low concentrations.
The maximum tolerated dose of givinostat was determined to be 100 mg twice daily. The overall response rate to givinostat, in a phase II study evaluating its efficacy in JAK2V617F+ patients with PV, was 80.6%, and all hematological parameters normalized in the majority of the patients, at the end of 3 and 6 treatment cycles. Reduction of severe pruritus was noted in 40% of the intention-to-treat population, and the symptom was completely resolved in 19%, compared to baseline, after 6 treatment cycles. Givinostat was well tolerated; the most common adverse effects were grade 1/2 thrombocytopenia and gastro-intestinal disorders.
Long-term results of the phase II clinical trial demonstrated 11% complete and 89% partial response rates, with significant clinical (phlebotomy independence) and molecular responses (reduction in JAK2V617F+ allele burden compared to baseline). In addition, considerable reduction in pruritus and a lower incidence of thrombotic events compared to historical controls treated with hydroxyurea, and good tolerability were noted in JAK2V617F+ PV patients.
A global, phase III clinical trial, evaluating the efficacy and safety of givinostat compared to hydroxyurea in JAK2V617F+ high-risk PV patients, has been planned to start in 2021.
This box summarizes the key points contained in the article.
Declaration of interest
P. Bose has received research support from Incyte Corporation, Celgene, CTI Biopharma, Kartos Therapeutics, Blueprint Medicines, Constellation Pharmaceuticals, NS Pharma, Promedior, Astellas, and Pfizer. P. Bose has received honoraria from Incyte Corporation, Celgene, CTI Biopharma, Kartos Therapeutics, and Blueprint Medicines. S. Verstovsek has received research support from Incyte Corporation, Roche, Celgene, Gilead, Promedior, CTI Biopharma, Genetech, Blueprint Medicines, NS Pharma, Novartis, Sierra Oncology, Pharma Essentia, Astra Zeneca, Italfarmaco, and Protagonist Therapeutics. S. Verstovsek has received consultancy fees from Constellation Pharmaceuticals, Pragmatist, Sierra Oncology, Incyte, Novartis, and Celgene. 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.