This paper presents a summary of the Evidence
Review Group report for the single technology
appraisal entitled Rituximab for the first-line
maintenance treatment of follicular non-Hodgkin’s
lymphoma
J Greenhalgh,* A Bagust, A Boland, M Blundell, J Oyee,
Y Dundar, J Hockenhull, C Proudlove and P Chu
Liverpool Reviews and Implementation Group (LRiG), University of Liverpool,
Liverpool, UK
*Corresponding author
Declared competing interests of authors: none
This report should be referenced as follows:
Greenhalgh J, Bagust A, Boland A, Blundell M, Oyee J, Dundar Y, et al. Rituximab for the first-line
maintenance treatment of follicular non-Hodgkin’s lymphoma. Southampton: NETSCC; 2012.
Single Technology Appraisal 2012
Rituximab for the first-line maintenance treatment of follicular
non-Hodgkin’s lymphoma
J Greenhalgh,* A Bagust, A Boland, M Blundell, J Oyee, Y Dundar,
J Hockenhull, C Proudlove and P Chu
Liverpool Reviews and Implementation Group (LRiG), University of Liverpool, Liverpool, UK
*Corresponding author
HTA 08/218/01
Date of ERG submission:
7 October 2010
TAR Centre(s):
Liverpool Reviews and Implementation Group (LRiG), University of Liverpool
List of authors:
J Greenhalgh, A Bagust, A Boland, M Blundell, J Oyee, Y Dundar, J Hockenhull, C Proudlove and P Chu
Contact details:
Dr Janette Greenhalgh, Research Fellow, Liverpool Reviews and Implementation Group, University of Liverpool,
Liverpool L69 3GB, UK
E-mail: Janette.Greenhalgh@liv.ac.uk
The research reported in this article was commissioned and funded by the HTA programme on behalf of
NICE as project number 08/218/01. The assessment report began editorial review in October 2010 and was
accepted for publication in January 2011. See the HTA programme website for further project information
(www.hta.ac.uk). This summary of the ERG report was compiled after the Appraisal Committee’s review.
The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the
Department of Health.
Discussion of Evidence Review Group reports is invited. Visit the HTA website correspondence forum (www.hta.
ac.uk/correspond).
Abstract
This paper presents a summary of the Evidence Review Group (ERG) report describing the
clinical effectiveness and cost-effectiveness of rituximab (RTX) within its licensed indication as
maintenance therapy for patients with previously untreated follicular non-Hodgkin’s lymphoma
(fNHL), whose disease has responded to induction therapy with RTX and chemotherapy
(R-CTX). It is based upon the evidence submission from Roche to the National Institute for
Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The
submitted clinical evidence discussed in this paper is derived from an unpublished randomised
controlled trial (RCT) that compared RTX maintenance treatment with observation in patients
with untreated fNHL who had responded to R-CTX induction therapy. The primary trial
outcome was progression-free survival (PFS); the range of secondary outcomes included eventfree survival and overall survival (OS). The trial had been closed early following an interim data
analysis; at the time of closure, median time to event could not be calculated for any outcome.
The results appeared to show a statistically significant benefit of RTX maintenance treatment
compared with observation alone for the primary outcome of PFS and a range of secondary
© Queen’s Printer and Controller of HMSO 2012. This work was produced by Greenhalgh et al. under the terms of a commissioning contract issued by
the Secretary of State for Health.
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Rituximab for the first-line maintenance treatment of follicular non-Hodgkin’s lymphoma
end points. For the outcomes of OS and transformation rate at first progression, lack of events
precluded meaningful analysis. The ERG considered that the RCT was well designed, but that
the data submitted by the manufacturer were too immature to draw definite conclusions as to
the clinical effectiveness of RTX as a first-line maintenance treatment for patients with fNHL.
The ERG considered that the cost-effectiveness of RTX maintenance treatment, compared with
observation only, could not be assessed given the limited clinical data available. The ERG report
concluded that the results of the trial appeared promising but, at the time of the appraisal, it was
not possible to draw any firm conclusions as to the clinical effectiveness and cost-effectiveness of
the treatment.
Introduction
The National Institute for Health and Clinical Excellence (NICE) is an independent organisation
within the NHS, which is responsible for providing national guidance on the treatment and care
of people using the NHS in England and Wales. One of the responsibilities of NICE is to provide
guidance to the NHS on the use of selected new and established health technologies, based on an
appraisal of those technologies.
NICE’s single technology appraisal (STA) process is specifically designed for the appraisal of a
single product, device or other technology, with a single indication, where most of the relevant
evidence lies with one manufacturer or sponsor.1 Typically, it is used for new pharmaceutical
products close to launch. The principal evidence for a STA is derived from a submission by the
manufacturer/sponsor of the technology. In addition, a report reviewing the evidence submission
is submitted by the Evidence Review Group (ERG), an external organisation independent of
the Institute. This paper presents a summary of the ERG report for the STA ‘Rituximab for the
first-line maintenance treatment of follicular non-Hodgkin’s lymphoma’.2
Description of the underlying health problem
Follicular lymphoma is one of a group of diseases known collectively as non-Hodgkin’s
lymphomas (NHLs) – cancers arising from the lymphoid cells of the immune system. These cells
normally have a key role in protecting the body from pathogenic microorganisms. Malignant
transformation of lymphocytes results in their uncontrolled replication, usually starting within
the lymph nodes, mainly those of the neck, armpits and groin. Swelling of these structures
often provides the first clinical manifestation of illness, though other symptoms including
fever, drenching night sweats, weight loss and tiredness may also be present at diagnosis or
develop later.
Most cases of NHL, including follicular NHL (fNHL), have no identifiable cause, although a
number of risk factors are known. These include chronic immunodeficiency caused by disease
or drugs and certain infectious agents (e.g. Helicobacter pylori infection, which is associated with
mucosa-associated lymphatic tissue lymphomas). Environmental factors, such as occupational
exposure to tetrachloroethylene and agricultural biocides, have also been suggested as possible
causes of lymphoma.3
In 2007, there were 10,917 new cases of NHL recorded in England and Wales;3 between 22% and
40% of these were likely to be fNHL.4 The majority of these fNHL cases (85%) would have been
diagnosed as stage III/IV cancers requiring systemic therapy.5 The age-standardised incidence
rate for NHL increased by more than one-third (35%) in the 20-year period between 1988
and 2007, mirroring the increases in many other countries.3 In the late 1990s and early 2000s,
incidence showed signs of levelling off, suggesting that the recent rapid growth in new cases of
Single Technology Appraisal 2012
NHL is slowing. The incidence of NHL is similar in men and women (M/F ratio 1.1 : 1.0) and
increases with age – rates increase sharply in people > 50 years and around two-thirds of all cases
are diagnosed in people > 60 years of age.3
Survival for patients with fNHL is prolonged; median survival of 8–10 years from diagnosis is
typical.6,7 Recent large population-based8 and single-institution studies show that survival is
improving, probably as a consequence of better treatment.9–11 Even at 8–10 years, survival is about
double that reported in the years before the advent of cytotoxic chemotherapy (CTX), indicating
that appropriate treatment does alter the long-term course of the disease.12 Despite this, most
patients with fNHL ultimately die of their disease.
Prognosis is partly determined by the extent of disease at diagnosis, which is usually described
using the Ann Arbor13 staging system.
Patients considered to have limited, stages I or II, disease (approximately 15%) may be candidates
for localised radiotherapy treatment, which can have a curative potential.14 Systemic therapy
is recommended only in patients with stages III and IV disease with evidence of systemic
symptoms, high tumour burden, rapid disease progression or other key features. No curative
therapy has been established for patients with advanced follicular lymphoma,14 so, once treatment
is required, the natural course of the disease follows a cycle of treatment-induced remission
followed by eventual relapse. Each remission duration becomes shorter and fewer patients
respond to each cycle of therapy.15,16
Approximately 93% of all eligible previously untreated patients with stages III–IV
follicular lymphoma in the UK currently receive rituximab (RTX) plus CTX (R-CTX) as
standard treatment.17
After a patient’s first response to R-CTX, the standard UK practice is to closely observe patients
until evidence of disease progression, at which point second-line therapy is initiated. The aim of
using RTX maintenance therapy in previously untreated fNHL patients responding to induction
therapy is to extend and deepen the first and often most durable remission.15,16 It would be
expected that extended progression-free survival (PFS) yielded by RTX maintenance would delay
time to relapse and therefore the burden of further CTX treatment.18,19 This approach may also
ultimately extend patient overall survival (OS), but will require a long period of follow-up to
become apparent.
Scope of the Evidence Review Group report
The ERG report presents the results of the assessment of the manufacturer’s (Roche Ltd) evidence
submission regarding the use of RTX maintenance compared with observation alone for the
first-line treatment of fNHL for patients whose disease responds to induction R-CTX. The
report includes an assessment of both the clinical effectiveness and cost-effectiveness evidence
submitted by the manufacturer. The primary clinical outcome measure was PFS with secondary
outcomes of event-free survival (EFS), OS, time to next anti-lymphoma treatment, overall
response rate, transformation rate at first progression, safety and quality of life (QoL). Costeffectiveness was measured in terms of incremental cost per quality-adjusted life-year (QALY)
gained.
Rituximab is licensed in Europe as a treatment for fNHL in combination with chemotherapy in
patients with advanced disease who have not been treated before. In December 2010, the license
was extended to include the use of rituximab as a maintenance treatment for patients whose
follicular lymphoma has responded to initial chemotherapy.
© Queen’s Printer and Controller of HMSO 2012. This work was produced by Greenhalgh et al. under the terms of a commissioning contract issued by
the Secretary of State for Health.
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Rituximab for the first-line maintenance treatment of follicular non-Hodgkin’s lymphoma
Methods
The ERG report comprised a critical review of the evidence for the clinical evidence and costeffectiveness of the technology based upon the manufacturer’s/sponsor’s submission to NICE as
part of the STA process.
The ERG evaluated the quality of the manufacturer’s clinical effectiveness review. Searches
conducted by the manufacturer were assessed for completeness and the single trial put forward
as evidence of clinical effectiveness was critically appraised using a standard tool.20 With regard
to cost-effectiveness evidence, the ERG assessed the manufacturer’s searches for completeness,
critically appraised the submitted economic model using a standard assessment tool21 and
conducted a detailed evaluation of the model. The ERG recalculated the base-case costeffectiveness results taking changes in parameters and assumptions into account, for example
omitted health states and pathways, mid-cycle correction, overall PFS utility value, patient age
and duration of treatment benefit.
Results
Summary of submitted clinical evidence
The main source of clinical evidence described in the manufacturer’s submission was the
unpublished PRIMA (Primary RItuximab and MAintenance) trial.22 The PRIMA22 trial included
1019 patients with high-tumour-burden untreated fNHL (90% stages III/IV) who had a complete
response (CR), unconfirmed complete response (CRu) or partial response (PR) to R-CTX
induction therapy and were then randomised to receive either RTX monotherapy or observation
for 2 years or until disease progression. The manufacturer reported clinical effectiveness results
at several time points. For the primary end point of PFS, the median time to event (MTE) for
patients in the RTX arm was not estimable owing to the lack of events (Table 1); the median PFS
in the observation arm was 48.36 months. For the secondary end points of EFS, time to next
anti-lymphoma treatment, time to next CTX treatment and overall response rate, and statistically
significant differences were reported in favour of RTX, although the MTE was calculable only
for EFS in the observation arm (see Table 1). For the outcomes of OS and transformation rate at
first progression, lack of events precluded meaningful analysis. Subgroup analyses of age, gender,
Follicular Lymphoma International Prognostic Index (FLIPI) prognosis, type of induction CTX
and response to induction indicated that all patients benefited equally from RTX treatment; the
trial was not powered to detect differences between subgroups. Incidences of adverse events
(AEs) were higher in the RTX arm than in the observation arm; however, no unexpected safety
findings were noted. No statistically significant differences were reported for QoL.
Summary of submitted cost-effectiveness evidence
In the absence of any relevant UK-based economic evaluations of RTX as a first-line maintenance
treatment for patients with fNHL, the manufacturer conducted a de novo economic evaluation.
The manufacturer developed a four-state Markov model, in which patients are assumed to be
within one of four possible discrete health states at any given time: ‘PFS/first-line maintenance’
(PFS1), ‘PFS/second-line treatment’ (PFS2), ‘progression’ (PD) or ‘death’. The model was
developed to reflect a 25-year lifetime horizon framework in order to capture all relevant
costs and benefits associated with treating a patient with fNHL. The perspective adopted in
the economic evaluation was that of the NHS and Personal Social Services (PSS) and costs
and benefits were discounted at 3.5% per annum. Clinical-effectiveness data from two RCTs
[PRIMA22 and European Organization for Research and Treatment of Cancer (EORTC)
2098118,19] were used to populate the submitted economic model. QALYs were estimated using
Single Technology Appraisal 2012
TABLE 1 Primary rituximab and maintenance (PRIMA) trial22 key outcomes
End point
RTX (n = 505)
Observation (n = 513)
HR (95% CI)
p-value
0.55 (0.44 to 0.68)
p < 0.0001
HR = 0.59 (0.48 to 0.72)
p < 0.0001
HR = 0.87 (0.45 to 1.47)
p = 0.6010
HR = 0.60 (0.47 to 0.76)
p < 0.0001
HR = 0.62 (0.47 to 0.81)
p = 0.0005
Primary: investigator-assessed PFS – June 2010 (median follow-up 38 months)
Median time to event (months)
NE
48.36
Secondary end points – January 2010 (median follow-up 36 months)
Event-free survival
Median time to event
NE
1381 days (45.4 months)
25th percentile
1000 days (32.8 months)
497 days (16.3 months)
One-year event-free rate (95% CI)
0.89 (0.86 to 0.92)
0.81 (0.78 to 0.84)
Median time to event
NE
NE
25th percentile
NE
NE
One-year event-free rate (95% CI)
0.99 (0.98 to1.00)
0.99 (0.98 to 1.00)
Median time to event
NE
NE
25th percentile
1328 days (43.6 months)
775 days (25.5 months)
One-year event-free rate (95% CI)
0.92 (0.89 to 0.94)
0.89 (0.87 to 0.92)
Overall survival
Time to next anti-lymphoma treatment
Time to next CTX treatment
Median time to event
NE
NE
25th percentile
NEa
975 days (32.0 months)
One-year event-free rate (95% CI)
0.92 (0.90 to 0.95)
0.91 (0.89 to 0.94)
CI, confidence interval; CTX, cytotoxic chemotherapy; ERG, Evidence Review Group; HR, hazard ratio; NE, not estimable; PFS, progression-free
survival; RTX, rituximab.
a The ERG notes that this NE is likely to be a typing error as this figure was reported at an earlier time point.
European Quality of Life-5 Dimensions (EQ-5D) data from a previously published Rochecommissioned study of UK patients with fNHL.23 In summary, the base-case incremental
cost-effectiveness ratio (ICER) for first-line RTX maintenance therapy versus observation was
estimated to be £15,978 per QALY gained. The manufacturer showed the ICER to be robust
when subjected to structural, deterministic analysis and probabilistic sensitivity analysis; the
manufacturer’s ICERs ranged from £8966 per QALY gained to £21,151 per QALY gained.
Commentary on the robustness of submitted clinical evidence
A single, international, multicentre open-label RCT made up the basis of the clinical effectiveness
and cost-effectiveness evidence in the manufaturer’s submission. The results of PRIMA22 were
at that time unpublished. Overall, the ERG considered that the PRIMA22 trial was well designed
with centralised random allocation and safeguards to mitigate against possible bias. The
treatments used in the PRIMA22 trial were similar to those used in UK clinical practice and the
patients recruited to the trial were similar to those who would be treated in UK clinical practice.
The ERG noted that several important protocol amendments (e.g. changing primary outcome
and increasing sample size) were made during the course of the trial and the trial was stopped
early; however, these actions appeared to have been permitted in accordance with the protocol.
The ERG noted that, at the time of closure, median PFS was not reached (and remains not
estimable) and that none of the patients in the trial had been followed up for more than 4 years
(recommended 7 years in the protocol). Although the clinical data appeared to show a benefit
© Queen’s Printer and Controller of HMSO 2012. This work was produced by Greenhalgh et al. under the terms of a commissioning contract issued by
the Secretary of State for Health.
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Rituximab for the first-line maintenance treatment of follicular non-Hodgkin’s lymphoma
for patients in the RTX arm, the ERG considered that data submitted were too immature to draw
definite conclusions as to the clinical effectiveness of RTX as a first-line maintenance treatment
for patients with fNHL.
The ERG was of the opinion that the cost-effectiveness of RTX as a first-line maintenance therapy
compared with observation in patients with fNHL who respond to first-line treatment could not
be assessed given the limited clinical data available. The ERG considered that too few events were
recorded in the PRIMA22 trial to make any firm conclusions regarding the clinical effectiveness,
and therefore cost-effectiveness, of RTX as a first-line maintenance treatment compared with
observation alone for patients with previously untreated fNHL who have responded to R-CTX
induction. The ERG considered that there were a number of errors and inconsistencies in
the economic model (e.g. omitted health states and pathways, use of PFS instead of EFS as
key outcome, use of non-comparable clinical effectiveness evidence from a second clinical
data source, non-standard use of discounting method, inaccurate costing of RTX treatment,
underestimation of AEs). However, the ERG acknowledged that their correction would probably
not substantially affect the size of the manufacturer’s base-case ICER. The ERG was more
concerned with the limited clinical trial data available to inform estimates of health gain in the
economic model. Finally, the ERG identified that the cost-effectiveness results were not robust to
two key model assumptions (e.g. patient age and duration of RTX benefit).
In summary, the ERG was of the opinion that the nature of the evidence submitted meant
that it was impossible to compare the cost-effectiveness of first-line RTX maintenance versus
observation in patients with fNHL with any confidence.
Conclusions
Although the results presented in the manufacturer’s submission appeared to be promising, the
early closure of the PRIMA22 trial, combined with limited follow-up, resulted in an immature
data set; too few patients have experienced events to draw any firm conclusions on clinical
effectiveness and cost-effectiveness from the available data.
The ERG considered that direct use of the submitted economic model results was too heavily
affected by extensive and unquantifiable uncertainty around the central claims of clinical benefit
to be useful for decision-making, i.e. the limited clinical data available made it impossible to
compare the cost-effectiveness of first-line RTX maintenance versus observation in patients with
fNHL with any confidence.
Summary of NICE guidance issued as a result of the STA
Following two further AC meetings, the guidance document issued by NICE on June 2010
states that:
Rituximab maintenance therapy is recommended as an option for the treatment of people with
follicular non-Hodgkin’s lymphoma that has responded to first-line induction therapy with
rituximab in combination with chemotherapy.
Single Technology Appraisal 2012
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