Treatment of Immune Thrombocytopenia (ITP) with Eltrombopag - Results of the 5^th Interim Analysis of the Study RISA, with Special Consideration of Treatment Discontinuations

Background: Immune thrombocytopenia (ITP) is an autoimmune disease characterized by isolated thrombocytopenia due to increased platelet clearance and decreased megakaryopoiesis. Eltrombopag (EPAG) is an oral thrombopoietin-receptor agonist, which is proved to be effective and safe in the treatment of ITP. Here we present data from the 5^th interim analysis of the RISA study, specially considering the reasons for treatment discontinuation and possible links to the safety profile of EPAG.

Methods: RISA is a prospective multicenter non-interventional study in Germany. It started in December 2015, and it will continue until December 2023. Statistical analysis is solely descriptive.

Results: Data cutoff for this 5^th interim analysis was 11^th Feb 2022. 313 patients with persistent or chronic primary ITP (pITP) were enrolled. 302 of them received at least one dose of EPAG and completed at least one post baseline visit. Mean duration of participation was 74.1 months. Mean±SD age was 62.8±17.4 years. 54.8% of the patients were female. Mean±SD duration of ITP at baseline was 5.4±7.5 years. Comorbidity was present in 245 (81.1%) patients. Mean±SD number of concomitant diseases was 2.9±3.0. 99 (32.8%) patients completed the entire treatment period of 24 months, which includes all scheduled visits before data cutoff. Median treatment duration was 14 months (minimum 1 day, maximum 6.1 years). Treatment with EPAG was carried out at a median dosage of 50 mg daily.

Median platelet counts increased from baseline 34.0x10⁹/L (N=292) to 91.5x10⁹/L (N=262) within one month. From then and until the end of the two-year observation period, platelet counts remained stable above 90x10⁹/L. The proportion of patients whose platelet count was at least 50x10⁹/L increased from 30.1% at baseline to 74.4% after one month and to 85.6% after twelve months. The number of bleeding events per patient-year decreased, from 1.35 at baseline to 0.59 and 0.16 after one and two years, respectively.

128 (42%) patients discontinued treatment, 51 (40%) of them before day 92. Reasons for discontinuation (multiple answers possible) were insufficient effectiveness in 55 (43%) cases, adverse events (AE) in 36 (28%) cases, death in 20 (16%) cases, non-compliance in 16 (13%) cases, lost to follow up in 10 (8%) cases, cessation of therapy due to complete response in 15 (12%) cases and other reasons in 10 (8%) cases. Across the data set, most frequent AE classified as non-serious adverse drug reactions (nsADR) were fatigue (5.3%), thrombocytopenia (3.3%), thrombocytosis (2.3%), diarrhea (3.0%) and dizziness (2.0%). The most common AE leading to discontinuation of treatment and classified as nsADR were thrombocytosis (1.3%), diarrhea (1.7%), fatigue (1.0%) and arthralgia (1.0%). The most frequent serious AE that led to treatment discontinuation and was rated as serious adverse drug reaction was pulmonary embolism, which occurred in 2 (0.7%) patients. Comorbidity was present in 109 (85.2%) of all patients who discontinued treatment. In this subgroup, the mean±SD number of concomitant diseases was 3.4±3.3.

Conclusions: We were able to confirm that EPAG therapy in ITP effectively increases platelet counts and reduces the risk of bleeding. For methodological reasons, we were unable to calculate the actual overall response rate. However, based on the proportion of total patients who were shown to discontinue treatment due to insufficient effectiveness (18%), one could assume that all other patients responded to EPAG at least temporarily. This would result in an overall response rate of 82%. This seems to be consistent with the results of the open extension study EXTEND [Wong RSM et al. Blood 2017; 130: 2527-36], in which a similarly high overall response rate (86%) was found.

In general, treatment with EPAG was well tolerated, with no new safety signals from our data set. In view of the high discontinuation rate, it should be borne in mind that about one in eight (12%) of these patients responded so well to EPAG therapy that this was taken as an opportunity for a discontinuation attempt. Other factors that may have contributed to treatment discontinuation included age and comorbidity of patients. Notably, the percentage and number of comorbidities in the discontinuation subgroup were even higher than in the overall study population. However, since this is a non-interventional observational study, results are descriptive and need to be interpreted with caution.

Meyer:Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Grifols: Consultancy, Honoraria; SOBI: Consultancy, Honoraria. Stauch:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Willy:Novartis: Current Employment.