Phase 1/2 trial of vorinostat in patients with sickle cell disease who have not benefitted from hydroxyurea

Okam, Maureen M.; Esrick, Erica B.; Mandell, Elyse; Campigotto, Federico; Neuberg, Donna; Ebert, Benjamin L.

doi:10.1182/blood-2015-03-635391

Cited by 23 publications

(14 citation statements)

References 9 publications

(14 reference statements)

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“…The safety and tolerability of vorinostat was recently demonstrated in a phase 1 study of 5 sickle cell patients. Although only 1 patient met criteria for success (4% absolute increase or a 100% relative increase in HbF %), the drug was well tolerated and a phase II trial is warranted to establish an optimal dosing profile (Okam et al 2015 ). A phase I clinical trial is currently in process for panobinostat, a pan-HDAC inhibitor in adult patients with severe SCD.…”

Section: Treatment Strategiesmentioning

confidence: 99%

Erythropoiesis: insights into pathophysiology and treatments in 2017

Zivot

Lipton

Narla

et al. 2018

Mol Med

100

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Erythropoiesis is a tightly-regulated and complex process originating in the bone marrow from a multipotent stem cell and terminating in a mature, enucleated erythrocyte.Altered red cell production can result from the direct impairment of medullary erythropoiesis, as seen in the thalassemia syndromes, inherited bone marrow failure as well as in the anemia of chronic disease. Alternatively, in disorders such as sickle cell disease (SCD) as well as enzymopathies and membrane defects, medullary erythropoiesis is not, or only minimally, directly impaired. Despite these differences in pathophysiology, therapies have traditionally been non-specific, limited to symptomatic control of anemia via packed red blood cell (pRBC) transfusion, resulting in iron overload and the eventual need for iron chelation or splenectomy to reduce defective red cell destruction. Likewise, in polycythemia vera overproduction of red cells has historically been dealt with by non-specific myelosuppression or phlebotomy. With a deeper understanding of the molecular mechanisms underlying disease pathophysiology, new therapeutic targets have been identified including induction of fetal hemoglobin, interference with aberrant signaling pathways and gene therapy for definitive cure. This review, utilizing some representative disorders of erythropoiesis, will highlight novel therapeutic modalities currently in development for treatment of red cell disorders.

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Section: Treatment Strategiesmentioning

confidence: 99%

Erythropoiesis: insights into pathophysiology and treatments in 2017

Zivot

Lipton

Narla

et al. 2018

Mol Med

100

View full text Add to dashboard Cite

show abstract

“…Histone deacetylase inhibitors increase levels of HbF in SCD [61, 62, 63, 64, 65, 66, 67]. A small study of sodium butyrate showed that treatment with intermittent doses, rather than continuous therapy, resulted in sustained increases in the levels of HbF, F-cells and total hemoglobin [61].…”

Section: Hemoglobin F Inducing and Anti-sickling Agentsmentioning

confidence: 99%

Advances in new drug therapies for the management of sickle cell disease

Ataga

Desai

2018

Expert Opinion on Orphan Drugs

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Introduction: Sickle cell disease (SCD) is an orphan disease in the United States, but is highly prevalent worldwide. Only two drugs, hydroxyurea and L-glutamine, are approved for this disease. With an improved understanding of the pathophysiology of SCD as well as the success of several recently approved drugs for other orphan diseases, there is an increased interest in the development of drugs for SCD. Areas covered: This review summarizes published studies of drug therapies and ongoing trials of novel agents. Expert opinion: The development of drugs with different mechanisms of action offers opportunities for combination and individualized therapy in SCD. In addition to acute pain crisis, the evaluation of other SCD-related complications, exercise capacity, patient reported outcomes and validated surrogate endpoints are necessary to advance drug development. It is important to involve sites in sub-Saharan Africa and India, which have the highest burden of SCD, in trials of novel therapies.

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“…Induction of γ-globin with an aim to increase fetal haemoglobin production using pharmacological agents has been tried for several years 24 . Despite numerous drugs having reached clinical trials, none has been efficacious enough to be recommended for routine clinical use 25 . Hydroxyurea, which has produced best results thus far is widely used to increase fetal haemoglobin production to prevent sickling crisis in patients with sickle cell disease but has not been shown to reduce the need for blood transfusion in patients with thalassaemia 26 .…”

Section: Emerging Therapiesmentioning

confidence: 99%

Management of Thalassaemia

Mettananda

2018

Sri Lanka J Child Health

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Phase 1/2 trial of vorinostat in patients with sickle cell disease who have not benefitted from hydroxyurea

Cited by 23 publications

References 9 publications

Erythropoiesis: insights into pathophysiology and treatments in 2017

Erythropoiesis: insights into pathophysiology and treatments in 2017

Advances in new drug therapies for the management of sickle cell disease

Management of Thalassaemia

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