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Thrombopoietin receptor agonists: ten years later.

ABSTRACT: The two thrombopoietin receptor agonists (TPO-RA), eltrombopag and romiplostim, were licensed in the US for treatment of immune thrombocytopenia (ITP) in 2008 and, since then, their use has progressively increased around the world; they are currently used in more than 100 countries. The six largest randomized controlled trials conducted in ITP have used one of these two agents. All studies have demonstrated a platelet response rate between 50-90%, depending on the criteria used, with good safety and tolerability. TPO-RA were shown to be effective in reducing bleeding and the need for concomitant or rescue medication. Many other investigations of their mechanism of effect, prospective and retrospective trials, and studies focusing on toxicity have been performed widening our knowledge of these two agents. Initial concerns on issues such as myelofibrosis have not been confirmed. Only a small number of patients develop moderate-severe reticulin fibrosis and/or collagen fibrosis; however, these are usually reversed after discontinuation of TPO-RA. Studies indicate, however, that TPO-RA may increase the risk of venous thromboembolism. Both TPO-RA are currently approved in patients with chronic ITP aged >1-year who are refractory to at least one other treatment. Eltrombopag has acquired two additional indications: severe aplastic anemia refractory to first-line treatment and hepatitis C patients undergoing treatment with interferon-ribavirin. Despite these wide-ranging studies, important questions still need to be answered. This summary review on TPO-RA will summarize what is known regarding efficacy in ITP, evaluate safety concerns in more depth, and focus on the questions that remain.

SUBMITTER: Ghanima W

PROVIDER: S-EPMC6545830 | biostudies-other | 2019 Jun

REPOSITORIES: biostudies-other

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Thrombopoietin receptor agonists: ten years later.

Ghanima Waleed W Cooper Nichola N Rodeghiero Francesco F Godeau Bertrand B Bussel James B JB

Haematologica 20190509 6

The two thrombopoietin receptor agonists (TPO-RA), eltrombopag and romiplostim, were licensed in the US for treatment of immune thrombocytopenia (ITP) in 2008 and, since then, their use has progressively increased around the world; they are currently used in more than 100 countries. The six largest randomized controlled trials conducted in ITP have used one of these two agents. All studies have demonstrated a platelet response rate between 50-90%, depending on the criteria used, with good safety ...[more]

PMID: 31073079

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Project description:The thrombopoietin receptor agonists (TPO-RAs) romiplostim, eltrombopag, avatrombopag, and lusutrombopag carry unique US Food and Drug Administration (US FDA)- and European Medicines Agency (EMA)-approved indications and may be used to increase platelet counts in a variety of conditions. Current indications for available TPO-RAs include treatment of chronic immune thrombocytopenia (ITP) in cases of insufficient response to prior treatment (avatrombopag, eltrombopag, romiplostim), management of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure (avatrombopag, lusutrombopag), management of severe aplastic anemia (eltrombopag), and management of thrombocytopenia associated with interferon-based therapy for hepatitis C (eltrombopag). Across current indications, pharmacists can assist in stabilizing platelet counts and help to reduce large undulations commonly seen when starting, stopping, or transitioning between these agents. If therapy modifications may benefit the patient, pharmacists should discuss possible changes with the patient's treatment team or treating physician. When used for ITP, romiplostim, eltrombopag, and avatrombopag stimulate TPO receptors on hematopoietic stem cells (also known as c-Mpl, or CD110) to promote platelet production; however, romiplostim is the only TPO-RA that binds at the same site as endogenous TPO. These subtle mechanistic differences may explain why switching TPO-RA may be clinically advantageous in some situations. As pharmacists are called to counsel patients on TPO-RA use, a deep understanding of potential adverse events and management strategies, as well as appropriate monitoring, will increase the likelihood that patients meet their goals of therapy in the shortest timeframe. Other uses of TPO-RAs are also discussed in this review, including use following hematopoietic stem cell transplant, use in myelodysplastic syndrome, and use in chemotherapy-induced thrombocytopenia.

Project description:Introduction PhD is the highest awarded degree offered by universities in different disciplines. Owners of a PhD can teach at universities, start independent research and receive a higher salary while further building a scientific career. We examined whether the publication output before the PhD degree has a correlation with subsequent research activities. Methods We downloaded publication and citation data from the Hungarian Scientific Bibliography for Hungarian researchers who obtained PhD between the ages of 24 and 45. The researchers were grouped into eleven scientific sections. We examined the number of Q1 publications published in the previous 5 years, the H-index, the total number of citations for the last complete year, and the biological age of the researcher. Each parameter was computed for the year at which the PhD was obtained and ten years later. Pre-PhD publications (and citations for these) were excluded when assessing post-PhD track records. Spearman rank correlation and Kruskal-Wallis test were computed. Results We analyzed all together 4,790 researchers. We obtained a positive correlation between the number of Q1 publications before and after PhD (corr. coeff. = 0.21–0.54, p<0.01 in all sections), between the H-index before and after PhD (corr. coeff. = 0.32–0.56, p<0.01 in all sections), and between the citations received before and after PhD (corr. coeff. = 0.34–0.51, p<0.01 in all sections). All three metrics measured ten years after the PhD were negatively correlated with the age of the researcher at the time of obtaining the PhD (number of publications corr. coeff. = -0.09–0.22, p<0.05; H-index corr. coeff. = -0.09–0.29, p<0.08; number of citations corr. coeff. = -0.14–0.30, p<0.01). Among all disciplines, Philosophy and History and Engineering sciences show the strongest correlation between pre- and post-PhD output. When running multiple regression analysis for all three metrics as dependent variables and the number of articles, the H-index, the number of citations in the year of the PhD, the calendar year of PhD, and the gender of the researcher as independent variables, the number of articles and the H-index in the year of PhD reached the strongest positive correlations while gender had a negative correlation. Conclusions We independently evaluated pre- and post-PhD publication performance. In connection with age, the discipline-specific reference values of scientometric parameters at the time of obtaining the PhD can help to select candidates for postdoctoral grants and positions.

Project description:Chronic liver disease (CLD) is a condition that progresses over time toward advanced disease state which is known as liver cirrhosis. Liver cirrhosis leads to dangerous health problems among people living across the world. One such problem that observed in about 75% of cirrhotic patients is thrombocytopenia; which in turn associated with poor prognosis and recovery from CLD. Beyond these, thrombocytopenia in cirrhotic patients led to impairment of coagulation cascade and significantly influenced the utilization of effective mechanism in the management of CLD. By nature, treatment of CLD involves invasive diagnostic and treatment procedures; therefore, in the presence of thrombocytopenia implementing these methods put the lives of patients in a critical health problem due to increased risk of bleeding and mortality. Because of these reasons, prophylactic transfusion of platelets is considered to be one of the most effective options that reduce the risk of bleeding in patients with CLD that required to undergo an invasive procedure. Although platelet transfusion presented with significant advantages in facilitating the invasive procedure in patients with CLD, refractoriness with repeated use and various problems associated with its transfusion limit the continuous utilization of this important option. With these challenges and current advance in the knowledge of thrombopoiesis, the development of relatively safe and alternative drugs that enhance the production of platelets by interacting with thrombopoietin receptor agonists provides a promising option to platelet transfusion. The discovery and approval of romiplostim and eltrombopag in August 2008 and November 2008, respectively, for the treatment of chronic immune thrombocytopenia paved a way and followed by the Food and Drug Administration (FDA) approval of 2 potentially advantageous drugs, lusutrombopag, and avatrombopag, in 2018 for the treatment of thrombocytopenia in patients with CLD that required to undergo elective surgery. Therefore, this review aims to assess pathogenesis of thrombocytopenia and its challenges in the management of liver-related issues and, more importantly, gives emphasis to address the potential use of avatrombopag in the treatment of thrombocytopenia underlying CLD, its pharmacokinetics and pharmacodynamics, as well as its toxicological profiles by presenting the most commonly reported adverse events in various trials.

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Thrombopoietin receptor agonists: ten years later.

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Thrombopoietin receptor agonists: ten years later.

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