Elsevier

The Lancet Oncology

Volume 17, Issue 1, January 2016, Pages 57-66
The Lancet Oncology

Articles
Bendamustine plus rituximab versus fludarabine plus rituximab for patients with relapsed indolent and mantle-cell lymphomas: a multicentre, randomised, open-label, non-inferiority phase 3 trial

https://doi.org/10.1016/S1470-2045(15)00447-7Get rights and content

Summary

Background

Fludarabine-based chemoimmunotherapy with rituximab is frequently used in patients with indolent and mantle-cell lymphomas who relapse after alkylating chemotherapy. We aimed to compare the efficacy and safety of rituximab with bendamustine or fludarabine in patients with relapsed, indolent, non-Hodgkin lymphoma and mantle-cell lymphoma.

Methods

For this randomised, non-inferiority, open-label, phase 3 trial, we recruited patients from 55 centres in Germany, who were subsequently randomised centrally according to prespecified randomisation lists with permuted blocks of randomly variable block size to rituximab (375 mg/m2, day 1) plus either bendamustine (90 mg/m2, days 1 and 2) or fludarabine (25 mg/m2, days 1–3) every 28 days for a maximum of six 28-day cycles. Patients were aged 18 years or older with a WHO performance status of 0–2 and had relapsed or refractory indolent or mantle-cell lymphoma; patients refractory to regimens that included rituximab, bendamustine, or purine analogue drugs were excluded. Patients were stratified by histological subtypes of lymphoma and by their latest previous therapies. Treatment allocation was not masked. The primary endpoint was progression-free survival and the final analysis was completed per protocol. Non-inferiority of bendamustine plus rituximab versus fludarabine plus rituximab was defined as a difference of less than 15% in 1-year progression-free survival. The protocol was amended in July, 2006, after approval of rituximab maintenance (375 mg/m2 every 3 months for up to 2 years), which was then given to patients achieving a response to either trial treatment. This study is registered with ClinicalTrials.gov, number NCT01456351 (closed to enrolment, follow-up is ongoing).

Findings

Between Oct 8, 2003, and Aug 5, 2010, we randomly assigned 230 patients to treatment groups (116 bendamustine plus rituximab, 114 fludarabine plus rituximab). 11 patients were excluded for protocol violations and were not followed up further (two in the bendamustine plus rituximab group and nine in the fludarabine plus rituximab group). Thus, 219 patients were included in the per-protocol analysis (114 bendamustine plus rituximab, 105 fludarabine plus rituximab). 1-year progression-free survival with bendamustine plus rituximab was 0·76 (95% CI 0·68–0·84) and 0·48 (0·39–0·58) with fludarabine plus rituximab (non-inferiority p<0·0001). At a median follow-up of 96 months (IQR 73·2–112·9), median progression-free survival with bendamustine plus rituximab was 34·2 months (95% CI 23·5–52·7) and 11·7 months (8·0–16·1) with fludarabine plus rituximab (hazard ratio [HR] 0·54 [95% CI 0·38–0·72], log-rank test p<0·0001). Safety outcomes were similar in both groups, with 46 serious adverse events recorded (23 in the bendamustine plus rituximab group and 23 in the fludarabine plus rituximab group), most commonly myelosuppression and infections.

Interpretation

In combination with rituximab, bendamustine was more effective than fludarabine, suggesting that bendamustine plus rituximab may be the preferred treatment option for patients with relapsed indolent and mantle-cell lymphomas.

Funding

Roche Pharma AG, Ribosepharm GmbH, Mundipharma GmbH, Studiengruppe indolente Lymphome (StiL).

Introduction

Non-Hodgkin lymphoma is among the most common cancers in the USA and Europe, with more than 70 000 and 93 000 new cases diagnosed every year, respectively.1 Indolent lymphomas represent 40% of all non-Hodgkin lymphoma subtypes, with follicular lymphoma being the most frequent.2 Characterised by a chronic relapsing and remitting disease course, patients with indolent lymphomas are often exposed to many and successive treatment regimens, eventually dying as a result of the disease. Mantle-cell lymphoma, which accounts for about 3–10% of all non-Hodgkin lymphomas, has a much more unfavourable disease course in terms of time to relapse and long-term survival.

The most common chemotherapies containing alkylators used in the front-line treatment of indolent non-Hodgkin lymphoma and mantle-cell lymphoma include CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) and CVP (cyclophosphamide, vincristine, and prednisone). In the relapsed setting, no prospective randomised trials have compared the efficacy of various chemoimmunotherapies; therefore, no standard treatment is recommended for patients relapsing after alkylating chemotherapy. At the initiation of our study, guidelines such as those from the National Comprehensive Cancer Network suggested various treatment options in patients with relapsed disease with no order of preference. The most common of these second-line treatments were fludarabine-based regimens combined with rituximab.

Research in context

Evidence before this study

So far, no randomised trials have compared the efficacy of one chemoimmunotherapy with another in patients with relapsed indolent and mantle-cell lymphoma. Treatment decisions for these patients are therefore challenging. Given that patients are typically elderly with comorbidities, effective treatment options that are well tolerated are needed for these patients. The combination of bendamustine and rituximab has been effective and well tolerated in previous phase 2 studies in patients relapsing after alkylator-containing chemotherapy.

Added value of this study

In this randomised, multicentre, phase 3 trial, progression-free survival for patients with relapsed indolent non-Hodgkin lymphoma and mantle-cell lymphoma who received bendamustine plus rituximab was non-inferior to—and indeed superior to—that with fludarabine plus rituximab. Overall survival was also longer with bendamustine plus rituximab than with fludarabine plus rituximab. No differences were reported in safety outcomes between treatment groups. A subset of patients receiving rituximab maintenance had longer overall survival than patients not receiving rituximab maintenance. Our study is the first to show a survival benefit of one chemoimmunotherapy compared with another, and suggests that the use of rituximab maintenance potentially further improves outcomes in patients who relapsed.

Implications of all the available evidence

Results of our study suggest that preference be given to bendamustine plus rituximab over fludarabine plus rituximab for treatment of relapsed indolent and mantle-cell lymphomas, as shown by the significant improvement in progression-free and overall survival. The combination of bendamustine and rituximab is effective and well tolerated and should be regarded as a key treatment option for these patients. Results of ongoing studies combining bendamustine plus rituximab as a backbone therapy with newer drugs—such as inhibitors of BTK (eg, ibrutinib), PI3K (eg, idelalisib), and Bcl-2 (eg, venetoclax)—will help to establish the role of novel combinations in this setting.

Given that patients who relapse are typically older with comorbidities, tolerable treatments that provide durable remission and prolonged survival are needed. A phase 2 study by Czuczmann and colleagues3 in treatment-naive and relapsed indolent non-Hodgkin lymphoma found that the combination of fludarabine and rituximab was well tolerated, with an overall response of 90% and complete response of 80%.3 The authors recommended that when combined with rituximab, fludarabine should be given at a dose of 25 mg/m2 over 3 consecutive days. Additionally, this combination was concluded to be a reasonable comparator for randomised studies examining new chemoimmunotherapies in indolent non-Hodgkin lymphoma.

As a cytotoxic alkylating agent, bendamustine has limited cross-resistance with other alkylators, remaining active in patients previously extensively treated with chemotherapy.4, 5 In a phase 2 study of rituximab plus bendamustine in relapsed or refractory indolent non-Hodgkin lymphoma and mantle-cell lymphoma, we previously reported an overall response of 90% and median progression-free survival of 24 months.6 These results were later supported by a phase 2 study by Robinson and colleagues,7 in which bendamustine plus rituximab achieved an overall response of 92% and median progression-free survival of 23 months in a comparable patient population. On the basis of these encouraging phase 2 study results, we initiated two randomised phase 3 trials that compared bendamustine plus rituximab with established chemoimmunotherapy regimens (StiL NHL [study group indolent lymphomas non-Hodgkin lymphoma] 1–2003 and StiL NHL 2–2003). One of these trials (StiL NHL 1–2003), published in 2013, reported longer progression-free survival with bendamustine plus rituximab (median 69·5 months) versus rituximab plus CHOP (R-CHOP; median 31·2 months; p<0·0001) in previously untreated indolent non-Hodgkin lymphoma and mantle-cell lymphoma.8 In this study (Stil NHL 2–2003) we aimed to compare the efficacy and safety of bendamustine or fludarabine in combination with rituximab in patients with relapsed, indolent, non-Hodgkin lymphoma and mantle-cell lymphoma.

Section snippets

Study design and participants

We did a randomised, controlled phase 3 trial with patients with relapsed indolent or mantle-cell lymphoma in 55 centres (university hospitals, general hospitals, and private practices) in Germany. The study is compliant with the Declaration of Helsinki, and was done in accordance with Good Clinical Practice guidelines. The protocol was approved by local ethics committee and institutional review boards in every participating centre. The study protocol is available online.

The trial included

Results

Patients were recruited between Oct 8, 2003, and Aug 5, 2010. 230 patients were enrolled and randomly assigned to receive bendamustine and rituximab (n=116) or fludarabine and rituximab (n=114). 11 were not eligible for analysis due to having other histology of a different type of lymphoma or leukaemia (five patients), absence of data (lost during follow-up, one patient), withdrawn informed consent (one patient), not receiving any chemotherapy (one patient), and not receiving assigned treatment

Discussion

We showed that progression-free survival for patients with relapsed, indolent, non-Hodgkin lymphoma and mantle-cell lymphoma who were treated with bendamustine plus rituximab was non-inferior—and indeed superior to—that for those treated with fludarabine plus rituximab, and no differences were reported in safety outcomes between treatment groups. Overall survival was also better with bendamustine plus rituximab than with fludarabine plus rituximab. At the time of the design and development of

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The StiL study investigators are listed in the appendix

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