title: Phase II study of single-agent bortezomib for the treatment of patients with fludarabine-refractory B-cell chronic lymphocytic leukemia.
abstract: Therapeutic options are limited and the prognosis is poor for patients with fludarabine-refractory B-cell chronic lymphocytic leukemia (CLL). Bortezomib induces apoptosis in vitro in CLL cells, both alone and in combination, including in cells resistant to fludarabine or other agents. The aim of the current randomized, open-label, Phase II study was to investigate the clinical activity of bortezomib in patients with fludarabine-refractory B-cell CLL. Twenty-two patients with histologically confirmed B-cell CLL were treated with bortezomib at doses of 1.0 mg/m2, 1.3 mg/m2, or 1.5 mg/m2 on Days 1, 4, 8, and 11 of a 21-day treatment cycle for a maximum of 9 cycles. None of 19 patients evaluable for response achieved complete remission or partial response; however, signs of biologic activity based on disease site responses (e.g., reduction in lymphocytosis, splenomegaly, and lymphadenopathy) were observed. In the 1.5 mg/m2 dose group, a higher proportion of patients had stable disease, and a lower proportion had progressive disease compared with the 2 lower-dose groups. Eleven patients, all in the 2 higher dose groups, experienced Grade 3/4 adverse events (AEs) (according to National Cancer Institute Common Toxicity Criteria [version 2.0]); 2 patients experienced Grade 4 neutropenia. Grade 3 hematologic AEs included anemia, neutropenia, thrombocytopenia, and hemolytic anemia; Grade 3 nervous system AEs included aphasia; peripheral neuropathy, not otherwise specified; and peripheral sensory neuropathy. Although no objective responses were achieved in patients with fludarabine-refractory B-cell CLL, single-agent bortezomib demonstrated biologic activity. In view of the evidence for its activity, further exploration of bortezomib in combination with other agents is warranted.
authors.affiliation: Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Faderl
authors.forename: Kanti
authors.initials: K
authors.lastname: Rai
authors.forename: John
authors.initials: J
authors.lastname: Gribben
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.forename: Ian W
authors.initials: IW
authors.lastname: Flinn
authors.forename: Susan
authors.initials: S
authors.lastname: O'Brien
authors.forename: Shihong
authors.initials: S
authors.lastname: Sheng
authors.forename: Dixie-Lee
authors.initials: DL
authors.lastname: Esseltine
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Keating
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001897:Boronic Acids / Q000008:administration & dosage / Q000627:therapeutic use*; D000069286:Bortezomib; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D011480:Protease Inhibitors / Q000627:therapeutic use*; D011719:Pyrazines / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D011480:Protease Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D014740:Vidarabine; C024352:fludarabine