Substantial Susceptibility of Chronic Lymphocytic Leukemia to BCL2 Inhibition: Results of a Phase I Study of Navitoclax in Patients With Relapsed or Refractory Disease

Roberts, AW; Seymour, JF; Brown, JR; Wierda, WG; Kipps, TJ; Khaw, SL; Carney, DA; He, SZ; Huang, DCS; Xiong, H; Cui, Y; Busman, TA; McKeegan, EM; Krivoshik, AP; Enschede, SH; Humerickhouse, R

Author(s): Roberts, AW; Seymour, JF; Brown, JR; Wierda, WG; Kipps, TJ; Khaw, SL; Carney, DA; He, SZ; Huang, DCS; Xiong, H; Cui, Y; Busman, TA; McKeegan, EM; Krivoshik, AP; Enschede, SH; Humerickhouse, R;
Details: Publication Year 2012-02-10,Volume 30,Issue #5,Page 488-496
Journal Title: JOURNAL OF CLINICAL ONCOLOGY
Publication Type: Journal Article
Abstract: 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. J Clin Oncol 30: 488-496. (C) 2011 by American Society of Clinical Oncology
Publisher: AMER SOC CLINICAL ONCOLOGY
Keywords: BH3 MIMETIC ABT-737; CELL-DEATH; ANTAGONIST ABT-737; LYMPHOMA-CELLS; FAMILY; CANCER; APOPTOSIS; CHEMOTHERAPY; SENSITIVITY; RESISTANCE
Research Division(s): Cancer And Haematology; Chemical Biology
Publisher's Version: https://doi.org/10.1200/JCO.2011.34.7898

Creation Date: 2012-02-10 12:00:00