Researchers Unveil Novel Sequential Effects of Eltrombopag in Patients With Chronic ITP

Researchers behind a recent study have revealed new sequential effects of eltrombopag in heavily-pretreated patients with chronic immune thrombocytopenia (ITP), which may help restore platelet homeostasis in responders (Haematologica. 2019 Jul 11. Epub ahead of print).

“Recently, incorporation of next-generation sequencing technologies allows identification of specific peptide sequence of complementarity-determining region 3 (CDR3) of TCRβ subunit (encoded by TRB gene),” said Haiyu Zhang, PhD, Department of Pathology, School of Medicine, Stanford University, California, and colleagues.

“Using this method, post-treatment polyclonal TRB repertoire was observed in 90% responders to rituximab-dexamethasone therapy, and in 50% of non-responders or relapsers,” they explained, adding that the relationship between TRB repertoires and eltrombopag therapy response remains unknown.

Seeking to fill that gap in literature, Dr Zhang and colleagues described the longitudinal effects of eltrombopag in 19 patients with chronic ITP who received eltrombopag monotherapy using whole blood transcriptome analysis.

Despite continued eltrombopag therapy and additional increases in platelet counts, at 1-month 5 genes (E2F1, PF4V1, CRYM, GLOD5, and NGFRAP1) remained induced in responders. The longitudinal expression pattern of the 208 eltrombopag-induced genes in patients who had sequencing data available pretreatment, at 1-week, and at 1-month) showed that responders shared a common trend of these genes.

Of note, the lowest expression at pretreatment was followed by the highest expression at the 1-week time point (which decreased at the 1-month time point to a level that was still higher than that at pretreatment).

Overall, the investigators observed a new long-term effect of eltrombopag treatment over time in responders and after the initial induction of eltrombopag-induced genes, the tapered expression in the context of continuous platelet response indicates that there are different stages of eltrombopag response.

Using next-generation sequencing-based TRB repertoire analysis in 5 responders and 5 nonresponders, Dr Zhang et al detected similar total numbers of TRB sequences (1.25 ± 0.8x106 vs 0.99 ± 0.57 x106) and unique CDR3 sequences (12.24 ± 0.45 x103 vs 10.00 ± 0.45 x103) between the 2 groups. There were no associations between response and gene usage of variable-diversity-joining segments of TRB observed.

“In summary, using unbiased genetic approaches to study a cohort of heavily-pretreated chronic ITP patients, we revealed novel sequential effects of eltrombopag which may help to restore platelet homeostasis in responders, and identified an association of TRB clonal populations and nonresponse to eltrombopag,” Dr Zhang and colleagues concluded.

“These findings provide unique insights into the mechanism of eltrombopag response and illuminate potential treatment options in patients with eltrombopag-resistant ITP,” they said.—Hina Khaliq and Janelle Bradley