title: Phase II study of cenersen, an antisense inhibitor of p53, in combination with fludarabine, cyclophosphamide and rituximab for high-risk chronic lymphocytic leukemia.
abstract: Patients with chronic lymphocytic leukemia (CLL) with deletion or mutation of TP53 have exceedingly poor clinical outcomes. Cenersen, an oligonucleotide targeting TP53, has been shown to abrogate the activity of TP53 gain-of-function mutants and to increase sensitivity of lymphoma cells to cytotoxic chemotherapy in vitro. We combined cenersen with fludarabine, cyclophosphamide and rituximab (FCR) as treatment for patients with high-risk CLL. The purpose of this phase II study was to determine the overall response rate, response duration and toxicity of cenersen administered in combination with FCR. Twenty patients with relapsed or high-risk CLL were evaluated. Nineteen patients were previously treated. The complete response rate was 18%; the overall response rate was 53%. Median progression-free and overall survival was 5.3 and 10.6 months, respectively. The most common serious adverse events were neutropenia and thrombocytopenia. In this single arm phase II study, cenersen combined with FCR yielded clinical responses with acceptable toxicity in patients with high-risk CLL.
authors.affiliation: Duke University Medical Center, Durham, NC 27710, USA. mark.lanasa@duke.edu
authors.forename: Mark C
authors.initials: MC
authors.lastname: Lanasa
authors.forename: Patricia H
authors.initials: PH
authors.lastname: Davis
authors.forename: Michael
authors.initials: M
authors.lastname: Datto
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Li
authors.forename: Jon P
authors.initials: JP
authors.lastname: Gockerman
authors.forename: Joseph O
authors.initials: JO
authors.lastname: Moore
authors.forename: Carlos M
authors.initials: CM
authors.lastname: DeCastro
authors.forename: Daphne R
authors.initials: DR
authors.lastname: Friedman
authors.forename: Louis F
authors.initials: LF
authors.lastname: Diehl
authors.forename: Catherine
authors.initials: C
authors.lastname: Rehder
authors.forename: Harry
authors.initials: H
authors.lastname: Cook
authors.forename: F Joseph
authors.initials: FJ
authors.lastname: Daugherty
authors.forename: Karen M B
authors.initials: KM
authors.lastname: Matta
authors.forename: J Brice
authors.initials: JB
authors.lastname: Weinberg
authors.forename: David
authors.initials: D
authors.lastname: Rizzieri
mesh_terms: D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003520:Cyclophosphamide / Q000008:administration & dosage; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009841:Oligonucleotides / Q000627:therapeutic use*; D011379:Prognosis; D012307:Risk Factors; D000069283:Rituximab; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000235:genetics; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D009841:Oligonucleotides; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000069283:Rituximab; C570305:cenersen; D003520:Cyclophosphamide; D014740:Vidarabine; C024352:fludarabine