title: Sequential therapy with fludarabine, high-dose cyclophosphamide, and rituximab in previously untreated patients with chronic lymphocytic leukemia produces high-quality responses: molecular remissions predict for durable complete responses.
abstract: OBJECTIVE
  Modern combination strategies are active in chronic lymphocytic leukemia (CLL) but can have significant myelosuppression and immunosuppression that may require dose attenuation for safety. We explored a sequential treatment strategy to allow safe delivery of active agents at full doses. Previously, we studied sequential therapy with fludarabine followed by cyclophosphamide (F-->C). In that study, cyclophosphamide consolidation improved the frequency of complete response (CR) four-fold. Subsequently, rituximab was added to this regimen (F-->C-->R).
  
  
  METHODS
  Thirty-six previously untreated CLL patients received therapy with fludarabine 25 mg/m(2) on days 1 through 5 every 4 weeks for six cycles, followed by consolidation with cyclophosphamide 3,000 mg/m(2) administered every 3 weeks for three cycles, followed by consolidation with weekly rituximab 375 mg/m(2) for four cycles. Evaluation for minimal residual disease included flow cytometry and a highly sensitive clonotypic polymerase chain reaction (PCR). The median age was 59 years (range, 37 to 71 years), 61% of patients had high-risk disease, and 58% had unmutated IgV(H) genes.
  
  
  RESULTS
  There were 32 responses (89%), including 22 CRs (61%). Consolidation with cyclophosphamide improved responses in 13 patients (36%); nine patients (25%) further improved their response with rituximab. Twenty patients (56%) achieved flow cytometric CRs, and 12 patients (33%) achieved a molecular CR (PCR negative). Patients achieving molecular CRs had an excellent prognosis with a plateau in the response duration curve, and 90% remain in clinical CR at 5 years. For the entire group, 5-year survival rate is 71% compared with a rate of 48% with our prior F-->C regimen (P = .10).
  
  
  CONCLUSIONS
  Sequential therapy with F-->C-->R yields improvement in quality of response, with many patients achieving a PCR-negative state.
authors.affiliation: Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Lamanna
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Jurcic
authors.forename: Ariela
authors.initials: A
authors.lastname: Noy
authors.forename: Peter
authors.initials: P
authors.lastname: Maslak
authors.forename: Alison N
authors.initials: AN
authors.lastname: Gencarelli
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Panageas
authors.forename: Mark L
authors.initials: ML
authors.lastname: Heaney
authors.forename: Renier J
authors.initials: RJ
authors.lastname: Brentjens
authors.forename: David W
authors.initials: DW
authors.lastname: Golde
authors.forename: David A
authors.initials: DA
authors.lastname: Scheinberg
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Zelenetz
authors.forename: Mark A
authors.initials: MA
authors.lastname: Weiss
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents / Q000008:administration & dosage; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D003520:Cyclophosphamide / Q000008:administration & dosage; D004334:Drug Administration Schedule; D005260:Female; D005434:Flow Cytometry; D005500:Follow-Up Studies; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D012074:Remission Induction; D000069283:Rituximab; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D000069283:Rituximab; D003520:Cyclophosphamide; D014740:Vidarabine; C024352:fludarabine