Immune thrombocytopenia (ITP) is an acquired autoimmune disorder, and management after failure of first-line corticosteroid therapy remains a significant clinical challenge. In recent years, emerging therapies targeting key pathways involved in B-cell and plasma cell survival have opened new avenues for ITP treatment. Among these, ianalumab, a monoclonal antibody with a dual mechanism of action combining BAFF receptor blockade and B-cell depletion, has attracted considerable attention.
Based on pivotal data from the Phase III VAYHIT2 trial, Professor Hanny Al-Samkari of Massachusetts General Hospital, Harvard Medical School, provides a comprehensive interpretation of the efficacy and safety of ianalumab combined with eltrombopag in early-stage ITP patients with inadequate response to first-line corticosteroids. He also discusses the potential disease-modifying effects of early intervention and the clinical considerations surrounding dose optimization, offering evidence-based guidance for precision treatment in the second-line setting.
Study Design and Methods
VAYHIT2 is a pivotal, randomized, double-blind, placebo-controlled Phase III clinical trial conducted in adults with primary ITP who failed first-line corticosteroid therapy and required second-line treatment. Eligible patients were randomly assigned to one of three treatment arms: high-dose ianalumab (9 mg/kg) plus eltrombopag, low-dose ianalumab (3 mg/kg) plus eltrombopag, or placebo plus eltrombopag. All patients received background eltrombopag therapy.
Ianalumab or placebo was administered as an intravenous infusion once monthly for four doses during the first four months of treatment. A prespecified eltrombopag tapering strategy was incorporated into the protocol. At week 16, patients were assessed against predefined platelet count criteria to determine eligibility for eltrombopag dose reduction, with the goal of complete discontinuation by week 24.
The study employed an innovative primary endpoint: time to treatment failure, defined as the time from randomization to the first occurrence of any of the following events: platelet count below 30 × 10⁹/L, new bleeding requiring clinical intervention, initiation of rescue therapy or a new ITP treatment, inability to taper or discontinue eltrombopag by week 24, or death from any cause.
Efficacy and Safety Outcomes
The results demonstrated that both ianalumab dose levels, when combined with eltrombopag, were significantly superior to placebo plus eltrombopag with respect to the primary endpoint. Treatment with ianalumab markedly prolonged time to treatment failure. Specifically, both the 9 mg/kg and 3 mg/kg dose groups achieved hazard ratios of approximately 0.55, indicating a statistically significant reduction in the risk of treatment failure compared with placebo.
The median time to treatment failure was 13.0 months in the 9 mg/kg group, substantially longer than the 4.7 months observed in the placebo group. In the 3 mg/kg group, the median time to treatment failure had not yet been reached at the time of analysis, suggesting a sustained treatment benefit. These findings indicate that early second-line use of ianalumab provides durable disease control and significantly extends the period during which patients can remain free from additional ITP-directed therapies.
From a safety perspective, ianalumab was generally well tolerated. No increase in the frequency or severity of infections was observed, and no new or unexpected serious safety signals emerged. In the 9 mg/kg dose group, the most common treatment-related adverse events were neutropenia and infusion-related reactions. Neutropenia was typically transient, lasting from days to weeks, while infusion reactions were predominantly mild to moderate and were effectively managed with standard premedication strategies.
Dose Optimization and Future Directions
Although both dose levels demonstrated clear benefit for the primary endpoint, differences emerged across certain secondary endpoints. The 9 mg/kg dose showed a more favorable trend in 6-month sustained response rates and overall platelet response rates. These findings raise important questions regarding optimal dose selection in clinical practice.
Data from the ongoing VAYHIT1 trial, which is evaluating ianalumab in combination with corticosteroids as first-line therapy, have not yet been reported and may provide further insight into dose selection. Future treatment strategies may ultimately adopt a more individualized approach, but the optimal dose and the potential for patient-specific dosing algorithms remain to be clarified through longer follow-up and additional studies. If long-term efficacy and safety profiles of the two doses ultimately prove comparable, the lower dose may offer a more practical and cost-effective option in routine care.
Summary
The VAYHIT2 study confirms that ianalumab combined with eltrombopag significantly prolongs time to treatment failure in patients with ITP who have failed first-line corticosteroids, achieving deep and durable disease control with a favorable safety profile. Beyond validating the efficacy of this combination in second-line ITP, the trial also introduces a novel and clinically meaningful study design, incorporating prespecified eltrombopag tapering goals and using time to treatment failure as the primary endpoint.
Importantly, the findings support the broader vision of early intervention with the potential to modify the natural history of ITP, rather than merely increasing platelet counts. While questions regarding optimal dosing and long-term disease-modifying effects remain to be fully answered, ongoing follow-up and future studies are expected to provide clarity. Undoubtedly, dual-mechanism agents such as ianalumab are helping to shift the treatment paradigm for ITP toward sustained treatment-free remission and, potentially, true alteration of disease course.
Research Abstract
LBA-2: Preliminary Results of the VAYHIT2 Study—A Randomized, Double-Blind, Phase III Trial of Ianalumab Plus Eltrombopag Versus Placebo Plus Eltrombopag in Patients With Primary Immune Thrombocytopenia After Failure of First-Line Corticosteroids
B cells and the B-cell activating factor (BAFF) pathway play a central role in the pathophysiology of immune thrombocytopenia (ITP). Ianalumab is a first-in-class monoclonal antibody that binds to the BAFF receptor, blocking its function while enhancing antibody-dependent cellular cytotoxicity to deplete B cells and inhibit their activation, maturation, proliferation, and survival. Early intervention with ianalumab may exert disease-modifying effects, potentially improving the typical disease course of ITP in a substantial proportion of patients.
VAYHIT2 (NCT05653219) is a randomized, double-blind, placebo-controlled Phase III trial in adults with primary ITP who had an inadequate response or relapse after first-line corticosteroid therapy (with or without IVIG), had platelet counts below 30 × 10⁹/L, and required second-line treatment. Patients were randomized 1:1:1 to receive eltrombopag plus ianalumab at 9 mg/kg, 3 mg/kg, or placebo. Ianalumab or placebo was administered intravenously once monthly for four doses, alongside daily eltrombopag for 16 weeks, followed by an 8-week eltrombopag tapering period.
Among 152 enrolled patients, baseline characteristics were well balanced across groups. Both ianalumab dose levels significantly prolonged time to treatment failure compared with placebo and improved sustained response rates, reduced fatigue, facilitated eltrombopag discontinuation, and delayed the need for subsequent therapies. Ianalumab was well tolerated, with no increase in infection risk compared with placebo. These findings suggest that early use of ianalumab in the ITP disease course may confer meaningful disease-modifying benefits.
Expert Profile
Hanny Al-Samkari, MD Massachusetts General Hospital, Harvard Medical School
Peggy S. Blitz Endowed Chair in Hematology/Oncology Associate Professor of Medicine (Hematology), Harvard Medical School Co-Director, Hereditary Hemorrhagic Telangiectasia Center of Excellence
Professor Al-Samkari is an internationally recognized expert in benign hematology and immune-mediated bleeding disorders, with a strong focus on translational and clinical research aimed at improving patient-centered outcomes.
