Proteins in the B cell CLL/lymphoma 2 (BCL-2) family are key regulators of the apoptotic process. This family comprises proapoptotic and prosurvival proteins, and shifting the balance toward the latter is an established mechanism whereby cancer cells evade apoptosis. The therapeutic potential of directly inhibiting prosurvival proteins was unveiled with the development of navitoclax, a selective inhibitor of both BCL-2 and BCL-2-like 1 (BCL-X(L)), which has shown clinical efficacy in some BCL-2-dependent hematological cancers. However, concomitant on-target thrombocytopenia caused by BCL-X(L) inhibition limits the efficacy achievable with this agent. Here we report the re-engineering of navitoclax to create a highly potent, orally bioavailable and BCL-2-selective inhibitor, ABT-199. This compound inhibits the growth of BCL-2-dependent tumors in vivo and spares human platelets. A single dose of ABT-199 in three patients with refractory chronic lymphocytic leukemia resulted in tumor lysis within 24 h. These data indicate that selective pharmacological inhibition of BCL-2 shows promise for the treatment of BCL-2-dependent hematological cancers.

A B S T R A C TPurpose BCL2 overexpression is a hallmark of chronic lymphocytic leukemia (CLL). The novel BH3 mimetic navitoclax (ABT-263) specifically inhibits BCL2 and related proteins BCL-x L and BCL-w, potently inducing apoptosis of CLL cells in vitro. A phase I trial in patients with CLL was conducted to evaluate the safety, pharmacokinetics, and biologic activity of oral navitoclax. Patients and MethodsTwenty-nine patients with relapsed or refractory CLL received daily navitoclax for 14 days (10, 110, 200, or 250 mg/d; n ϭ 15) or 21 days (125, 200, 250, or 300 mg/d; n ϭ 14) of each 21-day cycle. Dose escalation decisions were informed by continual reassessment methodology. ResultsLymphocytosis was reduced by more than 50% in 19 of 21 patients with baseline lymphocytosis. Among 26 patients treated with navitoclax Ն 110 mg/d, nine (35%) achieved a partial response and seven maintained stable disease for more than 6 months. Median treatment duration was 7 months (range, 1 to Ն 29 months). Median progression-free survival was 25 months. Activity was observed in patients with fludarabine-refractory disease, bulky adenopathy, and del(17p) CLL. Thrombocytopenia due to BCL-x L inhibition was the major dose-limiting toxicity and was doserelated. Low MCL1 expression and high BIM:MCL1 or BIM:BCL2 ratios in leukemic cells correlated with response. We determined that the navitoclax dose of 250 mg/d in a continuous dosing schedule was optimal for phase II studies. ConclusionBCL2 is a valid therapeutic target in CLL, and its inhibition by navitoclax warrants further evaluation as monotherapy and in combination in this disease.

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