EMATOLOGIA

In the 2018 immune thrombocytopenia (ITP) World Impact Survey, between one-third and one-half of patients reported a meaningful impact on their health-related quality of life (HRQoL), including fatigue, reduced ability to exercise, and high symptom burden.¹ The phase 3 VAYHIT2 trial (NCT05653219) demonstrated prolonged time to treatment failure and improved stable response rates at 6 months with ianalumab plus eltrombopag vs placebo plus eltrombopag in patients with ITP who had insufficient response to or relapsed after first-line corticosteroids. In addition, improvement in fatigue was observed using the Patient-Reported Outcomes Measurement Information System Short Form v1.0 Fatigue 13a.²

The aim of the study- led by Nichola Cooper (Imperial College London) is to further characterize the impact of ianalumab plus eltrombopag on patient-reported outcomes (PROs) using a disease-specific instrument validated to measure the burden of ITP symptoms and its treatment.

Patients (N=152) were randomized (1:1:1) to receive ianalumab 9 or 3 mg/kg or placebo, plus eltrombopag. Ianalumab or placebo was administered as four once-monthly intravenous infusions, alongside daily eltrombopag for 16 weeks. This was followed by an 8-week eltrombopag tapering period until discontinuation in eligible patients by week 25. PROs were collected at on-treatment visits and during post-treatment follow-up until end of study and assessed using the Immune Thrombocytopenic Purpura Patient Assessment Questionnaire (ITP-PAQ), a 44-item, 10-scale instrument for HRQoL in adults with ITP. Each scale was scored from 0 to100, with higher scores indicating better HRQoL. Scores were analyzed using repeated linear mixed models, with least-square (LS) mean changes from baseline calculated for each treatment group. This analysis focused on the ITP-PAQ scales of Symptoms, Fatigue, Bother, and Activity, as these were secondary endpoints of interest.

At data cutoff (June 20, 2025), the median duration of follow-up was 12.9, 13.6, and 11.6 months with ianalumab 9 mg/kg plus eltrombopag (hereafter referred to as the ianalumab 9 mg/kg group), ianalumab 3 mg/kg plus eltrombopag (ianalumab 3 mg/kg group), and placebo plus eltrombopag (placebo group), respectively. Across ITP-PAQ scales of Symptoms, Fatigue, Bother, and Activity, scores at most time points were highest in the ianalumab 9 mg/kg group (Figure); however, improvements were observed in all treatment groups, beginning early in the treatment period and extending through eltrombopag tapering and discontinuation (week 25), with LS-mean (95% confidence interval) changes from baseline for ITP-PAQ Symptoms being 21.6 (17.6‐25.7) and 18.4 (14.2‐22.5) with ianalumab 9 and 3 mg/kg, respectively, and 16.7 (12.8‐20.6) with placebo; for Fatigue, these figures were 21.2 (15.3‐27.2), 12.9 (6.6‐19.2), and 13.6 (7.7‐19.6). Corresponding improvements from baseline at week 25 for Bother were 26.4 (20.9‐31.8), 25.4 (19.7‐31.2), and 19.0 (13.5‐24.4); and 25.0 (18.0‐32.1), 22.8 (15.3‐30.3), and 20.5 (13.4‐27.5) for Activity.

Improvements in the ITP-specific PROs across the Symptoms, Fatigue, Bother, and Activity scales were observed in all groups, with greater and more consistent improvements observed in the ianalumab 9 mg/kg group. There was no indication of increased treatment-related bother or reduced HRQoL due to the addition of ianalumab.

Ianalumab is a monoclonal antibody targeting B cells through a novel dual mechanism of action (MoA) of enhanced B-cell depletion via antibody-dependent cellular cytotoxicity (ADCC) and inhibition of B cell activation and survival via B-cell activating factor (BAFF) receptor blockade. This dual MoA is expected to enable a broader and more potent depletion of B cells, as well as sustained modulation of B-cell activity. In the phase 2 VAYHIT3 trial (NCT05885555), a short course of ianalumab elicited a potent and sustained clinical response in a heavily pretreated population of patients with primary immune thrombocytopenia (ITP).

The aim of the study- run by Thomas Stauch et al. (University Hospital Jena)- is to examine the effect of ianalumab on B cell counts, selected biomarkers of B-cell activation and regulation, and vaccine titers to prior vaccinations. In VAYHIT3, patients with primary ITP who had previously received at least a corticosteroid and a thrombopoietin receptor agonist received four once-monthly infusions of ianalumab 9 mg/kg. B-cell counts in peripheral blood were measured as a secondary endpoint; exploratory endpoints included baseline and change from baseline measures in soluble B cell maturation antigen (sBCMA), soluble BAFF (sBAFF), T-, B-, and natural killer (NK) cell subsets, and antibody titers from tetanus and measles vaccinations.

In the full analysis set (N=41), sustained peripheral B-cell depletion (median change from baseline >92%) was observed until 29 weeks after the last infusion, B cell counts began to recover approximately 33 weeks after the ianalumab infusions ended. The median time from last infusion to B cell recovery (≥80% of baseline and ≥14.8 cells/µL, or ≥50 cells/µL) was 12.2 months.

In patients with baseline biomarker measurements, CD19+ B-cell counts and sBCMA concentrations decreased from treatment initiation to the end of treatment (EOT), with median changes of −99% and −48%, respectively, and remained reduced at week 25 (−100% and −44%). sBAFF levels were increased at EOT (+144%) and week 25 (+138%) (Figure). Depletion was observed across all measured circulating B-cell subsets, including naïve, transitional, memory, and regulatory B cells, plasmablasts and plasma cells. There was no depletion of either CD4+ or CD8+ T cells and NK cell populations generally remained stable. The potential effect of ianalumab on prior vaccine immunization was evaluated among 30 patients, with 29 patients reporting positive measles vaccine and 29 patients reporting protective tetanus vaccine titers at week 25. Vaccination history was unknown in the two patients who lost positive or protective vaccine titers (one each for measles and tetanus); both had received prior IVIG. Evaluable data at baseline and 1 year after the ianalumab infusion ended were available for 10 patients; all 10 maintained positive titers for measles and protective titers for tetanus and were in stable response. A short course of ianalumab resulted in a rapid, profound and sustained depletion of all B cell subsets in peripheral blood, consistent with ADCC. The increase in sBAFF indicates potent BAFF receptor blockade, while the decrease in sBCMA suggests reduced numbers of plasmablasts and plasma cells. Together, these findings support the novel dual MoA of ianalumab, which results in enhanced B cell depletion and inhibition of B cell activation and survival, while preserving T- and NK cell populations as well as preexisting vaccine-specific immune responses.