- Research article
- Open Access
- Open Peer Review
Cost-effectiveness analysis of bortezomib in combination with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (VR-CAP) in patients with previously untreated mantle cell lymphoma
© The Author(s). 2016
- Received: 26 April 2016
- Accepted: 27 July 2016
- Published: 4 August 2016
Mantle cell lymphoma (MCL) is a rare and aggressive form of non-Hodgkin’s lymphoma. Bortezomib is the first product to be approved for the treatment of patients with previously untreated MCL, for whom haematopoietic stem cell transplantation is unsuitable, and is used in combination with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (VR-CAP). The National Institute of Health and Care Excellence recently recommended the use of VR-CAP in the UK following a technology appraisal. We present the cost effectiveness analysis performed as part of that assessment: VR-CAP versus the current standard of care regimen of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) in a UK setting.
A lifetime economic model was developed with health states based upon line of treatment and progression status. Baseline patient characteristics, dosing, safety and efficacy were based on the LYM-3002 trial. As overall survival data were immature, survival was modelled by progression status, and post-progression survival was assumed equal across arms. Utilities were derived from LYM-3002 and literature, and standard UK cost sources were used.
Treatment with VR-CAP compared to R-CHOP gave an incremental quality-adjusted life year (QALY) gain of 0.81 at an additional cost of £16,212, resulting in a base case incremental cost-effectiveness ratio of £20,043. Deterministic and probabilistic sensitivity analyses showed that treatment with VR-CAP was cost effective at conventional willingness-to-pay thresholds (£20,000–£30,000 per QALY).
VR-CAP is a cost-effective option for previously untreated patients with MCL in the UK.
- Mantle cell lymphoma
- Cost effectiveness
Mantle cell lymphoma (MCL) is a rare, incurable and aggressive sub-type of non-Hodgkin’s lymphoma (NHL), accounting for approximately 6 % of all NHL cases . The incidence of MCL in the UK is 0.9 per 100,000 . The general pattern of disease progression in MCL is one of relapse and remission, with each relapse becoming more difficult to treat, and the depth and durability of any subsequent remissions achieved invariably inferior to those achieved with first-line treatment [2–6].
In patients first presenting with aggressive disease requiring treatment, the initial treatment decision is whether patients are suitable for high-intensity induction therapy, to be followed by haematopoietic stem cell transplantation (HSCT). There are no strict criteria against which patients are assessed; rather, haematologists will assess eligibility on a patient-by-patient basis, taking into account factors such as patient age, performance status and disease prognosis, disease severity, co-morbidities, and clinical risk [2, 5–10].
For patients who are not eligible for high-intensity induction therapy, that is those for whom HSCT is unsuitable, there had been no licensed induction therapy regimens prior to bortezomib. Rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) became the preferred first-line induction therapy in UK clinics because the large scale European MCL Elderly trial  demonstrated a survival benefit for R-CHOP when compared with rituximab in combination with fludarabine and cyclophosphamide (R-FC). Alternative rituximab-based chemotherapy induction regimens are also administered in the first-line setting, but usually only for the frailest of patients considered unsuitable for R-CHOP therapy; while alternatives are considered to be associated with lower toxicity, the evidence base supporting their use is considerably weaker . Median progression-free survival (PFS) associated with chemotherapy is less than 2 years, and median overall survival (OS) is less than 5 years [10, 13–19].
Bortezomib is the first product to be licensed for the treatment of patients with previously untreated MCL for whom HSCT is unsuitable. Bortezomib is administered in combination with the rituximab, cyclophosphamide, doxorubicin, prednisone backbone familiar to clinicians as part of the R-CHOP regimen. A randomised, open-label, multicentre Phase III study (LYM-3002) comparing bortezomib, rituximab, cyclophosphamide, doxorubicin and prednisolone (VR-CAP) to R-CHOP showed a significant improvement in PFS (24.7 versus 14.4 months; hazard ratio [HR] = 0.63, p < 0.001) based on the primary assessment of PFS by the independent review committee (IRC) . Duration of overall response for VR-CAP was more than double that of R-CHOP (median of 36.5 versus 15.1 months), resulting in an increase in the treatment free interval (TFI) of almost 20 months versus R-CHOP (median of 40.6 versus 20.5 months; HR = 0.50, p < 0.001) .
There have been no previous technology appraisals by the National Institute of Health and Care Excellence (NICE) within MCL; other therapies that are frequently used such as bendamustine and temsirolimus did not go through the UK health technology assessment (HTA) process due to lack of marketing authorisation approval and manufacturer non-submission, respectively. To gain NICE recommendation for VR-CAP, the cost effectiveness of VR-CAP had to be assessed over the long term and beyond the duration of clinical trial follow up. As median survival for VR-CAP had not been reached in the LYM-3002 trial, it was challenging to provide realistic and robust estimates of long-term OS. This challenge is common in UK HTAs and will become more pronounced as regulatory and HTA bodies come under pressure to provide earlier access to promising drugs.
The objective of this study was to assess the cost effectiveness of VR-CAP compared to R-CHOP, in a UK setting, which is currently seen as standard first-line treatment for patients with MCL.
Baseline characteristics of all patients versus non-HSCT eligible patients only in the LYM-3002 trial
All patients (n = 487)
Clinically ineligible for HSCT only (n = 407)
Age at baseline
Rest of the World
Mean patient weight (kg)
Body surface area (m2)
Transitions between health states
Goodness of fit and model parameters for the PFS, PrePS and PPS curves
PrePS and PPS
Because of the immaturity of OS data, survival functions were stratified by progression status at the end of the trial (pre-progression survival [PrePS] and post-progression survival [PPS]). For non-progressed patients this was also stratified by trial arm. PPS was assumed equal across model arms. This was justified by the observation that PPS was similar for the VR-CAP and R-CHOP arms in the LYM-3002 trial , and the expectation that different prior treatments would not be expected to impact PPS . Finally, two studies identified in a literature review of surrogate endpoints in MCL also indicated that PFS may be an appropriate surrogate for OS [25, 26].
All adverse events (AEs) that happened at Grade 3 or higher in at least 5 % of either treatment group, as well as Grade 2 peripheral sensory neuropathy and Grade 3 or higher alopecia and sepsis, were included in the model, with rates as reported within the LYM-3002 trial. These were selected based on expectation of an important impact on costs, utility or both. The annual rate for each AE was calculated from the number of events in the LYM-3002 trial and the total patient years on treatment. This annual rate was then used to calculate the weekly probability of each AE.
In the model, red blood cell and platelet transfusions were administered to patients to treat AEs and to avoid having to decrease chemotherapy doses. Again, the weekly probability of requiring a transfusion was based on annual rates of administration in LYM-3002 .
Medical resource use and costs
Medical resource use for disease management by health state (Source of costs: NHS reference costs 2013–2014 )
On treatment (first- or second-line)
Stable disease (off treatment)
At time of progression
Full blood count
3 per treatment cycle
1 per 2–3 monthsa
3 per treatment cycle
1 per 2–3 monthsa
3 per treatment cycle
Computerised tomography scan
In treatment Cycles 1, 3 and 6
In treatment Cycles 1, 3 and 6
1 per 2–3 monthsa
1 per 2–3 monthsa
Cost inputs used in the model
Drug costs per treatment cycle
Administration costs first treatment cycle
NHS reference costs 2013–2014 
Administration costs per subsequent treatment cycle
NHS reference costs 2013–2014 
Cost per 90 days of second-line treatment & administration
Cost of care at end of life
Quality of life
Utilities applied to the model
The outcome used in this cost-effectiveness analysis was the cost per quality-adjusted life year (QALY). QALYs were calculated by multiplying the time a patient spent in a specific health state by the utility value associated with that health state. Average lifetime QALYs per patient were calculated as well as average lifetime costs. These were used to calculate the incremental cost-effectiveness ratio (ICER).
A series of one-way sensitivity analyses were performed changing one parameter at a time to the upper and lower limit of their 95 % confidence interval, respectively, holding all other parameters constant. This was done to evaluate the sensitivity of the model to individual model inputs. Additionally, a probabilistic sensitivity analysis (PSA) was performed where all parameters at once were randomly sampled from their distribution. This was iterated 1,000 times, so that the uncertainty around the point estimate of the model outcome could be tested. Through empirical testing it was found that 1,000 iterations were sufficient to capture the uncertainty around the base case ICER.
Scenario analyses were also performed testing the assumptions around PFS, OS and utilities, by changing assumptions and using alternative data sources.
Discounted base case model outcomes
Progression-free survival from first-line treatment
Progressed from first-line treatment
Progression-free survival from second-line treatment
Progressed from second-line treatment
First line therapy medication costs
Administration of first line therapy
Adverse events, transfusions & concomitant medication
Disease management costs
Second line treatment (medication and administration)
Deterministic ICER (£/QALY gained)
Probabilistic ICER (£/QALY gained)
Table 6 shows that VR-CAP patients have a longer PFS, whereas R-CHOP patients spend more time in the ‘progressed from second-line treatment’ health state than VR-CAP patients. This is due to the difference in PFS, while PPS is assumed to be equal between arms, generating a smaller difference in OS than PFS. The treatment cost accounts for the majority of the overall costs (Table 6), and therefore uncertainty around resource use and cost sources other than drug costs will have only a minor impact on model outcomes.
Results of scenario analyses
Exponential survival function for PFS
Weibull survival function for PFS
Log-normal survival function for PFS
Gamma survival function for PFS
Gompertz survival function for PFS
Weibull survival function for PrePS and PPS
Log-logistic survival function for PrePS and PPS
Log-normal survival function for PrePS and PPS
Gamma survival function for PrePS and PPS
Gompertz survival function for PrePS and PPS
Equal PrePS across arms
OS by trial arm instead of PrePS and PPS
Primary IRC assessment of PFS
Investigator assessment of PFS
Patients clinically ineligible for HSCT only
All utilities based on Doorduijn 2005 
Using utility decrement for progressing based on Doorduijn 2005 
The base case ICER of £20,043 indicates that VR-CAP is a cost-effective treatment option for patients with previously untreated MCL, using the standard UK threshold of £20,000–30,000 per QALY.
In the analysis, PFS is used as a surrogate for OS. This approach assumes that there is no survival benefit after a patients disease has progressed following treatment. When OS data were used directly to model cost effectiveness, the ICER increased slightly to £21,357. In this scenario it is assumed that there is a continued benefit of VR-CAP over R-CHOP after disease progression. The observation that OS, as modelled in the base case, shows a good reflection of the LYM-3002 data supports the use of PFS as a surrogate in the base case. A targeted literature review of NICE appraisals for cancer drugs from 2010 onwards identified two recent examples where PFS was used as a surrogate for OS either directly or indirectly (by assuming the same post-progression survival [PPS]) [37, 38]. In both cases, this methodology came under substantial scrutiny. Additionally, three submissions were identified where the same PPS was applied for all treatment arms [39–41].
There are some differences between the LYM-3002 trial population and MCL patients in the UK. As is often the case in clinical trials, the mean age of participants in LYM-3002 (64 years) was relatively low, compared with most patients who present at a median age of 73.5 in clinical practice in the UK . Additionally, only 30 % of patients enrolled in LYM-3002 came from the European Union or North America, with no patients included from the UK. However, efficacy results showed consistency between geographic regions both in the size of benefit with VR-CAP and the absolute PFS for R-CHOP. It is therefore unlikely that the geographic spread of countries included in the trial and the lack of UK patients had any relevant impact upon the results.
The status of the OS data is the main uncertainty in assessing the cost effectiveness of treatment. Despite the conclusion that modelled OS was reasonably comparable to long-term datasets, OS data for VR-CAP are immature. Once the final analysis of OS for LYM-3002 is available, the model could be re-assessed to confirm robustness of the current analysis.
The model does not take into account rituximab maintenance (R-maintenance) treatment for patients that respond to induction therapy, which has been adopted in clinical practice in recent years based on the findings of the European MCL Elderly trial . At the time of initiation of LYM-3002, R-maintenance was not commonly adopted and thus was not included in the trial design. There is a believe that R-maintenance therapy results in similar benefit after any CHOP-like induction regimen, and therefore we would expect to be able to give R-maintenance after VR-CAP induction with a similar extension to median survival times as observed with R-maintenance after R-CHOP induction . As the European MCL Elderly trial was not designed to assess the clinical efficacy of induction therapy with versus without maintenance therapy, it could not be used to model R-maintenance.
When submitted to NICE, the evidence review group agreed that immature data may bias the extrapolation of survival data, and had some concerns about the methods used to overcome this. It was argued that if data are too immature to model OS for all patients, it would be questionable whether sufficient data are available to separately estimate long-term survival for patients with and without progression. However, the uncertainty was reduced for patients who had progressed as a smaller proportion of patients at risk were still alive at the time of evaluation. Furthermore, the data for the two treatment arms is pooled and thereby the total sample size is increased. The uncertainty of survival for patients who had not progressed may be increased by using this method, but this was accounted for by including general population mortality for patients that had not yet progressed. In doing so, it was assumed that all deaths in the PrePS curves (prior to adjustment for background mortality) in the trial were deaths from MCL. This was a reasonable assumption as the number of deaths reported in the LYM-3002 trial that were not due to progression or toxicity was very low. Of the 69 deaths in total in the VR-CAP group, there were only eight deaths that were not due to progression or AEs. In the R-CHOP group, there were a total of 87 deaths, of which 14 were not due to progression or AEs .
A submission for HTA was also made to the Scottish Medicines Consortium (SMC), who also noted that there are limitations arising from the maturity of the survival data, but found it unlikely that the approach taken would cause substantial bias in favour of VR-CAP. The SMC noted that this was supported by the literature providing evidence of an association between PFS and OS in MCL. In addition, it was noted that the modest impact on the ICER from uncertainty associated with varying survival inputs meant that the ICER for VR-CAP was robust .
In 2015 both NICE and the SMC accepted the overall approach taken in the cost-effectiveness model as a basis for their conclusion that VR-CAP represents a cost-effective treatment option for previously untreated MCL for whom HSCT is unsuitable, in the UK [22, 44]. VR-CAP is now recommended for use within the National Health Service.
The current model shows that VR-CAP is a cost effective treatment option for patients with previously untreated MCL, for whom haematopoietic stem cell transplantation is unsuitable, in the UK. Both NICE and SMC have recommended the use of VR-CAP in these patients.
AE, adverse event; ECOG, Eastern Cooperative Oncology Group; HMRN, Haematological Malignancy Research Network; HSCT, haematopoietic stem cell transplantation; HTA, health technology assessment; ICER, incremental cost-effectiveness ratio; IRC, independent review committee; IV, intravenous; MCL, mantle cell lymphoma; NHL, non-hodgkin lymphoma; NHS, National Health Services; NICE, National Institute for Health and Care Excellence; OS, overall survival; PFS, progression-free survival; PPS, post-progression survival; PrePS, pre-progression survival; PSA, probabilistic sensitivity analysis; QALY, quality-adjusted life year; R, rituximab; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone; R-FC, rituximab, fludarabine and cyclophosphamide; SEER, Surveillance, Epidemiology, and End Results Program; SMC, Scottish Medicines Consortium; TFI, treatment-free interval; UK, United Kingdom; VR-CAP, bortezomib, rituximab, cyclophosphamide, doxorubicin and prednisolone
We thank the patients who participated in the LYM-3002 study and their families; the investigators and all the staff members at all the clinical sites.
This research was funded by Janssen-Cilag.
Availability of data and materials
The datasets generated during and/or analysed during the current study are not publicly available due confidentiality of patient-level data but are available from the corresponding author on reasonable request.
MvK, KG and DL conducted the research. PT conducted statistical analyses to support the research. All authors (MvK, KG, DS, PT and DL) were involved in writing the paper and had final approval of the submitted and published versions. All authors read and approved the final manuscript.
KG was an employee of Janssen at the time of the research, DS and PT are employees of Janssen. MvK and DL are employees of BresMed who were paid by Janssen to conduct the research.
Consent for publication
Ethics approval and consent to participate
Study LYM-3002 was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements. The study protocol and amendments were reviewed and approved by a local Independent Ethics Committee or Institutional Review Board at each study site. These are detailed in the Additional file 1.
Subjects or their legally acceptable representatives provided their written consent to participate in the study after having been informed about the nature and purpose of the study, participation/termination conditions, and risks and benefits of treatment. Informed consent was obtained after the study was fully explained and before the performance of any study-related activity.
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