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

Abstract

Sustained response off-treatment (SROT) after thrombopoietin receptor agonist (TPO-RA) discontinuation has been reported in ITP. This prospective multicenter interventional study enrolled adults with persistent or chronic primary ITP and complete response on TPO-RAs. The primary endpoint was the proportion of patients achieving SROT (platelet count > 30x109/L and no bleeding) at W24 with no other ITP-specific medications. Secondary endpoints included the proportion of sustained complete response off-treatment (SCROT, platelet count > 100x109/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 median (IQR) age 58.5 years (41-73.5); 30/48 (63%) had chronic ITP at TPO-RA initiation. In the intention-to-treat analysis, 27/48 (56.2%, 95% CI, 41.2-70.5) achieved SROT; 15/48 (31.3%; 95% CI, 18.9-44.5) achieved SCROT at W24, and 25/48 (52.1%; 95% CI, 37.2-66.7) achieved respectively SROT and 14/48 (29.2%; 95% CI, 17.2-42.3) SCROT at W52. No severe bleeding episode occurred in patients who relapsed. Among patients re-challenged with TPO-RA, 11/12 achieved CR. We found no significant clinical predictors of SROT at W24. Single-cell RNA-seq revealed enrichment of a "TNFα 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 of progressive tapering and discontinuation of TPO-RAs for patients with chronic ITP who achieved a stable CR on treatment. Clinical trial number: NCT03119974

Sustained response off‐treatment in eltrombopag‐treated adult patients with ITP who are refractory or relapsed after first‐line steroids: Primary, final, and ad‐hoc analyses of the Phase II TAPER trial

“…These findings are consistent with those of other published studies of eltrombopag and romiplostim, which report SRoT in up to around one‐third of patients 8,9,11 . Results from a previously reported prospective Phase II clinical trial investigating the activity of eltrombopag in adult patients with ndITP or pITP after first‐line therapy showed that the proportion of patients achieving SRoT for at least 6 months was 25% (13/51 patients) 9 .…”

“…These findings are consistent with those of other published studies of eltrombopag and romiplostim, which report SRoT in up to around one-third of patients. 8,9,11 Results from a previously reported prospective Phase II clinical trial investigating the activity of eltrombopag in adult patients with ndITP or pITP after first-line therapy showed that the proportion of patients achieving SRoT for at least 6 months was 25% (13/51 patients). 9 SRoT in this case was defined as a platelet count of ≥30 Â 10 9 /L and at least a 2-fold increase from baseline count at the end of treatment (Week 24), tapering and discontinuation (up to Week 32) of eltrombopag, and subsequent maintenance of response in the absence of bleeding and rescue therapy (an additional 24 weeks).…”

“…[8][9][10][11] SRoT is an emerging treatment goal, with existing studies utilizing different thresholds for the components of SRoT, for example, platelet counts, and duration required to consider the response to be "off-treatment." 8,9,11 Results from one recent Phase II trial confirm that short-term (24 weeks) exposure to eltrombopag can induce SRoT, defined as platelet count ≥30 Â 10 9 /L and at least a two-fold increase from the baseline count for at least 6 months following treatment discontinuation, in adult patients with ITP that is relapsed/refractory to first-line CS therapy. 9 Previously published data from real-world clinical practice also suggest that eltrombopag is as effective and well tolerated in the early stages of ITP as it is in cITP.…”

“…There is evidence that a proportion of patients treated with TPO‐RAs (i.e., eltrombopag, romiplostim) can achieve sustained responses that are maintained after TPO‐RA tapering and discontinuation; however, much of the data are retrospective, with a few prospective and real‐world observational studies investigating sustained response off‐treatment (SRoT) having been conducted 8–11 . SRoT is an emerging treatment goal, with existing studies utilizing different thresholds for the components of SRoT, for example, platelet counts, and duration required to consider the response to be “off‐treatment.” 8,9,11 …”

“…7 There is evidence that a proportion of patients treated with TPO-RAs (i.e., eltrombopag, romiplostim) can achieve sustained responses that are maintained after TPO-RA tapering and discontinuation; however, much of the data are retrospective, with a few prospective and real-world observational studies investigating sustained response off-treatment (SRoT) having been conducted. [8][9][10][11] SRoT is an emerging treatment goal, with existing studies utilizing different thresholds for the components of SRoT, for example, platelet counts, and duration required to consider the response to be "off-treatment." 8,9,11 Results from one recent Phase II trial confirm that short-term (24 weeks) exposure to eltrombopag can induce SRoT, defined as platelet count ≥30 Â 10 9 /L and at least a two-fold increase from the baseline count for at least 6 months following treatment discontinuation, in adult patients with ITP that is relapsed/refractory to first-line CS therapy.…”