title: Fludarabine and mitoxantrone followed by yttrium-90 ibritumomab tiuxetan in previously untreated patients with follicular non-Hodgkin lymphoma trial: a phase II non-randomised trial (FLUMIZ).
abstract: BACKGROUND
  Follicular lymphoma is the most common form of lymphoma in Europe and the USA. In this prospective, single-arm, open-labelled, multicentre non-randomised phase II trial (FLUMIZ [FLUdarabine, MItoxantrone, Zevalin] trial) we aimed to assess the efficacy and safety of fludarabine and mitoxantrone plus radioimmunotherapy in untreated patients with follicular non-Hodgkin lymphoma (NHL).
  
  
  METHODS
  Patients with stage III or IV untreated indolent follicular NHL were enrolled between June 1, 2004, and April 15, 2006, at 13 Italian institutions, and were treated with oral fludarabine (40 mg/m2 on days 1 to 3) and intravenous mitoxantrone (10 mg/m2 on day 1) every 28 days for six cycles. Patients who had at least a partial response (PR) with normal platelet counts (>100x10(9)/L) and granulocyte counts (1.5x10(9)/L), and bone-marrow infiltration less than 25% 4-6 weeks after completion of the sixth cycle of chemotherapy were deemed eligible for consolidation treatment 6-10 weeks after the sixth cycle with one course of yttrium-90 ((90)Y)-labelled ibritumomab tiuxetan (Zevalin), which consisted of an initial infusion of intravenous rituximab (250 mg/m2) on day 1 followed by a second 250 mg/m2 infusion on day 7, 8, or 9. The second infusion was followed by a weight-based dose of 90Y-ibritumomab tiuxetan, administered as a slow intravenous push over 10 min. Primary endpoints were complete response (CR) and haematological toxic effects and secondary endpoints were overall survival and progression-free survival. Responses were classified according to the International Workshop for Response Criteria for non-Hodgkin's lymphomas. Analysis was per protocol. This trial is registered as a European Standard Controlled Trial on the EudraCT website http://oss-sper-clin.agenziafarmaco.it, number 2004-002211-92.
  
  
  RESULTS
  61 patients were enrolled in the trial and received six cycles of fludarabine and mitoxantrone, after which an overall response was noted in 98% (60 of 61) of patients (43 of 61 patients had CR and 17 of 61 patients had PR). 57 patients (43 with CR and 14 with PR) were deemed eligible for subsequent (90)Y-ibritumomab tiuxetan. Of the 14 patients who had PR after the initial treatment, 12 obtained CR after (90)Y-ibritumomab tiuxetan. By the end of the entire treatment regimen 55 of 57 patients achieved CR. With a median follow-up of 30 months (range 21-48), 3-year progression-free survival was estimated to be 76% (95% CI 72.3-82.4) and 3-year overall survival 100%. 36 of 57 patients had grade 3 or 4 haematological toxic effects, and blood transfusions were given to 21 of 57 patients.
  
  
  CONCLUSIONS
  This trial has provided evidence for the feasibility, tolerability, and efficacy of fludarabine and mitoxantrone plus (90)Y-ibritumomab tiuxetan in untreated patients with follicular NHL.
authors.affiliation: Institute of Haematology and Medical Oncology L & A Seràgnoli, University of Bologna, Bologna, Italy. plzinzo@med.unibo.it
authors.forename: Pier Luigi
authors.initials: PL
authors.lastname: Zinzani
authors.forename: Monica
authors.initials: M
authors.lastname: Tani
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pulsoni
authors.forename: Marco
authors.initials: M
authors.lastname: Gobbi
authors.forename: Alessio
authors.initials: A
authors.lastname: Perotti
authors.forename: Stefano
authors.initials: S
authors.lastname: De Luca
authors.forename: Alberto
authors.initials: A
authors.lastname: Fabbri
authors.forename: Alfonso
authors.initials: A
authors.lastname: Zaccaria
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Voso
authors.forename: Pierpaolo
authors.initials: P
authors.lastname: Fattori
authors.forename: Luciano
authors.initials: L
authors.lastname: Guardigni
authors.forename: Sonia
authors.initials: S
authors.lastname: Ronconi
authors.forename: Maria Giuseppina
authors.initials: MG
authors.lastname: Cabras
authors.forename: Luigi
authors.initials: L
authors.lastname: Rigacci
authors.forename: Amalia
authors.initials: A
authors.lastname: De Renzo
authors.forename: Enrica
authors.initials: E
authors.lastname: Marchi
authors.forename: Vittorio
authors.initials: V
authors.lastname: Stefoni
authors.forename: Mariapaola
authors.initials: M
authors.lastname: Fina
authors.forename: Cinzia
authors.initials: C
authors.lastname: Pellegrini
authors.forename: Gerardo
authors.initials: G
authors.lastname: Musuraca
authors.forename: Enrico
authors.initials: E
authors.lastname: Derenzini
authors.forename: Stefano
authors.initials: S
authors.lastname: Pileri
authors.forename: Stefano
authors.initials: S
authors.lastname: Fanti
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Piccaluga
authors.forename: Michele
authors.initials: M
authors.lastname: Baccarani
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007558:Italy; D053208:Kaplan-Meier Estimate; D008224:Lymphoma, Follicular / Q000401:mortality* / Q000473:pathology / Q000628:therapy*; D008228:Lymphoma, Non-Hodgkin / Q000401:mortality / Q000473:pathology / Q000628:therapy; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D008942:Mitoxantrone / Q000008:administration & dosage / Q000009:adverse effects; D009367:Neoplasm Staging; D011336:Probability; D016499:Radioimmunotherapy / Q000379:methods*; D018570:Risk Assessment; D016019:Survival Analysis; D014740:Vidarabine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D015021:Yttrium Radioisotopes
chemical_list: D000911:Antibodies, Monoclonal; D015021:Yttrium Radioisotopes; C422802:ibritumomab tiuxetan; D008942:Mitoxantrone; D014740:Vidarabine; C024352:fludarabine