End-of-study results from the ICON3 pines trial, a phase 3, randomized trial of eltrombopag vs. standard first-line treatment for newly diagnosed immune thrombocytopenia in children

The Pediatric ITP Newly diagnosed patients Eltrombopag vs Standard therapy (PINES) trial, NCT03939637, was an investigator-initiated, prospective, open label, randomized, multi-center trial sponsored by the ITP

Consortium of North America (ICON) and funded by Novartis. Patients (pts) ages 1-<18 with primary ITP, ≤3 months from diagnosis, with platelet count <30 x10⁹/L who required pharmacologic treatment per the treating clinician were randomized 2:1 to receive the experimental treatment, eltrombopag (epag), or investigator's choice of one of 3 standard first-line therapies (SOC): prednisone, IVIg, or anti-D globulin at specified doses. The primary platelet response endpoint within 12 weeks was achieved by 67% pts in the epag arm, compared with 35% pts in the SOC arm; the trial closed early for efficacy per DSMB recommendation (Shimano et al, ASH 2024). The authors now report secondary objectives from study completion.

Pts were followed on study for 1 year. From weeks 13-52, pts randomized to epag could continue the study drug, with dosage weans per protocol. Pts in the SOC arm who had persistent ITP and those in the epag arm who had not responded could receive second-line therapies after week 12. Platelet counts were measured at 6 months and 1 year, as well as at monthly intervals for those remaining on epag. Complete response (CR) at 1 year was defined as platelet count ≥150 x10⁹/L. Disease resolution at 1 year was defined as CR ≥3 months after discontinuing most recent platelet active medication, without having received rituximab or splenectomy. Pts were evaluable for secondary objectives if they received at least one dose of protocol therapy. Analyses were performed a) within the subgroup with known data at 1 year, and b) with last-observation carried-forward (LOCF) to address missing data. 78 pts were randomized to epag and 40 to SOC therapy. 12 pts came off study early due to withdrawal of consent (4), lost to follow-up (6), or other (2). Median duration of therapy in the epag arm was 111 days (range 7-390). 27 (35%) pts in the epag arm vs 22 (56%) in the SOC arm did not require any treatment after week 12, p=0.02, and 43 (55%) vs 25 (64%) did not require any treatment after 6 months, p=0.35. The most commonly used subsequent agents were romiplostim, rituximab, and mycophenolate mofetil in pts randomized to epag, and epag and romiplostim for pts randomized to SOC. 106 pts completed the full 1-year study (73 [94%] for epag; 33 [83%] for SOC).18 pts (25%) in the epag arm remained on study drug at 1 year. 24/73 (33%) pts in the epag arm vs 11/33 (33%) pts in the SOC arm remained on platelet active medication at 1 year. Disease resolution by 1 year occurred in 50 (47%) pts overall, and in 33 (45%) epag pts vs 17 (52%) SOC pts, p=0.55, with similar results for CR and for LOCF analyses. Disease resolution at 1 year was no different among age groups [15/28 (54%) epag arm vs 7/11 (64%) SOC ages 1-<6; 11/26 (42%) vs 5/12 (42%) ages 6-<12; and 7/19 (37%) vs 5/10 (50%) ages 12-<18].

Disease resolution at 1 year occurred in 16/26 (62%) epag vs 10/13 (77%) SOC treatment-naïve pts who enrolled on the trial as upfront therapy. 33 (45%) pts in epag arm vs 15 (45%) in SOC arm had “primary remission,” defined as CR at 1 year with no second-line agents and ≥3 months after discontinuing most recent platelet active medication. 8 (11%) in epag arm vs 3 (9%) in SOC arm had “disease stability,” defined as platelets between 50-150 x10⁹/L and were ≥3 months after discontinuing most recent platelet active medication. Sustained response off treatment (SROT, inclusive of those with disease resolution or disease stability) occurred in 41 (56%) in epag arm vs 20 (61%) in SOC. There were 14 adverse events (AEs) (including 4 serious AEs) during weeks 13-52 in 9 pts (6 epag, 3 SOC).

In this population of pediatric pts with newly diagnosed ITP, 47% overall had disease resolution by 1 year, with no difference between treatment arms in 1-year response rates. SROT at 12 months was 56% in epag and 61% in SOC. Many pts on the epag arm were able to discontinue medication quickly, within a median of 4 months. Given these findings and the improved sustained platelet response to epag compared to SOC during weeks 6-12, epag should be considered for upfront and early use in pediatric pts with newly diagnosed ITP who require pharmacologic treatment in order to obtain a more stable platelet count.

Primary results from VAYHIT2, a randomized, double-blind, phase 3 trial of ianalumab plus eltrombopag versus placebo plus eltrombopag in patients with primary immune thrombocytopenia (ITP) who failed first-line corticosteroid treatment

B cells and the B-cell activating factor (BAFF) pathway are key in immune thrombocytopenia (ITP) pathophysiology. Ianalumab is a novel, first-in-class monoclonal antibody which binds to and blocks BAFF receptor, causing enhanced depletion of B cells via antibody-dependent cellular cytotoxicity and inhibition of B-cell activation, maturation, proliferation, and survival. The authors hypothesize that early intervention with ianalumab may provide a disease-modifying effect, such that the typical natural history of ITP is ameliorated in a significant proportion of patients (pts).

VAYHIT2 (NCT05653219) is a randomized, double-blind, placebo-controlled, Phase 3 study of ianalumab in adults with primary ITP. Pts had insufficient response to/relapse after first-line corticosteroid therapy (± intravenous [IV] immunoglobulin), platelet (PLT) count <30×10⁹/L, and were naive to and had indication for second-line ITP treatment. Pts were randomized (1:1:1) to receive eltrombopag plus either ianalumab 9mg/kg or 3mg/kg or placebo. Ianalumab or placebo was administered as four once-monthly IV infusions, simultaneously with daily eltrombopag for 16 weeks then an 8-week eltrombopag tapering period. The primary endpoint was time to treatment failure (TTF), defined as time from randomization until PLT count <30×10⁹/L or start of rescue therapy 8 weeks after randomization, start of a new ITP therapy at any time, inability to taper or discontinue eltrombopag by week 24, or death. The key secondary endpoint was stable response at 6 months (SR6), defined as having ≥75% of PLT counts between weeks 19 and 25 being ≥50x10⁹/L without rescue or new ITP treatment. Ontreatment safety outcomes were assessed from first study drug infusion to 28 days following the last infusion; adverse events (AEs) associated with B-cell depletion were assessed until end of study.

Of 152 pts enrolled, 50 were randomized to ianalumab 9mg/kg, 51 to ianalumab 3mg/kg, and 51 to placebo. Pt characteristics were generally balanced between arms. Median (interquartile range) followup: 12.9 (8.6–18.0), 13.6 (8.4–18.1), and 11.6 (8.1–18.2) months in the ianalumab 9mg/kg, 3mg/kg, and placebo arms, respectively. TTF was significantly longer with ianalumab 9mg/kg (HR 0.55, 95% CI 0.32– 0.92; log-rank p=0.021) and ianalumab 3mg/kg (HR 0.58, 95% CI 0.34–0.98; log-rank p=0.023), vs placebo; median (95% CI) TTF was 13.0 (5.1–not estimable [NE]), NE (3.7–NE), and 4.7 (3.9–5.6) months, respectively. Significantly more pts achieved SR6 with ianalumab 9mg/kg (31 [62.0%]) vs placebo (20 [39.2%]), CochranMantel-Haentzel (CMH) p=0.023; and ianalumab 3mg/kg (29 [56.9%], not reaching statistical significance compared with placebo, CMH p=0.035). At 6 months, response (PLT≥50x10 9 /L) and complete response (PLT≥100×10 9 /L) rates were 73.5% and 55.1%, respectively with ianalumab 9mg/kg and 48.0% and 26.0%, respectively with placebo. At the end of the eltrombopag tapering period, PROMIS short-form v1.0 fatigue 13a showed reduction of fatigue (mean [SD] change in T-score from baseline) of -7.7 [8.9], and -3.6 [7.0] with ianalumab 9 mg/kg and placebo, respectively. All-grade AE rates were similar between arms (84.0%–94.0%). Grade ≥3 AEs occurred in 12 (24.0%), 10 (20.0%), and 2 (3.9%) pts in the ianalumab 9mg/kg, ianalumab 3mg/kg and placebo arms, respectively. All SAEs as assessed by investigator were unrelated to study drug except for 1 event (Grade 1 palpitations) in the ianalumab 3mg/kg arm. Frequency and severity of infections (including Grade ≥3) were similar across arms. In the ianalumab 9mg/kg, ianalumab 3mg/kg, and placebo arms, respectively: infusion-related reactions (14.0%, 8.0%, and 7.8%, all Grade 1/2), neutropenia (14.0%,10.0%, and 2.0%) and allergic hypersensitivity reactions (0%, 0% and 2.0%) occurred. Grade ≥3 neutropenia occurred in 5 (10.0%) and 2 (4.0%) pts in the ianalumab 9mg/kg and 3mg/kg arms, respectively. There were no on-treatment AEs leading to ianalumab discontinuations; 1 reported in post-treatment period (started >28 days posttreatment).  Ianalumab in combination with eltrombopag prolonged TTF, improved SR6, reduced fatigue, facilitated tapering off eltrombopag, and delayed need for subsequent therapy in pts with primary ITP previously treated with corticosteroids. Ianalumab was well tolerated, with no observed increase in infection risk relative to placebo. Ianalumab may be disease-modifying when used early in the course of ITP.