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- Andrew W Roberts, John F Seymour, Jennifer R Brown, William G Wierda, Thomas J Kipps, Seong Lin Khaw, Dennis A Carney, Simon Z He, David C S Huang, Hao Xiong, Yue Cui, Todd A Busman, Evelyn M McKeegan, Andrew P Krivoshik, Sari H Enschede, and Rod Humerickhouse.
- MBBS, Department of Clinical Haematology and BMT, The Royal Melbourne Hospital, 2 Centre, Grattan St, Parkville 3050, Victoria, Australia. roberts@wehi.edu.au
- J. Clin. Oncol. 2012 Feb 10; 30 (5): 488-96.
PurposeBCL2 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 = 15) or 21 days (125, 200, 250, or 300 mg/d; n = 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 ≥ 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 ≥ 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 dose-related. 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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