Substantial Susceptibility of Chronic Lymphocytic Leukemia to BCL2 Inhibition: Results of a Phase I Study of Navitoclax in Patients With Relapsed or Refractory Disease
AuthorRoberts, AW; Seymour, JF; Brown, JR; Wierda, WG; Kipps, TJ; Khaw, SL; Carney, DA; He, SZ; Huang, DCS; Xiong, H; ...
Source TitleJournal of Clinical Oncology
PublisherAMER SOC CLINICAL ONCOLOGY
University of Melbourne Author/sSeymour, John; Khaw, Seong; Roberts, Andrew; Huang, David; CARNEY, DENNIS; He, Simon
AffiliationMedical Biology (W.E.H.I.)
Document TypeJournal Article
CitationsRoberts, A. W., Seymour, J. F., Brown, J. R., Wierda, W. G., Kipps, T. J., Khaw, S. L., Carney, D. A., He, S. Z., Huang, D. C. S., Xiong, H., Cui, Y., Busman, T. A., McKeegan, E. M., Krivoshik, A. P., Enschede, S. H. & Humerickhouse, R. (2012). Substantial Susceptibility of Chronic Lymphocytic Leukemia to BCL2 Inhibition: Results of a Phase I Study of Navitoclax in Patients With Relapsed or Refractory Disease. JOURNAL OF CLINICAL ONCOLOGY, 30 (5), pp.488-496. https://doi.org/10.1200/JCO.2011.34.7898.
Access StatusAccess this item via the Open Access location
Open Access at PMChttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4979082
C1 - Journal Articles Refereed
PURPOSE: 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 METHODS: Twenty-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. RESULTS: Lymphocytosis 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. CONCLUSION: BCL2 is a valid therapeutic target in CLL, and its inhibition by navitoclax warrants further evaluation as monotherapy and in combination in this disease.
KeywordsChemotherapy; Haematological Tumours; Molecular Targets; Cancer and Related Disorders
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