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).
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.
Zinzani
Pier Luigi
PL
Institute of Haematology and Medical Oncology L & A Seràgnoli, University of Bologna, Bologna, Italy. plzinzo@med.unibo.it
Tani
Monica
M
Pulsoni
Alessandro
A
Gobbi
Marco
M
Perotti
Alessio
A
De Luca
Stefano
S
Fabbri
Alberto
A
Zaccaria
Alfonso
A
Voso
Maria Teresa
MT
Fattori
Pierpaolo
P
Guardigni
Luciano
L
Ronconi
Sonia
S
Cabras
Maria Giuseppina
MG
Rigacci
Luigi
L
De Renzo
Amalia
A
Marchi
Enrica
E
Stefoni
Vittorio
V
Fina
Mariapaola
M
Pellegrini
Cinzia
C
Musuraca
Gerardo
G
Derenzini
Enrico
E
Pileri
Stefano
S
Fanti
Stefano
S
Piccaluga
Pier Paolo
PP
Baccarani
Michele
M
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
D000911:Antibodies, Monoclonal; D015021:Yttrium Radioisotopes; C422802:ibritumomab tiuxetan; D008942:Mitoxantrone; D014740:Vidarabine; C024352:fludarabine