title: U.S. Food and drug administration approval: rituximab in combination with fludarabine and cyclophosphamide for the treatment of patients with chronic lymphocytic leukemia.
abstract: OBJECTIVE
  To describe the clinical studies that led to the FDA approval of rituximab in combination with fludarabine and cyclophosphamide (FC) for the treatment of patients with chronic lymphocytic leukemia (CLL).
  
  
  METHODS
  The results of two multinational, randomized trials in CLL patients comparing rituximab combined with fludarabine and cyclophosphamide versus FC were reviewed. The primary endpoint of both studies was progression-free survival (PFS).
  
  
  RESULTS
  The addition of rituximab to FC decreased the risk of a PFS event by 44% in 817 previously untreated patients and by 24% in 552 previously treated patients. Median survival times could not be estimated. Exploratory analysis in patients older than 70 suggested that there was no benefit to patients when rituximab was added to FC. The safety profile observed in both trials was consistent with the known toxicity profile of rituximab, FC, or CLL.
  
  
  CONCLUSIONS
  On the basis of the demonstration of clinically meaningful prolongation of PFS, the FDA granted regular approval to rituximab in combination with FC for the treatment of patients with CLL. The magnitude of the treatment effect in patients 70 years and older is uncertain.
authors.affiliation: Division of Biological Oncology Products, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Building 22, Room 5223, Silver Spring, Maryland 20993, USA. Sandra.Casak@fda.hhs.gov
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Casak
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Lemery
authors.forename: Yuan Li
authors.initials: YL
authors.lastname: Shen
authors.forename: Mark D
authors.initials: MD
authors.lastname: Rothmann
authors.forename: Aakanksha
authors.initials: A
authors.lastname: Khandelwal
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.forename: Gina
authors.initials: G
authors.lastname: Davis
authors.forename: Vaishali
authors.initials: V
authors.lastname: Jarral
authors.forename: Patricia
authors.initials: P
authors.lastname: Keegan
authors.forename: Richard
authors.initials: R
authors.lastname: Pazdur
mesh_terms: D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects; D017277:Drug Approval; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D016032:Randomized Controlled Trials as Topic; D000069283:Rituximab; D014481:United States; D014486:United States Food and Drug Administration; D014740:Vidarabine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D000069283:Rituximab; D003520:Cyclophosphamide; D014740:Vidarabine; C024352:fludarabine