title: Obatoclax in combination with fludarabine and rituximab is well-tolerated and shows promising clinical activity in relapsed chronic lymphocytic leukemia.
abstract: Obatoclax is a small molecule mimetic of the BH3 domain of BCL-2 family proteins. This phase 1 study combining obatoclax with FR was undertaken in chronic lymphocytic leukemia (CLL) patients relapsed after at least one prior therapy. Obatoclax was given as a 3-h infusion on days 1 and 3 and escalated through three dose levels, with standard dose FR days 1-5. Thirteen patients were enrolled, with a median of two prior therapies. One dose-limiting toxicity (DLT) of a 2-week treatment delay for persistent grade 2-3 neutropenia was observed at the highest obatoclax dose (20 mg/m2), but no maximum tolerated dose (MTD) was reached. The overall response rate (ORR) was 85%, with 15% complete responses (CRs) by NCI-96 criteria and 54% by IWCLL 2008 criteria. Median time to progression was 20 months. It is concluded that obatoclax can be safely administered to relapsed CLL patients in combination with FR and shows promising clinical activity.
authors.affiliation: a Department of Medical Oncology , Boston , MA , USA.|c Department of Medicine , Harvard Medical School , Boston , MA , USA.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Brown
authors.affiliation: a Department of Medical Oncology , Boston , MA , USA.|c Department of Medicine , Harvard Medical School , Boston , MA , USA.
authors.forename: Bethany
authors.initials: B
authors.lastname: Tesar
authors.affiliation: a Department of Medical Oncology , Boston , MA , USA.|c Department of Medicine , Harvard Medical School , Boston , MA , USA.
authors.forename: Lijian
authors.initials: L
authors.lastname: Yu
authors.affiliation: b Department of Biostatistics and Computational Biology , Dana-Farber Cancer Institute , Boston , MA , USA.
authors.forename: Lillian
authors.initials: L
authors.lastname: Werner
authors.affiliation: d Investigational Drug Branch, National Cancer Institute, National Institutes of Health , Bethesda , MD , USA.
authors.forename: Naoko
authors.initials: N
authors.lastname: Takebe
authors.affiliation: a Department of Medical Oncology , Boston , MA , USA.
authors.forename: Evgeny
authors.initials: E
authors.lastname: Mikler
authors.affiliation: a Department of Medical Oncology , Boston , MA , USA.
authors.forename: Hazel M
authors.initials: HM
authors.lastname: Reynolds
authors.affiliation: a Department of Medical Oncology , Boston , MA , USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Thompson
authors.affiliation: a Department of Medical Oncology , Boston , MA , USA.|c Department of Medicine , Harvard Medical School , Boston , MA , USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Fisher
authors.affiliation: b Department of Biostatistics and Computational Biology , Dana-Farber Cancer Institute , Boston , MA , USA.
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.affiliation: a Department of Medical Oncology , Boston , MA , USA.|c Department of Medicine , Harvard Medical School , Boston , MA , USA.
authors.forename: A S
authors.initials: AS
authors.lastname: Freedman
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D015415:Biomarkers; D002869:Chromosome Aberrations; D003131:Combined Modality Therapy; D018450:Disease Progression; D005260:Female; D006801:Humans; D007211:Indoles; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D011758:Pyrroles / Q000008:administration & dosage; D012008:Recurrence; D019233:Retreatment; D000069283:Rituximab / Q000008:administration & dosage; D016896:Treatment Outcome; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D015415:Biomarkers; D007211:Indoles; D011758:Pyrroles; D000069283:Rituximab; D014740:Vidarabine; C024352:fludarabine; C520962:obatoclax
keywords: BCL-2; Chronic lymphocytic leukemia; fludarabine; obatoclax; phase I–III trials; rituximab