Follicular lymphoma - rituximab
Rituximab for the treatment of follicular lymphoma (TA110)
3. The manufacturer’s submission
The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of rituximab and a review of this submission by the evidence review group (ERG) (appendix B).
3.1. Both the clinical effectiveness and the cost effectiveness evidence in the manufacturer’s submission were based on the registration study M39021. This study compared rituximab plus CVP with CVP alone in 322 patients with previously untreated stage III and IV follicular lymphoma. In this study the median age of the participants was 53 years. Approximately one third were diagnosed with grade 1 lymphoma, half with grade 2 lymphoma and 10% with grade 3 lymphoma. The primary end point in the trial was time to treatment failure (TTF), a composite outcome based on the time to the first of: progressive disease or relapse after response, death, new antilymphoma treatment, and stable disease after cycle 4 of treatment.
3.2. The registration study M39021 showed a statistically significant difference in median TTF after a median of 42 months follow-up (range 1.5–60 months). The median TTF in the rituximab plus CVP arm was 27 months compared with 6.6 months in the CVP-alone arm (risk reduction 66%, 95% confidence interval 55 to 74%). The median overall survival was not estimable for either arm, but Kaplan–Meier estimates for overall survival at 36 months were 89% in the rituximab plus CVP arm and 81% in the CVP arm (p = 0.07). In the rituximab plus CVP arm, 71% of patients experienced an adverse event in the first 24 hours of treatment compared with 51% of patients in the CVP arm. The manufacturer’s submission states that this difference was mainly attributable to rituximab-related infusion reactions. In addition, a greater proportion of patients in the rituximab plus CVP arm experienced neutropenia as compared to patients in the CVP arm (24.1% compared with 14.5%, respectively).
3.3. Four additional studies (GLSG, MMHSG, OSHO39 and FL-2000) were included in the manufacturer’s submission as supporting evidence. These all investigated the impact of rituximab as a first-line therapy for patients with follicular lymphoma, but not within the licensed indication of rituximab plus CVP. In all four studies patients were given an anthracycline-containing chemotherapy regimen either with or without rituximab. One of the four studies (MMHSG) also included a third arm of patients who received rituximab monotherapy. Three of the four studies (GLSG, OSHO39, FL-2000) showed statistically significant differences in measures of survival without disease favouring the addition of rituximab, and two of the four (GLSG, OSHO39) showed statistically significant differences in measures of overall survival, again favouring the rituximab-containing arms.
3.4. The economic analyses provided by the manufacturer were modelled using a three-state Markov model with a life time horizon. Progression-free survival following first-line therapy was taken from the registration study M39021, and was assumed to translate into a gain in overall survival. The initial age of the cohort entering the model was assumed to be 53 years, reflecting the median age of the participants in the registration study. Survival following first-line relapse was modelled using data taken from the Scottish and Newcastle lymphoma group (SNLG) database and was assumed to be the same for both the rituximab plus CVP and the CVP arms. Rituximab as a second-line or subsequent therapy was not included as a treatment option in either the rituximab plus CVP or the CVP arm. Cost data for first-line therapy were not taken from trial M39021 but were sourced from published literature. Cost data for second-line and subsequent therapies were sourced from a single study which investigated the average lifetime cost of treating a patient with follicular lymphoma. Utilities were sourced from a study of 215 patients with follicular lymphoma commissioned by the manufacturer. Neither costs nor disutilities associated with adverse events were included in the model.
3.5. The manufacturer provided a cost-effectiveness estimate of £8290 per incremental quality-adjusted life year (QALY) gained. One-way sensitivity analyses gave estimates of cost effectiveness ranging from £6790 to £26,602 per incremental QALY gained. A sensitivity analysis including the costs of chlorambucil but assuming equal efficacy with CVP gave an estimate of £9752 per incremental QALY gained.
3.6. The ERG identified no further studies of rituximab for the treatment of first-line stage III and IV follicular lymphoma. They noted that CVP is one of a number of possible comparators for rituximab plus CVP, and that treatment options include alkylator-based regimens, anthracycline-based regimens and fludarabine-based regimens. The ERG assessed the characteristics of the patients included in the registration trial and concluded that they were representative of the general population of patients in England and Wales, except that they tended to be relatively younger than might be expected for patients with follicular lymphoma.
3.7. The ERG analysed the manufacturer’s model. Initially, they made adjustments to minor assumptions in the model and some model formulae. These adjustments only marginally altered the cost per incremental QALY, which remained approximately £8500. In addition to these minor adjustments the ERG explored key assumptions firstly around the age of the cohort and secondly around the translation of gains in progression-free survival into overall survival. The first of these analyses suggested that if the initial age of the cohort included in the model was 60 years, 70 years or 75 years rather than 53 years, the costs per incremental QALY gained would be approximately £9000, £11,000 and £17,000, respectively. The second set of analyses, which assumed that 0%, 30% and 50% of progression-free survival translated into overall survival, gave estimates of the cost per incremental QALY gained of approximately £27,500, £14,500 and £12,000, respectively.
3.8. Full details of all the trials are in the manufacturer’s submission and evidence review group report, which are available from www.nice.org.uk/TA110.
