2015 Clinical trials update in sickle cell anemia

Abstract

Polymerization of HbS and cell sickling are the prime pathophysiological events in sickle cell disease (SCD). Over the last 30 years, a substantial understanding at the molecular level has been acquired on how a single amino acid change in the structure of the beta chain of hemoglobin leads to the explosive growth of the HbS polymer and the associated changes in red cell morphology. O2 tension and intracellular HbS concentration are the primary molecular drivers of this process, and are obvious targets for developing new therapies. However, polymerization and sickling are driving a complex network of associated cellular changes inside and outside of the erythrocyte, which become essential components of the inflammatory vasculopathy and result in a large range of potential acute and chronic organ damages. In these areas, a multitude of new targets for therapeutic developments have emerged, with several ongoing or planned new therapeutic interventions. This review outlines the key points of SCD pathophysiology as they relate to the development of new therapies, both at the pre-clinical and clinical levels.

Pharmacotherapeutical strategies in the prevention of acute, vaso-occlusive pain in sickle cell disease: a systematic review

“…Encouragingly, the number of clinical trials in SCD has increased recently, and many novel therapies are currently under investigation. [25][26][27] …”

“…However, preclinical developments and early trials have already been extensively discussed in other reviews. [25][26][27] In this review, we aimed to focus on interventions in advanced stages of evaluation that are closer to clinical implementation.…”

“…Many are currently under investigation in preclinical or early-phase trials, as extensively discussed in other reviews. [25][26][27] However, some treatments have already been evaluated in phase 2 or 3 randomized clinical trials (RCTs), but a clear overview of these studies and their findings does not exist. The objective of this study was to systematically review the currently available controlled clinical trials, investigating new pharmacotherapeutical strategies in the prevention of VOCs in SCD.…”

Quality of Life, Clinical Effectiveness, and Satisfaction in Pediatric and Young Adult Patients with Sickle Cell Disease Receiving Hydroxyurea Therapy

“…Clinical trials have shown that HU is beneficial, safe, and cost-effective in reducing the frequency and intensity of painful events in as young as 9 months of age, infants, children, and adults with homozygous SCA (HbSS) and HbS/β 0 -thalassemia (HbSβ 0 ). 1,5,6 Despite documented laboratory and clinical benefits of HU for pediatric and young adults with SCD, there is still limited experience with the use of HU in these age groups and its long-term efficacy, safety, and acceptance remains poorly defined. 7,8 To better understand the potential impact of the therapeutic approach for SCD regarding use of inducers of hemoglobin F synthesis, it is important to understand the clinical effectiveness, patient acceptability, and side effects of HU in addition to patient's health related quality of life (HRQoL).…”

“…[1][2][3][4] Sickle cell anemia (SCA) is the homozygoid form of SCD which includes a group of genetic disorders characterized by production of an abnormal hemoglobin S, hemolysis, and vasoocclusive phenomena with recurrent painful episodes, acute chest syndrome, splenic sequestration, stroke, and cholelithiasis that can lead to life-long disabilities and death. Since a significant amount of hemoglobin F interferes with hemoglobin S polymerization, the presence of fetal hemoglobin (hemoglobin F) seems to play a compara-tively protective role in the pathophysiologic mechanism of vasoocclusive symptoms of this condition.…”