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
Mathias Rummel, Ulrich Kaiser, Christina Balser, Martina Stauch, Wolfram Brugger, Manfred Welslau, Norbert Niederle, Christoph Losem, Hans-Peter Boeck, Eckhart Weidmann, Ulrich von Gruenhagen, Lothar Mueller, Michael Sandherr, Lars Hahn, Julia Vereshchagina, Frank Kauff, Wolfgang Blau, Axel Hinke, Juergen Barth, for the Study group indolent Lymphomas (StiL)*
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).
Lancet Oncol 2015 Published Online December 4, 2015 http://dx.doi.org/10.1016/
S1470-2045(15)00447-7 See Online/Comment http://dx.doi.org/10.1016/
S1470-2045(15)00517-3
*The StiL study investigators are listed in the appendix Department of Haematology and Oncology, Justus-Liebig Universität, Giessen, Germany (Prof M Rummel MD,
J Vereshchagina MD, F Kauff PhD, W Blau MD, J Barth Pharmacist); Innere Medizin II, St Bernward Krankenhaus, Hildesheim, Germany (Prof U Kaiser MD); Medical Office Haematology and Oncology, Marburg
(C Balser MD), Kronach
(M Stauch MD), Aschaffenburg (M Welslau MD), Neuss
(C Losem MD),Offenbach (H-P Boeck MD), Cottbus (U von Gruenhagen MD),
Weilheim (M Sandherr MD), and Herne (L Hahn MD), Germany; Schwarzwald-Baar Klinikum, Akad, Lehrkrankenhaus der University Freiburg, Villingen- Schwenningen, Germany
(Prof W Brugger MD); Klinikum Leverkusen, Leverkusen, Germany (Prof N Niederle MD); Department of Hematology and Oncology, Krankenhaus Nordwest, Frankfurt, Germany (Prof E Weidmann MD); Onkologie UnterEms, Leer, Germany (L Mueller MD); and Wissenschaftlicher Service Pharma (WISP) Research Institute, Langenfeld, Germany
Introduction
Non-Hodgkin lymphoma is among the most common cancers in the USA and Europe, with more than 70 000
1
Indolent lymphomas represent 40% of all non-Hodgkin lymphoma subtypes, with follicular lymphoma being the
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
(A Hinke PhD) Correspondence to: Prof Mathias Rummel,
Medizinische Klinik IV, University Hospital, 35392 Giessen, Germany [email protected]. uni-giessen.de
See Online for appendix
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.
For the National
Comprehensive Cancer Network’s guidelines see www.
nccn.org
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.
Given that patients who relapse are typically older with comorbidities, tolerable treatments that provide durable remission and prolonged survival are needed. A
3 in treatment-naive and relapsed indolent non-Hodgkin lymphoma found that the combination of fludarabine and rituximab was well tolerated, with an overall response
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
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
6These results were later supported by a phase 2 study by Robinson and
7in 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
8In 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.
Methods
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 patients with relapsed or refractory disease; patients refractory to regimens that included rituximab, bendamustine, or purine analogue drugs were excluded. Patients were included in the study if they were aged 18 years or older with a WHO performance status of 0–2 and with one of the following CD20-positive lymphoma entities confirmed by a histology report (not older than 6 months): follicular lymphoma (grade 1 and 2), lymphoplasmacytic lymphoma (Waldenström’s macroglobulinaemia), small lymphocytic lymphoma, nodular and generalised marginal zone lymphoma, or mantle-cell lymphoma. Patients had to have stage II (with bulky disease >7·5 cm), III, or IV disease. Patients with comorbidities such as severe disorders of the heart, lung, liver, or kidneys, severe hypertension, or diabetes, active autoimmune diseases, and active infections (eg, hepatitis) in need of antibiotics were excluded. HIV-positive patients, patients with severe psychiatric diseases, anamnestic malignancies, or secondary malignancies, and breast-feeding or pregnant women were excluded. Potentially curable patients or patients in whom non- compliance could be expected were also not included. Except for those with mantle-cell lymphoma, patients were included only if they had a defined indication for treatment, including B symptoms, haemopoietic failure (haemoglobin <110 g/L, granulocytes <1500 per μL, and thrombocytes <100 000 cells per μL), large tumour burden (three areas >5 cm or one area >7·5 cm), rapid progression (increase of tumour mass >50% in 6 months), and complications due to disease (eg, pain, infarction of
Treatment consisted of rituximab (375 mg/m² on day 1) plus either bendamustine (90 mg/m² on days 1 and 2, administered as a 30-min infusion) or fludarabine (25 mg/m² on days 1–3) every 4 weeks (one cycle) for a maximum of six cycles. Prophylactic use of antibiotics or granulocyte-colony stimulating factor (G-CSF) was not generally recommended except in cases of severe granulocytopenia. In case of therapy-induced myelo- suppression, dose modification was done progressively in three stages: stage 1, reduction of bendamustine to 70 mg/m² on days 1 and 2 and fludarabine to 20 mg/m² on days 1–3; stage 2, reduction of bendamustine to 60 mg/m² on days 1 and 2 and fludarabine to 25 mg/m² on days 1 and 2; and stage 3, reduction of bendamustine to 50 mg/m² on days 1 and 2, and fludarabine to 20 mg/m² on days 1 and 2.
Restaging of patients’ disease was done by use of clinical assessment and CT imaging after three treatment cycles. In case of response, treatment was continued for a maximum of six cycles. If a complete response with a confirmatory bone marrow biopsy occurred before the end of the sixth cycle, two consolidative cycles could be administered for a maximum of six cycles. Duration of remission, or progression-free survival, was assessed by clinical assessment every 3 months, and by CT scan and sonographic examination every 6 months until relapse.
During the study, rituximab maintenance treatment was approved for patients with relapsed follicular lymphoma. We therefore needed to amend the protocol in 2006 (3 years into the study) to allow administration of
For the StiL trial protocol see http://www.stil-info.de/index. php?id=257 (in German)
spleen, or hyperviscosity syndrome). All patients provided written informed consent.
Randomisation and masking
Patients were randomised centrally (1:1), under concealment, by the StiL at the head office (Giessen,
Germany; by Wissenschaftlicher Service Pharma GmbH), according to prespecified randomisation lists with permuted blocks of randomly variable block size to receive rituximab in combination with either bendamustine or fludarabine. Patients were stratified by histological subtypes of lymphoma and by the latest previous therapies they had received. Patients, physicians, and individuals assessing outcomes and analysing data were not masked to treatment allocation. All data were recorded at the StiL head office.
Procedures
Patient evaluations included physical examination, complete blood count, serum chemistry, serum immunoelectrophoresis, immunoglobulin concentrations, chest radiograph, CT scan of the chest and abdomen,
sonography of the abdomen, bone marrow aspiration, and biopsy. Evaluations were completed locally at participating centres and were not centrally reviewed.
Figure 1: Trial profile
*Assessment for inclusion completed by referring doctors in participating centres, no data available for patients initially assessed. †Absence of indolent lymphoma according to reference histology or transformation.
Bendamustine plus rituximab (n=114)
Fludarabine plus rituximab (n=105)
treatment received, an alternative treatment was given, and withdrawal of informed consent.
Age
Median (years) 68·5 (59·0–74·0) 66·4 (59·3–73·7)
Patients aged >70 years 43 (38%) 37 (35%)
Cancer stage
III 25 (22%) 25 (24%)
IV 80 (70%) 62 (59%)
Histology
Follicular lymphoma 58 (51%) 53 (50%)
Mantle-cell lymphoma 24 (21%) 23 (22%)
Waldenström’s macroglobulinaemia 13 (11%) 11 (10%)
Marginal zone lymphoma 10 (9%) 8 (8%)
Lymphocytic lymphoma 8 (7%) 9 (9%)
Low grade, unclassifiable 1 (1%) 1 (1%)
B symptoms 28 (25%) 30 (29%)
Bone marrow involved 60 (53%) 51 (49%)
LDH >240 μ/L 39 (34%) 42 (40%)
Bulky disease 23 (20%) 25 (24%)
Prognostic groups for all patients (IPI >2) 38 (33%) 35 (33%) Prognostic groups for patients with follicular lymphoma*
Low risk FLIPI (0–1 risk factor) 10 (17%) 15 (28%)
Intermediate risk FLIPI (2 risk factors) 21 (36%) 14 (26%)
Poor risk FLIPI (3–5 risk factors) 25 (43%) 21 (40%)
Patients refractory to previous treatment 4 (4%) 5 (5%)
Number of previous treatments
Median 1 (1–2) 1 (1–2)
1 75 (66%) 54 (51%)
2 23 (20%) 34 (32%)
>2 16 (14%) 17 (16%)
Previous treatment
Bendamustine 13 (11%) 14 (13%)
Fludarabine or cladribine 10 (9%) 10 (10%)
CHOP 61 (54%) 54 (51%)
Chlorambucil or CVP 15 (13%) 10 (10%)
MCP 7 (6%) 8 (8%)
APBSCT 4 (4%) 4 (4%)
Other 4 (4%) 5 (5%)
Previous rituximab treatment (%)
Yes 44 (39%) 47 (45%)
No 70 (61%) 58 (55%)
Data are median (IQR) or n (%). LDH=lactate dehydrogenase. IPI=International Prognostic Index. CHOP=cyclophosphamide, doxorubicin, vincristine, and prednisone. CVP=cyclophosphamide, vincristine, and prednisone. MCP=mitoxantrone, chlorambucil, and prednisone. APBSCT=high-dose therapy with autologous peripheral blood stem cell transplantation. FLIPI=follicular lymphoma IPI. *Of 58 patients in bendamustine plus rituximab group and of 53 patients in fludarabine plus rituximab.
Table 1: Baseline characteristics of per-protocol population
Outcomes
The primary endpoint was progression-free survival for the per-protocol population, defined as the time between first treatment and one of the following events: progressive disease, relapse after response, or death from any cause. Secondary endpoints were overall response, complete response, overall survival, acute toxic effects, and late toxic effects of treatment. Evaluation of remission
9which was the standard assessment method at the time of the protocol development in 2002.
Statistical analysis
Analysis of progression-free survival, overall response, and overall survival was done in the per-protocol population. Non-inferiority of bendamustine plus rituximab versus fludarabine plus rituximab was defined as a difference of less than 15% in progression-free survival after 1 year (α=5%, β=20%). On the basis of the assumption that fludarabine plus rituximab treatment would result in a progression-free survival of 55% after 1 year, a sample size of two groups of 78 patients (156 patients in total) was planned to exclude a 15% lower progression-free survival with the bendamustine plus rituximab regimen after 1 year. Taking into consideration a drop-out rate of 10% in 3 years and assuming exponential survival curves, 86 patients were needed in each group. In the course of the protocol amendment, the sample size was increased to a total of 240 patients to obtain adequate numbers for the comparison of subgroups with or without maintenance therapy. The trial was originally planned as a non- inferiority trial. After formally accepting the non-inferiority hypothesis, based on the confidence interval of the hazard ratio (HR) for the primary endpoint, we did a post-hoc analysis of superiority of the experimental group, again using the limits of the confidence interval (95%) and comparing these to an HR of 1·0. The post-hoc superiority analysis was supplemented with a two-sided p value from the corresponding log-rank test. This approach is in agreement with the recommendations issued by the US
10and European Medicines
11guidelines. HRs were obtained from Cox models. Covariates included in the prognostic analyses were: age, sex, histology, number of previous treatment regimens, previous treatment with rituximab, International
12bone marrow involvement,
lactate dehydrogenase (LDH), and B symptoms.
rituximab maintenance therapy (375 mg/m² rituximab alone once every 3 months for up to 2 years) for patients who responded to rituximab in combination with either bendamustine or fludarabine.
Patients were excluded from the per-protocol analysis in case of major protocol violations which were defined as: histology other than specified by the protocol, no
Survival curves were estimated by the Kaplan-Meier method, the log-rank test was applied for comparisons, and the Cox proportional hazards model with a stepwise backward variable selection approach (p<0·1) was used for multivariate analysis and to calculate HRs with confidence intervals. The proportional hazard assumption was checked by tests of non-zero slope in a generalised
linear regression of the scaled Schoenfeld residuals on time. Toxic effects were compared with Fisher’s exact or the χ² test. Except for the primary endpoint, all statistical tests including subgroup and interaction analyses were exploratory and not prospectively defined, and no adjustments for multiplicity were applied.
All tests were two-sided, and a p value of less than 0·05 was deemed significant. Calculations were done with SPlus (version 6.2), Testimate (version 6.5), and Microsoft Excel 2010.
This study is registered with ClinicalTrials.gov (NCT01456351) and in the database of the Federal Institute for Drugs and Medical Devices of Germany
100
80
60
40
20
0
(BfArM4021337). 0 12 24 36 48 60 72 84 96 108 120
Role of the funding source
The funders of the study had no role in study design,
Number at risk B-R F-R
114
105
87
49
65
36
48
26
43
21
Time (months) 35
15
29
10
22
7
13
5
8
4
2
0
data collection, data analysis, data interpretation, or writing of the report. The study idea was generated by the corresponding author; the study was designed by the steering committee of the StiL. The StiL Head Office (Giessen, Germany) gathered the data. Statistical analysis was done by AH and the corresponding author. The authors attest to the completeness and validity of the data presented, and approved the final version of the manuscript. The corresponding author, JB, and FK had full access to all the data in the study and had final responsibility for the decision to submit for publication.
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 (one patient; figure 1). These patients were excluded from analysis per protocol, and were not followed up. 219 patients (114 receiving bendamustine plus rituximab and 105 receiving fludarabine plus rituximab) were therefore included in the analyses of efficacy and toxic effects as per protocol.
Patient characteristics—including age, cancer stage, LDH, IPI score, follicular lymphoma IPI, bone marrow infiltration, and extranodal involvement—were similar between groups (table 1). Median patient age was 67 years (IQR 59–74). Most patients had stage III or stage IV disease (table 1). All patients had received previous treatment before being recruited; the median number of treatments was one (IQR 1–2), and most patients were previously treated with CHOP-based chemotherapy. Histological subtypes were distributed equally between the groups (table 1).
Figure 2: Kaplan-Meier plot of progression-free survival in the per-protocol population B-R=bendamustine plus rituximab. F-R=fludarabine plus rituximab.
The median follow-up was 96 months (IQR 73·2–112·9), and median progression-free survival for patients treated with bendamustine and rituximab was 34·2 months (95% CI 23·5–52·7) versus 11·7 months (8·0–16·1) in the fludarabine plus rituximab group (HR 0·54 [95% CI 0·38–0·72], log-rank test p<0·0001; figure 2) 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). A sensitivity analysis of the primary endpoint, based on all 230 patients randomly assigned, yielded similar results (HR 0·54, 95% CI 0·38–0·72, p<0·0001). Exploratory subgroup testing showed that the increase in progression-free survival in the bendamustine plus rituximab group was reported in patients with follicular lymphoma (HR 0·56, 95% CI 0·34–0·87), mantle-cell lymphoma (0·45,
0·22–0·76), and small lymphocytic lymphoma subentities (0·28, 0·07–0·62; figure 3). Additional information for the subset of patients with mantle-cell lymphoma is in the appendix (p 4). Although age, mantle- cell lymphoma histology, number of previous regimens, previous rituximab treatment, IPI score, and LDH were univariably significant prognostic factors, only mantle- cell lymphoma (p<0·0001) was significant in a multivariable Cox model that included all patients in the per-protocol population (p=0·0014). Although visual inspection of the Kaplan-Meier curves indicates some deviation from proportional hazards, because the effect on outcome seems to develop during the first 2 years, with parallel curves thereafter, we recorded no major evidence against the proportionality hazard assumption (p=0·1; figure 2), using tests of non-zero slope in a generalised linear regression of the scaled Schoenfeld residuals on time.
Overall and complete responses were significantly higher with bendamustine plus rituximab than with
fludarabine plus rituximab (table 2). In a univariate analysis, only the IPI score showed significant prognostic
AFollicular lymphoma 100
80
60
40
20
B-R: n=58, 35 events, median 54·5 months (95% CI 23·0–not reached) F-R: n=53, 40 events, median 22·9 months (95% CI 11·7–32·3)
Log-rank test: p=0·01
effects. In a logistic regression model, both IPI and treatment group were significant (p=0·01 and p=0·00017, respectively). Additionally, more patients did not respond to therapy and had progressive disease with fludarabine plus rituximab than with bendamustine plus rituximab (p<0·0001; table 2, appendix p 3).
Patients receiving bendamustine plus rituximab had longer median overall survival than those receiving fludarabine plus rituximab (109·7 months [95% CI 50·2–not reached] vs 49·1 months [36·2–59·0]; HR 0·64, 95% CI 0·45–0·91, p=0·012; figure 4). There were 55 deaths in the bendamustine plus rituximab group and 71 deaths in the fludarabine plus rituximab group.
0
0 12 24 36 48 60 72 84 96 108 120 132
Three patients died (two in bendamustine plus rituximab,
Number at risk B-R F-R
58
53
48
31
28
24
32
16
29
14
23
10
18
7
12
6
8
5
6
4
1
0
0
0
one in fludarabine plus rituximab group) without disease progression: one patient aged 86 years, 4 years after study inclusion of unknown cause; one aged 83 years, 7 years
BMantle-cell lymphoma 100
80
60
40
20
0
B-R: n=24, 20 events, median 17·6 months (95% CI 9·4–26·8) F-R: n=23, 23 events, median 4·7 months (95% CI 2·5–10·2) Log-rank test: p=0·01
after study inclusion due to heart failure; and one aged 71 years, 2 years after study inclusion due to infection that was most likely progressive multifocal leukoencephalopathy.
We did log-rank tests to determine whether there were differences in outcomes between centres that recruited a small (≤three patients) number of patients versus those that recruited a large (>three patients) number of patients. We noted no differences between the two groups of centres for progression-free survival (p=0·47) or for overall survival (p=0·92; appendix p 1).
After approval of rituximab for maintenance therapy in 2006 by the EMA, the protocol was amended accordingly for patients who responded to either bendamustine plus
0 12 24 36 48 60 72 84 96 108 120 rituximab or fludarabine plus rituximab. As a result, a
Number at risk
B-R
24
14
10
4
4
2
2
2
1
1
0
subanalysis was completed to assess the effect
of
F-R 23 4 3 3 1 0 0 0 0 0 0 rituximab maintenance therapy for patients who had
CSmall lymphocytic lymphoma
100 B-R: n=8, 5 events, median 69·2 months (95% CI 4·8–not reached) F-R: n=9, 9 events, median 9·0 months (95% CI 3·2–12·4)
Log-rank test: p=0·02 80
60
responded to either study treatment. In the group of 152 responding patients, 44 patients had received rituximab maintenance after treatment with either bendamustine plus rituximab (25 patients) or fludarabine plus rituximab (19 patients), whereas 108 patients (bendamustine plus rituximab: 69 patients, fludarabine plus rituximab: 39 patients) did not. Patient char- acteristics were similar for those who had and had not received maintenance (appendix p 6). The median
40
20
0
Number at risk B-R F-R
0
8
9
12
6
3
24
5
1
36
4
0
48
Time (months) 3
0
60
3
0
72
2
0
84
2
0
96
0
0
progression-free survival was significantly longer for patients who had received rituximab maintenance than those who had not (72·1 months [95% CI 54·1–not reached] vs 30·4 months [24·7–36·5]; HR 0·52, [95% CI 0·37–0·86], p=0·01; appendix p 2). Moreover, rituximab maintenance significantly increased overall survival, with the median overall survival not reached (95% CI 93·6–not reached) in the rituximab maintenance
subgroup versus a median of 69·7 months
Figure 3: Kaplan-Meier plot of progression-free survival for patients with follicular lymphoma (A), mantle-cell lymphoma (B), and small lymphocytic lymphoma (C)
B-R=bendamustine plus rituximab. F-R=fludarabine plus rituximab.
(49·4–not reached) for patients who did not have maintenance therapy (HR 0·52, 95% CI 0·34–0·92, p=0·03; appendix p 2).
Bendamustine Fludarabine p value
plus rituximab plus
(n=114) rituximab (n=105)
Overall response 94 (82%) 54 (51%) <0·0001
Complete response 46 (40)% 18 (17%) 0·0002
Partial response 48 (42%) 36 (34%) 0·2345
Stable disease 7 (6%) 16 (15%) 0·0282
Progressive disease 8 (7%) 30 (29%) <0·0001
Not evaluable 5 (4%) 5 (5%) 0·8941
Table 2: Patient responses
100
80
60
40
20
0
In this small group of responding patients who received rituximab maintenance, no difference in
Number at risk
012 24 36 48 60 72 84 96 108 120
Time (months)
progression-free survival was noted between those who had originally received bendamustine plus rituximab
B-R
F-R
114
105
100
87
84
78
75
64
67
50
57
37
48
30
40
25
26
18
16
10
3
1
(25 patients; median progression-free survival 72·1 months [95% CI 52·7–not reached]) and those who had receive fludarabine plus rituximab (19 patients;
median progression-free survival 93·6 months [45·0–not reached]; HR 1·02 [95% CI 0·42–2·50], p=0·96). By contrast, patients who before the protocol amendment in 2006 did not received rituximab maintenance had significantly longer progression-free survival if they were treated with bendamustine plus rituximab than with fludarabine plus rituximab (25·0 months [95% CI 15·2–34·8] vs 8·6 months [5·8–12·2]; HR 0·49 [95% CI 0·33–0·65], p<0·0001). 13 patients with previous bendamustine treatment were randomly assigned to bendamustine plus rituximab and had an overall response of 77% (ten of 13 patients; appendix p 7). Subsequent treatments were at physician’s choice. However, in-depth analysis of this information was beyond the scope of our study. Data for subsequent treatments are available for 90 of 161 patients with disease progression (appendix p 8).
The mean number of cycles given was 5·4 (SD 1·3) in the bendamustine plus rituximab group and 4·7 (1·7) in the fludarabine plus rituximab group. In the bendamustine plus rituximab group, 96·3% of the full dose of both drugs was received by patients and in the fludarabine plus rituximab group this figure was 99·5%; dose reductions were needed for 20 patients in both groups. No patient discontinued treatment because of drug-related toxic effects.
No substantial differences were noted between groups in the occurrence of adverse events such as alopecia, stomatitis, erythema, allergic reactions, or infectious episodes (table 3). Most infections included pneumonia and gastrointestinal and urogenital infections, and no specific pattern of infections could be observed. Haematological toxic effects were also similar between treatment groups (per cycle in table 4; per patient in the appendix p 9). G-CSF use was similar between patient groups: 7% (35 of 516) of cycles and 15 (13%) of 114 patients in the bendamustine plus rituximab group versus 8% of
Figure 4: Kaplan-Meier plot of overall survival in the per-protocol population B-R=bendamustine plus rituximab. F-R=fludarabine plus rituximab.
cycles (32 of 419) and 13 (12%) of 105 patients in the fludarabine plus rituximab group. The overall incidence of serious adverse events was similar for both treatment groups, with 23 events in the bendamustine plus rituximab group and 23 events in the fludarabine plus rituximab group. Most common adverse events were infections (11 in the bendamustine plus rituximab group and eight in the fludarabine plus rituximab group) and myelosuppression (three in the bendamustine plus rituximab group and two in the fludarabine plus rituximab group).
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 our study protocol during 2002–03, no standard treatment approach had been established for relapsed patients with indolent lymphomas or mantle-cell lymphoma that were ineligible for stem cell transplant. Therefore, at the time, inclusion of all these histological subtypes in the study was
reasonable, because fludarabine plus rituximab comparator was frequently used to treat these cancers.
In the past few decades, the management of patients with follicular lymphoma and other indolent lymphomas has been one of the most controversial and highly debated areas in haematology and oncology. So far, no randomised studies have compared the efficacy of one treatment regimen with another in relapsed indolent and mantle- cell lymphoma, making treatment decisions somewhat subjective. Our study provides clear insight into this
Bendamustine plus rituximab (n=114)
Fludarabine plus rituximab (n=105)
bendamustine plus rituximab achieved an overall response of about 90% and median progression-free
Nausea and emesis
Grade 1* Grade 2* Grade 3† Grade 4† Grade 1* Grade 2* Grade 3† Grade 4†
26 (23%) 10 (9%) 4 (4%) ·· 21 (20%) 5 (5%) 1 (1%) ··
survival of about 2 years. The longer progression-free survival reported in our study compared with previous studies might be accounted for by many factors: we did
Fatigue 11 (10%) 3 (3%) 1 (1%) ··
Alopecia 10 (9%) 5 (4%) ·· ··
8(8%) 2 (2%) ·· ··
9(9%) 7 (7%) 1 (1%) 1 (1%)
not include patients’ refractory to rituximab, bendamustine, or fludarabine; duration of treatment in
SGOT or SGPT
22 (19%) ··
··
··
9 (9%) ··
··
··
our study was longer (six vs four cycles); and we gave rituximab maintenance to a subset of patients. With
Creatinine 7 (6%) ·· ·· ·· 12 (11%) ·· ·· ··
Infections 18 (16%) 15 (13%) 1 (1%) 1 (1%) 13 (12%) 10 (10%) 5 (5%) ··
Diarrhoea ·· ·· ·· 1 (1%) ·· ·· ·· ··
Obstipation ·· ·· ·· ·· ·· ·· 1 (1%) ··
Dysponea ·· ·· 2 (2%) ·· ·· ·· ·· ··
Vertigo ·· ·· ·· ·· ·· ·· 1 (1%) ··
exclusion of patients who received rituximab maintenance from our analysis, progression-free survival was about 2 years in the bendamustine plus rituximab group and 8·6 months in the fludarabine plus rituximab group, supporting the results of two previous phase 2
6,7 In the fludarabine plus rituximab treatment
Allergic ··
reaction Hypotension ··
Pain ··
Weight loss ··
Proteinuria ··
Stomatitis ··
Skin‡ ··
··
··
··
··
··
··
··
1(1%) 2 (2%) ··
3(3%) ·· ··
1 (1%) ·· ··
1 (1%) ·· ··
·· ·· ··
1 (1%) ·· ··
1 (1%) ·· ··
··
··
··
··
··
··
··
4(4%) 1 (1%)
·· ··
1(1%) ··
·· ··
2(2%) ··
·· ··
·· ··
group, overall response was higher in the study by
3 than in our trial (90% vs
3 These differences in results could be because the two-thirds of patients in the Czuczman and colleagues’
3 had not been treated previously, patients had a lower median age than in our study (53 years vs 67 years), and their recruitment was from one study centre compared with the multiple study centres (including
Toxic hepatitis Sepsis
··
··
··
··
·· ·· ··
1 (1%) 1 (1%) ··
··
··
1(1%) ··
·· ··
community-based sites) used in ours.
13,14 using cladribine with rituximab in mantle-cell lymphoma reported higher overall responses
SGOT=serum glutamic oxaloacetic transaminase. SGPT=serum glutamic pyruvic transaminase. *Grade 1 and 2 events occurring in at least 10% of patients in one or both treatment groups. †All grade 3 and 4 adverse events. ‡Including erythema.
Table 3: Grade 1–4 adverse events in both treatment groups
Bendamustine plus rituximab (n=585) Fludarabine plus rituximab (n=452)
than overall response with fludarabine plus rituximab in
13
29 patients received the cladribine plus rituximab combination as initial therapy, achieving an overall response of 66%. A second study by Spurgeon and
14 reported an overall response of 87% in a retrospective study of 31 patients newly diagnosed with
Grade 1–2 Grade 3 Grade 4 Grade 1–2 Grade 3 Grade 4
Leucocytopenia 228 (39%) 56 (10%) 15 (3%) 167 (37%) 46 (10%) 10 (2%)
Neutropenia 103 (18%) 35 (6%) 18 (3%) 72 (16%) 20 (4%) 21 (5%)
Thrombocytopenia 77 (13%) 9 (2%) 2 (<1%) 52 (12%) 5 (1%) 6 (1%)
Anaemia 132 (23%) 7 (1%) 1 (<1%) 74 (16%) 6 (1%) 2 (<1%) Table 4: Haematological toxic events of all grades per number of cycles in patients receiving at least
one dose of study treatment
debate by showing the greater efficacy of bendamustine plus rituximab than fludarabine plus rituximab.
Patients with relapsed indolent non-Hodgkin lymphoma and mantle-cell lymphoma are usually elderly and often present with comorbidities; effective treatment options that are well tolerated in this setting are therefore needed. The median age in our study was 67 years and about a third of patients were older than 70 years, suggesting that our patient population is representative of that typically noted in clinical practice. Results of our study showed bendamustine plus rituximab to be efficacious and well tolerated, providing a treatment option that meets the needs of these patients.
Our results support the efficacy of bendamustine plus 6,7 in which
mantle-cell lymphoma who were treated with cladribine
14 However, these studies were in newly diagnosed patients, whereas our study was in patients who had relapsed. This difference might account for differences noted between the fludarabine plus rituximab group in our study and the cladribine plus rituximab group in previous studies.
For the interpretation of our study, four limitations should be considered. First, the use of fludarabine plus rituximab as the comparator posed some limitations in the context of current recommendations for treatment. As previously discussed, at the time that our study was initiated, fludarabine-based regimens containing rituximab were commonly used in patients with relapsed indolent non-Hodgkin lymphoma and mantle-cell lymphoma. We regarded the use of fludarabine, cyclophosphamide, and mitoxantrone or fludarabine, and cyclophosphamide as potential comparators for bendamustine plus rituximab when we designed our protocol, but deemed these regimens to be too toxic in our expected elderly patient population. We therefore chose fludarabine plus rituximab as the best comparator, because the paper by Czuczman
3 clearly recommended this regimen be used in comparative studies examining new regimens.
show that the efficacy
3,8 in the first-line setting and safety of bendamustine plus
administration of rituximab maintenance in patients responding to either study treatment. We subsequently
rituximab is better than that of R-CHOP. Although these results cannot be extrapolated to the relapsed setting, we again noted that the bendamustine combination was well tolerated even in this older patient population, suggesting that this regimen should be considered as one of the preferred salvage treatment options. Fludarabine was given for 3 days instead of 5 days, as recommended by
3 who concluded that a 3-day dosing should be given to maintain efficacy with reduced haematological toxic effects. Therefore, we suggest that the efficacy of bendamustine plus rituximab is better than fludarabine plus rituximab, using the dosing given to patients in our study.
Second, since the study was initiated in 2003, and patients had received their first treatment before enrolment, fewer than half of all patients (91 [42%] of 219) had previously received rituximab. Overall response of these patients was lower than patients who had not had rituximab (52 [57%] of 91 vs 96 [75%] of 128; appendix p 9). Because most patients now receive rituximab-based chemotherapy in the first-line setting, results might not be fully generalisable to these patients; however, previous rituximab use was equally distributed between groups and should therefore not have affected analyses that compared the efficacy and safety of fludarabine plus rituximab with bendamustine plus rituximab.
Third, there was a difference between both groups in the number of previous therapies and in follicular lymphoma IPI scores (table 2). This difference between study groups occurred by chance, since patients had been stratified before randomisation according to histology and the type of previous treatment, but not by the number of previous treatments. On one hand, patients in the fludarabine plus rituximab group had a greater number of previous treatments than those in the bendamustine plus rituximab group (≥two previous treatment lines: 51 [49%] of 105 vs 39 [34%] of 114 patients). We cannot fully exclude that this imbalance might have confounded the progression-free survival result. On the other hand, the proportion of patients with an intermediate or a poor risk follicular lymphoma IPI score was higher in the bendamustine plus rituximab group than in the fludarabine plus rituximab group (46 [79%] of 114 vs 35 [66%] of 105 patients). Taken together, it seems unlikely that these minor imbalances substantially affected the overall results.
Finally, results from the subset of patients given rituximab maintenance must be interpreted with caution, given that this was a post-hoc analysis, included a small sample size, and patients were not randomly assigned between groups. At the beginning of our study, rituximab maintenance was not yet approved for relapsed patients and was not part of standard clinical practice. After it was approved in 2009 by the EMA when our study was ongoing, we amended the protocol to allow the
completed an unplanned subanalysis in this small subset of patients, which suggested improved outcomes in patients treated with rituximab maintenance compared with those who did not receive maintenance. These results are in accordance with those from previous randomised
15–18 and from a 2012 systematic review and meta-
19in the upfront and relapsed settings. Our results are similar to those of the study by van Oers and
20which was the first other trial to report a survival benefit after rituximab maintenance. In an update
17 a trend towards a survival benefit remained, but was not significant (p=0·07). The patient population of the study
17,20 was similar to that of our study, because both trials were in the relapsed setting and not all patients had previously been treated with rituximab.
16 in which no overall survival difference had been noted, was done with patients not previously treated who have a much longer progression-free survival, with or even without maintenance, than do patients with relapsed disease.
Safety outcomes were comparable between the study groups, supporting results from previous studies that suggest bendamustine plus rituximab is well tolerated in
6,7 Despite the fact that up to six cycles of treatment were given in our study compared
6 safety results were similar. Myelosuppression was the primary toxic effect, with grade 3 and 4 leucocytopenia occurring in about 12% of cycles (for both groups) in this study. Administration of rituximab maintenance therapy did not seem to adversely affect tolerability, which is in line
21
In conclusion, results of our study suggest that preference may be given to bendamustine plus rituximab over fludarabine plus rituximab for the treatment of relapsed indolent and mantle-cell lymphomas, as shown by the improvement in progression-free survival and overall survival. Because the bendamustine plus rituximab combination is effective and well tolerated, this regimen could be a key treatment option for these patients. Results of ongoing studies combining bendamustine plus rituximab as a backbone therapy with novel drugs—such as inhibitors of BTK (ibrutinib [NCT01974440]), PI3K (idelalisib [NCT01732926]), and Bcl-2 (venetoclax [NCT02187861])—will help to establish the role of novel combinations in patients with relapsed indolent and mantle-cell lymphomas.
Contributors
MR conceptualised the study. The StiL steering committee designed the study. AH and MR did the statistical analysis. MR developed an early draft, and all investigators reviewed and approved the submitted manuscript. WBr, NN, MR created the study idea and design proposal; WBr and MR wrote the study protocol; JB, WBr, and MR did the data analysis and interpretation; and CB, H-PB, WBl, UvG, LH, FK, UK, CL, LM, NN, MSa, MSt, JV, EW, MW and the StiL head office collected data.
CB, H-PB, JB, WBr, WBl, AC, AH, FK, UvG, LH, UK, CL, LM, NN, MR, MSa, MSt, JV, EW, and MW did manuscript writing, drafting and editing. CB, H-PB, JB, WBl, UvG, AH, LH, FK, UK, CL, LM, NN, MSa, MSt, JV, EW, and MW did manuscript evaluations and consultations.
Declaration of interests
MR reports personal fees and research grants from Roche Pharma AG and Mundipharma GmbH, during the study. CB reports travel grants and advisory board fees from Roche Pharma AG, outside the study. WBr, NN, and JB report personal fees from Roche Pharma AG and Mundipharma GmbH. MW reports personal fees from Roche, Amgen, Novartis, Johnson
& Johnson, and Celgene. EW reports personal fees for sponsorship of conferences and advisory board from Mundipharma GmbH, outside the study. All other authors declare no competing interests.
Acknowledgments
We thank Anna Christofides, who contributed to the development of the paper by providing medical writing assistance. Roche Pharma AG, Ribosepharm, and Mundipharma GmbH provided financial support for this study. We thank the study investigators, coordinators, nurses, and patients and their families for their contributions; the team of the StiL study group office, and particularly Ingeborg Dietz for her long-term support. The sponsor of this trial was the StiL group, represented by the principal investigator of the study, MR.
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