Blood transcriptome and clonal T cell correlates of response and nonresponse to eltrombopag therapy in a cohort of patients with chronic immune thrombocytopenia. Blood transcriptome and clonal T cell correlates of response and nonresponse to eltrombopag therapy in a cohort of patients with chronic immune thrombocytopenia

We evaluated the longitudinal effect of eltrombopag, a thrombopoietin receptor agonist, on gene expression in heavily pretreated patients with chronic immune thrombocytopenia (ITP) using blood transcriptome analysis on pretreatment, and following 1 week and 1 month of treatment samples. A strong stimulation of 208 eltrombopag-induced genes was identified in responders at 1-week time point. 90% of these genes are present in platelets, with GATA1, THPO, VIPAS39 and TGFB1 as top upstream regulators. Subsequently, despite a continued increase in platelet in responders, the eltrombopag-induced gene expression decreased at 1 month compared with the level at 1-week time point. This novel observation of the longitudinal effect of eltrombopag therapy over time suggests different stages of eltrombopag response. Non-responders did not exhibit eltrombopag-induced gene expression changes. This study provides novel insights into the mechanisms of eltrombopag response and nonresponse. Overall design: With informed consent, 17 patients with chronic ITP receiving eltrombopag monotherapy (75 mg daily via oral administration) during the period of blood sample collections were enrolled in this study. The criteria for response assessment are modified from the International Working Group guidelines (Rodeghiero F, 2009, PMID: 19005182). Response (R) in this study includes both complete response (platelet count >100 x 109/L and absence of bleeding) and response (platelet count ranges from 30 to 100 x 109/L, and at least a two-fold increase of the baseline count without bleeding) that defined in the International Working Group guideline. Nonresponse (NR) was defined as platelet count 2; average transcript per million (TPM) > 0.25; and q-value < 0.05. As we performed globin mRNA reduction procedure before 3SEQ library construction, the expressions of hemoglobin subunit alpha 1 (HBA1), alpha 2 (HBA2), and beta (HBB) were excluded from the SAMseq analysis.