Immune thrombocytopenia (ITP) is an immune-mediated thrombocytopenic disorder that can lead to severe bleeding and markedly impair quality of life. At the 67th Annual Meeting of the American Society of Hematology (ASH), multiple important advances were reported in the field of ITP. Among them, ianalumab, a novel fully human anti-BAFF-R monoclonal antibody, demonstrated significant efficacy in the VAYHIT2 and VAYHIT3 studies and emerged as a major highlight in ITP therapy. Oncology Frontier · Hematology Frontier invited Professor Yang Linhua from the Second Hospital of Shanxi Medical University to provide an in-depth interpretation of these two landmark studies and to discuss the clinical significance and future potential of ianalumab in ITP management.
Study 1
LBA-2: Primary Results of the Phase III VAYHIT2 Study — A Randomized, Double-Blind Trial of Ianalumab Plus Eltrombopag versus Placebo Plus Eltrombopag in Patients with Primary ITP Who Failed First-Line Corticosteroids
Author: Hanny Al-Samkari, Division of Hematology-Oncology, Massachusetts General Hospital, Boston, USA
Background B cells and the B-cell activating factor (BAFF) pathway play a central role in the pathophysiology of immune thrombocytopenia. Ianalumab is a first-in-class monoclonal antibody that binds to the BAFF receptor, blocks its function, enhances B-cell depletion through antibody-dependent cell-mediated cytotoxicity, and suppresses B-cell activation, maturation, proliferation, and survival. It was hypothesized that early intervention with ianalumab could exert a disease-modifying effect, improving the typical natural course of ITP in a subset of patients.
Methods VAYHIT2 (NCT05653219) is a randomized, double-blind, placebo-controlled phase III study evaluating ianalumab in adults with ITP who had an inadequate response to first-line corticosteroids, with or without intravenous immunoglobulin, or who relapsed after such therapy. Eligible patients had platelet counts <30×10⁹/L and an indication for second-line therapy but had not yet received it. Patients were randomized 1:1:1 to eltrombopag plus ianalumab 9 mg/kg, eltrombopag plus ianalumab 3 mg/kg, or eltrombopag plus placebo. Ianalumab or placebo was administered as four monthly intravenous infusions, combined with daily oral eltrombopag for 16 weeks, followed by an 8-week eltrombopag taper. The primary endpoint was time to treatment failure (TTF). The key secondary endpoint was stable response at 6 months (SR6). Safety was assessed throughout treatment and follow-up.
Results A total of 152 patients were enrolled. Median follow-up was approximately 12–14 months across groups. Compared with placebo, both ianalumab 9 mg/kg and 3 mg/kg significantly prolonged TTF. Median TTF was 13.0 months in the 9 mg/kg group, not estimable in the 3 mg/kg group, and 4.7 months in the placebo group. The proportion of patients achieving SR6 was higher in the 9 mg/kg group (62.0%) than in the placebo group (39.2%). At 6 months, response and complete response rates were also higher with ianalumab 9 mg/kg. Fatigue scores improved more markedly in the ianalumab 9 mg/kg group. Adverse event rates were generally similar across groups, with manageable safety and no increased infection risk compared with placebo.
Conclusion In patients with primary ITP previously treated with corticosteroids, ianalumab plus eltrombopag prolonged time to treatment failure, increased stable response rates, reduced fatigue, facilitated eltrombopag tapering, and delayed the need for subsequent therapies. Ianalumab was well tolerated, with no excess infection risk. Early use of ianalumab may confer disease-modifying effects in ITP.
Study 2
Abstract 884: Secondary Analyses of the Phase II VAYHIT3 Study Evaluating Ianalumab in Patients with Primary ITP Previously Treated with at Least Second-Line Therapy
Author: Philip Choi, Department of Hematology, Canberra Hospital, Australia
Background Unmet clinical needs remain in primary ITP, particularly among patients refractory to multiple lines of therapy. Ianalumab is a fully human IgG1 monoclonal antibody targeting BAFF-R, with a dual mechanism of enhancing B-cell depletion via ADCC and blocking BAFF-BAFF-R signaling. The primary analysis of VAYHIT3 showed significant efficacy and good tolerability of short-course ianalumab in heavily pretreated ITP patients. This report focuses on key secondary and subgroup analyses.
Methods This open-label, single-arm phase II study enrolled adults with ITP and platelet counts <30×10⁹/L who had previously received corticosteroids and at least one thrombopoietin receptor agonist. Patients received ianalumab 9 mg/kg intravenously every 4 weeks for four doses. The primary endpoint was confirmed response, defined as platelet counts ≥50×10⁹/L on two consecutive assessments without rescue therapy. Efficacy was analyzed across subgroups by prior lines of therapy, age, and sex.
Results All 41 enrolled patients completed the 25-week study period or discontinued early. Median age was 55 years, and the median number of prior treatment lines was six. Rapid and profound B-cell depletion was observed. At week 25, stable response rates were observed across all subgroups, including heavily pretreated and older patients. Complete response rates increased over time. Bleeding events markedly decreased after the second infusion. No new safety signals emerged with longer follow-up.
Conclusion These additional analyses further support the efficacy of ianalumab in heavily pretreated primary ITP. The treatment rapidly induces deep B-cell depletion, provides consistent benefit across subgroups, and improves bleeding outcomes.
Professor Yang Linhua’s Commentary The two ASH studies from the United States and Australia, VAYHIT2 and VAYHIT3, confirm the clinical value of ianalumab in ITP treatment. They reflect a paradigm shift in refractory and relapsed ITP, moving beyond platelet count elevation toward upstream immune modulation. As the first fully human monoclonal antibody targeting BAFF-R, ianalumab exerts dual actions by blocking BAFF-R signaling and enhancing ADCC-mediated B-cell depletion, reconstructing immune homeostasis at the disease origin and demonstrating disease-modifying potential across key patient populations.
In patients failing first-line corticosteroids, ianalumab combined with eltrombopag significantly prolonged time to treatment failure, improved stable response rates, reduced fatigue, and enabled tapering of background therapy, suggesting an impact beyond short-term platelet support toward long-term disease course modification. In heavily pretreated, refractory ITP, short-course therapy achieved deep and durable B-cell depletion and reduced bleeding even in elderly and highly treated subgroups, offering a new effective option for difficult clinical scenarios.
ITP has now entered an era of precision immunotherapy, with parallel development of agents targeting different immune pathways, including CD38 monoclonal antibodies, FcRn antagonists, BTK inhibitors, Syk inhibitors, and CAR-T therapies. Compared with approaches acting downstream on antibodies or effector cells, ianalumab targets upstream B-cell activation and survival, providing clear mechanistic complementarity. These studies support a future strategy of segmented immune-pathway intervention, guided by immune profiling, to achieve mechanism-driven rather than empirical therapy.
Nevertheless, limitations remain. Longer follow-up is needed to fully assess long-term safety, particularly infection risk. Larger, controlled studies are required to validate subgroup findings and to explore optimal sequencing or combination strategies. Immune phenotyping before treatment may help identify patients most likely to benefit.
Overall, the disease-modifying potential and mechanistic complementarity of ianalumab position it as an indispensable option for refractory ITP. With further elucidation of the BAFF-R pathway and optimization of combination strategies, ITP management may progress from symptom control to restoration of immune homeostasis, ushering in a new era of precision immunomodulation.
Expert Profile
Professor Yang Linhua Second Hospital of Shanxi Medical University
Director, Hematology Research Center, Shanxi Medical University Department of Hematology, Second Hospital of Shanxi Medical University Second-Class Professor, PhD Supervisor, Recipient of the State Council Special Allowance Shanxi “Sanjin Talent” High-Level Leader, First-Class Renowned Physician of Shanxi Province Member of the 12th and 13th National People’s Congress Former Standing Committee Member, Chinese Society of Hematology Vice Chair, China Hematology Specialty Alliance Vice Chair, Chinese Medical Education Association Hematology Committee Vice Chair, Chinese Association of Rehabilitation Medicine Hematologic Rehabilitation Committee Vice Chair, Precision Hematology Committee, Chinese Research Hospital Association Standing Committee Member, Hematology Committee, Cross-Strait Medical and Health Exchange Association Standing Committee Member, Hematology and Immunology Branch, Chinese Society of Pathophysiology Standing Committee Member, Chinese Female Physicians Association Hematologic Oncology and Rare Diseases Committee Deputy Head, Experimental Hematology and Vascular Biology Group, Chinese Society of Pathophysiology Chair, Shanxi Society of Hematology Physicians Chair, Leukemia and Lymphoma Committee, Shanxi Anti-Cancer Association Editorial Board Member of Hemophilia, Blood (Chinese edition), Chinese Journal of Hematology, Chinese Journal of Internal Medicine, Chinese Journal of General Practitioners, and Chinese Journal of Cell and Stem Cell Research
