title: Substantial susceptibility of chronic lymphocytic leukemia to BCL2 inhibition: results of a phase I study of navitoclax in patients with relapsed or refractory disease.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  BCL2 is a valid therapeutic target in CLL, and its inhibition by navitoclax warrants further evaluation as monotherapy and in combination in this disease.
authors.affiliation: MBBS, Department of Clinical Haematology and BMT, The Royal Melbourne Hospital, 2 Centre, Grattan St, Parkville 3050, Victoria, Australia. roberts@wehi.edu.au
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Roberts
authors.forename: John F
authors.initials: JF
authors.lastname: Seymour
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Brown
authors.forename: William G
authors.initials: WG
authors.lastname: Wierda
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kipps
authors.forename: Seong Lin
authors.initials: SL
authors.lastname: Khaw
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Carney
authors.forename: Simon Z
authors.initials: SZ
authors.lastname: He
authors.forename: David C S
authors.initials: DC
authors.lastname: Huang
authors.forename: Hao
authors.initials: H
authors.lastname: Xiong
authors.forename: Yue
authors.initials: Y
authors.lastname: Cui
authors.forename: Todd A
authors.initials: TA
authors.lastname: Busman
authors.forename: Evelyn M
authors.initials: EM
authors.lastname: McKeegan
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Krivoshik
authors.forename: Sari H
authors.initials: SH
authors.lastname: Enschede
authors.forename: Rod
authors.initials: R
authors.lastname: Humerickhouse
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000814:Aniline Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D014408:Biomarkers, Tumor / Q000378:metabolism; D002872:Chromosome Deletion; D004334:Drug Administration Schedule; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D013921:Thrombocytopenia / Q000139:chemically induced; D016896:Treatment Outcome
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D014408:Biomarkers, Tumor; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; C528561:navitoclax