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)

doi:10.1016/S1470-2045(08)70039-1

The Lancet Oncology

Volume 9, Issue 4, April 2008, Pages 352-358

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https://doi.org/10.1016/S1470-2045(08)70039-1 Get rights and content

Summary

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 (>100×10⁹/L) and granulocyte counts (1·5×10⁹/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 (⁹⁰Y)-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.

Findings

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 ⁹⁰Y-ibritumomab tiuxetan. Of the 14 patients who had PR after the initial treatment, 12 obtained CR after ⁹⁰Y-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.

Interpretation

This trial has provided evidence for the feasibility, tolerability, and efficacy of fludarabine and mitoxantrone plus ⁹⁰Y-ibritumomab tiuxetan in untreated patients with follicular NHL.

Funding

Italian Association for Leukaemias, Lymphomas, and Myeloma, Bologna, Italy.

Introduction

Follicular lymphoma accounts for around 30% of all newly diagnosed non-Hodgkin lymphomas (NHL), and is the most common form of lymphoma in the USA and Europe.¹ The Follicular Lymphoma International Prognostic Index (FLIPI) is an accurate, simple, validated prognostic index that uses clinical parameters for patients with follicular lymphoma.² Several trials clearly show that the combination of a chemotherapy regimen (ie, cyclophosphamide, vincristine, and prednisolone [CVP]; cyclophosphamide, doxorubicin, vincristine, and prednisolone [CHOP]; or fludarabine-containing regimens) with rituximab, significantly increases progression-free survival compared with the same chemotherapy regimen alone for follicular lymphoma.3, 4, 5, 6 However, no consensus exists on the optimum chemotherapy regimen to be combined with rituximab.

Radioimmunotherapy is an important treatment option for patients with B-cell NHL. Yttrium-90 (⁹⁰Y)-ibritumomab is a murine monoclonal immunoglobulin G1 kappa antibody to CD20, a surface antigen that is expressed on 90% of B-cell lymphomas,⁷ and is conjugated to the metal chelator tiuxetan for retention of the beta emitter ⁹⁰Y when used as a treatment. Thus, B-cell lymphomas, which are inherently sensitive to radiation, are specifically targeted by ⁹⁰Y-ibritumomab tiuxetan.⁸

In an initial phase I/II trial of ⁹⁰Y-ibritumomab tiuxetan, responses were seen in 28 of 34 patients with pretreated indolent NHL, including complete remissions in nine patients.⁹ In a randomised controlled phase III trial,¹⁰ Witzig and colleagues compared ⁹⁰Y-ibritumomab tiuxetan with a standard dose of rituximab in relapsed or refractory indolent follicular NHL, and showed that the overall response rate and complete remission were significantly higher with ⁹⁰Y-ibritumomab tiuxetan than with rituximab. Data from other studies also confirm the safety and efficacy of ⁹⁰Y-ibritumomab tiuxetan in pretreated patients with follicular NHL.11, 12

On the basis of these data, radioimmunotherapy with iodine-131 (¹³¹I)-tositumomab has been studied as a consolidation treatment after treatment with chemotherapy in patients with follicular NHL.13, 14 Initial reports from these studies have shown acceptable toxic effects with promising antilymphoma activity, and randomised studies are in progress for indolent follicular NHL. We recently reported a phase II study on the role of fludarabine and mitoxantrone chemotherapy followed by ⁹⁰Y-ibritumomab tiuxetan in patients with previously untreated indolent non-follicular NHL;¹⁵ all patients who completed the sequential treatment (chemotherapy plus radioimmunotherapy) achieved a complete response.

In view of these findings, we decided to investigate the efficacy and safety of combining induction chemotherapy in the form of fludarabine (oral formulation) and intravenous mitoxantrone with ⁹⁰Y-ibritumomab tiuxetan as consolidation treatment in a phase II trial for patients with previously untreated follicular NHL.

Section snippets

Patients

Patients aged 18 years or older with biopsy-proven, bidimensionally measurable, stage III or IV untreated indolent follicular NHL that expressed the CD20 antigen were deemed eligible for this trial, which was done at 13 Italian cooperative institutions, if they had a WHO performance status of 0 to 2.

All diagnostic biopsies were reviewed by an expert pathologist (SP) to ensure that diagnoses of follicular lymphoma grade I–II were in accordance with the WHO classification.¹⁶ All patients had

Results

61 patients (25 men and 36 women) were included in the trial in 13 Italian cooperative institutions between June 1, 2004, and April 15, 2006, when the study reached completion and was closed. Patient characteristics are shown in table 1. Median age was 54 years (range 30–72) and the median time from diagnosis to study entry was 3 months (range 1–5). 23 patients had stage III disease and 38 had stage IV disease (31 patients had bone-marrow involvement). 15 patients had bulky disease (≥10 cm).

Discussion

This study has established the feasibility, tolerability, and efficacy of sequential treatment with six cycles of fludarabine and mitoxantrone chemotherapy followed by ⁹⁰Y-ibritumomab tiuxetan as a front-line treatment for untreated patients with follicular NHL. In particular, the data represent the first evidence of a role of ⁹⁰Y-ibritumomab tiuxetan after a fludarabine-containing regimen in the treatment of follicular NHL. These data confirm the recently reported preliminary findings of the

References (29)

P Solal-Celigny et al.
Follicular lymphoma international prognostic index
Blood
(2004)
R Marcus et al.
CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma
Blood
(2005)
KC Anderson et al.
Expression of human B cell-associated antigens on leukemias and lymphomas: a model of human B cell differentiation
Blood
(1984)
GW Wiseman et al.
Ibritumomab tiuxetan radioimmunotherapy for patients with relapsed or refractory non-Hodgkin's lymphoma and mild thrombocytopenia: a phase II multicenter trial
Blood
(2002)
W Hiddemann et al.
Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group
Blood
(2005)
R Buckstein et al.
What is remission in follicular lymphoma and what is its relevance?
Best Pract Res Clin Haematol
(2005)
PL Zinzani et al.
Fludarabine: an active agent in the treatment of previously-treated and untreated low-grade non-Hodgkin's lymphoma
Ann Oncol
(1993)
PL Zinzani et al.
Fludarabine-mitoxantrone combination-containing regimen in recurrent low-grade non-Hodgkin's lymphoma
Ann Oncol
(1997)
A Rambaldi et al.
Monitoring of minimal residual disease after CHOP and rituximab in previously untreated patients with follicular lymphoma
Blood
(2002)
SJ Horning et al.
The natural history of initially untreated low-grade non-Hodgkin's lymphomas
N Engl J Med
(1984)

MS Czuczman et al.

Prolonged clinical and molecular remission in patients with low-grade or follicular non-Hodgkin's lymphoma treated with rituximab plus CHOP chemotherapy: 9-year follow-up

J Clin Oncol

(2004)

PL Zinzani et al.

Fludarabine plus mitoxantrone with and without rituximab versus CHOP with and without rituximab as front-line treatment for patients with follicular lymphoma

J Clin Oncol

(2004)

SJ Horning et al.

The natural history of initially untreated low-grade non-Hodgkin's lymphomas

N Engl J Med

(2004)

OW Press

Radiolabeled antibody therapy of B-cell lymphomas

Semin Oncol

(1999)

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Histologic transformation (HT) of indolent non-Hodgkin lymphomas is an event that results in considerable morbidity and mortality. The introduction of chemoimmunotherapy regimens has resulted in an improvement in the management of this disease, and consolidation of responses with autologous stem cell transplantation appears efficacious. Many patients are not eligible for high-dose therapy, however. Radioimmunotherapy (RIT) has demonstrated single-agent efficacy in HT and can be used safely as consolidation after chemoimmunotherapy. For these reasons, RIT consolidation after chemoimmunotherapy induction has been our standard treatment approach at the University of Rochester for patients with HT who were ineligible for autologous stem cell transplantation.
A retrospective cohort study was performed to describe the clinical outcomes of these patients. Twenty-one patients were identified who received RIT consolidation. The Kaplan-Meier method was used to estimate the distributions of overall survival and progression-free survival. Comparisons were made between patients with pathologic HT and the combination of clinical HT and composite lymphoma using the log-rank test to compare survival curves.
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Comparing the cost-effectiveness of rituximab maintenance and radioimmunotherapy consolidation versus observation following first-line therapy in patients with follicular lymphoma
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To evaluate and compare the economic impact of MR and RIT consolidation versus observation, respectively, following the first-line induction therapy for patients with advanced-stage FL.
We developed Markov models to estimate patients’ lifetime costs, quality-adjusted life-years (QALYs), and life-years (LYs) after MR, RIT, and observation following frontline FL treatment from the US payer’s perspective. Progression risks, adverse event probabilities, costs, and utilities were estimated from clinical data of Primary RItuximab and MAintenance (PRIMA) trial, Eastern Cooperative Oncology Group (ECOG) trial (for MR), and First-line Indolent Trial (for RIT) and the published literature. We evaluated the incremental cost-effectiveness ratio for direct comparisons between MR/RIT and observation. Model robustness was addressed by one-way and probabilistic sensitivity analyses.
Compared with observation, MR provided an additional 1.089 QALYs (1.099 LYs) and 1.399 QALYs (1.391 LYs) on the basis of the PRIMA trial and the ECOG trial, respectively, and RIT provided an additional 1.026 QALYs (1.034 LYs). The incremental cost per QALY gained was $40,335 (PRIMA) or $37,412 (ECOG) for MR and $40,851 for RIT. MR and RIT had comparable incremental QALYs before first progression, whereas RIT had higher incremental costs of adverse events due to higher incidences of cytopenias.
MR and RIT following frontline FL therapy demonstrated favorable and similar cost-effectiveness profiles. The model results should be interpreted within the specific clinical settings of each trial. Selection of MR, RIT, or observation should be based on patient characteristics and expected trade-offs for these alternatives.
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Citation Excerpt :
The results of RIT with yttrium-90 ibritumomab tiuxetan in the setting of first-line therapy consolidation are also very promising, demonstrating a significant progression-free survival advantage over observation [18]. Also, several phase II trials confirmed the feasibility and efficacy of RIT as consolidation treatment after first-line therapy [19-22]. On the other hand, autologous stem cell transplantation (ASCT) is a suitable option for relapsed FL patients [23-25].
Major concerns about radioimmunotherapy (RIT) administration early in the course of follicular lymphoma (FL) are long-term toxicity and the theoretical impairment of hematopoietic stem cell (HSC) harvest, but few data are available about mobilization rates after RIT. This study evaluates the impact of prior therapy with RIT (yttrium-90 ibritumomab tiuxetan) and different chemotherapy regimens in all FL patients (N = 103) attempting HSC mobilization at our institution over the last 7 years. Sixty-nine patients received R-CHOP (rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone) or CHOP-like regimens, 21 patients received R-FM (rituximab-fludarabine-mitoxantrone), and 13 patients received RIT before HSC mobilization. Median CD34+ cell yield at first mobilization was 7.2 × 10⁶/kg in the R-CHOP group versus 4.3 in the R-FM group versus 1.7 in the RIT group (P = .02 R-CHOP versus R-FM; P < .0001 R-CHOP versus RIT; P < .02 R-FM versus RIT). Although 8 of 13 patients initially failed to collect enough HSC after RIT, a second and/or salvage harvest was successfully performed in 7 patients, with 10 of 13 patients (77%) finally undergoing autologous stem cell transplantation (ASCT). No differences in engraftment kinetics were observed between the three groups (R-CHOP versus R-FM versus RIT). Although mobilization was significantly impaired in patients previously treated with RIT, a salvage HSC harvest and ASCT after RIT were safe and feasible in most patients.

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Fast track — ArticlesFludarabine 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)

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Patients

Results

Discussion

Blood

Blood

Blood

Blood

Blood

Best Pract Res Clin Haematol

Ann Oncol

Ann Oncol

Blood

The natural history of initially untreated low-grade non-Hodgkin's lymphomas

N Engl J Med

Prolonged clinical and molecular remission in patients with low-grade or follicular non-Hodgkin's lymphoma treated with rituximab plus CHOP chemotherapy: 9-year follow-up

J Clin Oncol

Fludarabine plus mitoxantrone with and without rituximab versus CHOP with and without rituximab as front-line treatment for patients with follicular lymphoma

J Clin Oncol

The natural history of initially untreated low-grade non-Hodgkin's lymphomas

N Engl J Med

Radiolabeled antibody therapy of B-cell lymphomas

Semin Oncol

Fast track — Articles
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)