EFFECTS OF IANALUMAB TREATMENT ON B CELL ACTIVATION, MATURATION, AND MAINTENANCE OF VACCINE TITERS IN PATIENTS WITH PRIMARY IMMUNE THROMBOCYTOPENIA IN THE PHASE 2 VAYHIT3 STUDY
Thomas Stauch et al
University Hospital Jena, Department of Internal Medicine II, Hematology and Oncology, Jena, Germany
Background
- 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 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.
Methods
- 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.
Results
- 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.
Conclusion
- 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.
