TY - JOUR
T1 - Givinostat
T2 - an emerging treatment for polycythemia vera
AU - Chifotides, Helen T.
AU - Bose, Prithviraj
AU - Verstovsek, Srdan
N1 - Funding Information:
This article was supported, in part, by the MD Anderson Cancer Center Support Grant P30 CA016672 from the National Cancer Institute (National Institutes of Health).
Funding Information:
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.
Publisher Copyright:
© 2020, © 2020 Informa UK Limited, trading as Taylor & Francis Group.
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - Clinical trial
KW - HDAC
KW - HSP90
KW - JAK2
KW - epigenetic
KW - givinostat
KW - histone deacetylase inhibitor
KW - myeloproliferative neoplasm (MPN)
KW - polycythemia vera (PV)
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UR - http://www.scopus.com/inward/citedby.url?scp=85088472127&partnerID=8YFLogxK
U2 - 10.1080/13543784.2020.1761323
DO - 10.1080/13543784.2020.1761323
M3 - Article
C2 - 32693648
AN - SCOPUS:85088472127
SN - 1354-3784
SP - 525
EP - 536
JO - Expert Opinion on Investigational Drugs
JF - Expert Opinion on Investigational Drugs
ER -