Effect of the nonpeptide thrombopoietin receptor agonist eltrombopag on megakaryopoiesis of patients with lower risk myelodysplastic syndrome

Mavroudi, Irene; Pyrovolaki, Katerina; Pavlaki, Konstantia I.; Kozana, Androniki; Psyllaki, Maria; Kalpadakis, Christina; Pontikoglou, Charalampos; Papadaki, Helen Α.

doi:10.1016/j.leukres.2010.06.029

Cited by 36 publications

(26 citation statements)

References 26 publications

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“…In preclinical studies, eltrombopag increased megakaryocyte differentiation and formation of normal megakaryocyte colonies in patients with AML and both lower‐ and higher‐risk MDS. At a range of eltrombopag concentrations (0·1–30 mg/ml), marrow mononuclear cells of patients with AML and high‐risk MDS did not demonstrate increased proliferation or increased clonogenic capacity in vitro , but increased megakaryocyte differentiation and formation of normal megakaryocyte colonies without affecting proliferation rate or survival characteristics of patient CD34 + cells (Will et al , ; Mavroudi et al , ).…”

Section: Summary Of Tsa Studies In Mdsmentioning

confidence: 99%

Thrombopoiesis‐stimulating agents and myelodysplastic syndromes

Brierley

Steensma

2015

Br J Haematol

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SummaryThrombocytopenia in patients with myelodysplastic syndromes (MDS) is a frequent cause of haemorrhage-related morbidity and mortality, and is associated with increased risk of leukaemic transformation and reduced overall survival. In addition, thrombocytopenia in MDS limits the tolerability and therapeutic efficacy of disease-modifying therapies, such as azacitidine or lenalidomide. The recombinant human erythropoietin (rHuEPO) erythropoiesis-stimulating agents, epoetin and darbepoetin, are an established component of anaemia management in lower-risk MDS. Their success has, in turn, driven the development of haematopoietic growth factors targeting thrombocytopenia. While recombinant thrombopoietin (THPO) proved too immunogenic for clinical use, novel thrombopoiesis-stimulating agents (TSAs) have the potential to reduce bleeding events, decrease dependency on platelet transfusions and extend exposure to disease-modifying therapies. Two TSAs, eltrombopag and romiplostim, have demonstrated benefit in chronic immune thrombocytopenia purpura (ITP) and safety and efficacy data for use of these agents in MDS is growing. However, important safety concerns remain, such as the potential for stimulation of neoplastic myeloid clones by THPO agonists. In this narrative review, we discuss the rationale and biological mechanism for TSAs in MDS, describe the agents currently available and their mechanism of action, and present current clinical data relating to TSA safety and efficacy in the context of MDS.

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Section: Summary Of Tsa Studies In Mdsmentioning

confidence: 99%

Thrombopoiesis‐stimulating agents and myelodysplastic syndromes

Brierley

Steensma

2015

Br J Haematol

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“…No published trials have evaluated eltrombopag in the setting of MDS clinically, although one in-vitro study found that eltrombopag increases megakaryocytic colony formation without affecting CD34 þ colony proliferation or survival characteristics [45]. Clinical studies are in early stages.…”

Section: Myelodysplastic Syndromementioning

confidence: 99%

Thrombopoietin-receptor agonists

Basciano¹,

Bussel

2012

Current Opinion in Hematology

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“…7,8 Despite concerns that some leukemia blast cells express TPO-R, we and others have reported previously that EP does not stimulate leukemia or MDS cell growth, but may rather lead to a modest inhibition while continuing to stimulate normal megakaryopoiesis in BM samples of patients with AML or MDS. 9,10 One study using a close chemical derivative of EP found a toxic effect on myeloid leukemia cells, suggesting that the entire substance class, including EP itself, may possess antileukemic activity. 11 Studies using cell lines further suggested that the growth-inhibitory effect of EP is not related to expression levels of TPO-R. 12 However, this hypothesis has not yet been formally tested, and the mechanism through which EP exerts its potential antileukemic effect is not known.…”

Section: Introductionmentioning

confidence: 99%

Eltrombopag inhibits the proliferation of leukemia cells via reduction of intracellular iron and induction of differentiation

Roth

Will

Simkin

et al. 2012

Blood

145

123

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Eltrombopag (EP) is a small-molecule, nonpeptide thrombopoietin receptor (TPO-R) agonist that has been approved recently for the treatment of thrombocytopenia in patients with chronic immune thrombocytopenic purpura. Prior studies have shown that EP stimulates megakaryopoiesis in BM cells from patients with acute myeloid leukemia and myelodysplastic syndrome, and the results also suggested that it may inhibit leukemia cell growth. In the present study, we studied the effects of EP on leukemia cell proliferation and the mechanism of its antiproliferative effects. We found that EP leads to a decreased cell division rate, a block in G 1 phase of cell cycle, and increased differentiation in human and murine leukemia cells. Because EP is species specific in that it can only bind TPO-R in human and primate cells, these findings further suggested that the antileukemic effect is independent of TPO-R. We found that treatment with EP leads to a reduction in free intracellular iron in leukemic cells in a dose-dependent manner. Experimental increase of intracellular iron abrogated the antiproliferative and differentiation-inducing effects of EP, demonstrating that its antileukemic effects are mediated through modulation of intracellular iron content. Finally, determination of EP's antileukemic activity in vivo demonstrated its ability to prolong survival in 2 mouse models of leukemia. (Blood. 2012;120(2):386-394) IntroductionSurvival in acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) has remained poor despite recent efforts to treat patients with novel therapeutic regimens. [1][2][3][4] In addition, complications secondary to thrombocytopenia and bleeding occur frequently in AML and MDS, leading to significant morbidity and mortality. 5,6 Given that the median age of patients with AML is close to 70 years, novel antileukemia agents with limited BM toxicity are needed to improve outcomes.Eltrombopag (EP) is an oral, nonpeptide, small-molecule thrombopoietin receptor (TPO-R) agonist that has proven efficacy in treating chronic immune thrombocytopenic purpura (ITP) and hepatitis C-related thrombocytopenia. 7,8 Despite concerns that some leukemia blast cells express TPO-R, we and others have reported previously that EP does not stimulate leukemia or MDS cell growth, but may rather lead to a modest inhibition while continuing to stimulate normal megakaryopoiesis in BM samples of patients with AML or MDS. 9,10 One study using a close chemical derivative of EP found a toxic effect on myeloid leukemia cells, suggesting that the entire substance class, including EP itself, may possess antileukemic activity. 11 Studies using cell lines further suggested that the growth-inhibitory effect of EP is not related to expression levels of However, this hypothesis has not yet been formally tested, and the mechanism through which EP exerts its potential antileukemic effect is not known. The concentrations at which EP inhibits leukemia cell proliferation in vitro are clinically achievable with few side effects and hav...

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Effect of the nonpeptide thrombopoietin receptor agonist eltrombopag on megakaryopoiesis of patients with lower risk myelodysplastic syndrome

Cited by 36 publications

References 26 publications

Thrombopoiesis‐stimulating agents and myelodysplastic syndromes

Thrombopoiesis‐stimulating agents and myelodysplastic syndromes

Thrombopoietin-receptor agonists

Eltrombopag inhibits the proliferation of leukemia cells via reduction of intracellular iron and induction of differentiation

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