• Major finding: A phase I study shows that navitoclax monotherapy elicits durable responses in CLL.

  • Mechanism: Navitoclax is a BH3 mimetic that selectively targets the antiapoptotic protein BCL-2.

  • Impact: BCL-2 is clinically validated as a useful therapeutic target in CLL.

Elevated expression of the antiapoptotic protein B-cell lymphoma 2 (BCL-2) is a hallmark of chronic lymphocytic leukemia (CLL) and is thought to drive the accumulation of mature leukemic lymphocytes. Roberts and colleagues report the results of a phase I study in which 29 patients with relapsed or refractory CLL were treated with navitoclax, a BCL-2 homology domain 3 (BH3) mimetic agent that selectively binds BCL-2 and BCL-xL, thus inducing the mitochondrial apoptotic pathway by preventing BCL-2–mediated sequestration and inactivation of proapoptotic proteins. Strikingly, 90% of patients with peripheral blood lymphocytosis achieved at least a 50% reduction in lymphocytosis within days of starting navitoclax treatment, which was associated with increased apoptosis of circulating CLL cells, confirming the on-target effects of navitoclax. The median progression-free survival of CLL patients treated with navitoclax was 25 months. Nine patients (31%) achieved a partial response, and stable disease was observed in 18 patients. The responses were durable, as 7 patients maintained features of stable disease for more than 12 months after starting navitoclax. The most common serious adverse event was grade 4 thrombocytopenia, which was anticipated due to the known role of BCL-xL in platelet homeostasis. To identify potential biomarkers for the response to navitoclax, the expression of BCL-2 family proteins was analyzed in a subset of patients. No correlation between BCL-2 level and response was observed; however, navitoclax is also thought to kill cells expressing the related prosurvival factor MCL-1 by displacing its inhibitor, BIM, from a stable complex with BCL-2. Consistent with such a mechanism of action, high BIM:MCL-1 ratios were associated with achievement of a partial response. These findings establish BCL-2 as a valid therapeutic target in CLL and indicate that navitoclax has promising single-agent activity in heavily pretreated CLL patients.

Roberts AW, Seymour JF, Brown JR, Wierda WG, Kipps TJ, Khaw SL, et al. Substantial susceptibility of chronic lymphocytic leukemia to BCL2 inhibition: results of a phase I study of navitoclax in patients with relapsed or refractory disease. J Clin Oncol 2011 Dec 19. [Epub ahead of print].

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