Preclinical evaluation of eltrombopag in a PDX model of myelodysplastic syndromes

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.

Automated summary

Preclinical research utilizing a patient-derived xenograft (PDX) model for myelodysplastic syndromes (MDS) demonstrates the efficacy and safety of the thrombopoietin receptor agonist eltrombopag. The study shows that eltrombopag effectively promotes thrombopoiesis in MDS PDX without impacting patients' clonal composition, suggesting the PDX model as a valuable tool for testing new therapeutic concepts in MDS before clinical trials.