BCL2 Inhibitor Navitoclax Shows Antileukemic Activity in CLL
Results of a phase 1 study show that navitoclax, a new BH3 mimetic that targets BCL2 and related antiapoptotic intracellular proteins in cancer cells, inhibits the development of lymphocytosis in patients with chronic lymphoyctic leukemia (CLL; Roberts AW, et al. J Clin Oncol. Epub December 19, 2011).
CLL is characterized by overexpression of BCL2, whose antiapoptotic effects lead to the accumulation of mature leukemic lymphocytes. The BH3 mimetic is a new class of anticancer drugs that focus on the mitochondrial apoptotic pathway for destroying cancer cells and target BCL2.
In this early-stage study, 29 patients with relapsed or refractory CLL received oral navitoclax once daily in 21-day cycles. Exploratory efficacy end points included progression-free survival (PFS), overall response rate (ORR), time to disease progression, and duration of overall response.
After a median treatment of 7 months, peripheral blood lymphocyte count dropped by 50% in 19 of 21 patients who had lymphocytosis at baseline. A significant reduction was observed within days of starting the first cycle, and the maximum reduction occurred after 3 cycles.
Among 26 patients who received ≥110 mg of navitoclax daily, 9 achieved a partial response and 7 maintained stable disease for >6 months; the ORR was 35%. The median PFS was 25 months. Durable responses were seen in patients with fludarabine-refrac-tory disease, bulky adenopathy, and del(17p) CLL.
The low expression of MCL1, which mediates resistance to navitoclax in vitro, was significantly correlated with a maximum reduction in lymphocytosis.