Abstract Background Immune thrombocytopenia (ITP) is characterized by immune mediated platelet destruction and suboptimal platelet production, resulting in thrombocytopenia and bleeding risk. The primary goals of treating ITP are to: 1) achieve sustained, hemostatic platelet counts to prevent bleeding; 2) improve health related quality of life (HRQoL); and 3) provide long-term, treatment-free remission or cure. Platelet count 30×10⁹/L is used as threshold for initiating treatment. Corticosteroids (CS) remain the initial treatment of ITP. Despite high initial response to CS, 70% relapse and require a subsequent treatment. Thrombopoietin receptor agonists (TPO-RAs) and rituximab are the main 2nd line therapies. Methods Patients with persistently low platelet counts who are unresponsive to or dependent on CS face a high risk of bleeding and require subsequent therapy. Selecting an appropriate 2nd line treatment remains a challenge in the management of ITP. Despite extensive clinical experience and widespread use of TPO-RAs and rituximab, there is a lack of head-to-head studies directly comparing their efficacy in terms of response durability, treatment-free remission, treatment failure, patient-reported outcomes, and cost-effectiveness. Such comparative evidence is essential to support informed decision-making by both physicians and patients when selecting the optimal 2nd line therapy. The HOLISTIC study (NCT07051915) is an open-label multicenter, pragmatic randomized controlled superiority trial to assess the difference in durable response rate defined as platelet count 50x109/L in 3 or more measurement between weeks 20 and 28, between avatrombopag and rituximab in adult ITP patients who fail to achieve an adequate response to CS. Secondary endpoints include change in patients' reported outcomes (PROs) (SF-36, FACIT fatigue score and patients' satisfaction questionnaire), sustained response off-treatment (SROT) and, treatment failure, in addition to the exploration of potential prognostic biomarkers for ITP. Eligible patients are adults with primary ITP of less than 1 year duration, who have previously been treated with CS but require subsequent therapy. Exclusion criteria include previous use of any 2nd line therapy, pregnancy, secondary ITP, active hepatitis B infection, severe immunosuppression or serious comorbidity that interfere with treatment or study participation, allergy to one of the drugs, or urgent clinical need for immediate treatment (e.g. due to severe bleeding). Eligible patients will be randomized 1:1 to avatrombopag (starting dose 20 mg daily) or rituximab (1000 mg iv on day 1 and 15). The study comprises 3 phases.The first phase extends from randomization to week 28); the primary endpoint, durable response rates, will be evaluated at the end of this phase.The second phase extends from week 28 to 78. During this phase patients on avatrombopag with stable platelet count 70x109/L will start a dose-tapering period of up to 8 weeks until discontinuation. All patients will be followed until week 78 regardless of response. The rates of SROT, PROs, and rates of treatment failure will be assessed at week 78.The third extends from week 78 till the end of the trial and will be completed when the last patient completes week 78. Follow up data on SROT, treatment failure, other treatments started and more will be collected in this phase. Results: This study is a trial in progress. The study is scheduled to begin in August 2025 and is expected to be completed by 2029. To detect a 20% difference between the two arms (60% vs 40% durable response rate) with a 2-sided alpha level of 5% and a power of 80%, 100 patients will be needed in each arm. By adding 10% to compensate dropouts, we aim to randomise 220 participants. Patients will be recrtuted from around 20 centres in Norway, Sweden, Egypt and Oman. Conclusions: This trial aims to determine which of the two most widely used second-line therapies, rituximab or TPO-RA (avatrombopag) offers the better outcome and should be selected first, and whether specific patient subgroups may benefit more from one approach than the other. Furthermore, we seek to acquire knowledge on patient's perspectives, incorporating their preferences and experiences in treatment decisions, especially in relation to HRQoL. Funding statement: The study is sponsored by Østfold Hospital, Norway and supported by a grant from the Norwegian Regional Health Authority and SOBI.
Olsen et al. (Mon,) studied this question.