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James B. Bussel - One of the best experts on this subject based on the ideXlab platform.
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use of Thrombopoietin Receptor agonists for immune thrombocytopenia in pregnancy results from a multicenter study
Blood, 2020Co-Authors: Marc Michel, Waleed Ghanima, Marco Ruggeri, Louis Terriou, Tomas Jose Gonzalezlopez, Salam Alkindi, Stephane Cheze, Tor Henrik Anderson Tvedt, Mikael Ebbo, James B. BusselAbstract:Management of immune thrombocytopenia (ITP) during pregnancy can be challenging because treatment choices are limited. Thrombopoietin Receptor agonists (Tpo-RAs), which likely cross the placenta, are not recommended during pregnancy. To better assess the safety and efficacy of off-label use of Tpo-RAs during pregnancy, a multicenter observational and retrospective study was conducted. Results from 15 pregnant women with ITP (pregnancies, n = 17; neonates, n = 18) treated with either eltrombopag (n = 8) or romiplostim (n = 7) during pregnancy, including 2 patients with secondary ITP, were analyzed. Median time of Tpo-RA exposure during pregnancy was 4.4 weeks (range, 1-39 weeks); the indication for starting Tpo-RAs was preparation for delivery in 10 (58%) of 17 pregnancies, whereas 4 had chronic refractory symptomatic ITP and 3 were receiving eltrombopag when pregnancy started. Regarding safety, neither thromboembolic events among mothers nor Tpo-RA-related fetal or neonatal complications were observed, except for 1 case of neonatal thrombocytosis. Response to Tpo-RAs was achieved in 77% of cases, mostly in combination with concomitant ITP therapy (70% of responders). On the basis of these preliminary findings, temporary off-label use of Tpo-RAs for severe and/or refractory ITP during pregnancy seems safe for both mother and neonate and is likely to be helpful, especially before delivery.
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use of Thrombopoietin Receptor agonists for immune thrombocytopenia in pregnancy results from a multicenter study
Blood, 2020Co-Authors: Marc Michel, Waleed Ghanima, Marco Ruggeri, Louis Terriou, Tomas Jose Gonzalezlopez, Salam Alkindi, Stephane Cheze, Tor Henrik Anderson Tvedt, Mikael Ebbo, James B. BusselAbstract:Management of immune thrombocytopenia (ITP) during pregnancy can be challenging since treatment choices are limited. Thrombopoietin Receptor agonists (Tpo-RAs), which likely cross the placenta, are not recommended during pregnancy. To better assess safety and efficacy of off-label use of Tpo-RA during pregnancy, a multicenter observational and retrospective study was set up. Results from 15 pregnant women with ITP (17 pregnancies and 18 neonates) treated with either eltrombopag (N=8) or romiplostim (n=7) during pregnancy, including 2 patients with secondary ITP, were analyzed. Median time of Tpo-RA exposure during pregnancy was 4.4 weeks [range: 1-39 weeks]; the indication for starting Tpo-RA was preparation for delivery in 10/17 (58%) pregnancies whereas 4 had chronic refractory symptomatic ITP and 3 were on eltrombopag when the pregnancy started. Regarding safety, neither thromboembolic events among mothers nor Tpo-RA-related fetal or neonatal complications were observed except for one case of neonatal thrombocytosis. Response to Tpo-RA was achieved in 77% of cases, mostly in combination (70% of responders) with concomitant ITP therapy. Based on these preliminary findings, temporary off-label use of a Tpo-RA for severe and/or refractory ITP during pregnancy seems safe for both mother and neonate and likely to be helpful especially prior to delivery.
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Thrombopoietin Receptor agonists ten years later
Haematologica, 2019Co-Authors: Waleed Ghanima, Nichola Cooper, Bertrand Godeau, F Rodeghiero, James B. BusselAbstract: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.
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immune thrombocytopenia is associated with persistently deranged fibrosis related seromarker profiles but low bone marrow fibrosis grades a 2 year observational study on Thrombopoietin Receptor agonist treatment
Platelets, 2019Co-Authors: Waleed Ghanima, Julia T Geyer, Christina Lee, Leonardo Boiocchi, Attilio Orazi, Sif Gudbrandsdottir, Xingmin Feng, Peter Junker, James B. BusselAbstract:Bone marrow (BM) fibrosis is a potential side effect of Thrombopoietin Receptor agonist (TPO-RA) treatment. We aimed to investigate stromal seromarker profiles and growth factors in order to elucidate pathogenic and dynamic aspects of immune thrombocytopenia (ITP)-related BM fibrosis before and during TPO-RA treatment.Connective tissue metabolites [procollagen I and III peptides (PINP/PIIINP); hyaluronan (HYA), C-terminal-telopeptide (ICTP), and fibrosis-related growth factors (transforming growth factor-beta (TGF-beta), HGF, basic fibroblast growth factor)] were measured in blood samples acquired before initiation of TPO-RA and subsequently at 6-month intervals for up to 2 years.BM fibrosis was graded MF-0 in 8 (18%), MF-1 30 (65%), and MF-2 8 (18%) in the last available BM biopsy. In the 21 patients having more than one biopsy, the grade of fibrosis from the first to the last available biopsy decreased in 2 (10%), remained unchanged in 15 (71%), and increased in 4 (19%). Pretreatment levels of P...
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Circulating microRNAs in patients with immune thrombocytopenia before and after treatment with Thrombopoietin-Receptor agonists
2019Co-Authors: Lamya Garabet, James B. Bussel, Waleed Ghanima, Maria Luisa Lozano, Anbjørg Rangberg, Raul Teruel-montoya, Constantino Martinez, Camilla F. Nystrand, Per Morten Sandset, Christine M JonassenAbstract:MicroRNAs (miRNAs) are small non-coding RNAs involved in the regulation of gene expression. Dysregulated expression of several miRNAs has been found in primary immune thrombocytopenia (ITP) suggesting that miRNAs are likely involved in the pathogenesis of ITP. We aimed to explore the differential expression of miRNAs in patients with ITP before and after starting treatment with Thrombopoietin-Receptor agonists (TPO-RAs) to clarify their roles in the pathophysiology of ITP, and as potential diagnostic and prognostic markers of this disorder. We performed a profiling study where 179 miRNAs were analyzed in eight ITP patients before and during treatment with TPO-RAs and in eight controls using miRNA PCR panel; 81 miRNAs were differentially expressed in ITP patients compared to controls, and 14 miRNAs showed significant changes during TPO-RA-treatment. Ten miRNAs were selected for validation that was performed in 23 patients and 22 controls using droplet digital PCR. Three miRNAs were found to be differentially expressed in ITP patients before TPO-RA-treatment compared to controls: miR-199a-5p was down-regulated (p = 0.0001), miR-33a-5p (p = 0.0002) and miR-195-5p (p = 0.035) were up-regulated. Treatment with TPO-RAs resulted in changes in six miRNAs including miR-199a-5p (p = 0.001), miR-33a-5p (p = 0.003), miR-382-5p (p = 0.004), miR-92b-3p (p = 0.005), miR-26a-5p (p = 0.008) and miR-221-3p (p = 0.023); while miR-195-5p remained unchanged and significantly higher than in controls, despite the increase in the platelet count, which may indicate its possible role in the pathophysiology of ITP. Regression analysis revealed that pre-treatment levels of miR-199a-5p and miR-221-3p could help to predict platelet response to TPO-RA-treatment. ROC curve analysis showed that the combination of miR-199a-5p and miR-33a-5p could distinguish patients with ITP from controls with AUC of 0.93. This study identifies a number of differentially expressed miRNAs in ITP patients before and after initiation of TPO-RAs with potential roles in the pathophysiology, as well as with a possible utility as diagnostic and prognostic biomarkers. These interesting findings deserve further exploration and validation in future studies.
Connie L Ericksonmiller - One of the best experts on this subject based on the ideXlab platform.
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effect of the nonpeptide Thrombopoietin Receptor agonist eltrombopag on bone marrow cells from patients with acute myeloid leukemia and myelodysplastic syndrome
Blood, 2009Co-Authors: Britta Will, Connie L Ericksonmiller, Masahiro Kawahara, Julia P Luciano, Ingmar Bruns, Samir Parekh, Manuel Aivado, Amit Verma, Ulrich SteidlAbstract:Thrombocytopenia is a frequent symptom and clinical challenge in patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Eltrombopag is a small molecule Thrombopoietin Receptor agonist that might be a new option to treat thrombocytopenia in these diseases, provided that it does not stimulate malignant hematopoiesis. In this work, we studied the effects of Eltrombopag on proliferation, apoptosis, differentiation, colony formation, and malignant self-renewal of bone marrow mononuclear cells of patients with AML and MDS. Malignant bone marrow mononuclear cells did not show increased proliferation, or increased clonogenic capacity at concentrations of Eltrombopag ranging from 0.1 to 30 μg/mL. On the contrary, we observed a moderate, statistically nonsignificant (P = .18), decrease of numbers of malignant cells (mean, 56%; SD, 28%). Eltrombopag neither led to increased 5-bromo-2-deoxyuridine incorporation, decreased apoptosis, an increase of malignant self-renewal, nor enhanced in vivo engraftment in xenotransplantations. Furthermore, we found that Eltrombopag was capable of increasing megakaryocytic differentiation and formation of normal megakaryocytic colonies in patients with AML and MDS. These results provide a preclinical rationale for further testing of Eltrombopag for treatment of thrombocytopenia in AML and MDS.
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comparative analyses of the small molecule Thrombopoietin Receptor agonist eltrombopag and Thrombopoietin on in vitro platelet function
Experimental Hematology, 2009Co-Authors: Joseph A Erhardt, Connie L Ericksonmiller, Manuel Aivado, Melanie Abboud, Kodandaram Pillarisetti, John R ToomeyAbstract:Objective The Thrombopoietin Receptor (TPOR) is a therapeutic target for treatment of thrombocytopenia because stimulation of this Receptor results in enhanced megakaryocyte proliferation, differentiation, and ultimately platelet production. In addition to effects on megakaryocytes, TPOR stimulation also impacts platelet function. The present study examined platelet function following stimulation with the small molecule TPOR agonist eltrombopag. Materials and Methods Platelets were obtained from healthy volunteers, and signal transduction pathway activation was examined in washed platelet preparations. Platelet aggregation was examined in both washed platelet preparations and platelet-rich plasma. Platelet α-granule release was determined via fluorescein-activated cell sorting measurement of CD62P. Results In signal transduction studies of washed human platelets, eltrombopag induced the phosphorylation signal transducers and activators of transcription (STAT) proteins with no phosphorylation of Akt, whereas recombinant human TPO (rhTPO) induced the phosphorylation of Akt as well as STAT-1, -3, and -5. In studies conducted at subthreshold/submaximal concentrations of adenosine diphosphate (ADP) or collagen, eltrombopag pretreatment did not result in platelet aggregation. In contrast, rhTPO acted in synergy with submaximal concentrations of ADP or collagen to induce maximal aggregation under all conditions examined. Similarly, platelet activation as examined via surface expression of CD62P was not enhanced by eltrombopag pretreatment as compared to rhTPO. Conclusions These results demonstrate that the nonpeptidyl TPOR agonist eltrombopag stimulates platelet signal transduction with little or no effect on overall platelet function, in contrast to TPO, which significantly primes platelet activation. These data demonstrate that effects of TPOR ligands on platelet function can vary depending on the specific mechanism utilized to stimulate the TPOR.
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preclinical activity of eltrombopag sb 497115 an oral nonpeptide Thrombopoietin Receptor agonist
Stem Cells, 2009Co-Authors: Connie L Ericksonmiller, Evelyne Delorme, Christopher B Hopson, Shinshay Tian, Amy Landis, Elizabeth I Valoret, Teresa S Sellers, Jon Rosen, Stephen G Miller, Juan I LuengoAbstract:Eltrombopag is a first-in-class, orally bioavailable, small-molecule, nonpeptide agonist of the Thrombopoietin Receptor (TpoR), which is being developed as a treatment for thrombocytopenia of various etiologies. In vitro studies have demonstrated that the activity of eltrombopag is dependent on expression of TpoR, which activates the signaling transducers and activators of transcription (STAT) and mitogen-activated protein kinase signal transduction pathways. The objective of this preclinical study is to determine if eltrombopag interacts selectively with the TpoR to facilitate megakaryocyte differentiation in platelets. Functional thrombopoietic activity was demonstrated by the proliferation and differentiation of primary human CD34(+) bone marrow cells into CD41(+) megakaryocytes. Measurements in platelets in several species indicated that eltrombopag specifically activates only the human and chimpanzee STAT pathways. The in vivo activity of eltrombopag was demonstrated by an increase of up to 100% in platelet numbers when administered orally (10 mg/kg per day for 5 days) to chimpanzees. In conclusion, eltrombopag interacts selectively with the TpoR without competing with Tpo, leading to the increased proliferation and differentiation of human bone marrow progenitor cells into megakaryocytes and increased platelet production. These results suggest that eltrombopag and Tpo may be able to act additively to increase platelet production.
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phase 1 clinical study of eltrombopag an oral nonpeptide Thrombopoietin Receptor agonist
Blood, 2007Co-Authors: Julian Jenkins, Daphne Williams, Yanli Deng, Valerie S Kitchen, David Collins, Connie L EricksonmillerAbstract:Eltrombopag (SB-497 115) is a first-in-class, oral, small-molecule, nonpeptide agonist of the Thrombopoietin Receptor (TpoR), being developed as a treatment for thrombocytopenia of various etiologies. In this phase 1 placebo-controlled clinical trial in 73 healthy male subjects, eltrombopag was administered as once-daily oral capsules for 10 days at doses of 5, 10, 25, 30, 50, and 75 mg. The pharmacokinetics of eltrombopag were dose dependent and linear, and eltrombopag increased platelet counts in a dose-dependent manner. There were no apparent differences in the incidence or severity of adverse events in subjects receiving active or placebo study medication. These observations indicate that eltrombopag is a once-daily, oral TpoR agonist with demonstrated thrombopoietic activity in human subjects, encouraging further studies in patients with thrombocytopenia.
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discovery and characterization of a selective nonpeptidyl Thrombopoietin Receptor agonist
Experimental Hematology, 2005Co-Authors: Connie L Ericksonmiller, Evelyne Delorme, Christopher B Hopson, Shinshay Tian, Elizabeth I Valoret, Kenneth Stark, Leslie Giampa, Kevin J Duffy, Juan L Luengo, Jon RosenAbstract:Objective Peptide and other small molecule agonists have been described for several cytokines and growth factors. Hydrazone compounds described here as Thrombopoietin Receptor agonists were identified as activating STAT proteins in a Tpo responsive cell line. Methods STAT activation and analysis of signal transduction pathways in cell lines and normal human platelets was elucidated by Western blot and electrophoretic mobility shift assays. Proliferation assays in cell types responsive to other cytokines determined specificity for Tpo Receptor. Flow cytometry quantified differentiation of CD34 + cells into CD41 + megakaryocytes and platelet production in vitro. Results Activation of STAT5, mitogen-activated protein kinase, p38, and early response genes by SB 394725 was similar to that induced by Tpo. SB 394725 induced a reporter gene response under a STAT activation promoter as well as the megakaryocyte-specific gpIIb promoter. The compound induced proliferation of Tpo responsive lines but demonstrated no activity in cell lines responding to other cytokines, i.e., erythropoietin, granulocyte-colony stimulating factor, interleukin-3, interferon-γ. The response of normal human Tpo Receptors was elucidated by measuring growth and differentiation of human bone marrow in vitro. Activation of endogenous Tpo Receptors by SB 394725 was demonstrated in human and chimp platelets, but not in platelets of other species including mouse, dog, rabbit, or cynomolgus monkey. Conclusions SB 394725, a small molecule with a molecular weight of 452 Da, is capable of activating Tpo-specific signal transduction, proliferation, and differentiation responses similar to the responses and functions of the protein growth factor, Tpo.
Waleed Ghanima - One of the best experts on this subject based on the ideXlab platform.
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use of Thrombopoietin Receptor agonists for immune thrombocytopenia in pregnancy results from a multicenter study
Blood, 2020Co-Authors: Marc Michel, Waleed Ghanima, Marco Ruggeri, Louis Terriou, Tomas Jose Gonzalezlopez, Salam Alkindi, Stephane Cheze, Tor Henrik Anderson Tvedt, Mikael Ebbo, James B. BusselAbstract:Management of immune thrombocytopenia (ITP) during pregnancy can be challenging because treatment choices are limited. Thrombopoietin Receptor agonists (Tpo-RAs), which likely cross the placenta, are not recommended during pregnancy. To better assess the safety and efficacy of off-label use of Tpo-RAs during pregnancy, a multicenter observational and retrospective study was conducted. Results from 15 pregnant women with ITP (pregnancies, n = 17; neonates, n = 18) treated with either eltrombopag (n = 8) or romiplostim (n = 7) during pregnancy, including 2 patients with secondary ITP, were analyzed. Median time of Tpo-RA exposure during pregnancy was 4.4 weeks (range, 1-39 weeks); the indication for starting Tpo-RAs was preparation for delivery in 10 (58%) of 17 pregnancies, whereas 4 had chronic refractory symptomatic ITP and 3 were receiving eltrombopag when pregnancy started. Regarding safety, neither thromboembolic events among mothers nor Tpo-RA-related fetal or neonatal complications were observed, except for 1 case of neonatal thrombocytosis. Response to Tpo-RAs was achieved in 77% of cases, mostly in combination with concomitant ITP therapy (70% of responders). On the basis of these preliminary findings, temporary off-label use of Tpo-RAs for severe and/or refractory ITP during pregnancy seems safe for both mother and neonate and is likely to be helpful, especially before delivery.
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use of Thrombopoietin Receptor agonists for immune thrombocytopenia in pregnancy results from a multicenter study
Blood, 2020Co-Authors: Marc Michel, Waleed Ghanima, Marco Ruggeri, Louis Terriou, Tomas Jose Gonzalezlopez, Salam Alkindi, Stephane Cheze, Tor Henrik Anderson Tvedt, Mikael Ebbo, James B. BusselAbstract:Management of immune thrombocytopenia (ITP) during pregnancy can be challenging since treatment choices are limited. Thrombopoietin Receptor agonists (Tpo-RAs), which likely cross the placenta, are not recommended during pregnancy. To better assess safety and efficacy of off-label use of Tpo-RA during pregnancy, a multicenter observational and retrospective study was set up. Results from 15 pregnant women with ITP (17 pregnancies and 18 neonates) treated with either eltrombopag (N=8) or romiplostim (n=7) during pregnancy, including 2 patients with secondary ITP, were analyzed. Median time of Tpo-RA exposure during pregnancy was 4.4 weeks [range: 1-39 weeks]; the indication for starting Tpo-RA was preparation for delivery in 10/17 (58%) pregnancies whereas 4 had chronic refractory symptomatic ITP and 3 were on eltrombopag when the pregnancy started. Regarding safety, neither thromboembolic events among mothers nor Tpo-RA-related fetal or neonatal complications were observed except for one case of neonatal thrombocytosis. Response to Tpo-RA was achieved in 77% of cases, mostly in combination (70% of responders) with concomitant ITP therapy. Based on these preliminary findings, temporary off-label use of a Tpo-RA for severe and/or refractory ITP during pregnancy seems safe for both mother and neonate and likely to be helpful especially prior to delivery.
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Thrombopoietin Receptor agonists ten years later
Haematologica, 2019Co-Authors: Waleed Ghanima, Nichola Cooper, Bertrand Godeau, F Rodeghiero, James B. BusselAbstract: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.
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effect of Thrombopoietin Receptor agonists on markers of coagulation and p selectin in patients with immune thrombocytopenia
Platelets, 2019Co-Authors: Lamya Garabet, Waleed Ghanima, Christine M Jonassen, Vibe Skov, Rene Holst, Mariechristine Mowinckel, Hans Carl Hasselbalch, Torben A Kruse, Mads Thomassen, Howard A LiebmanAbstract:Thrombopoietin-Receptor-agonists (TPO-RA) are effective treatments of immune thrombocytopenia (ITP). Previous long-term TPO-RA clinical trials have shown that thrombotic events occurred in 6% of TP...
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immune thrombocytopenia is associated with persistently deranged fibrosis related seromarker profiles but low bone marrow fibrosis grades a 2 year observational study on Thrombopoietin Receptor agonist treatment
Platelets, 2019Co-Authors: Waleed Ghanima, Julia T Geyer, Christina Lee, Leonardo Boiocchi, Attilio Orazi, Sif Gudbrandsdottir, Xingmin Feng, Peter Junker, James B. BusselAbstract:Bone marrow (BM) fibrosis is a potential side effect of Thrombopoietin Receptor agonist (TPO-RA) treatment. We aimed to investigate stromal seromarker profiles and growth factors in order to elucidate pathogenic and dynamic aspects of immune thrombocytopenia (ITP)-related BM fibrosis before and during TPO-RA treatment.Connective tissue metabolites [procollagen I and III peptides (PINP/PIIINP); hyaluronan (HYA), C-terminal-telopeptide (ICTP), and fibrosis-related growth factors (transforming growth factor-beta (TGF-beta), HGF, basic fibroblast growth factor)] were measured in blood samples acquired before initiation of TPO-RA and subsequently at 6-month intervals for up to 2 years.BM fibrosis was graded MF-0 in 8 (18%), MF-1 30 (65%), and MF-2 8 (18%) in the last available BM biopsy. In the 21 patients having more than one biopsy, the grade of fibrosis from the first to the last available biopsy decreased in 2 (10%), remained unchanged in 15 (71%), and increased in 4 (19%). Pretreatment levels of P...
Leonardo Boiocchi - One of the best experts on this subject based on the ideXlab platform.
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immune thrombocytopenia is associated with persistently deranged fibrosis related seromarker profiles but low bone marrow fibrosis grades a 2 year observational study on Thrombopoietin Receptor agonist treatment
Platelets, 2019Co-Authors: Waleed Ghanima, Julia T Geyer, Christina Lee, Leonardo Boiocchi, Attilio Orazi, Sif Gudbrandsdottir, Xingmin Feng, Peter Junker, James B. BusselAbstract:Bone marrow (BM) fibrosis is a potential side effect of Thrombopoietin Receptor agonist (TPO-RA) treatment. We aimed to investigate stromal seromarker profiles and growth factors in order to elucidate pathogenic and dynamic aspects of immune thrombocytopenia (ITP)-related BM fibrosis before and during TPO-RA treatment.Connective tissue metabolites [procollagen I and III peptides (PINP/PIIINP); hyaluronan (HYA), C-terminal-telopeptide (ICTP), and fibrosis-related growth factors (transforming growth factor-beta (TGF-beta), HGF, basic fibroblast growth factor)] were measured in blood samples acquired before initiation of TPO-RA and subsequently at 6-month intervals for up to 2 years.BM fibrosis was graded MF-0 in 8 (18%), MF-1 30 (65%), and MF-2 8 (18%) in the last available BM biopsy. In the 21 patients having more than one biopsy, the grade of fibrosis from the first to the last available biopsy decreased in 2 (10%), remained unchanged in 15 (71%), and increased in 4 (19%). Pretreatment levels of P...
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bone marrow fibrosis in 66 patients with immune thrombocytopenia treated with Thrombopoietin Receptor agonists a single center long term follow up
Haematologica, 2014Co-Authors: Waleed Ghanima, Julia T Geyer, Christina Lee, Leonardo Boiocchi, Allison Imahiyerobo, Attilio Orazi, James B. BusselAbstract:Thrombopoietin-Receptor agonists increase platelet counts by stimulating the Thrombopoietin Receptor. Bone marrow fibrosis has been reported in patients receiving Thrombopoietin-Receptor agonists. This study determined the extent of myelofibrosis, its clinical relevance, and incidence of phenotypic or karyotypic abnormalities in patients with immune thrombocytopenia treated with Thrombopoietin-Receptor agonists. The grade of myelofibrosis was assessed before (n=15), during (n=117) and after (n=9) treatment in bone marrow biopsies from 66 patients. The proportion of bone marrow biopsies showing no fibrosis (myelofibrosis grade 0) decreased from 67% pre-treatment to 22% at last biopsy, of which 59% had grade 1 myelofibrosis and 18% had grade 2 myelofibrosis. The median duration of treatment with Thrombopoietin-Receptor agonists to last bone marrow biopsies was 29 months; patients who had two or more biopsies significantly more frequently had myelofibrosis grades 2/3 in the last bone marrow biopsies as compared to the first. Older age was associated with higher grades of fibrosis. No differences in blood counts or lactate dehydrogenase levels were found between patients with myelofibrosis grades 0/1 and those with grade 2. No clonal karyotypic or immunophenotypic abnormalities emerged. This study found that Thrombopoietin-Receptor agonists induce myelofibrosis grades 2/3 in approximately one-fifth of patients with immume thrombocytopenia, increasingly with >2 years of treatment with Thrombopoietin-Receptor agonists. Annual/biannual follow-up with bone marrow biopsies is, therefore, recommended in patients being treated with Thrombopoietin-Receptor agonists in order to enable prompt discontinuation of these drugs should grades 2/3 myelofibrosis develop. Discontinuation of Thrombopoietin-Receptor agonists may prevent development of clinical manifestations by stopping progression of fibrosis in grade 2/3.
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Thrombopoietin Receptor agonist therapy in primary immune thrombocytopenia is associated with bone marrow hypercellularity and mild reticulin fibrosis but not other stromal abnormalities
Modern Pathology, 2012Co-Authors: James B. Bussel, Waleed Ghanima, Leonardo Boiocchi, Attilio Orazi, Melissa Arabadjief, Julia T GeyerAbstract:Primary immune thrombocytopenia is an acquired autoimmune disorder characterized by platelet count of <100 × 109/l in the absence of other causes of thrombocytopenia. Primary immune thrombocytopenia is defined as ‘chronic’ when it has been present for more than 12 months without spontaneous remission or maintenance of complete response to therapy. Recently, Thrombopoietin Receptor agonists became available for treatment of chronic primary immune thrombocytopenia. Anecdotal reports have raised concerns about a possible association between therapy with Thrombopoietin Receptor agonists and an increase in bone marrow fibrosis. To investigate this association we studied eight patients with primary immune thrombocytopenia in detail comparing fibrosis and other morphological features in pre-therapy and on-therapy bone marrow biopsies, with the longest follow-up reported to date. A slight but significant increase to MF-1 in reticulin fibrosis was observed during therapy, but collagen was never present. On-therapy bone marrows were hypercellular due to panmyelosis with increased trilineage hematopoiesis. Megakaryocytes were increased in number, with acquisition of evident pleomorphism, nuclear hyperlobulation and tendency in some cases to form clusters. The overall picture of the on-therapy marrows was characterized by myeloproliferative neoplasm-like features, resembling essential thrombocythemia or occasionally early primary myelofibrosis. As Thrombopoietin Receptor agonists are becoming a mainstream treatment for primary immune thrombocytopenia, general pathologists and especially hematopathologists need to be aware of the characteristic morphological changes associated with use of these therapeutic agents, in order to avoid misdiagnosis of a myeloid neoplasm.
David J. Kuter - One of the best experts on this subject based on the ideXlab platform.
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the structure function and clinical use of the Thrombopoietin Receptor agonist avatrombopag
Blood Reviews, 2021Co-Authors: David J. KuterAbstract:Thrombopoietin regulates platelet production through activation of the Thrombopoietin Receptor (TPO-R). TPO-R agonists (TPO-RAs) are available to treat thrombocytopenia in chronic immune thrombocytopenia (ITP), chronic liver disease (CLD) patients who are undergoing a procedure, severe aplastic anemia (SAA), and hepatitis C virus (HCV) infection. There are four TPO-RAs approved in the US and Europe: romiplostim (ITP), eltrombopag (ITP, SAA, HCV), avatrombopag (ITP, CLD), and lusutrombopag (CLD). It is important to understand pharmacological characteristics of these agents when evaluating treatment options. Avatrombopag interacts with the transmembrane domain of the TPO-RA and does not compete with endogenous Thrombopoietin for TPO-R binding. Structural differences between avatrombopag and other TPO-RAs may impart differential downstream effects on cell signaling pathways, potentially resulting in clinically relevant differences in outcome. Avatrombopag has a favorable pharmacological profile with similar exposure in Japanese, Chinese, or Caucasian patients and no drug-drug interactions, food interactions, or potential for chelation.
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optimal use of Thrombopoietin Receptor agonists in immune thrombocytopenia
Therapeutic advances in hematology, 2019Co-Authors: Hanny Alsamkari, David J. KuterAbstract:The Thrombopoietin Receptor agonists (TPO-RAs) are a class of platelet growth factors commonly used to treat immune thrombocytopenia (ITP). There are three agents that have been investigated for th...
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optimal use of Thrombopoietin Receptor agonists in immune thrombocytopenia
Therapeutic advances in hematology, 2019Co-Authors: Hanny Alsamkari, David J. KuterAbstract:The Thrombopoietin Receptor agonists (TPO-RAs) are a class of platelet growth factors commonly used to treat immune thrombocytopenia (ITP). There are three agents that have been investigated for the treatment of chronic ITP: the peptide agent romiplostim and the small molecule agents eltrombopag and avatrombopag. These agents offer a higher clinical response rate than most other ITP therapies but may require indefinite use. This review is a critical appraisal of the TPO-RAs in adult ITP, defining the optimal patient groups to receive these agents and assisting the hematologist with agent choice, goals of treatment, dosing strategies, and toxicity management. Use of endogenous Thrombopoietin levels to predict response to eltrombopag and romiplostim treatment is discussed and alternative dosing protocols suited for certain patient subgroups are described. Finally, indications for discontinuation and combination therapy with other agents are considered.
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Thrombopoietin Receptor Agonists
Platelets, 2019Co-Authors: David J. KuterAbstract:Abstract Thrombopoietin (TPO) is the major physiological regulator of platelet production. It is produced by the liver at a constant rate and cleared from the circulation by TPO Receptors on circulating platelets thereby providing an efficient feedback system regulating platelet production by bone marrow megakaryocytes. When TPO binds the megakaryocyte TPO Receptor, signal transduction pathways are activated that promote viability, endomitosis and maturation, and increase platelet production. When TPO is eliminated by genetic manipulation or antibody, megakaryocyte and platelet number decline to about 15% of normal. Humans with TPO deficiency due to liver disease or TPO mutation have thrombocytopenia while TPO overproduction due to genetic mutations produces lifelong thrombocythemia. Early recombinant forms of TPO (rHuTPO and PEG-rHuMGDF) were effective in increasing platelet counts in patients with ITP or undergoing chemotherapy or platelet apheresis. Current clinically available TPO Receptor agonists (romiplostim, eltrombopag) increase platelet counts in > 90% of ITP patients with minimal adverse effects and have also been shown to be effective in a wide range of other thrombocytopenic disorders. The TPO Receptor agonists avatrombopag and lusutrombopag have been approved for the treatment of thrombocytopenia in adults with chronic liver disease scheduled to undergo a procedure.
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avatrombopag an oral Thrombopoietin Receptor agonist results of two double blind dose rising placebo controlled phase 1 studies
British Journal of Haematology, 2018Co-Authors: David J. Kuter, Lee F AllenAbstract:Avatrombopag is an oral Thrombopoietin Receptor agonist that has been recently approved for treating thrombocytopenia in chronic liver disease patients needing invasive procedures. Clinical trials supporting this new treatment were guided by two double-blind, dose-rising, placebo-controlled Phase 1 studies in healthy adults reported here that assessed safety, tolerability and pharmacokinetic profile of avatrombopag, and its effect on platelet counts. Subjects were randomised (2:1) in the single-dose study (N = 63) to avatrombopag (1, 3, 10, 20, 50, 75 and 100 mg) or placebo, and in the multiple-dose study (N = 29) to avatrombopag (3, 10 and 20 mg) or placebo daily for 14 days. There were no serious adverse events (AEs), dose-limiting toxicities, deaths, AEs causing withdrawal, thromboses or liver function abnormalities. In both studies, avatrombopag peak concentration and exposure increased proportionally relative to dose; half-life was 18-21 h and independent of dose, supporting once-daily dosing. Effects on platelet counts depended on dose, concentration and treatment duration. Platelet count increases began 3-5 days post-administration, with maximum changes of >370 × 109 /l over baseline with 20 mg daily after 13-16 days. These data support continued development of avatrombopag for treatment of other thrombocytopenic conditions and provide important guidance for the haematologist in the use of this new Thrombopoietin Receptor agonist.