Carolyn McGarry

Change in frequency of Nkp46+ NK cells in the peripheral blood of patients with ianalumab treatment (3.0 mg/kg), as assessed by flow cytometry.

VAF (%) kinetics for patients with baseline ibrutinib resistance mutation.

Model predicted receptor occupancy (RO) in (A) serum, (B) tissue assuming 30% tissue penetration.

Percentage of immunoglobulin change across visits.

Baseline counts of NK cells and NKG2D-expressing NK cells in the peripheral blood of patients.

. Changes in CLL cells in bone marrow measured by flow cytometry by baseline ibrutinib resistance mutation status, at baseline and C9D1

Ianalumab serum concentration-time profiles dose (escalation phase and expansion phase).

Changes in B cell concentration by baseline ibrutinib resistance mutation status, at baseline and C9D1.

Effector-related gene expression from PBMCs of (A) ETS1, KLRD1, ISG20, and PRF1 in NK cells, (B) ETS1, CD53, ISG20, and PRF1 in CD8-positive T cells, and (C) IL6ST, ADAM10, BIRC3, ITK, and CASP6 in CD4-positive T cells at C1D1.

Purpose:This phase Ib dose-escalation/expansion trial (NCT03400176) enrolled patients with CLL who did not achieve a complete response (CR) with ibrutinib or had developed resistance mutations. Ianalumab (VAY736), an anti–B cell–activating factor receptor monoclonal antibody, combined with ibrutinib significantly improved survival and reduced tumor burden in preclinical chronic lymphocytic leukemia (CLL) models.Patients and Methods:Patients received intravenous ianalumab (escalation: 0.3–9.0 mg/kg; expansion: 3.0 mg/kg) once every 2 weeks and continued ibrutinib (420 mg) once daily for up to eight cycles of 28 days. The study aimed to evaluate the safety, tolerability, recommended dose, and antitumor activity of this combination.Results:Thirty-nine patients were treated (escalation: n = 15; expansion: n = 24). No dose-limiting toxicities were observed. Of the 39 patients, 38.5% were in CR or CR with incomplete marrow recovery at cycle 9 (C9). At C9 day 1, 17 patients (43.6%) achieved undetectable measurable residual disease in blood or bone marrow. Grade ≥3 adverse events occurred in 16 patients (41.0%), which were treatment-related in nine (23.1%). No on-treatment deaths were reported; one patient died because of COVID-19 during the posttreatment period. Seventeen patients (43.6%) discontinued ibrutinib at or after C9 day 1 and remained off therapy for 12.1 to 24.5 months. Preliminary RNA sequencing and flow cytometry data support both NK- and T-cell activation with ianalumab.Conclusions:The combination was well tolerated, with 43.6% of patients discontinuing ibrutinib therapy. Biomarker data suggest that ianalumab increased NK- and T-cell activation. These data support further evaluations of ianalumab in combination with Bruton tyrosine kinase inhibitors for patients with CLL.