title: A randomized phase II trial of fludarabine, cyclophosphamide and mitoxantrone (FCM) with or without rituximab in previously treated chronic lymphocytic leukaemia.
abstract: Combination fludarabine (F), cyclophosphamide (C) and rituximab (R) is the standard front-line therapy in chronic lymphocytic leukaemia (CLL), but appropriate treatment of relapsed/refractory CLL is less clear. Combined FC and mitoxantrone (M) has been reported to be effective in a single arm study, and rituximab when added to chemotherapy in CLL is synergistic. A randomized, two-stage, Phase II trial of FCM and FCM-R was conducted in relapsed CLL. The primary endpoint was response rate 2 months after therapy, assessed according to the 2008 International Workshop CLL criteria. In addition, minimal residual disease (MRD) in the marrow was studied 2 months after therapy, with MRD negativity defined as <0·01% CLL cells. Fifty-two patients were entered, 26 in each arm. The overall response rates to FCM and FCM-R were 58% and 65% respectively. Combined complete response (CR) and CR with incomplete marrow recovery [CR(i)] was 15% (95% confidence interval [CI]:4-35%) for FCM and 42% (95%CI:23-63%) for FCM-R, with eight patients achieving MRD negativity (3 FCM; 5 FCM-R). The toxicity of both regimens was acceptable. In conclusion, the addition of rituximab to FCM improves the response rates in relapsed CLL, resulting in more complete remissions and without additional safety concerns. Efficacy and safety should be fully tested in a randomized Phase III trial.
authors.affiliation: Department of Haematology, Leeds Teaching Hospitals NHS Trust, St. James’s University Hospital, Beckett Street, Leeds, UK. peter.hillmen@nhs.net
authors.forename: Peter
authors.initials: P
authors.lastname: Hillmen
authors.forename: Dena R
authors.initials: DR
authors.lastname: Cohen
authors.forename: Kim
authors.initials: K
authors.lastname: Cocks
authors.forename: Andrew
authors.initials: A
authors.lastname: Pettitt
authors.forename: Hazem A
authors.initials: HA
authors.lastname: Sayala
authors.forename: Andy C
authors.initials: AC
authors.lastname: Rawstron
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Kennedy
authors.forename: Christopher
authors.initials: C
authors.lastname: Fegan
authors.forename: Don W
authors.initials: DW
authors.lastname: Milligan
authors.forename: John
authors.initials: J
authors.lastname: Radford
authors.forename: Jane
authors.initials: J
authors.lastname: Mercieca
authors.forename: Claire
authors.initials: C
authors.lastname: Dearden
authors.forename: Raphael
authors.initials: R
authors.lastname: Ezekwisili
authors.forename: Alexandra F
authors.initials: AF
authors.lastname: Smith
authors.forename: Julia
authors.initials: J
authors.lastname: Brown
authors.forename: Gillian A
authors.initials: GA
authors.lastname: Booth
authors.forename: Abraham M
authors.initials: AM
authors.lastname: Varghese
authors.forename: Christopher
authors.initials: C
authors.lastname: Pocock
mesh_terms: D000328:Adult; D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone / Q000008:administration & dosage / Q000009:adverse effects; D018365:Neoplasm, Residual; D000069283:Rituximab; D016019:Survival Analysis; D016896:Treatment Outcome; D014740:Vidarabine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D000069283:Rituximab; D003520:Cyclophosphamide; D008942:Mitoxantrone; D014740:Vidarabine; C024352:fludarabine