Ianalumab retreatment in adults with primary immune thrombocytopenia (ITP) or warm-antibody autoimmune hemolytic anemia (wAIHA) who benefitted from previous ianalumab treatment: A phase 2 exploratory study

Abstract Background: Immune thrombocytopenia (ITP) is a rare, acquired, immune-mediated disease characterized by a decrease in platelet count, leading to an increased risk of bleeding. The goal of ITP therapy is to maintain safe platelet counts to minimize bleeding while limiting treatment-related risks. Corticosteroids (CS) are recommended as first-line treatment in ITP, while second-line recommendations include thrombopoietin receptor agonists (TPO-RAs), rituximab, or splenectomy (Neunert et al. Blood Adv. 2019). Warm autoimmune hemolytic anemia (wAIHA) is also a rare immune-mediated condition characterized by erythrocyte destruction by self-reactive IgG, resulting in anemia of varying severity. The cornerstone of first-line treatment is CS, with rituximab becoming the preferred second-line therapy for wAIHA (Yui JC, Brodsky RA. Hematol Oncol Clin North Am. 2022). In both ITP and wAIHA, treatment options are limited when patients experience relapse or treatment resistance, necessitating cycling through limited therapeutic classes with diminishing efficacy. Ianalumab is a fully human monoclonal antibody that binds B-cell-activating factor receptor (BAFF-R) with a novel dual mechanism of action of BAFF/BAFF-R blockade and enhanced antibody-dependent cellular cytotoxicity-mediated B-cell depletion. Primary analysis of Week (Wk) 25 data of the VAYHIT3 phase 2 trial in heavily pretreated patients with primary ITP found nearly half of the patients achieving a confirmed response with adverse events consistent with ianalumab's safety profile from trials in other indications. To establish ianalumab as a treatment capable of inducing durable responses, two phase 3 trials in adult patients with ITP (VAYHIT1 in first-line and VAYHIT2 in second-line) and one phase 3 trial in patients with wAIHA (VAYHIA) are ongoing. Aims: This study (VAY RE-HIT, NCT07039422) aims to assess the efficacy and safety of a second course of ianalumab in patients with primary ITP or primary/secondary wAIHA who benefitted from their first treatment course. Methods: In this multicenter, phase 2 exploratory study, adult patients with primary ITP or primary/secondary wAIHA, who benefited from the first course of ianalumab in the parent pivotal trials but later experienced treatment failure (≥2 years after the last infusion ianalumab/placebo in VAYHIT1 and 2 trials) or lost durable response (≥2 years in blinded cohorts or Wk 20 in the cross-over arm in VAYHIA trial) and subsequently needed further therapy, will be included. Rescue medication and/or bridging therapy with CS (ITP, wAIHA) or TPO-RAs (ITP) are allowed at the defined timepoints. Patients with Evans syndrome or other cytopenias (except anemia due to blood loss or iron deficiency), secondary wAIHA with bone marrow involvement of the primary lymphoid malignancy, neutrophils <1000/mm3 or IgG <5 g/L at screening will be excluded. Once the parent trials are unblinded, patients who received placebo will not be eligible. Ianalumab will be administered intravenously with the same dose (lower dose or higher dose) used in the parent trials (a total of 4 doses) until the data readout; thereafter, the recommended dose will be administered for all newly recruited patients. The study consists of a screening period (up to 14 days before the first dose), treatment period (until Wk 17 Day 1 visit), and follow-up (FU) period up to 2 years after the last dose (efficacy and safety FU; safety FU only for treatment failure or if loss of durable response occurs). The primary endpoints are (i) treatment failure by 12 months (any of the following - platelet count <30 G/L, use of bridging or rescue therapy after 8 wks, new ITP treatment, death or inability to taper TPO-RA by Wk 24 when treated as bridging therapy) after the start of the second course of ianalumab for patients with ITP and (ii) durable response (Hb ≥10 g/dL and ≥2 g/dL increase from baseline) for at least 8 consecutive wks (during Wks 9-25) without rescue treatment for patients with wAIHA. Patients who were randomized to placebo in the corresponding parent study will not be included in the population of the primary estimand. The secondary endpoints for both patients with ITP and wAIHA include response and complete response rates and the number and proportion of patients receiving rescue treatment and/or new ITP/wAIHA therapy. Additionally, safety, pharmacokinetics, and immunogenicity assessments will be conducted. Results: None.Conclusion: Enrollment is ongoing.