Maintenance rituximab following response to first-line therapy in mantle cell lymphoma

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1 LONDON CANCER NEW DRUGS GROUP RAPID REVIEW Maintenance rituximab following response to first-line therapy in mantle cell lymphoma Maintenance rituximab following response to first-line therapy in mantle cell lymphoma Contents Summary 1 Background 2 Cost 4 References 6 Summary MCL is a moderately aggressive type of NHL with an incidence of approximately 1.2 per 100,000 population per year. For those patients who are unsuitable for high-dose therapy, first-line treatment regimens used most often in the UK include R-CHOP and R-FC. Although the disease often responds well to initial chemotherapy, durations of response are short and overall survival is poor (median of 3 years). Maintenance treatment has therefore been investigated as a way of prolonging duration of remission. A randomised, controlled study has compared R-CHOP and R-FC induction in older MCL patients unsuitable for high-dose therapy, and also compared rituximab and interferon alfa as maintenance therapy in responders. Rituximab maintenance (375mg/m 2 every two months) was found to reduce the risk of progression compared to interferon alfa (4-year remission rate of 58% versus 29%, respectively; HR 0.55; 95% CI ; p=0.01), with a median duration of remission of 75 months in the rituximab group and 27 months in the interferon group (p<0.001). Of note, the effects of rituximab were seen to differ according to the induction regimen received, and the influence of rituximab maintenance therapy on duration of remission was detected only for patients who received R-CHOP. Produced for the London New Drugs Group Contact: Nicky Pocock Medicines Information Pharmacist London & South East Medicines Information Service Guy s Hospital London SE1 9RT Although overall there was no statistically significant difference between the two maintenance regimens in terms of overall survival (secondary endpoint), rituximab was associated with higher 4-year survival than interferon alfa in those patients who had received CHOP-R (87% versus 63%; p=0.005). No effect on overall survival was seen in those who had received and responded to R-FC. It is not clear if the study was however powered for these analyses according to induction regimen received and overall survival was a secondary endpoint this finding would therefore require confirmation in further studies. The authors do not provide any reasoning as to why the response to rituximab maintenance may differ depending on the first-line treatment regimen used. Tel: Fax: Nicola.pocock@gstt.nhs.uk Produced for use within the NHS. Not to be reproduced for commercial purposes

2 Background Mantle cell lymphoma (MCL) is a rare type of B-cell non-hodgkin s lymphoma (NHL) that has a moderately aggressive course and is rarely curable with currently available standard treatment. The registered 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 (1). MCL is now recognised as having the worst outlook of all subtypes of lymphoma (3). Most patients present with advanced-stage disease, which warrants systemic treatment. Although the disease 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 (1-3). No standard of care for MCL is currently recognised, and an individualised approach to treatment is frequently needed. There is a lack of definitive data to guide treatment of this condition; due in part to it being relatively uncommon, and that it was only recognised as a specific entity in revised classifications published in In addition, MCL patients have often been included with other NHL types in clinical trials (3). Autologous peripheral blood stem cell transplantation (ASCT) may be an option for younger patients without significant co-morbidities, but only a few patients are suitable and it is associated with considerable morbidity and mortality (4). For those in whom this is not feasible, a range of chemotherapy options are available, and there is currently no gold standard (3). The most common first-line regimens used in the UK include R-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone and rituximab) and R-FC (fludarabine, cyclophosphamide and rituximab) (1). Only a small minority of patients with MCL achieve sustained remission after first-line therapy, and sequential therapies must normally be used (2). As well as being used in combination with chemotherapy for the treatment of patients with MCL, rituximab has been investigated as a maintenance therapy. Rituximab is not currently licensed for the treatment of MCL (5). Clinical guidelines The British Committee for Standards in Haematology (BCSH) published an updated guideline on the investigation and management of MCL in This notes that rituximab appears to prolong duration of response after chemotherapy but not overall survival, and the authors do not recommend its use as a maintenance therapy outside of a clinical trial (3). US guidelines from the National Comprehensive Cancer Network (NCCN) note that post-induction maintenance with rituximab may provide extended disease control for patients who are not physically fit or eligible to undergo aggressive first-line treatment regimens and stem cell transplantation. They recommend the use of rituximab maintenance (every 8 weeks until disease progression) for patients in remission following R-CHOP, who are not candidates for stem cell transplantation (6). Of note, neither guideline makes any recommendation as to the use of interferon alfa as maintenance therapy, which is what was used as the control in the main study (discussed below). Although the authors of this study say that maintenance interferon showed a tendency towards prolongation of progression-free survival in MCL and was therefore considered standard therapy in a previous trial, it does not appear as if this has been taken up as standard of care in clinical practice in the UK. A review article comments that although maintenance interferon was found to be effective, side-effects were frequently observed (7). Published data One published controlled trial has assessed rituximab maintenance in patients with MCL. This enrolled 560 patients (532 in the intention-to-treat [ITT] analysis) with stage II-IV MCL who were aged 60 years and above (median 70 years) and who would not have been eligible for high-dose treatment (8). They were first randomised to first-line open-label treatment with one of two induction regimens six cycles of R-FC (rituximab 375mg/m 2 day 1, fludarabine 30mg/m 2 days 1-3, cyclophosphamide 250mg/m 2 days 1-3) every 28 days (n=280; 265 ITT) or 8 cycles of R-CHOP (rituximab 375mg/m 2, cyclophosphamide 750mg/m 2, doxorubicin 50mg/m 2 and vincristine 1.4mg/m 2 on day 1; oral prednisone 100mg on days 1-5) every 21 days (n=280; 267 ITT). Patients who responded to firstline treatment and who had a leukocyte count >3x10 9 per litre and a platelet count >100 x 10 9 /litre (or >75 x 10 9 /litre, according to a subsequent protocol amendment) were offered the option of participating in the second randomisation to receive open-label maintenance therapy with either interferon alfa (3mU three times a week of standard interferon alfa or 1mcg/kg/week peginterferon alfa [with dose reductions/treatment interruptions in the event of toxicity]; n=161) or rituximab (375mg/m 2 every 2 months; n=155), given until disease progression. The primary endpoint for the induction regimen comparison was the rate of complete remission. The primary analysis included those patients who underwent randomisation and had started treatment in accordance with the randomisation result (n=485).

3 All secondary efficacy analyses were performed in the ITT population (n=532). Of note, the ITT population excluded patients who did not start treatment (n=9) and those who had no documented response (either as they were not staged for response or they were lost to follow-up; n=19), and the primary analysis excluded a further 47 patients, including 28 (14 in each group) who stopped treatment early, 17 patients who were found not to have MCL, and 2 who had stage I disease. The authors report that there was no statistically significant difference between R-FC and R-CHOP in terms of rate of complete remission (40% versus 34%; p=0.10) or overall response (78% and 86%, respectively; p=0.06). The rate of progression (secondary endpoint) was however higher during R- FC (14% versus 5% with R-CHOP) and the 4-year overall survival rate (secondary endpoint) was lower (47% versus 62% with R-CHOP; p=0.005). More patients who received R-FC died from infection (19 versus 12 in R-CHOP arm) or from a secondary cancer (9 versus 3), and 10% in the R-FC arm died during disease remission (versus 4% who received R-CHOP). Haematological adverse effects occurred more frequently in those receiving R-FC, although the rates of grade 3/4 infections were similar (17% versus 14%). The independent data and safety monitoring committee recommended closing the R- FC group due to the observed difference in overall survival. Duration of remission was the primary endpoint for the maintenance treatment comparison. A total of 316 patients underwent randomisation for maintenance therapy (184 who had received R-CHOP and 132 who had received R-FC). The main reasons for patients not undergoing randomisation in this phase (aside from not responding to induction) included persistent cytopenia, premature stop of the induction regimen, contra-indications, loss to follow-up, and patient/physician decision. A total of 274 of the randomised 316 were included in the primary analysis; the main reason for exclusion from this analysis was non-receipt of maintenance treatment (mainly due to cytopenia). The main results of the maintenance analysis, with a median follow-up of 36 months, were as follows: There was a large difference in the median duration of maintenance therapy 25 months with rituximab and 7 months with interferon alfa. At four years, 58% of the rituximab group and 29% of the interferon alfa group were in remission (HR for progression of death = 0.55; 95% CI ; p=0.01). In the ITT analysis the respective results were 57% and 34%. This would be equivalent to a number needed to treat (NNT) of 3-4. The median duration of remission was 75 months in the rituximab group and 27 months in the interferon group (p<0.001). As the effects of rituximab were seen to differ significantly according to the induction regimen received, stratified effects were reported. The influence of rituximab maintenance therapy on the duration of remission was detected only in patients who received R-CHOP. Overall survival did not differ between rituximab and interferon groups overall (4-year rates of 79% versus 67%; p=0.13). However there was again a significant modification of effect according to the induction regimen, and rituximab was found to be associated with improved overall survival in those who had received R-CHOP (4- year rates of 87% versus 63%; p=0.005) but not in those who received R-FC (p=0.48). The authors performed an additional analysis including 83 patients who had a response to induction therapy but who did not undergo maintenance randomisation prior to closure although not based on a randomised comparison, the response duration and survival time in those who received R-CHOP and no maintenance were much shorter than those who received R-CHOP followed by interferon maintenance (suggesting that the benefit seen for rituximab was not due to the fact that interferon maintenance was associated with worse outcomes compared to no maintenance). Toxic effects during the maintenance period were more pronounced with interferon alfa, with a higher incidence of leukocytopenia (83% versus 68% all grades; 33% versus 19% grade 3/4), thrombocytopenia (57% versus 33% all grades; 15% versus 6% grade 3/4), and fatigue (53% versus 29% all grades; 5% versus 1% grade 3/4). Rituximab maintenance was associated with more grade 1 and 2 infections (31% versus 17%). Improvements in overall survival with rituximab maintenance were only seen in patients who had previously received and responded to R-CHOP. The study was not however powered for these analyses according to induction regimen received and overall survival was a secondary endpoint this finding would therefore require confirmation in further studies. The authors do not offer any possible reasons as to why the effects of maintenance therapy may differ depending on the initial chemotherapy regimen received. Due to the exclusions applied, the patient group receiving maintenance therapy consisted of those who were in remission (fully documented), had not stopped induction therapy prematurely, and who had no persisting cytopenia. In addition the patients who were lost to follow-up or who withdrew were not accounted for in the analysis

4 (although small numbers 8). Although other studies utilising a rituximab maintenance regimen in patients with MCL who have responded to various chemotherapy regimens are available, they have not included any control group and therefore they have not been considered. Cost In the main study, rituximab was administered at a dose of 375mg/m 2 every 2 months and continued until disease progression. The median duration of rituximab therapy was 25 months in the rituximab group the average cost of treatment per patient (based on a BSA of 1.8m 2 ) can therefore be estimated as follows (including 20% VAT): Cost per dose of rituximab 675mg (1x500mg vial and 2x100mg vials) = 1,470 Cost per average course (based on median of 12 doses) = 17,600 Based on an average of two years of maintenance treatment and an eligible patient population of 0.61 per 100,000, the cost of providing rituximab maintenance therapy can be estimated as 5,380 per 100,000 for the first year, rising to 10,760 per 100,000 in year 2, after which it would stabilise. This is based on the following assumptions regarding the eligible population: Incidence of MCL: 1.2 per 100,000 population Proportion receiving R-CHOP or R-FC firstline: 80% (0.96) Proportion responding to induction therapy: 80% (0.77) Proportion of responders who are eligible for maintenance*: 80% (0.61) [*This estimation is based on the proportion of patients in the study who responded to treatment who actually went on to the randomisation for maintenance treatment.] Please note that these estimations have considered the results of patients who received both R-CHOP and R-FC as first-line chemotherapy and therefore they may be slightly different if maintenance treatment is used only in patients who have received and responded to R-CHOP chemotherapy. No controlled data for the use of rituximab maintenance following other chemotherapy regimens in the firstline treatment of MCL are available. Service implications The use of maintenance rituximab would increase resource use due to the need for intravenous infusion every 2 months. Summary of Costings Drug Indication Incidence (number of patients per 100,000 eligible for this treatment) Rituximab 375mg/m 2 every 2 months until disease progression Maintenance therapy in patients with MCL who have responded to first-line chemotherapy Average duration of treatment 0.61* 24 months (12 doses) Cost per 100,000 population* 5,380 in year 1 rising to 10,760 in year 2 *based on assumptions outlined in the cost section

5 References 1. NICE: Bendamustine in combination with rituximab for the first-line treatment of mantle cell lymphoma final scope w w w. n i c e. o r g. u k / n i c e m e d i a / live/13804/62172/62172.pdf 2. LCNDG review: Rituximab for mantle cell lymphoma (updated May 2011) Drug-Specific-Reviews/Rituximab-for-Mantle- Cell-Lymphoma/?query=mantle+cell&rank=92 3. British Committee for Standards in Haematology: Guidelines for the investigation and management of mantle cell lymphoma. Br J Haem atol; 159(4): /documents/ mcl_guideline.pdf 4. Martindale: The Complete Drug Reference; accessed via (accessed 8/2/2013) 5. Mabthera SPC (last revised 25/5/2012) 6. National Comprehensive Cancer Network Guideline: Non-Hodgkin s Lymphoma (version 1, 2013) 7. Witzens-Harig M et al (2012) Current treatment of mantle cell lymphoma: results of a national survey and consensus meeting. Ann Hematol; 91: Kluin-Nelemans HC et al (2012) Treatment of older patients with mantle cell lymphoma. NEJM; 367: Details of search strategy: EMBASE; exp *MANTLE CELL LYMPHOMA/ AND exp *RITUXIMAB/ [Limit to: Human and English Language] MEDLINE; exp *LYMPHOMA, MANTLE-CELL/ AND rituximab.af [Limit to: English Language and Humans]; Other reference sources used: NICE National Comprehensive Cancer Network Electronic Medicines Compendium National Electronic Library for Medicines Micromedex Healthcare Series; Martindale via Please direct any comments to Nicola Pocock, London & South East Medicines Information Service, Guy s Hospital, Great Maze Pond, London SE1 9RT Tel: , Fax: mailto:nicola.pocok@gstt.nhs.uk The document reflects the views of LCNDG and may not reflect those of the reviewers