The ‘Stop TPO-Receptor Agonist in ITP Patients’ (STIP) Study: Clinical and Immune Modulatory Effects of Romiplostim Tapering

Immune thrombocytopenia (ITP) is an auto-immune bleeding disorder characterized by isolated thrombocytopenia due to an accelerated platelet destruction and impaired platelet production. Thrombopoietin receptor agonists (TPO-RAs, e.g. romiplostim) are recommended as a subsequent treatment option for patients who failed first-line therapy with corticosteroids. Long lasting use of TPO-RAs, however, is associated with high costs and a persisting burden for patients. Strikingly, sustained remissions after tapering of TPO-RAs have been reported in 10-50% of the patients with primary ITP. These findings suggest that TPO-RAs, besides stimulating platelet production, may also have an immune modulatory effect via a hitherto unknown mechanism. No distinct clinical factors or biomarkers have been identified that can reliably predict successful tapering of TPO-RAs.

The STIP study is a prospective multi-center single-arm intervention trial in the Netherlands aimed to determine the rate of sustained remission off-treatment (SROT) after 1 year of romiplostim treatment. Thirty-nine adult patients with primary ITP lasting for more than 3 months and an indication for second-line treatment received romiplostim for 1 year. Subsequently, romiplostim was tapered within 6 weeks and patients were followed for 1 year. SROT was defined as platelet counts > 30 x 10⁹/L, no bleeding symptoms and no need for treatment. Data about clinical parameters were gathered to identify potential predictors for SROT. Moreover, blood samples were taken at six different time points before, during and after romiplostim treatment. These samples were assessed for anti-glycoprotein (anti-GP) antibodies by monoclonal antibody immobilization of platelet antigen tests and for endogenous TPO levels by an enzyme-linked immunosorbent assay. Indium-111 scans were performed before and after +/- 1 year of romiplostim treatment to assess changes in platelet sequestration sites and clearance rate.

Seventy-seven percent (30/39) of the included patients had chronic ITP and 41% (16/39) had received 2 or more treatment lines prior to inclusion. Twenty-nine patients completed the first year of treatment of which 86% (25/29) started the tapering phase. Censored survival analysis showed that 23.6% (95% CI: 11.0-50.5%) had a SROT at 1 year after tapering (n=5, uncensored: 20%). The median time to relapse was 58 days. Only mild bleeding symptoms (WHO scale ≤ 1) were observed in 41% (7/17) of the patients who relapsed. Five of the 17 patients who relapsed did not restart therapy. Hence, romiplostim tapering resulted in a treatment-free response of at least 12 months in 40% (10/25). Patients with SROT at 1 year had higher platelet levels during romiplostim treatment (median: 332.5 vs. 84.5 x10⁹/L) and required lower doses at start tapering (median: 1.0 vs. 4.5 μg/kg) compared to patients who relapsed.

Anti-GP antibodies were detected in 8/25 patients at baseline, of which 5 (2/3 patients with SROT and 3/5 with relapse) showed an substantial decrease (OD value ≥ 0.10) in antibody levels. We found that the endogenous TPO levels were similar for patients with SROT and relapse at the start of the tapering (median: 13 vs. 10.5 IE/ml). The indium-111 scan showed for 75.0% (3/4, missing: n= 1) of the patients with SROT compared to only 7.1% (1/14, missing: n= 3) of those who relapsed clearance rates within a normal range at the start of tapering (>62% circulatory platelet-associated radioactivity at 48hrs). The median difference in splenic: liver ratio between scans in patients who relapsed was 0.0 (range: -1.8 - 1.4, data evaluable in n= 13), while in those with SROT a median increase of 0.6 was observed (range: 0.1 - 1.9, n= 5).

The STIP study demonstrates a sustained remission rate after romiplostim treatment of 23.6% in a diverse and largely unselected group of patients with ITP. Moreover, we have observed that tapering romiplostim using a standardized protocol is relatively safe, if closely monitored. We observed that patients with SROT tended to use lower romiplostim doses during treatment resulting in higher platelet counts. Normalization of the platelet clearance rate before tapering may be indicative of reaching remission in individual cases. Although more research into the underlying mechanisms leading to immune modulation is needed, these observations can be useful to identify patients who may benefit from TPO-RA treatment and subsequent tapering.