Bendamustine for relapsed follicular lymphoma refractory to rituximab

LONDON CANCER NEW DRUGS GROUP RAPID REVIEW Bendamustine for relapsed follicular lymphoma refractory to rituximab Bendamustine for relapsed follicular lymphoma refractory to rituximab Contents Summary 1 Background 2 Safety 4 Cost 4 Reference 6 Summary The manufacturer of bendamustine (Napp Pharmaceuticals) was invited to submit evidence for a NICE single technology appraisal (STA) in May 2010. In June 2010, the manufacturer informed NICE that it would not be making an evidence submission because it was unable to identify comparative clinical evidence suitable for a NICE appraisal in people with rituximab refractory disease. The manufacturer indicated that further research was ongoing but data would not be available in a time frame that would allow NICE to produce timely guidance. NICE therefore terminated this single technology appraisal. The manufacturer plan to make a resubmission to NICE when data from a comparative trial is available but there is no date as to when this will be. The best available evidence to support bendamustine for this indication comes from two phase II non comparative trials. Both trials assessed bendamustine in patients with indolent B-cell lymphoma, of which follicular lymphoma made up the largest proportion of patients. Study 1, which included 62% of patients with follicular lymphoma, reported an overall response rate of 75% (95% CI 65 83%). Study 2 reported that among the 45 patients with follicular lymphoma, the ORR was 82% including 7 complete responses and 10 unconfirmed complete responses. An updated analysis of studies 1 and 2 combined reported that after a median follow-up of 25.3 months (range 24 27.8 months), the DOR was 10 months (range 8.3 14 months) and the median PFS was 9.7 months (95% CI 8.2 12.4 months). Produced for the London New Drugs Group Contact: Angela Bennett Medicines Information Pharmacist London & South East Medicines Information Service Guy s Hospital London SE1 9RT The most commonly seen toxicities were haematological and the trials included a significant number of patients who suffered grade 3/4 neutropenia and thrombocytopenia which often led to dose delays or dose reductions. Secondary malignancies and infusion related reactions were also reported. Tel: 020 7188 5026 Fax: 020 7188 3857 Email: Anegla.bennett@gstt.nhs.uk Further copies of this document are available from URL http://www.nelm.nhs.uk/en/ NeLM-Area/Evidence/Drug- Specific-Reviews/ Produced for use within the NHS. Not to be reproduced for com-

Background Follicular lymphoma is the most common subtype of indolent NHL, and accounts for around 22% of all new cases of NHL (1). The Follicular Lymphoma International Prognostic Index (FLIPI) is a prognostic scoring system based on age, Ann Arbor stage, number of nodal sites involved, haemoglobin levels, and serum LDH levels. The FLIPI was developed based on a large set of retrospective data from patients with follicular lymphoma, and established three distinct prognostic groups (low risk, intermediate risk, and high risk) with 5-year survival outcomes ranging from 52.5% to 91% (1). In a more recent study conducted by the International Follicular Lymphoma Prognostic Factor Project, a prognostic model (FLIPI-2) was developed based on prospective collection of data from patients with newly diagnosed follicular lymphoma treated in the era of rituximab-containing chemoimmunotherapy regimens. The final prognostic model included age, haemoglobin levels, longest diameter of largest involved lymph node, beta-2 microglobulin levels, and bone marrow involvement. FLIPI-2 was highly predictive of treatment outcomes, and also separated patients into three distinct risk groups, with three-year progression-free survival (PFS) rates ranging from 51% to 91%; the FLIPI-2 also defined distinct risk groups among the subgroup of patients treated with rituximab-containing regimens, with a PFS rate ranging from 57% to 89% (1). Both the FLIPI-1 and -2 predict for prognosis, but these index scores have not yet been established as a means of selecting treatment options (1). The National Comprehensive Cancer Network recommends a rituximab-based regimen as initial therapy for patients with stage II to IV follicular lymphoma (1). However, indolent lymphoma remains incurable with standard therapy and eventually becomes refractory to rituximab, often within 3 years (2). Although yttrium-90 ibritumomab tiuxetan and iodine-131 tositumomab have demonstrated activity in patients who are refractory to single-agent rituximab, their use has been limited by strict eligibility criteria (3). Bendamustine Bendamustine is a novel alkylator whose mechanisms of action involve induction of apoptosis through activation of DNA-damage stress responses, inhibition of mitotic checkpoints, and induction of mitotic catastrophe. Bendamustine also contains a benzimidazole ring, which may confer purine analogue-like properties in addition to the alkylating properties (3). The manufacturer of bendamustine (Napp Pharmaceuticals) was invited to submit evidence for a NICE single technology appraisal (STA) in May 2010. In June 2010, the manufacturer informed NICE that it would not be making an evidence submission because it was unable to identify comparative clinical evidence suitable for a NICE appraisal in people with rituximab refractory disease. The manufacturer indicated that further research was ongoing but data would not be available in a time frame that would allow NICE to produce timely guidance. NICE therefore terminated this single technology appraisal (4). The manufacturer plan to make a resubmission to NICE when data from a comparative trial is available but there is no date as to when this will be (personal communication with manufacturer). Epidemiology The estimated incidence of follicular lymphoma in Europe is 2.18 cases per 100,000 persons per year (5). Follicular lymphoma most frequently presents in middle-aged individuals and the elderly, with a median age at diagnosis of 60 years. Less than 10% of patients treated with initial chemoimmunotherapy will not respond to treatment (i.e. refractory disease) (5). This means that approximately 0.2/100,000 population would be eligible for bendamustine in this setting. Published data There are three multicentre, open-label, single arm trials evaluating the efficacy and safety of bendamustine in patients with rituximab-refractory, indolent B-cell NHL. The third study has not been discussed in this review because it did not specify the number of patients who were refractory to rituximab and included patients who refractory to, or relapsed from, any prior therapy (6). Study 1 Kahl B et al. was the pivotal trial for bendamustine in this patient population (3). The primary endpoints included overall response rate (ORR) and the duration of response (DOR). Secondary endpoints included progression-free survival (PFS) and the safety profile. Patients aged 18 years with a World Health Organisation performance status 2 were eligible if they had documented rituximab-refractory, indolent B-cell lymphoma, and had received between 1 and 3 previous chemotherapy regimens. Exclusion criteria included: Chemotherapy, immunotherapy, radioimmunotherapy, or investigational therapy within 28 days before the start of cycle 1 or failure to recover from adverse events associated with prior treatment Myeloid growth factor treatment within 14 days (chronic erythropoietic-stimulating agent was allowed) Concurrent treatment with therapeutic doses of

systemic steroids within 14 days Transformed disease History of prior high-dose chemotherapy with allogeneic stem cell support Concurrent active malignancy (except nonmelanoma skin cancer, in situ cervical cancer, or localised prostate cancer treated with hormone therapy) Pregnancy or lactation Expected survival <3 months Bendamustine 120mg/m 2 was administered intravenously over 60 120 minutes on days 1 and 2 every 21 days. Treatment was planned for 6 to 8 cycles as long as a response or stable disease was observed. One hundred patients were enrolled and included in the study analysis. The median age was 60 years (range 31 84 years), and 76% of patients had advanced-stage disease at enrolment. Histologies included follicular lymphoma (n=62), small lymphocytic lymphoma (n=21), lymphoplasmacytoid lymphoma (n=1), and marginal zone lymphoma (n=16). The median number of prior chemotherapy regimens was 2 (range 0 6). Nine patients were in violation of the protocol, which required at least 1 but no more than 3 prior chemotherapy regimens. They were included in the primary analysis, consistent with prespecified analysis conditions. In the 100 patients who received at least one dose of bendamustine, an ORR of 75% (95% CI 65 83%) was achieved. In patients with follicular histologies, the ORR was 72%, 77%, and 72% for patients who had FLIPI low-risk, intermediate-risk, and high-risk disease, respectively. The ORR in patients who were sensitive to their last chemotherapy regimen (i.e. patients who had at least a partial response) was 88%, whereas patients who were refractory to their last chemotherapy regimen (i.e. patients who had no response) demonstrated an ORR of 64%. The median DOR in patients who achieved an objective response was 9.2 months (95% CI 7.1 10.8 months). The DOR was 10 months in chemosensitive patients compared with 6.3 months in chemorefractory patients. After a median follow-up of 11.8 months, the median PFS for the overall study population was 9.3 months (95% CI 8.1 11.9 months). The median PFS for patients who were sensitive and refractory to their last chemotherapy regimen was 11.8 months (95% CI 9 13 months) and 7.5 months (95% CI 4.4 12 months), respectively. Study 2 The multicentre study conducted by Friedberg JW et al. was designed to investigate the efficacy and safety of bendamustine in rituximab-refractory patients with indolent or transformed B-cell NHL (2). The primary endpoint was overall response rate (ORR). Secondary endpoints included safety, PFS, and duration of response. Eligibility criteria included: Age 18 years with a WHO performance status no greater than 2 and an initial diagnosis of indolent NHL or indolent disease that transformed to a more aggressive subtype. Patients to have received prior rituximab (alone or combined with other treatment) and were considered refractory to (defined as no response or progression within 6 months of completing therapy) or intolerant of continued rituximab. A maximum of 3 prior unique chemotherapy regimens, including ASCT. Exclusion criteria included: Previous chemotherapy/immunotherapy within 3 weeks before study entry or failure to recover from associated adverse events Investigational treatment within 28 days Haematopoietic growth factor treatment within 14 days (chronic erythropoietin was allowed) Therapeutic doses of systemic steroids Allogeneic transplant Concurrent active malignancy (except excised nonmelanoma skin cancer or in situ cervical or bladder cancer) CNS lymphoma Expected survival less than 3 months. Intravenous bendamustine was administered at a dose of 120mg/m 2 on days 1 and 2 every 3 weeks. Patients were treated for 6 cycles as long as they were responding or had stable disease, but could have up to 6 additional cycles until disease progression or unacceptable toxicity occurred. Seventy-six patients were included in the analysis. The median age was 63 years (range 38 84 years). Sixty-one patients had indolent B-cell NHL (46 follicular, 12 small lymphocytic lymphoma (SLL), one lymphoplasmacytoid, two marginal zone), and 15 had transformed disease (including 1 Burkett s lymphoma). Patients with follicular histologies (n=46) were categorised according to the following FLIPI risk groups: low-risk (26%), intermediate-risk (30%), and high-risk (33%). Sixty-seven patients had advanced stage disease. Patients had received a median of two (range 1 5) prior unique chemotherapy regimens. Of the 76 treated patients, 51 were refractory to single-agent rituximab, 18 were refractory to a rituximab-chemotherapy combination, and five were refractory to radioimmunotherapy.

The ORR for 74 assessable patients was 77%. Among the 45 patients with follicular lymphoma, the ORR was 82% including 7 complete responses and 10 unconfirmed complete responses. The median duration of response for responders was 6.7 months (95% CI 5.1 9.9 months); for patients with indolent lymphoma, it was 9 months (95% CI 5.8 16.7). Based on a median follow-up period of 26 months, median PFS was 7.1 months for all patients and 8.3 months (95% CI 6.6 10.9 months) for patients with indolent disease. Safety Study 1 The median number of cycles completed was 6 (range 1 8 cycles). Forty patients discontinued treatment early for the following reasons: adverse events (n=27), disease progression (n=10), patient decision (n=1), bone marrow transplantation referral (n=1), and an excessive treatment delay (n=1). Twenty-four patients (24%) had dose reductions because of adverse events. Neutropenia and thrombocytopenia were the most common reasons for dose reductions or delays. The mean relative dose intensity was 88%. Grade 3/4 neutropenia was noted in 61% of patients over the course of the study and led to GCSF administration in 38% of patients. Grade 3/4 thrombocytopenia was noted in 25% of patients and was the second most common reason for dose delays or reductions. Secondary malignancies were reported in 2 patients (myelodysplastic syndrome which was considered by the investigator to be possibly related to bendamustine, and squamous cell carcinoma that was considered unrelated to bendamustine). One or more serious adverse events were reported in 39 patients. In addition, 7 patients experienced serious adverse events that resulted in death. Four additional deaths were attributed to disease progression. Study 2 Patients received a median of 5 cycles of bendamustine (range 1-9 cycles). Thirty-four patients received at least 6 cycles. Forty-three patients discontinued bendamustine treatment before completing six cycles because of adverse events (n=23), disease progression (n=14), or patient or investigator decision (n=6). Thrombocytopenia was the most common reason for early study termination. Haematological toxicities, including neutropenia, anaemia, and thrombocytopenia were primarily grade 1/2 in severity, although there were 23 patients reporting grade 3 neutropenia (30%), 12 patients experiencing grade 3 thrombocytopenia (16%), 12 patients experiencing grade 3 anaemia, and 18 patients experiencing grade 4 neutropenia (24%). Secondary malignancies developed in three patients, all of whom eventually died. There were seven cases of infusional reactions, identified due to symptoms observed and recurrence with rechallenge. The symptoms included fever, hypotension, pain (back or muscle), and chills/ rigors occurring within 24 hours after receiving bendamustine. None of the patients experienced grade 4 reactions. Three patients discontinued bendamustine because of the infusional reaction syndrome. The remaining patients continued bendamustine with corticosteroid premedication. Updated analysis Cheson BD et al. pooled the data from studies 1 and 2 described above and subjected the data to additional analyses. Study 1 was ongoing at the time of the original publication and the updated analysis includes the final follow-up data from this study (7). Of the 176 patients in the two studies, 119 patients had follicular lymphoma (68%). Patients had received a median of 2 previous chemotherapy regimens (range 0 6 regimens). The median age was 61 years. Patients with transformed disease were excluded from the efficacy analysis, leaving 161 patients. The ORR was 76%, including 23% with complete response or unconfirmed complete response. At a median follow-up of 25.3 months (range 24 27.8 months), the DOR was 10 months (range 8.3 14 months). The median PFS was 9.7 months (95% CI 8.2 12.4 months). Cost The costs of bendamustine vials are 83 for 25mg vial and 330 for 100mg vial (which includes VAT). Using the dose of 120mg/m 2 and an average BSA of 1.75m 2, each dose would be 210mg and cost 745. Bendamustine is administered on days 1 and 2 of each cycle and so the cost per cycle would be 1490. Patients in study 1 had a median of 6 cycles and patients in study 2 had a median of 5 cycles. The cost of bendamustine for 1 patient for an average of 6 cycles would be 8900. Assuming epidemiology of 0.2/100,000, the cost per 100,000 population for 6 cycles would be 1800. Service implication Bendamustine is an intravenous infusion that would be administered on days 1 and 2 of a 21-day cycle as an outpatient appointment. The infusion is administered over 30 60 minutes. Because of the potential for infusion-related reactions, patients may require corticosteroid premedication.

Summary The manufacturer of bendamustine (Napp Pharmaceuticals) was invited to submit evidence for a NICE single technology appraisal (STA) in May 2010. In June 2010, the manufacturer informed NICE that it would not be making an evidence submission because it was unable to identify comparative clinical evidence suitable for a NICE appraisal in people with rituximab refractory disease. The manufacturer indicated that further research was ongoing but data would not be available in a time frame that would allow NICE to produce timely guidance. NICE therefore terminated this single technology appraisal. The manufacturer plan to make a resubmission to NICE when data from a comparative trial is available but there is no date as to when this will be. An updated analysis of studies 1 and 2 combined reported that after a median follow-up of 25.3 months (range 24 27.8 months), the DOR was 10 months (range 8.3 14 months) and the median PFS was 9.7 months (95% CI 8.2 12.4 months). The most commonly seen toxicities were haematological and the trials included a significant number of patients who suffered grade 3/4 neutropenia and thrombocytopenia which often led to dose delays or dose reductions. Secondary malignancies and infusion related reactions were also reported. The best available evidence to support bendamustine for this indication comes from two phase II non comparative trials. Both trials assessed bendamustine in patients with indolent B-cell lymphoma, of which follicular lymphoma made up the largest proportion of patients. Study 1, which included 62% of patients with follicular lymphoma, reported an overall response rate of 75% (95% CI 65 83%). Study 2 reported that among the 45 patients with follicular lymphoma, the ORR was 82% including 7 complete responses and 10 unconfirmed complete responses. Drug Indication Incidence (number of patients per 100,000 eligible for this treatment) Bendamustine Relapsed follicular lymphoma refractory to rituximab Average duration of treatment (taken from trial data) Cost per mont h/ cycle 0.2/100,000 6 cycles 1490 per cycle Cost per 100,000 population per month/ cycle 300 per cycle Cost per 100,000 for average treatment duration 1800 for 6 cycles

References 1. National Comprehensive Cancer Network guideline. Non-Hodgkin s lymphomas. Version 1. 2013. Available at http://www.nccn.org/ professionals/physician_gls/pdf/nhl.pdf 2. Friedberg JW et al. Bendamustine in patients with rituximab-refractory indolent ad transformed non-hodgkin s lymphoma: results from a phase II multicenter, single agent study. Journal of clinical oncology. 2008; 26(2):204 210 3. Kahl BS et al. Bendamustine is effective therapy in patients with rituximab-refractory, indolent B- cell non-hodgkin lymphoma. Results from a multicenter study. Cancer. 2010; 116:106 114 4. NICE terminated appraisal. Bendamustine for the treatment of indolent (low-grade) non- Hodgkin s lymphoma that is refractory to rituximab (terminated appraisal). October 2010. Available at http://www.nice.org.uk/nicemedia/ live/13254/51330/51330.pdf 5. Freedman JS, Aster JC. Clinical manifestations, pathological features, diagnosis, and prognosis of follicular lymphoma. Accessed 2/1/13. Available at http://www.uptodate.com/ contents/clinical-manifestations-pathologicfeatures-diagnosis-and-prognosis-of-follicularlymphoma 6. Ohmachi K et al. Multicenter phase II study of bendamustine for relapsed or refractory indolent B-cell non-hodgkin lymphoma and mantle cell lymphoma. Cancer science. 2010; 101 (9):2059 2064 7. Cheson BD et al. Bendamustine produces durable responses with an acceptable safety profile in patients with rituximab-refractory indolent non-hodgkin lymphoma. Clinical lymphoma, myeloma and leukemia. 2010; 10 (6):452 457 Details of search strategy: 1. EMBASE; BENDAMUSTINE/; 1276 results. 2. EMBASE; FOLLICULAR LYMPHOMA/; 7705 results. 3. EMBASE; 1 AND 2; 234 results. 4. EMBASE; *BENDAMUSTINE/; 410 results. 5. EMBASE; 2 AND 4; 62 results. 6. MEDLINE; bendamustine.ti,ab; 296 results. 7. MEDLINE; LYMPHOMA, FOLLICULAR/; 4058 results. 8. MEDLINE; 6 AND 7; 25 results. 9. EMBASE,MEDLINE; Duplicate filtered: [2 AND 4], [6 AND 7]; 87 results. 10. EMBASE; NONHODGKIN LYMPHOMA/; 44625 results. 11. EMBASE; 4 AND 10; 127 results. 12. MEDLINE; LYMPHOMA, NON-HODGKIN/; 29429 results. 13. MEDLINE; 6 AND 12; 45 results. 14. EMBASE,MEDLINE; Duplicate filtered: [4 AND 10], [6 AND 12]; 172 results The document reflects the views of LCNDG and may not reflect those of the reviewers Please direct any comments to Angela Bennett, London & South East Medicines Information Service, Guy s Hospital, Great Maze Pond, London SE1 9RT Tel: 020 7188 5026, Fax: 020 7188 3857, email: Angela.bennett@gstt.nhs.uk