Ibrutinib Plus Ianalumab Shows Promising Results in Early-Phase Trial

According to findings from a dose-escalation/expansion trial presented at the 2021 ASH Annual Meeting, adding ianalumab to ibrutinib was well-tolerated, with clinical activity in several patients with chronic lymphocytic leukemia (CLL). Many patients achieved undetectable measurable residual disease (MRD) status in peripheral blood and bone marrow, allowing six participants to discontinue ibrutinib therapy for an extended period.

The B-cell activating factor receptor (BAFF-R) enhances the survival and regulation of normal and malignant B cells, the investigators explained. Ianalumab is a human monoclonal antibody targeting BAFF-R that targets BAFF-R+ B cells for elimination by antibody-dependent cell-mediated cytotoxicity (ADCC). “In preclinical models, adding [ianalumab] to ibrutinib significantly improved survival and reduced disease burden, suggesting that this combination may augment the anti-leukemia response and allow patients to discontinue ibrutinib,” the authors wrote.

The trial enrolled 32 patients with CLL who were undergoing either first- or second-line therapy with ibrutinib and whose disease failed to achieve a complete response (CR) after more than one year of therapy, or who had CLL with a mutation associated with ibrutinib resistance.

Participants received oral ibrutinib 420 mg once daily and ianalumab at 0.3, 1, 3, or 9 mg/kg once every two weeks. In the expansion phase, patients were enrolled into two arms depending on whether ibrutinib resistance mutations were present at baseline. The ianalumab + ibrutinib combination was administered for up to six 28-day cycles. After six cycles, patients with a CR discontinued ianalumab and received ibrutinib for an additional two cycles; all other participants continued ianalumab + ibrutinib for those two cycles. Patients achieving undetectable measurable residual disease (MRD) at cycle nine day one could discontinue ibrutinib at the investigator’s discretion.

Of the 32 patients enrolled, 19 completed therapy and four discontinued ianalumab + ibrutinib (primarily due to disease progression). Another four patients remain on ianalumab + ibrutinib and five patients continue to receive ibrutinib.

Twelve patients (38%) experienced grade ≥3 adverse events, the most common of which (occurring in ≥2 patients) were neutrophil count decreased (n = 5), lymphocyte count decreased (n = 2), hypophosphatemia (n = 2), and elevated lipase (n = 2).

The overall response for 21 evaluable patients was 38% CR, 5% CRi, 14% and PR, 24%. Thirteen patients (41%) achieved undetectable MRD in blood, while eight patients (42%) had undetectable MRD in blood and bone marrow at the end of treatment. Among those, six patients were elected to discontinue ibrutinib and remained off-treatment for 0.2 to 26.2 months. These patients were still off therapy at the data cutoff. “These data provide clinical evidence of the potent anti-leukemia activity of [ianalumab] and the potential to safely discontinue ibrutinib or other BTK inhibitors by [ianalumab] add-on therapy,” the authors concluded.