Adding Ianalumab to Ibrutinib May Enable Fixed-Duration Therapy in CLL

Results from a phase 1b study (NCT03400176) published in Clinical Cancer Research show that adding the monoclonal antibody ianalumab (VAY736) to ibrutinib (Imbruvica) was well tolerated and led to complete responses (CRs) in patients with chronic lymphocytic leukemia (CLL), allowing some to discontinue and remain off ibrutinib therapy for 1 to 2 years.^1,2

Among 39 patients treated with the regimen, 38.5% achieved a CR or CR with incomplete marrow recovery by cycle 9. At the start of cycle 9, 43.6% (n = 17) had achieved undetectable measurable residual disease in blood or bone marrow, allowing them to discontinue ibrutinib and remain off therapy for 12.1 to 24.5 months. This finding suggests that the combination of ianalumab and ibrutinib may offer a potential treatment strategy that enables fixed-duration therapy in CLL, contrasting with the standard continuous ibrutinib approach.

“Patients who experience deep responses can stop daily medication, a powerful shift that removes the constant reminder of cancer,” said John C. Byrd, MD, University of Pittsburgh Hillman Cancer Center and study senior author, in a news release.² “Taking a medicine every day can be a reminder of sickness for patients, so it is very symbolic for patients with blood cancers to be able to go off therapy.”

Regarding safety, no dose-limiting toxicities were observed. Grade ≥3 treatment-related adverse events occurred in 23.1% of patients, with no deaths occurring during treatment. The safety profile, coupled with the high rates of deep responses, supports further investigation of ianalumab in combination regimens for CLL.

The Clinical Rationale for Ianalumab

Although the Bruton tyrosine kinase inhibitor (BTKi) ibrutinib has significantly improved outcomes in patients with CLL, it often fails to induce deep, lasting remissions. In CLL, most patients treated with ibrutinib require continuous administration, as discontinuation is frequently associated with disease progression. Long-term therapy can be complicated by cumulative toxicity, intolerance, and the development of resistance mutations, threatening patients’ quality of life.

Ianalumab is a monoclonal antibody that targets the B cell-activating factor (BAFF) receptor.¹ In preclinical studies, the agent demonstrated potent depletion of malignant B cells through antibody-dependent cellular cytotoxicity and blockade of BAFF-mediated survival signaling.³ In vivo activity as monotherapy was also observed in CLL models, and when combined with ibrutinib, the regimen resulted in prolonged survival compared with either agent alone, supporting its advancement into the clinical setting.

The multicenter, open-label phase 1b study was thus designed to evaluate the safety, tolerability, recommended dose, and antitumor activity of the combination in patients with CLL who had received ibrutinib for 1 year without achieving a CR or those who developed resistance mutations to ibrutinib.⁴ The study enrolled a total of 39 adult patients in the US across dose-escalation (n = 15) and -expansion (n = 24) phases.

During dose escalation, patients received intravenous (IV) ianalumab at escalating doses from 0.3 mg/kg to 9.0 mg/kg once every 2 weeks and continued ibrutinib at 420 mg once daily for up to 8 28-day cycles. In dose expansion, patients received the recommended dose of 3.0 mg/kg of IV ianalumab, following the same administration schedule as in escalation.

“I think the thing that I wasn’t expecting was to see this many patients in a phase 1 [trial] that had elimination of the CLL [who] were able to stop treatment,” said Kerry Rogers, MD, hematologist/oncologist at The Ohio State University Comprehensive Cancer Center–James and lead author of the study, in a previous interview with Targeted Oncology. “I’d say that was kind of a surprise especially because it wasn’t what the study was powered to detect, but it was really great to see that kind of efficacy already.”

As such, the results provide a strong rationale for continued studies exploring ianalumab as part of combination therapy in CLL, which could address some of the study’s present limitations, including small sample size and lack of long-term follow-up.

“A larger trial is needed to confirm whether this approach can become a standard strategy for reducing BTKi treatment duration,” added Byrd in the news release.²

REFERENCES

1. Rogers KA, Yan P, Flinn IW, et al. Addition of Ianalumab (VAY736) to Ibrutinib in Patients with Chronic Lymphocytic Leukemia on Ibrutinib Therapy: Results from a Phase Ib Study. Clin Cancer Res. 2025;31(24):5145-5158. doi:10.1158/1078-0432.ccr-25-0210

2. A combination treatment may help cut lifelong ibrutinib for chronic lymphocytic leukemia. News release. American Association for Cancer Research. November 6, 2025. Accessed January 20, 2026. https://tinyurl.com/msfs94d8

3. McWilliams EM, Lucas CR, Chen T, et al. Anti-BAFF-R antibody VAY-736 demonstrates promising preclinical activity in CLL and enhances effectiveness of ibrutinib. Blood Adv. 2019;3(3):447-460. doi:10.1182/bloodadvances.2018025684

4. VAY736 in combination with ibrutinib in patients with CLL on ibrutinib. ClinicalTrials.gov. Updated May 16, 2025. Accessed January 21, 2026. https://clinicaltrials.gov/study/NCT03400176