Journal Article

Preclinical evaluation of eltrombopag in a PDX model of myelodysplastic syndromes

Jawhar, Ahmed, Nolte Florian, Mehralivand Arwin, Knaflic Antje, Johann-Christoph, Jann, Boch Tobias, Riabov Vladimir, Uhlig, Stefanie, Haselmann Verena, Weis Cleo-Aron, Wolf-Karsten, Hofmann, Danner, Justine, Weimer, Nadine, Palme, Iris, Obländer Julia, Steiner Laurenz, Flach, Johanna, Xu, Qingyu, Metzgeroth Georgia, Jawhar Mohamad, Nowak, Daniel, Darwich, Ali, Marx, Alexander, Altrock Eva, Nowak Verena, Schmitt Nanni, Streuer Alexander

2022

Overview

Preclinical research of myelodysplastic syndromes (MDSs) is hampered by a lack of feasible disease models. Previously, we have established a robust patient-derived xenograft (PDX) model for MDS. Here we demonstrate for the first time that this model is applicable as a preclinical platform to address pending clinical questions by interrogating the efficacy and safety of the thrombopoietin receptor agonist eltrombopag. Our preclinical study included n = 49 xenografts generated from n = 9 MDS patient samples. Substance efficacy was evidenced by FACS-based human platelet quantification and clonal bone marrow evolution was reconstructed by serial whole-exome sequencing of the PDX samples. In contrast to clinical trials in humans, this experimental setup allowed vehicle- and replicate-controlled analyses on a patient–individual level deciphering substance-specific effects from natural disease progression. We found that eltrombopag effectively stimulated thrombopoiesis in MDS PDX without adversely affecting the patients’ clonal composition. In conclusion, our MDS PDX model is a useful tool for testing new therapeutic concepts in MDS preceding clinical trials.

• Publisher: Nature Publishing Group
• Subject: Bone marrow / Clinical trials / Disorders / Flow cytometry / Myelodysplastic syndrome / Myelodysplastic syndromes / Patients / Thrombopoiesis / Thrombopoietin / Xenografts / Xenotransplantation