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 Blood, 29 October 2009, Vol. 114, No. 18, pp. 3899-3908.
Prepublished online as a Blood First Edition Paper on August 26, 2009; DOI 10.1182/blood-2009-04-219493.

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MYELOID NEOPLASIA

Effect of the nonpeptide thrombopoietin receptor agonist Eltrombopag on bone marrow cells from patients with acute myeloid leukemia and myelodysplastic syndrome

Britta Will1, Masahiro Kawahara1, Julia P. Luciano1, Ingmar Bruns2, Samir Parekh3, Connie L. Erickson-Miller4, Manuel A. Aivado4, Amit Verma3,5, and Ulrich Steidl1

1 Department of Cell Biology and Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY; 2 Department of Hematology, Oncology, and Clinical Immunology, Heinrich Heine University, Duesseldorf, Germany; 3 Department of Medicine, Albert Einstein College of Medicine, Bronx, NY; 4 GlaxoSmithKline, Collegeville, PA; and 5 Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY

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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