Combo Therapy Effective for Relapsed CLL

The Bruton tyrosine kinase (BTK) inhibitor ibrutinib (Imbruvica; Pharmacyclics and Janssen) combined with standard therapy significantly improved outcomes for patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), according to a large phase III trial. The results were presented on May 30 at the American Society of Clinical Oncology Annual Meeting in Chicago, IL.

In the HELIOS study, 578 patients with CLL and SLL were randomly assigned to receive bendamustine and rituximab (Rituxan; Genentech)—the current standard of care—alone or in combination with ibrutinib. After a median follow-up of 17.2 months, the median progression-free survival (PFS) was not reached in the ibrutinib group compared with 13.3 months in the standard therapy group. Patients taking ibrutinib had an 80% reduced risk of disease progression or death compared with controls, and an overall response rate (ORR) of 82.7% versus 67.8% in the placebo group.

“We found a remarkable improvement in ORR and an impressive decrease in the risk of progression and death,” said the study's principal investigator Asher Chanan-Khan, MD, professor of medicine at the Mayo Clinic in Jacksonville, FL, at a press briefing. “This is an important point in the history of CLL where the standard of treatment will no longer be bendamustine/rituximab but bendamustine/rituximab with ibrutinib.”

The risk of death from CLL and SLL was reduced by 37% in the ibrutinib group compared with placebo, Chanan-Khan noted, despite the fact that 90 patients whose disease had progressed crossed over from the placebo to the ibrutinib group by the time of the analysis in March 2015. Patients with the 17p deletion, which is associated with poor response to chemoimmunotherapy, were excluded from the study, but PFS benefits of the ibrutinib combination were consistent across all other high-risk subgroups.

The main side effects of ibrutinib were comparable to standard therapy, including neutropenia and thrombocytopenia, said Chanan-Khan. However, patients taking ibrutinib were more likely than controls to experience bleeding (30% versus 17%) and atrial fibrillation (7% versus 0.7%).

The protein BTK, which is overexpressed in CLL and several other lymphoid malignancies, is involved in the B-cell receptor signaling pathway and is a main driver of B-cell proliferation and survival. By inhibiting BTK, ibrutinib blocks B-cell activation and signaling and prevents the growth of malignant cells.

The FDA approved ibrutinib last year as a single-agent treatment for relapsed or refractory CLL and SLL; it is also approved to treat mantle cell lymphoma and Waldenström macroglobulinemia. HELIOS, which enrolled patients in 21 countries, is the first large randomized trial to test the effectiveness of combination therapy with ibrutinib in relapsed CLL and SLL.

CLL and SLL are currently incurable, so the goal of post-relapse therapy is to control the disease and provide long, durable remission, said Chanan-Kahn. Adding ibrutinib to existing therapies has the potential to extend remission even further.

“This is very exciting news for CLL patients,” said Merry-Jennifer Markham, MD, assistant professor of medicine, Division of Hematology & Oncology, at the University of Florida in Gainesville. “Ibrutinib is now going to be an important drug in combination with an established chemotherapy regimen that can help these patients live longer and have better quality of life.”