Combination therapy offers hope for ending lifelong chronic lymphocytic leukemia treatment

Bottom Line: Adding the investigational antibody ianalumab (VAY736) to ibrutinib (Imbruvica) allowed some patients with chronic lymphocytic leukemia (CLL) to discontinue daily therapy and potentially improve their quality of life.

Journal in which the study was published: Clinical Cancer Research, a journal for the American Association for Cancer Research (AACR).

Authors: John C. Byrd, MD, director of the UPMC Hillman Cancer Center and associate vice chancellor for cancer affairs at the University of Pittsburgh School of Medicine. Kerry A. Rogers, MD, associate professor from The Ohio State University

Background: Ianalumab targets the B-cell activating factor receptor (BAFR) and ibrutinib belongs to a class of therapeutics called Bruton's tyrosine kinase inhibitors (BTKi).

CLL is the most prevalent adult leukemia in the Western Hemisphere, affecting approximately 200,000 people in the United States. "BTKis have revolutionized CLL treatment, but patients typically stay on them indefinitely and the therapy can cause long-term toxicity," said 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 serves as a daily reminder of illness, which many patients find psychologically burdensome, added Byrd, who is currently director of the UPMC Hillman Cancer Center and associate vice chancellor for cancer affairs at the University of Pittsburgh School of Medicine.

How the study was conducted: Byrd, Rogers, and other investigators tested this 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 blocks signals from the BAFR, preventing cancerous B cells from surviving and maturing, and also marks the cells so the natural killer (NK) cells in the immune system can destroy them. "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 enrolling 39 patients who did not have complete remission on ibrutinib or had developed resistance mutations. Participants received intravenous ianalumab every two weeks alongside a standard dose of ibrutinib for up to eight cycles. The study evaluated safety, tolerability, and antitumor activity, as well as whether the combination could deepen responses enough to discontinue BTKi therapy.

Results: The combination therapy had no dose-limiting toxicities, according to Byrd. Grade 3 or greater adverse events occurred in 41% of patients, primarily low levels of neutrophils. Overall response was nearly 60%, and 43.6% 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 patients had uMRD in both blood and bone, while four patients had uMRD solely in bone, which Bryd noted as deep responses. "Patients who experience deep responses can stop daily medication, a powerful shift that removes the constant reminder of cancer," said Byrd.

Authors' comments: "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 noted.

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 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," said Byrd.