A Phase 3 Study of Eltrombopag Vs. Standard First-Line Management for Newly Diagnosed Immune Thrombocytopenia in Children: Trial in Progress Update

Background: Immune thrombocytopenia (ITP) causes low platelet counts, variable bleeding symptoms, and reductions in health-related quality of life (HRQoL). Despite this, novel therapies for newly diagnosed ITP have not been introduced in over 30 years. Eltrombopag, a thrombopoietin receptor agonist (TPO-RA), was FDA approved for children with chronic ITP in 2015. The use of eltrombopag for adults with newly diagnosed ITP has been described in two small single-center trials (Tripathi et al, Int J Hematol, 2014; Gόmez-Almaguer et al, Blood, 2014), and pediatric hematologists do use TPO-RAs off-label in some cases of newly diagnosed ITP (Neunert et al, Pediatr Blood Cancer, 2016). TPO-RAs may be an efficacious and more durable first-line therapy for children with newly diagnosed ITP who require treatment. This abstract provides a 4-year interval update on the Pediatric ITP Newly diagnosed patients Eltrombopag vs Standard therapy (PINES) trial in progress.

Study Design and Methods: The PINES trial, NCT03939637, is an investigator-initiated prospective, open label, randomized, multi-center trial sponsored by the ITP Consortium of North America (ICON) and funded by Novartis. The primary objective is to determine if the proportion of patients with a platelet response, defined as ≥3 of 4 platelet counts >50 x10 ⁹/L during weeks 6-12 without rescue treatment, is significantly greater in patients with newly diagnosed ITP treated with eltrombopag compared to those treated with standard first-line therapy. Patients (n=162) from 30 ICON centers (Figure) are randomized 2:1, stratified by age and treatment status, to receive the experimental treatment, eltrombopag, or investigator's choice of 3 standard first-line therapies: prednisone, intravenous immune globulin or anti-D globulin at standardized doses.

Eligible patients are ages 1 to <18 with primary ITP, within 3 months of diagnosis, with platelet count <30 x10 ⁹/L who require pharmacologic treatment from the perspective of the treating clinician. Baseline treatment status is 1) upfront treatment, or patients within 10 days of ITP diagnosis with no prior treatment, and 2) treatment failure, or patients previously managed with observation or a first-line standard agent. Patients are ineligible if they can be observed without medication or have severe bleeding.

A one-sided z-test, at alpha=0.025, will be used to compare the proportion of patients who have a platelet response between the two treatment arms. All randomized patients will be analyzed in the intention-to-treat analysis. Secondary objectives include treatment arm comparison of bleeding scores (WHO Bleeding Scale and Modified Buchanan Score), changes in HRQoL (measured by the Kids ITP Tool, Hockenberry Fatigue Scale, PROMIS, and Global Change Scale), and changes in percentage of CD4 ⁺25 ⁺Foxp3 ⁺ regulatory T (Treg) cells.

Due to challenges related to recruitment and the logistics and safety of obtaining frequent assessments during the COVID-19 pandemic, the primary endpoint was re-defined in 2021 to what is considered a clinically equivalent definition of response, from ≥6 of 8 weekly to ≥3 of 4 biweekly platelet counts >50 x10 ⁹/L during weeks 6-12.

Baseline Characteristics: Since first site activation in 2019, 100 patients have been enrolled (Table). Subjects include 42 patients aged 1-<6 years, 34 patients aged 6-<12 years, and 24 patients aged 12-<18 years. Thirty-six patients received upfront treatment and 64 patients had treatment failure prior to enrollment. Median baseline platelet count at enrollment was 5 x10 ⁹/L (range 1 - 28 x10 ⁹/L). Median WHO Bleeding Scale at enrollment was 1 (range 0 - 3) and median modified Buchanan Overall Score was 3 (range 0 - 3). Baseline HRQoL surveys have been obtained for >80% of eligible subjects. Treg samples have been obtained for 95% of subjects, and 74% of subjects have consented to optional biology studies.

Conclusion: Despite historical difficulty completing interventional trials in pediatric ITP and pandemic-related enrollment challenges, PINES trial enrollment is progressing successfully and will ultimately provide definitive data regarding the efficacy of eltrombopag in children with newly diagnosed ITP. There are no current data supporting the use of TPO-RAs for newly diagnosed ITP in children, or as monotherapy for newly diagnosed ITP in adults. Results from this trial therefore carry the potential to change management practices in ITP.