ASH15: Ibrutinib superior to chlorambucil in Phase III chronic lymphocytic leukemia trial

Among individuals aged 65 years of age or older with chronic lymphocytic leukemia (CLL) who have not received any treatment, the tyrosine kinase inhibitor ibrutinib has recently been demonstrated to be significantly more effective than traditional chemotherapy with chlorambucil.

This conclusion is the result of the international randomized Phase III RESONATE-2 trial involving 269 individuals. The trial findings appeared this week in The New England Journal of Medicine and where also presented at the 57th Annual Meeting of the American Society of Hematology (5–8 December, 2015, FL, USA). Overall, the results demonstrated a 24-month survival rate of 97.8 % for patients taking ibrutinib compared with 85.3 % for those on chlorambucil.

“Ibrutinib was superior to chlorambucil in CLL patients with no prior treatment, as measured by progression-free survival, overall survival, and response,” explained study lead Jan Burger of The University of Texas MD Anderson Cancer Center (TX, USA). “The study also revealed significant improvements in hemoglobin and platelet levels.”

Malignant B lymphoctye growth in CLL is driven by the B cell receptor, which transmits growth signals into the cells using enzymes, including Bruton’s tyrosine kinase (BTK). Ibrutinib is able to target and attach to BTK, preventing the kinase from transmitting growth signals and promoting cell death. Ibrutinib also disables tissue anchor signals on the leukemia cells, removing CLL cells from the nurturing environment within lymph nodes, causing them to starve.

Patients involved in the open-label RESONTE-2 trial had a median age of 73 years and 44% of the 269 individuals had advanced disease. All participants were randomized to treatment with either chlorambucil or the BTK inhibitor ibrutinib.

The median follow-up was 18.4 months, with 87 % of ibrutinib-treated patients still continuing their treatment at the time of analysis. Adverse effects were observed in 20 % of patients and included diarrhea, fatigue, cough and nausea.

“CLL is the most common adult leukemia in western countries, and primarily affects older patients with a median age of 72 years at diagnosis,” continued Burger. “In many countries, chlorambucil has remained the standard first-line therapy for such patients since the 1960s. This study paves the way for the use of ibrutinib in the front-line therapy setting.”

Sources: Burger JA, Tedeschi A, Barr PM et al. Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia. N Engl J Med. DOI: 10.1056/NEJMoa1509388 (2015) (Epub ahead of print); The University of Texas MD Anderson Cancer Center press release