Adding the investigational antibody ianalumab (VAY736; Novartis), a humanized defucosylated engineered antibody directed against BAFF-R, to ibrutinib (Imbruvica®; Pharmacyclics/Johnson & Johnson) allows some patients diagnosed with chronic lymphocytic leukemia (CLL) to discontinue daily therapy and potentially improve their health related Quality of Life (hrQoL).*
This is the conclusion from a study, funded by Novartis Pharmaceuticals, published in Clinical Cancer Research, a journal for the American Association for Cancer Research (AACR).[1]
Chronic lymphocytic leukemia is the most prevalent adult leukemia in the Western Hemisphere, affecting approximately 200,000 people in the United States.[2]
“Bruton tyrosine kinase inhibitors (BTKi) have revolutionized CLL treatment, but patients typically stay on them indefinitely and the therapy can cause long-term toxicity,” noted John C. Byrd, MD, senior author of the study, who was chair of the Department of Internal Medicine at the University of Cincinnati College of Medicine.**
“Taking ibrutinib [also] serves as a daily reminder of illness, which many patients find psychologically burdensome,” Byrd added.
Study design
Byrd, who worked together with Kerry A. Rogers, MD, associate professor from The Ohio State University and other investigators tested the new treatment approach that could potentially help patients with CLL avoid long-term therapy.
They selected ianalumab because preclinical studies from Byrd’s lab demonstrated superior activity in combination with BTKi drugs when tested against CLL. Ianalumab, a Novel Anti-B-Cell Activating Factor (BAFF) Receptor (BAFF-R), blocks signals from the BAFR, and prevents cancerous B cells from surviving and maturing. In addition, it also marks the cells so the natural killer (NK) cells in the immune system can destroy them.[3][4]
“We tested whether this antibody could eliminate residual disease and even resistant clones, offering patients a chance to come off therapy,” Byrd explained.
Byrd and colleagues conducted a phase I, open-label, multicenter trial (NCT03400176) enrolling 39 patients who did not have complete remission on ibrutinib or had developed resistance mutations (escalation: n = 15; expansion: n = 24). Participants received intravenous ianalumab once every two weeks (escalation: 0.3–9.0 mg/kg; expansion: 3.0 mg/kg) alongside a standard dose of ibrutinib (420 mg) once daily for up to eight cycles of 28 days. The study evaluated safety, tolerability, and anti-tumor activity, as well as whether the combination could deepen responses enough to discontinue BTKi therapy.
Study outcomes
The combination therapy had no dose-limiting toxicities. Grade 3 or greater adverse events occurred in 16 patients (41%), primarily low levels of neutrophils. In 9 patients (23.1%) these adverse events were treatment related. The researchers did not report any treatment related deaths; one patients died as a results of SAR-CoV2/COVID-19 infection during the post-treatment period. Overall response was nearly 60%, and 43.6% (n = 17) had undetectable measurable residual disease (uMRD) in blood or bone marrow.
Byrd noted that 17 patients were able to stop ibrutinib and remain off therapy for 12 to 24 months. Biomarker analyses indicated that ianalumab enhanced NK and T-cell activation, supporting its proposed mechanism of action.
Thirteen (13) patients had uMRD in both blood and bone, while four patients had uMRD solely in bone, which Bryd noted as deep responses.
Mental health
“Patients who experience deep responses can stop daily medication, a powerful shift that removes the constant reminder of cancer,” Byrd observed. And this is important for the mental health of patients because “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,” Byrd explained.
The findings have important implications for patients living with CLL, Bryd added. Data showed that this approach could help patients avoid the cumulative toxicity associated with lifelong BTKi therapy. The infection rates in the patients in this trial were lower than those historically reported with single-agent BTKi therapy, suggesting that adding ianalumab did not increase infection risk.
“These results [of the study] point to potentially using fixed-duration combination therapy to achieve remission and reduce the burden of continuous treatment,” Byrd said.
Study limitations
The limitation of this study is the 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,” Byrd concluded.
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Note: * Ianalumab targets the B-cell activating factor receptor (BAFR) and ibrutinib belongs to a class of therapeutics called Bruton’s tyrosine kinase inhibitors (BTKi).
**John C. Byrd, MD, is currently director of the UPMC Hillman Cancer Center and associate vice chancellor for cancer affairs at the University of Pittsburgh School of Medicine.
Abbreviation:
BAFF = B-cell activating factor
BAFF-R = B-cell activating factor receptor
Clinical trials
VAY736 in Combination With Ibrutinib in Patients With CLL on Ibrutinib – ClinicalTrials.gov ID NCT03400176
Highlights of prescribing information
Ibrutinib (Imbruvica®; Pharmacyclics/Johnson & Johnson)[Prescribing Information]
Reference
[1] Rogers KA, Yan P, Flinn IW, Stephens DM, Kipps TJ, Larson SM, Martz L, Chen X, Wang H, Hopping E, Bundschuh R, Turkoglu A, Lozanski G, McGarry C, Acosta A, Sechaud R, Baldoni D, Chaudhury A, Whalen J, Hassounah NB, Orwitz N, Otero J, Woo J, Byrd JC. 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 Nov 6:OF1-OF14. doi: 10.1158/1078-0432.CCR-25-0210. Epub ahead of print. PMID: 41194375.
[2] Cancer Stat Facts: Leukemia — Chronic Lymphocytic Leukemia (CLL); Surveillance, Epidemiology, and End Results (SEER). National Cancer Institute. Online. Last accessed on November 7, 2025.
[3] McWilliams EM, Lucas CR, Chen T, Harrington BK, Wasmuth R, Campbell A, Rogers KA, Cheney CM, Mo X, Andritsos LA, Awan FT, Woyach J, Carson WE 3rd, Butchar J, Tridandapani S, Hertlein E, Castro CE, Muthusamy N, Byrd JC. Anti-BAFF-R antibody VAY-736 demonstrates promising preclinical activity in CLL and enhances effectiveness of ibrutinib. Blood Adv. 2019 Feb 12;3(3):447-460. doi: 10.1182/bloodadvances.2018025684. PMID: 30737226; PMCID: PMC6373734.
[4] Cuker A, Al-Samkari H, Barcellini W, Cooper N, Ghanima W, Michel M, Wong RSM, Zaja F, Zhang F, Urban P , Rached RA, Kuter DJ. Ianalumab, a Novel Anti-B-Cell Activating Factor (BAFF) Receptor (BAFF-R) Monoclonal Antibody (mAb) in Development for Immune Thrombocytopenia (ITP) and Warm Autoimmune Hemolytic Anemia (wAIHA), Has Demonstrated a Favorable Safety Profile in Sjögren’s Syndrome (SjS), Systemic Lupus Erythematosus (SLE) and Chronic Lymphocytic Leukemia (CLL).
Blood (2023) 142 (Supplement 1): 5427. DOI: 10.1182/blood-2023-180055 [Article]
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