title: Flavopiridol, fludarabine, and rituximab in mantle cell lymphoma and indolent B-cell lymphoproliferative disorders.
abstract: OBJECTIVE
  Flavopiridol downmodulates antiapoptotic proteins associated with resistance to fludarabine and rituximab and is effective against p53-mutated chronic lymphocytic leukemia (CLL). We conducted a phase I study of flavopiridol, fludarabine, and rituximab (FFR) in patients with mantle-cell lymphoma (MCL), indolent B-cell non-Hodgkin's lymphomas (B-NHL), and CLL to determine the activity of FFR.
  
  
  METHODS
  Therapy included fludarabine 25 mg/m(2) intravenously (IV) days 1 to 5 and rituximab 375 mg/m(2) day 1 every 28 days for 6 cycles. We administered flavopiridol 50 mg/m(2) by 1-hour IV bolus (IVB) day 1 (n = 15); day 1 to 2 (n = 6); 20 mg/m(2) 30-minute IVB + 20 mg/m(2) 4-hour IV infusion (n = 3); or 30 mg/m(2) + 30 mg/m(2) (n = 14).
  
  
  RESULTS
  Thirty-eight patients (median age, 62 years) with MCL (n = 10); indolent B-NHL including follicular (n = 9), marginal zone (n = 4), lymphoplasmacytic (n = 1), or small lymphocytic lymphoma (n = 3); and CLL (n = 11), were enrolled. Twenty-two patients were previously untreated; 16 had received one to two prior therapies. Two patients in cohort 2 developed grade 3 dose-limiting toxicity (seizures, renal insufficiency). The median number of treatment cycles was 4, with cytopenias (n = 10) and fatigue (n = 3) the most common reasons for early discontinuation. Overall response rate was 82% (complete response, 50%; unconfirmed complete response, 5%; partial response, 26%), including 80% of patients with MCL (median age, 68; seven complete responses, one partial response). Median progression-free survival (PFS) was 25.6 months. Median PFS of patients with nonblastoid variant MCL (n = 8) was 35.9 months.
  
  
  CONCLUSIONS
  FFR was active in MCL, indolent B-NHL, and CLL and should be studied for older patients with MCL who are not candidates for aggressive chemotherapy.
authors.affiliation: Division of Hematology and Oncology, The Ohio State University, Center for Biostatistics, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Lin
authors.forename: Kristie A
authors.initials: KA
authors.lastname: Blum
authors.forename: Diane Beth
authors.initials: DB
authors.lastname: Fischer
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Mitchell
authors.forename: Amy S
authors.initials: AS
authors.lastname: Ruppert
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Porcu
authors.forename: Eric H
authors.initials: EH
authors.lastname: Kraut
authors.forename: Robert A
authors.initials: RA
authors.lastname: Baiocchi
authors.forename: Mollie E
authors.initials: ME
authors.lastname: Moran
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Johnson
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Schaaf
authors.forename: Michael R
authors.initials: MR
authors.lastname: Grever
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001402:B-Lymphocytes; D005260:Female; D005419:Flavonoids / Q000008:administration & dosage; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy; D016393:Lymphoma, B-Cell / Q000188:drug therapy; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy*; D008232:Lymphoproliferative Disorders / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000008:administration & dosage; D000069283:Rituximab; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D005419:Flavonoids; D010880:Piperidines; C077990:alvocidib; D000069283:Rituximab; D014740:Vidarabine; C024352:fludarabine