Effect of the Nonpeptide Thrombopoietin Receptor Agonist Eltrombopag on Bone Marrow Cells from Patients with Acute Myeloid Leukemia and Myelodysplastic Syndrome

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2009 Aug 28

PMID 19710504

Citations 52

Authors

Britta Will

Masahiro Kawahara

Julia P Luciano

Ingmar Bruns

Samir Parekh

Connie L Erickson-Miller

Manuel A Aivado

Amit Verma

Ulrich Steidl

Affiliations

Soon will be listed here.

Abstract

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 microg/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.

Citing Articles

Avatrombopag for the salvage treatment of platelet transfusion refractoriness.

Qin Y, Wang Y, Zhang Y, Jiao Y, Ye J Ther Adv Hematol. 2024; 15:20406207241237606.

PMID: 38481948 PMC: 10935753. DOI: 10.1177/20406207241237606.

Current Understanding of Immune Thrombocytopenia: A Review of Pathogenesis and Treatment Options.

Mititelu A, Onisai M, Rosca A, Vladareanu A Int J Mol Sci. 2024; 25(4).

PMID: 38396839 PMC: 10889445. DOI: 10.3390/ijms25042163.

Eltrombopag increases the hematopoietic supporting ability of mesenchymal stem/stromal cells.

Muntion S, Preciado S, Sanchez-Luis E, Corchete L, Diez-Campelo M, Osugui L Ther Adv Hematol. 2023; 13:20406207221142137.

PMID: 36601635 PMC: 9806379. DOI: 10.1177/20406207221142137.

Avatrombopag for the treatment of thrombocytopenia post hematopoietic stem-cell transplantation.

Zhou M, Qi J, Gu C, Wang H, Zhang Z, Wu D Ther Adv Hematol. 2022; 13:20406207221127532.

PMID: 36185780 PMC: 9523859. DOI: 10.1177/20406207221127532.

Megakaryopoiesis impairment through acute innate immune signaling activation by azacitidine.

Okoye-Okafor U, Javarappa K, Tsallos D, Saad J, Yang D, Zhang C J Exp Med. 2022; 219(11).

PMID: 36053753 PMC: 9441716. DOI: 10.1084/jem.20212228.

References

Jadersten M, Malcovati L, Dybedal I, Della Porta M, Invernizzi R, Montgomery S . Erythropoietin and granulocyte-colony stimulating factor treatment associated with improved survival in myelodysplastic syndrome. J Clin Oncol. 2008; 26(21):3607-13. DOI: 10.1200/JCO.2007.15.4906. View

Kantarjian H, Giles F, List A, Lyons R, Sekeres M, Pierce S . The incidence and impact of thrombocytopenia in myelodysplastic syndromes. Cancer. 2007; 109(9):1705-14. DOI: 10.1002/cncr.22602. View

Greenberg P . Treatment of myelodysplastic syndromes. Blood Rev. 1991; 5(1):42-50. DOI: 10.1016/0268-960x(91)90007-y. View

Konstantopoulos K, Lauren L, Hast R, Reizenstein P . Survival, hospitalization and cause of death in 99 patients with the myelodysplastic syndrome. Anticancer Res. 1989; 9(4):893-6. View

Oke A, Pearce D, Wilkinson R, Crafter C, Odedra R, Cavenagh J . AZD1152 rapidly and negatively affects the growth and survival of human acute myeloid leukemia cells in vitro and in vivo. Cancer Res. 2009; 69(10):4150-8. PMC: 2684546. DOI: 10.1158/0008-5472.CAN-08-3203. View

Erickson-Miller C, Delorme E, Tian S, Hopson C, Landis A, Valoret E . Preclinical activity of eltrombopag (SB-497115), an oral, nonpeptide thrombopoietin receptor agonist. Stem Cells. 2008; 27(2):424-30. PMC: 2729672. DOI: 10.1634/stemcells.2008-0366. View

Lu S, Alpdogan O, Lin J, Balderas R, Campos-Gonzalez R, Wang X . STAT-3 and ERK 1/2 phosphorylation are critical for T-cell alloactivation and graft-versus-host disease. Blood. 2008; 112(13):5254-8. PMC: 2597618. DOI: 10.1182/blood-2008-03-147322. View

Corazza F, Hermans C, DHondt S, Ferster A, Kentos A, Benoit Y . Circulating thrombopoietin as an in vivo growth factor for blast cells in acute myeloid leukemia. Blood. 2005; 107(6):2525-30. DOI: 10.1182/blood-2005-06-2552. View

Steidl U, Rosenbauer F, Verhaak R, Gu X, Ebralidze A, Otu H . Essential role of Jun family transcription factors in PU.1 knockdown-induced leukemic stem cells. Nat Genet. 2006; 38(11):1269-77. DOI: 10.1038/ng1898. View

10.

Bennett J, Catovsky D, Daniel M, Flandrin G, GALTON D, Gralnick H . Proposals for the classification of the myelodysplastic syndromes. Br J Haematol. 1982; 51(2):189-99. View

11.

Valent P, Horny H, Bennett J, Fonatsch C, Germing U, Greenberg P . Definitions and standards in the diagnosis and treatment of the myelodysplastic syndromes: Consensus statements and report from a working conference. Leuk Res. 2007; 31(6):727-36. DOI: 10.1016/j.leukres.2006.11.009. View

12.

Higuchi M, OBrien D, Kumaravelu P, Lenny N, Downing J . Expression of a conditional AML1-ETO oncogene bypasses embryonic lethality and establishes a murine model of human t(8;21) acute myeloid leukemia. Cancer Cell. 2002; 1(1):63-74. DOI: 10.1016/s1535-6108(02)00016-8. View

13.

Bennett J, Catovsky D, Daniel M, Flandrin G, GALTON D, Gralnick H . Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group. Br J Haematol. 1976; 33(4):451-8. DOI: 10.1111/j.1365-2141.1976.tb03563.x. View

14.

Bussel J, Provan D, Shamsi T, Cheng G, Psaila B, Kovaleva L . Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet. 2009; 373(9664):641-8. DOI: 10.1016/S0140-6736(09)60402-5. View

15.

Agliano A, Martin-Padura I, Mancuso P, Marighetti P, Rabascio C, Pruneri G . Human acute leukemia cells injected in NOD/LtSz-scid/IL-2Rgamma null mice generate a faster and more efficient disease compared to other NOD/scid-related strains. Int J Cancer. 2008; 123(9):2222-7. DOI: 10.1002/ijc.23772. View

16.

Hellstrom-Lindberg E, Malcovati L . Supportive care and use of hematopoietic growth factors in myelodysplastic syndromes. Semin Hematol. 2008; 45(1):14-22. DOI: 10.1053/j.seminhematol.2007.10.004. View

17.

Huntly B, Shigematsu H, Deguchi K, Lee B, Mizuno S, Duclos N . MOZ-TIF2, but not BCR-ABL, confers properties of leukemic stem cells to committed murine hematopoietic progenitors. Cancer Cell. 2004; 6(6):587-96. DOI: 10.1016/j.ccr.2004.10.015. View

18.

Foucar K, Langdon 2nd R, Armitage J, Olson D, Carroll Jr T . Myelodysplastic syndromes. A clinical and pathologic analysis of 109 cases. Cancer. 1985; 56(3):553-61. DOI: 10.1002/1097-0142(19850801)56:3<553::aid-cncr2820560323>3.0.co;2-q. View

19.

Steidl U, Bork S, Schaub S, Selbach O, Seres J, Aivado M . Primary human CD34+ hematopoietic stem and progenitor cells express functionally active receptors of neuromediators. Blood. 2004; 104(1):81-8. DOI: 10.1182/blood-2004-01-0373. View

20.

McHutchison J, Dusheiko G, Shiffman M, Rodriguez-Torres M, Sigal S, Bourliere M . Eltrombopag for thrombocytopenia in patients with cirrhosis associated with hepatitis C. N Engl J Med. 2007; 357(22):2227-36. DOI: 10.1056/NEJMoa073255. View