Bendamustine with rituximab for the first-line treatment of
advanced indolent non-Hodgkin's and mantle cell lymphoma
April 2013Contents Summary 1 Background 2 Epidemiology 3 Cost 4 References 6 Summary
The combination of bendamustine and rituximab (BR) is not currently li-censed for the first-line treatment of indolent NHL and mantle cell lymphoma (MCL); however a submission to the European Medicines Agency has been made and related NICE technology appraisals are in development. A sub-mission to extend the license of bendamustine to include first-line treatment of indolent NHL has already been made to the US FDA but no decision has been made as yet, and the FDA has reportedly requested further data. According to the NICE final scope documents, the evaluation of BR in MCL will consider patients who are unsuitable for stem cell transplantation, who currently receive rituximab in combination with other chemotherapy regimens (e.g. R-CHOP [most frequently used], R-FC and R-CVP). The evaluation of BR in indolent NHL will consider patients with advanced disease who require therapy, and will include similar standard comparators (e.g. CHOP, R-CVP).
For both indolent NHL and MCL, the main supporting data consist of the Phase III study (StiL NHL 1-2003), which compared BR to R-CHOP in the first-line treatment of advanced (stage III or IV) MCL (19%) or indolent NHL (mainly follicular [54%]). The primary endpoint was median progression-free survival (PFS) – in the per protocol population, this was extended by around 38 months in the BR group (69.5 months versus 31.2 months; HR 0.58; 95% CI 0.44-0.74; p<0.0001). Separate analyses according to histological sub-type found the benefit of BR to be consistent in all apart from marginal zone lymphoma. For MCL patients, the PFS benefit was 13.3 months (35.4 months versus 22.1 months; HR 0.49; 0.28-0.79; p=0.0044).
R-CHOP was associated with a higher rate of serious adverse events (29% versus 19%; NNH of 10), including grade 3/4 neutropenia (69% versus 29%; p<0.0001; NNH 2-3) and leukocytopenia (72% versus 37%; p<0.0001; NNH 2-3). R-CHOP was also associated with a higher number of infectious epi-sodes and more frequent use of G-CSF. BR was associated with a higher rate of drug-associated skin reactions (erythema or allergic reactions). The StiL study did not include any maintenance or consolidation treatment, and it is therefore not known how BR compares to R-CHOP followed by maintenance rituximab, or if rituximab maintenance has a role after first-line BR chemotherapy. Also data on the longer- safety of bendamustine are cur-rently limited. There are no data comparing BR to other, alternative first-line treatment options (e.g. R-CVP), which clinicians may use if they wish to with-hold anthracycline treatment.
The results of the BRIGHT study have been presented in conference; this study however had a primary endpoint of complete response rate and time-to-event data (evaluated as secondary endpoints) were too immature for analysis at the time.
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The incidence of non-Hodgkin’s lymphoma (NHL) in the UK is approximately 18 per 100,000 people, and 40-50% of these have indolent (low-grade) disease, usually advanced (stage III/IV) at presentation (1). Types of NHL classified as indolent include follicular lymphoma (FL), small lymphocytic lymphoma (SLL), lymphoplasmacytic lymphoma and marginal zone lymphomas (MZL). Mantle cell lymphoma (MCL) has characteristics of aggressive as well indolent lym-phoma (2). Indolent B cell lymphoid malignancies are characterised by slow and continuous growth, a high initial response rate, but a relapsing and pro-gressive disease course (2).
The clinical presentation, rate of disease progres-sion and patterns of treatment for patients with indo-lent NHL vary widely. Active surveillance (‘watchful waiting’) may be an appropriate treatment option for many, with appropriate interventions when symp-toms develop. There may be multiple episodes of remission and relapse, and the nature of the dis-ease can change at relapse, sometimes transform-ing to a more aggressive type (3).
The most commonly used first-line treatment for symptomatic, advanced indolent NHL is rituximab plus combination chemotherapy, for example R-CVP (cyclophosphamide, vincristine, prednisolone and rituximab) or R-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone and rituxi-mab). Chlorambucil ± rituximab may be given to people who are unsuitable for these regimens (3). R-CHOP is the most widely used of these regimens (4).
Mantle cell lymphoma
MCL is a rare type of B-cell NHL that has a moder-ately aggressive course and is rarely curable with currently available standard treatment. The regis-tered annual incidence of NHL in England and Wales is around 10,400, with MCL accounting for around 5 to 8% (around 670 new diagnoses per year, or 1.2 per 100,000). It usually occurs in older adults (the median age of presentation is 60 years) and has a male predominance (5).
There is no current gold standard treatment for ad-vanced-stage MCL, due to a lack of definitive data to guide treatment decisions (it is relatively uncom-mon and has often been included with other types of NHL in clinical trials). In the UK, patients unsuitable for autologous peripheral blood stem cell transplan-tation (ASCT) are most commonly treated first-line with R-CHOP or R-FC (cyclophosphamide in combi-nation with rituximab) (final scope). Although MCL usually responds well to initial chemotherapy (response rates of 50-70% with many regimens), durations of response are short and overall survival is poor (median of 3 years) (5, 6).
Bendamustine (Levact®) is currently licensed in the UK for use as monotherapy in the treatment of pa-tients with indolent NHL who have progressed dur-ing or within 6 months followdur-ing treatment with ri-tuximab or a riri-tuximab containing regimen. It is not licensed for use in combination with rituximab or in the first-line setting for indolent NHL, and is not li-censed for the treatment of MCL (7).
An application to extend the licence of benda-mustine to include its use in combination with rituxi-mab for the first-line treatment of indolent NHL and MCL has been submitted to the European Medi-cines Agency and a decision is expected towards the end of 2013 (1, 8). An application was filed in the US in December 2011 for use of bendamustine, in combination with rituximab, as a first-line therapy for indolent B-cell NHL. According to the New Drugs Online database, the FDA requested further data in October 2012 (no details of the data re-quested are given) (1).
Rituximab (MabThera®) is licensed in the UK for the treatment of previously untreated patients with stage III-IV follicular lymphoma in combination with chemotherapy. The SPC discusses the results of three randomised trials using rituximab in combina-tion with chemotherapy – CVP, CHOP, MCP (melphalan, chlorambucil, and prednisone) and C H V P ( c y c l o p h o s p h a m i d e , doxorubicin, etoposide, and prednisone)/ interferon-α (9). It is not licensed for use in the treatment of MCL or other indolent lymphomas. NICE guidance
NICE is undertaking two separate technology ap-praisals on:
1. Bendamustine in combination with rituximab for the first-line treatment of advanced indo-lent non-Hodgkin's lymphoma (expected in October 2013).
This will look at its use in patients with previously untreated advanced, indolent NHL that requires therapy, with standard comparators including R-CVP, R-CHOP, and chlorambucil plus rituximab in those unsuitable for the former two regimens (10). 2. Bendamustine in combination with rituximab
for the first-line treatment of mantle cell lym-phoma (expected date of issue TBC). This will look at its use in patients who are unsuit-able for stem cell transplantation, with standard comparators including R-CHOP, R-FC (plus R-CVP and chlorambucil plus rituximab in those unsuitable for the former two regimens) (11).
The incidence of NHL in the UK is approximately 18 per 100,000 people. If it is assumed that 45% have indolent disease, 85%* of these have stage III or IV disease, 94%* are eligible for chemotherapy, and 90% are considered suitable for bendamustine, then the population eligible for first-line treatment with BR can be estimated as around 6 per 100,000.
[*These data were obtained from the costing state-ment from the NICE guidance on ‘Rituximab for the for the first-line maintenance treatment of stage III-IV follicular non-Hodgkin’s lymphoma’ (TA 243) (12)].
The incidence of MCL in the UK is approximately 1.2 per 100,000 people. If it is assumed that 85% have advanced disease, 90% are unsuitable for ASCT and 90% of these are considered suitable for bendamustine then the population eligible for first-line treatment with BR can be estimated as around 0.8 per 100,000.
StiL NHL 1-2003
This multicentre Phase III non-inferiority study com-pared bendamustine in combination with rituximab (BR) to R-CHOP in the first-line treatment of adults with advanced (stage III or IV) MCL (19%) or indo-lent NHL, the latter including follicular (54%), lym-phoplasmacytic (Waldenstrom’s macroglobulinae-mia) (8%), small lymphocytic (4%), and marginal zone lymphoma (13%) (4). Participants were ran-domised to open-label treatment with BR (rituximab 375mg/m2 on day 1 plus bendamustine 90mg/m2 on
days 1+2 every 4 weeks; n=274) or R-CHOP (rituximab 375mg/m2 on day 1 plus
cyclophos-phamide 750mg/m2, doxorubicin 50mg/m2 and vin-cristine 1.4mg/m2 on day 1 and prednisone 100mg
daily for 5 days; n=275), for up to six cycles. No maintenance or consolidation treatment was admin-istered. The primary endpoint was progression-free survival (PFS), and the aim was to demonstrate non-inferiority of BR to R-CHOP (the non-inferiority margin was set at 10%).
A total of 549 patients were randomised to treat-ment and 514 were available for analysis (per proto-col: 261 in the BR group and 253 in the R-CHOP group). The median age of the group was 64 years (range 34-83) and the majority had stage IV (77%) or III (19%) disease. A median of six cycles of treat-ment per patient was administered in both treattreat-ment arms, and full doses of treatment were given in 95.9% of BR cycles and 88.8% of R-CHOP cycles.
The main results reported were as follows:
•At a median follow-up of 45 months, median PFS was 69.5 months (IQR 26.1-not yet reached) for BR versus 31.2 months (15.2-65.7) for CHOP-R (HR 0.58; 95% CI 0.44-0.74; p<0.0001).
•When separate analyses were conducted for his-tological subtypes, a significant benefit for BR in terms of PFS was shown for all except marginal zone lymphoma, with no significant treatment-by-subgroup interaction. For MCL, PFS was 35.4 months (IQR 28.8-54.9) in BR and 22.1 months (15.1-33.8) for R-CHOP (HR 0.49; 0.28-0.79; p=0.0044)
•Overall response rates (ORR) did not differ be-tween groups (93% with BR and 91% with R-CHOP), however more complete responses were seen in the BR group (40% versus 30%, respec-tively (p=0.021).
•The BR group also had a longer time to next an-tilymphoma treatment (not reached versus 42.3 months, respectively; HR 0.52; 95% CI 0.39-0.69; p<0.0001).
•No difference in OS was seen (43 deathsin the B-R arm and 45 in the CHOP-R arm) but follow-up was limited, and the median OS had not been reached in either group.
R-CHOP was more frequently associated with seri-ous adverse events (29% versus 19% in the BR group), with a higher incidence of grade 3/4 neutro-penia (69% versus 29%; p<0.0001) and leukocyto-penia (72% versus 37%; p<0.0001). In addition it was associated with a higher overall rate of infec-tious episodes (any grade; 50% versus 37%; p=0.0025) and sepsis (3% versus <1%, respec-tively; p=0.019). One patient in the BR group and five in the R-CHOP group died from sepsis. G-CSF was more often used in CHOP-R treated pts (20% versus 4% of all cycles; p<0.0001). The BR regimen was associated with a lower rate of alopecia (0% versus 100%), stomatitis (6% versus 19%) and parasthesia (7% versus 29%), but a higher rate of drug-associated skin reactions (erythema [16% ver-sus 9%] or allergic reactions [15% verver-sus 6%]) than R-CHOP.
Although R-CHOP is the most widely used chemo-therapy regimen for the first-line treatment of indo-lent NHL and MCL, some clinicians may prefer to withhold the anthracycline, both to improve tolerabil-ity and to hold for use in the future event of histo-logical transformation. There have been no random-ised studies comparing BR to alternative treatments (e.g. R-CVP) in this setting. The StiL study did not include any maintenance or consolidation treatment, and it is therefore not known how BR compares to R-CHOP followed by maintenance rituximab, or if rituximab maintenance has a role after first-line BR chemotherapy (13).
Although bendamustine is well tolerated in the short term, its long-term toxicity profile may not yet be appreciated, particularly for the risk of myelodyspla-sia and leukaemia. There are scarce data on the effects of bendamustine on stem cell viability and collection for future ASCT, and whether its use af-fects response rates to subsequent treatments at relapse (13).
This Phase III study compared BR to standard treat-ment regimens (R-CHOP or R-CVP) in the first-line treatment for indolent NHL or MCL. The results of the study have not been fully published and these data have been taken from a conference abstract (presented at ASH in 2012) (14).
A total of 477 participants were randomised to re-ceive either BR (regimen as per StiL study) or R-CHOP/R-CVP (the choice of standard regimen was determined by the investigator prior to randomisa-tion). The primary objective was to demonstrate non-inferiority of BR to standard treatment in terms of CR rate, with a non-inferiority margin (ratio) of 0.88. Tumour response was determined by a blinded independent review committee (IRC).
A total of 436 randomised patients received treat-ment and 419 were evaluable for efficacy (BR n=213; CHOP/CVP n=206 [CHOP 97; R-CVP n=109]). The median age of the groups was 59 years, 64% had an ECOG performance status of 0, 62% had Ann Arbor stage IV disease, and 83% had indolent NHL. Most patients completed six cycles of treatment (92% for BR and 91% for R-CHOP/R-CVP), with high relative dose intensity (>96%).The main results reported in the abstract are as follows:
•Among randomised patients, the rate of CR was 31% with BR and 23% with standard treatment (HR 1.34; 0.98-1.83; p=0.0084 for non-inferiority). Results were similar in the evaluable population (31% versus 25%; HR 1.25; 95% CI 0.93-1.73; p=0.0225 for non-inferiority).
•Among randomised patients, the CR rate for those with indolent NHL was 27% for BR and 23% for standard treatment (HR 1.16; 95% CI 0.81-1.65; p=0.1289). For those with MCL it was 51% and 24%, respectively (HR 1.95; 95% CI 1.01-3.77; p=0.0180 for superiority)
For randomised patients, the ORR was 94% for BR and 84% for R-CHOP/R-CVP. Time-to-event data are immature and will be analysed at a later date. The most common adverse events for BR and R-CHOP/R-CVP, respectively, were nausea (139 vs. 102 patients), fatigue (113 vs. 107), neutropenia (76 vs. 85), constipation (65 vs. 90), and alopecia (8 vs.
74). Laboratory grade 3/4 haematological toxicities for BR and R-CHOP/R-CVP included lymphopenia (137 vs. 64), neutropenia (98 vs. 151), leukopenia (84 vs. 116), thrombocytopenia (16 vs. 15), and anaemia (6 vs. 9), respectively. The most frequent investigator-reported non-haematological grade 3/4 adverse events for BR and R-CHOP/R-CVP were infusion-related reactions (13 vs. 8 patients). G-CSF was administered at the discretion of the investiga-tor (per ASCO recommendations) to 29% of the BR group and 43% of the R-CHOP/R-CVP group. Fatal adverse events occurred in six patients receiving BR patients (pneumonia, respiratory failure, and sepsis; acute respiratory failure; cardiac arrest; pneumonia; chronic obstructive pulmonary disease; lung cancer) and in one patient who received R-CHOP/R-CVP (sepsis).
Bendamustine is available in 25mg and 100mg vials at a cost of £69.45 and £275.81, respectively (excluding VAT) (15). The total cost of benda-mustine given at a dose of 90mg/m2 on days 1 and
2 for six cycles (assuming an average BSA of 1.8m2) can be calculated as follows:
•162mg x 2 = 324mg per course
•324mg = 3x100mg vials plus 1x25mg vial = £1,076 (inc. VAT) per cycle
•Total for six courses = £6,460
The dose of rituximab used in the BR regimen is the same as that employed in the current standard regi-mens (e.g. R-CHOP, R-CVP). The cost implications of treating eligible patients first-line with BR instead of these current standard regimens will therefore be based on the additional cost of bendamustine when compared with CHOP and CVP. The costing state-ment for TA243 (Rituximab for the first-line treat-ment of stage III–IV follicular lymphoma) states that the CHOP component costs £229 per cycle (12), which would work out as a total cost of £1650 (inc. VAT) for six cycles. Therefore the use of BR instead of R-CHOP would be associated with additional costs of around £4,810 per patient treated.
The total estimated population that could be eligible for BR in the first-line treatment of indolent NHL or MCL can be estimated at around 6.8 per 100,000 (see epidemiology section). Based on the above calculations, the additional costs associated with use of this instead of R-CHOP would be approxi-mately £32,700 per 100,000 population.
The use of BR instead of R-CHOP would be associ-ated with increased service delivery costs [based upon the DH Chemotherapy Regimens List 2012-13].
Drug Indication Incidence (number of patients per 100,000 eligible for this treat-ment) Average dura-tion of treat-ment (taken from trial data)
Cost per month/ cycle Cost per 100,000 popula-tion per month/ cycle Cost per 100,000 for average treatment duration Bendamustine
plus rituximab First-line treatment of MCL and indolent NHL
6.8 Six cycles *£800 *£5,440 *£32,640
*costs presented are the additional costs, using R-CHOP as the standard comparator (i.e. the difference between benda-mustine and CHOP, as the same rituximab dose is used in both regimens)
Details of search strategy:
EMBASE: exp BENDAMUSTINE/ AND exp RITUXIMAB/ AND exp *NONHODGKIN LYMPHOMA/ [Limit to: Human and English Language]
MEDLINE: bendamustine.af AND rituximab.af and exp *LYMPHOMA, NON-HODGKIN [Limit to: English Lan-guage and Humans]
1. New Drugs Online database; accessed via www.ukmi.nhs.uk
2. Vidal L et al (2012) Bendamustine for patients with indolent B cell lymphoid malignancies including chronic lymphocytic leukaemia. Cochrane Database of Systematic Reviews 2012, Issue 9 http://onlinelibrary.wiley.com/ doi/10.1002/14651858.CD009045.pub2/ abstract
3. Lymphoma (non Hodgkin's) - bendamustine (with rituximab): appendix B - final scope http://guidance.nice.org.uk/TA/Wave25/15/ Scope/pdf/English
4. Rummel MJ et al (2013) Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. The Lancet; published early online 20th February 2013
5. Lymphoma (mantle cell) - bendamustine (1st line, with rituximab): final scope http://
6. McKay P et al (2012) Guidelines for the inves-tigation and management of mantle cell lym-phoma. British Journal of Haematology doi:10.1111/bjh.12046 http://
7. Bendamustine (Levact®) SPC (last revised 3/8/10)
8. Personal communication with Napp Pharma-ceuticals Ltd medical information (8/4/2013) 9. Rituximab (Mabthera®) SPC (last revised
10. NICE technology appraisal in development (ID434): Bendamustine in combination with rituximab for the first-line treatment of ad-vanced indolent non-Hodgkin's lymphoma http://guidance.nice.org.uk/TA/Wave25/15 11. NICE technology appraisal in development
(ID609): Bendamustine in combination with rituximab for the first-line treatment of mantle cell lymphoma http://guidance.nice.org.uk/ index.jsp?action=byId&o=13804
12. Rituximab for the first-line treatment of stage III–IV follicular lymphoma (review of NICE technology appraisal guidance 110) – cost-ing statement http://www.nice.org.uk/ nicemedia/live/13650/57920/57920.pdf 13. Jacobson CA, Freedman AS (2013)
First-line treatment of indolent lymphoma: axing CHOP? The Lancet; published early online 20th February 2013
14. Flinn IW et al (2012) An open-label, random-ized study of bendamustine and rituximab (BR) compared with rituximab, cyclophos-phamide, vincristine, and prednisone (R-CVP) or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in first-line treatment of patients with advanced indolent non-hodgkin's lymphoma (NHL) or mantle cell lymphoma (MCL): The bright study. Blood; 120(21); abstract 902 http://abstracts.hematologylibrary.org/cgi/ content/abstract/120/21/902? maxto-show=&hits=10&RESULTFORMAT=&fulltext =bright&searchid=1&FIRSTINDEX=0&volum e=120&issue=21&resourcetype=HWCIT 15. British National Formulary edition 64
Please direct any comments to Nicola Pocock, London & South East Medicines Information Service, Guy’s Hospital, Great Maze Pond, London SE1 9RT
Tel: 020 7188 3853, Fax: 020 7188 3857 mailto:firstname.lastname@example.org