Prolonged response after TPO-RA discontinuation in primary ITP: results of a prospective multicenter study

•High rate of sustained response after TPO-RA discontinuation in patients with persistent or chronic ITP achieving initial CR on treatment.•Increased expression of CD69 on CD8+ T cells at the time of tapering TPO-RA could predict relapses. [Display omitted] Sustained response off treatment (SROT) after thrombopoietin receptor agonist (TPO-RA) discontinuation has been reported in immune thrombocytopenia (ITP). This prospective multicenter interventional study enrolled adults with persistent or chronic primary ITP and complete response (CR) on TPO-RAs. The primary end point was the proportion of patients achieving SROT (platelet count >30 × 109/L and no bleeding) at week 24 (W24) with no other ITP-specific medications. Secondary end points included the proportion of sustained CR off-treatment (SCROT, platelet count >100 × 109/L and no bleeding) and SROT at W52, bleeding events, and pattern of response to a new course of TPO-RAs. We included 48 patients with a median age of 58.5 years; 30 of 48 had chronic ITP at TPO-RA initiation. In the intention-to-treat analysis, 27 of 48 achieved SROT, 15 of 48 achieved SCROT at W24; 25 of 48 achieved SROT, and 14 of 48 achieved SCROT at W52. No severe bleeding episode occurred in patients who relapsed. Among patients rechallenged with TPO-RA, 11 of 12 achieved CR. We found no significant clinical predictors of SROT at W24. Single-cell RNA sequencing revealed enrichment of a tumor necrosis factor α signaling via NF-κB signature in CD8+ T cells of patients with no sustained response after TPO-RA discontinuation, which was further confirmed by a significant overexpression of CD69 on CD8+ T cells at baseline in these patients as compared with those achieving SCROT/SROT. Our results strongly support a strategy based on progressive tapering and discontinuation of TPO-RAs for patients with chronic ITP who achieved a stable CR on treatment. This trial was registered at www.clinicaltrials.gov as #NCT03119974. Guillet et al present results of thrombopoietin receptor agonist (TPO-RA) discontinuation in a selected population of patients with persistent or chronic immune thrombocytopenia (ITP). They report that in patients in stable remission with a platelet count of >100 × 109/L for at least 2 months (48 of 388 patients), 56% maintained a platelet count of >30 × 109/L off therapy. This suggests that a subset of patients on chronic treatment with TPO-RA can be successfully tapered off therapy.