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									TITLE: Rituximab for Non-Hodgkin’s Lymphoma: A Review of the Clinical and Cost-
       Effectiveness and Guidelines

DATE: 11 January 2010

CONTEXT AND POLICY ISSUES:

Non-Hodgkin’s lymphoma is the most common hematological malignancy in adults.1
Approximately 85% of non-Hodgkin’s lymphomas in adults are of B-cell origin.2 Non-Hodgkin’s
lymphomas are often classified as indolent (low grade) or aggressive (high grade).1 Although
slow growing, indolent lymphomas are usually incurable. In contrast, aggressive lymphomas
can rapidly lead to death but are often curable.1

Diffuse large B-cell lymphoma and follicular lymphoma and are the most common subtypes of
non-Hodgkin’s lymphoma accounting for about 31% and 22%, respectively, of new cases.2
Although considered aggressive in nature, diffuse large B-cell lymphomas can be treated with
curative intent using combination chemotherapy regimens.3 However, relapse is still common
following treatment in these patients.4 Follicular lymphoma is a low-grade lymphoma
characterized by slow disease progression and a median survival of eight to ten years.5
Although patients with follicular lymphoma can often sustain prolonged remissions, they
inevitably relapse and require subsequent courses of therapy that lead to fewer and shorter
remissions.5 Hence, treatment with combination chemotherapy in patients with follicular
lymphoma focuses on the palliation of symptoms.

Rituximab (Rituxan®, Hoffmann-La Roche Ltd.), a genetically engineered monoclonal antibody,
represents a novel approach to the management of non-Hodgkin’s lymphoma.1 Rituximab
targets a specific protein known as CD20 on the surface of B-cells resulting in cell death.6
Health Canada has approved rituximab for the treatment of relapsed or refractory low grade or
follicular lymphoma, for patients with diffuse large B-cell lymphoma in combination with
cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy, for patients
with previously untreated advanced (stage III or IV) follicular lymphoma in combination with
cyclophosphamide, vincristine, and prednisolone (CVP) chemotherapy, and for the maintenance
of remission in patients with follicular lymphoma who have responded to induction therapy with

Disclaimer: The Health Technology Inquiry Service (HTIS) is an information service for those involved in planning and providing health care in
Canada. HTIS responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to provide a list
of sources and a summary of the best evidence on the topic that CADTH could identify using all reasonable efforts within the time allowed.
HTIS responses should be considered along with other types of information and health care considerations. The information included in this
response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a
particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness
particularly in the case of new and emerging health technologies, for which little information can be found, but which may in future prove to be
effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date,
CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the
report.

Copyright: This report contains CADTH copyright material. It may be copied and used for non-commercial purposes, provided that attribution is
given to CADTH.

Links: This report may contain links to other information available on the websites of third parties on the Internet. CADTH does not have control
over the content of such sites. Use of third party sites is governed by the owners’ own terms and conditions.
either CHOP or CHOP plus rituximab (R-CHOP).6 Although better tolerated than conventional
chemotherapy regimens, rituximab has been associated with rare cases of serious adverse
effects including fatal infusion reactions, bowel obstruction, gastrointestinal perforation,
mucocutanous reactions, renal toxicity, reactivation of viral infections, and progressive multifocal
leukoencephalopathy.6 Furthermore, rituximab is costly compared with other treatment options.7

Clinical trials for the evaluation of new therapeutic agents, such as rituximab, measure efficacy
based on improvements in symptoms, the induction of remission, time to relapse, disease
progression, and survival.8 This report reviews evidence for the clinical effectiveness, safety,
and cost-effectiveness of rituximab relative to other treatment options for the management of
non-Hodgkin’s lymphoma. Current evidence-based guidelines for the use of rituximab in non-
Hodgkin’s lymphoma will be presented.

RESEARCH QUESTIONS:

1.     What is the clinical effectiveness and safety of rituximab for the treatment of patients
       with non-Hodgkin’s lymphoma?

2.     What is the cost-effectiveness of rituximab for the treatment of patients with non-
       Hodgkin’s lymphoma?

3.     What are the guidelines for the use of rituximab in non-Hodgkin’s lymphoma?

4.     What date is used for time zero in clinical trials evaluating survival following treatment for
       non-Hodgkin’s lymphoma? Are there any guidelines for survival analysis when rituximab
       is used?

METHODS:

A limited literature search was conducted on key health technology assessment resources,
including OVID Medline, The Cochrane Library (Issue 4, 2009), University of York Centre for
Reviews and Dissemination (CRD) databases, ECRI, EuroScan, international health technology
agencies, and a focused Internet search. The search was limited to English language articles
published between 2003 and November 2009. Filters were applied to limit the retrieval to health
technology assessments, systematic reviews, meta-analyses, randomized controlled trials
(RCTs), economic studies, and guidelines. This search was supplemented by hand searching
the bibliographies of selected papers.

Full text peer-reviewed studies evaluating the use of rituximab for follicular lymphoma or diffuse
large B-cell lymphoma were included in the summary of findings. Due to the large number of
clinical trials identified, the inclusion of systematic reviews and RCTs was limited to those
published in the last two years. RCTs not included in the identified systematic reviews were
appraised separately in the report.

HTIS reports are organized so that the higher quality evidence is presented first. Therefore,
health technology assessment reports, systematic reviews, and meta-analyses are presented
first. These are followed by RCTs, economic evaluations, and evidence-based guidelines.




 Rituximab for Non-Hodgkin’s Lymphoma                                                                2
SUMMARY OF FINDINGS:

Three systematic reviews,9-11 five RCTs,12-16 nine economic evaluations,17-25 and seven
evidence-based guidelines26-32 were identified for the use of rituximab in non-Hodgkin’s
lymphoma. Recommendations for clinical trials evaluating survival in patients with malignant
lymphoma were also retrieved.8 No health technology assessments were identified.

Systematic reviews and meta-analyses

Three systematic reviews and meta-analyses were identified.9-11 Results are summarized in
Table 1. The majority of the published RCTs included in the three systematic reviews measured
survival from the date of randomization.33-40 Some RCTs used the date of start of therapy for
survival analyses.41-43

Gao et al. conducted a systematic review and meta-analysis to examine the clinical
effectiveness of the addition of rituximab to chemotherapy for the induction of remission in
patients with B-cell non-Hodgkin’s lymphoma.9 Twelve RCTs (n=4,996) published up to July
2008 were identified. The primary outcome was overall survival. Secondary outcomes included
overall response, disease control (made up of event-free survival, time to treatment failure,
progression-free survival, and time to progression) and adverse events. Relative risks (RR) with
95% confidence intervals (CI) were estimated and pooled using the fixed-effect model. A RR
greater than one favored rituximab in combination with chemotherapy. Pooled results showed
that rituximab in combination with chemotherapy statistically significantly improved overall
survival, overall response, and disease control when compared with chemotherapy alone in
patients with diffuse large B-cell lymphoma or follicular lymphoma. Pooled results for mantle cell
lymphoma, another subtype of B-cell non-Hodgkin’s lymphoma, showed that improvements with
rituximab in combination with chemotherapy were statistically significant for overall response
when compared with chemotherapy alone. The most commonly reported severe adverse events
were hematologic toxicity (i.e., leukocytopenia, thrombocytopenia, or granulocytopenia), fever,
and infection. The odds ratio (OR) for developing fever or leukocytopenia was statistically
significantly higher in patients treated with rituximab plus chemotherapy compared with patients
treated with chemotherapy alone. There was no difference between groups with respect to risk
of infection or treatment-related deaths. The authors concluded that treatment with rituximab
and chemotherapy should be considered standard of care for patients with diffuse large B-cell
lymphoma and follicular lymphoma.

Vidal et al. conducted a systematic review and meta-analysis to evaluate the clinical effect of
maintenance treatment with rituximab during remission in patients with follicular lymphoma.10,44
Five RCTs (n=1,056) published up to June 2007 were included. The primary outcome was
overall survival. Secondary outcomes were event-free survival, progression-free survival, and
adverse events. Hazard ratios (HR) of death and RR with 95% CI were estimated and pooled
using the fixed effect model. A HR of death of less than 1 favored rituximab maintenance
therapy. Pooled results showed that patients receiving maintenance treatment with rituximab
had statistically significant improvements in overall survival, event-free survival, and
progression-free survival compared to observation alone. However, a subgroup analysis
showed that overall survival was statistically significantly improved in patients with relapsed or
refractory follicular lymphoma (maintenance after two or more inductions) but not in patients



 Rituximab for Non-Hodgkin’s Lymphoma                                                                3
with previously untreated follicular lymphoma (maintenance after first induction). Based on data
from one trial, no difference in overall survival was observed when rituximab maintenance was
compared with treatment with rituximab at disease progression. The rate of infection-related
adverse events was statistically significantly higher in the rituximab maintenance therapy arm
than in the observation arm. The authors concluded that rituximab maintenance therapy for up
to two years should be used for patients with relapsed or refractory follicular lymphoma following
successful induction of remission while considering the higher risk of infections.

Aksoy et al. performed a systematic review and meta-analysis to investigate the infectious
complications of rituximab maintenance therapy in patients with lymphoma.11 A systematic
literature search identified five RCTs (n=1,060) published through November 2008. The
outcome measures were any grade of infection or neutropenia, and treatment-related mortality.
RR with 95% CI were estimated and pooled using the fixed effect model. A RR greater than 1
indicated increased rates of infection and neutropenia with rituximab maintenance therapy.
Pooled results showed that rituximab maintenance therapy significantly increased the relative
risk of both infections and neutropenia. Two of the five included RCTs described the specific
infections observed (one case each of pneumonia, hepatitis, and septic shock in one trial and
ear-nose-throat infections in the other trial). The authors concluded that patients receiving
maintenance therapy with rituximab are more susceptible to infectious complications and
require extended monitoring.

Table 1: Systematic Reviews for the use of Rituximab in Non-Hodgkin’s Lymphoma

   Author,                       Study Design                                    Results
    Year

  Gao et al.,                 Inclusion criteria:                           Overall survival:
   20099                RCTs comparing rituximab plus                Diffuse large B-cell lymphoma:
                 chemotherapy with chemotherapy alone for        RR 1.11 (95% CI 1.06 to 1.16; p<0.0001)
                  the induction of remission in adult patients            Follicular lymphoma:
                     with B-cell non-Hodgkin’s lymphoma          RR 1.08 (95% CI 1.04 to 1.12; p<0.0001)
                                                                          Mantle cell lymphoma:
                             Included studies:                    RR 1.16 (95% CI 1.00 to 1.36; p=0.06)
                            12 RCTs (n=4,996)
                      Median follow-up: 18 to 42 months                     Overall response:
                                                                      Diffuse large B-cell lymphoma:
                               Patient Population:                RR 1.09 (95% CI 1.01 to 1.19; p=0.03)
                              Previously untreated:                        Follicular lymphoma:
                          Diffuse large B-cell (4 RCTs)           RR 1.19 (95% CI 1.07 to 1.33; p=0.001)
                         Follicular lymphoma (3 RCTs)                      Mantle cell lymphoma:
                      Follicular lymphoma or mantle cell          RR 1.22 (95% CI 1.07 to 1.40; p=0.004)
                                lymphoma (1 RCT)
                         Mantel cell lymphoma (1 RCT)                        Disease control:
                  B-cell lymphoma (subtype not specified) (1          Diffuse large B-cell lymphoma:
                                       RCT)                      RR 2.00 (95% CI 1.59 to 2.53; p<0.00001)
                             Relapsed or refractory:                       Follicular lymphoma:
                          Follicular lymphoma (1 RCT)            RR 2.58 (95% CI 1.61 to 4.12; p<0.0001)
                      Follicular lymphoma or mantel cell                   Mantle cell lymphoma:
                                lymphoma (1 RCT)                  RR 1.82 (95% CI 0.99 to 3.34; p=0.05)




 Rituximab for Non-Hodgkin’s Lymphoma                                                                  4
  Author,                       Study Design                                    Results
   Year


                             Interventions:                                Adverse events:
                     R-CHOP versus CHOP (7 RCTs)                               Fever:
                  *R-CHOP like versus CHOP like (1 RCT)         OR 4.18 (95% CI 1.55 to 11.28; p<0.001)
                      R-CNOP versus CNOP (1 RCT)                           Leukocytopenia:
                       R-FCM versus FCM (1 RCT)                 OR 1.32 (95% CI 1.10 to 1.58; p=0.003)
                       R-CVP versus CVP (1 RCT)
                       R-MCP versus MCP (1 RCT)

Vidal et al.,                Inclusion criteria:                           Overall survival:
 200910,44        RCTs comparing rituximab maintenance                         Overall:
                 therapy with observation or treatment with     HR 0.60 (95% CI 0.45 to 0.79; p=0.0003)
                  rituximab at relapse in adult patients with            Previously untreated:
                             follicular lymphoma                 HR 0.68 (95% CI 0.37 to 1.25; p=0.21)
                                                                          Relapsed/refractory:
                            Included studies:                   HR 0.58 (95% CI 0.42 to 0.79; p=0.0006)
                            5 RCTs (n=1,143)
                  Treatment duration: 8 months to 2 years                 Event-free survival:
                     Median follow-up: 26 to 41 months          HR 0.46 (95% CI 0.37 to 0.57; p<0.00001)

                             Patient Population:                      Progression-free survival:
                             Follicular lymphoma:               HR 0.53 (95% CI 0.42 to 0.66; p<0.00001)
                        Previously untreated (1 RCT)
                       Relapsed or refractory (3 RCTs)                       Infections:
                        Both previously untreated and            RR 1.99 (95% CI 1.21 to 3.27; p=0.007)
                         relapsed/refractory (1 RCT)

                           Induction regimen:
                           Rituximab (2 RCTs)
                            CVP or FC (1 RCT)
                         FCM ± rituximab (1 RCT)
                         CHOP ± rituximab (1 RCT)

                               Interventions:
                Rituximab maintenance versus observation
                        during remission (4 RCTs)
                 Rituximab maintenance during remission
                    versus rituximab at relapse (1 RCT)

Aksoy et al.,                Inclusion criteria:                             Infections:
  200911          RCTs comparing rituximab maintenance           RR 2.82 (95% CI 1.28 to 6.23; p=0.010)
                 therapy with observation for infections and
                   neutropenia in patients with lymphoma                    Neutropenia:
                                                                 RR 2.39 (95% CI 1.47 to 3.88; p<0.010)
                            Included studies:
                            5 RCTs (n=1,060)
                  Treatment duration: 8 months to 2 years
                     Median follow-up: 26 to 42 months




Rituximab for Non-Hodgkin’s Lymphoma                                                                  5
   Author,                        Study Design                                        Results
    Year


                              Patient Population:
                          Diffuse large B-cell (1 RCT)
                         Follicular lymphoma (2 RCTs)
                       Follicular lymphoma or mantle cell
                               lymphoma (1 RCT)
                        Mantel cell lymphoma (1 RCT)

                              Induction regimen:
                              Rituximab (2 RCTs)
                            FCM ± rituximab (1 RCT)
                           CHOP ± rituximab (2 RCTs)

                                Interventions:
                  Rituximab maintenance versus observation
                          during remission (5 RCTs)

CHOP=cyclophosphamide, doxorubicin, vincristine, and prednisone; CI=confidence interval;
CNOP=cyclophosphamide, mitoxantrone, vincristine, and prednisone; CVP=cyclophosphamide, vincristine, and
prednisone; FC=fludarabine and cyclophosphamide; FCM=fludarabine, cyclophosphamide, and mitoxantrone;
HR=hazard ratio of death; MCP=mitoxantrone, chlorambucile, and prednisolone; OR=odds ratio; R-=rituximab plus
specific chemotherapy regimen; RCT=randomized controlled trial; RR=relative risk
*CHOP-like regimens included CHOEP (the addition of etoposide to the CHOP regimen), MACOP-B (methotrexate,
doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin), and PMitCEBO (prednisone, mitoxantrone,
cyclophosphamide, etoposide, bleomycin, and vincristine).

Randomized controlled trials

Diffuse Large B-cell Lymphoma:

Details from two RCTs12,13 of rituximab for diffuse large B-cell lymphoma are summarized in
Table 2. In one RCT (n=269), Haioun et al. noted that improvements in event-free survival with
rituximab maintenance therapy during remission were not statistically significant (p=0.099) when
compared with observation in patients with aggressive large B-cell lymphoma.12 Serious
adverse effects observed in patients receiving rituximab maintenance therapy included
neutropenia (6%), thrombocytopenia (2%), and herpes zoster infection (1%). Another RCT
(n=225) by Vellenga et al. showed that the addition of rituximab to second-line chemotherapy
statistically significantly improved failure-free survival and progression-free survival but not
overall survival when compared with chemotherapy alone in patients with relapsed or refractory
aggressive non-Hodgkin’s lymphoma.13 No increased infection rate was observed in patients
receiving rituximab.




  Rituximab for Non-Hodgkin’s Lymphoma                                                                            6
Table 2: RCTs Evaluating Rituximab for the Management of Diffuse Large B-Cell Lymphoma

    Author,                                  Study Design                                      Results
      Year
  Haioun et al.,                         Patient Population:                             Event-free survival:
     200912           Patients 18 to 60 years with aggressive diffuse large B-cell        Observation: 71%
                      lymphoma in remission following first-line ACE or ACVBP           (95% CI 62% to 78%)
                       induction chemotherapy, high-dose chemotherapy, and                 Rituximab: 80%
                                 autologous stem-cell transplantation                   (95% CI 72% to 86%)
                                                                                              (p=0.099)
                                         Interventions:
                                       Observation (n=130)
                                              versus
                     Rituximab maintenance therapy given weekly for four weeks
                                             (n=139)

                                           Primary Endpoint:
                                           Event-free survival:
                       Time from randomization to disease progression during or
                      after treatment, a required change in treatment regimen, or
                                       death without progression

                                           Median follow-up:
                                                4 years

   Vellenga et                           Patient Population:                           Failure-free survival:
   al., 200813       Patients 18 to 65 years with aggressive relapsed or refractory     Chemotherapy: 24%
                       B-cell non-Hodgkin’s lymphoma (89% diffuse large B-cell         R-Chemotherapy: 50%
                                              lymphoma)                                      (p<0.001)

                                             *Interventions:                             Progression-free
                                          Chemotherapy (n=112)                              survival:
                                                  versus                                Chemotherapy: 31%
                                         R-Chemotherapy (n=113)                        R-Chemotherapy: 52%
                                                                                            (p<0.002)
                                           Study Endpoints:
                                          Failure-free survival:                         Overall survival:
                      Time from start of treatment to no response, progression,         Chemotherapy: 52%
                              relapse, or death as a result of any cause               R-Chemotherapy: 59%
                                      Progression free survival:                            (p=0.15)
                     Time from randomization to disease progression or death as
                                        the result of any cause
                                            Overall survival:
                      Time from start of treatment to death irrespective of cause

                                               Follow-up:
                                               24 months

ACE=doxorubicin, cyclophosphamide, and etoposide; ACVBP=doxorubicin, cyclophosphamide, vincristine,
bleomycin, and prednisone; CI=confidence interval; DHAP=cisplatin, cytarabine, dexamethasone; R=rituximab;
VIM=etoposide, ifosfamide, and methotrexate
*Second-line chemotherapy consisting of DHAP-VIM-DHAP regimen followed by autologous stem-cell transplantation
with or without rituximab




  Rituximab for Non-Hodgkin’s Lymphoma                                                                       7
Follicular Lymphoma:

Details from three RCTs14-16 in patients with follicular lymphoma are summarized in Table 3.
One RCT (n=311) by Hochster et al. showed that maintenance therapy with rituximab
statistically significantly improved progression-free survival but not overall survival when
compared with observation in patients with previously untreated advanced-stage indolent
lymphoma.14 There were no significant differences between groups in the rate of severe
infections. Another RCT (n=358) by Salles et al. showed that the addition of rituximab to
chemotherapy plus interferon for the first-line treatment of patients with follicular lymphoma
statistically significantly increased event-free survival but not overall survival.15 No significant
differences were observed between the two treatment arms for serious adverse effects
(including severe infections and cardiac events) except for statistically significantly higher
neutrophil toxicity in the chemotherapy plus interferon arm (38% versus 6% in patients receiving
rituximab in addition to chemotherapy and interferon; p<0.001). Another RCT (n=321) by
Marcus et al. showed that the addition of rituximab to CVP statistically significantly improved the
time to treatment failure and overall survival in patients with previously untreated stage III or IV
follicular lymphoma when compared with patients receiving CVP chemotherapy alone.16
Statistically significant improvements were also noted in patients receiving R-CVP for other
secondary endpoints including time to progression, response rates, duration of response, time
to next antilymphoma treatment or death, and disease-free survival (all p<0.0001 versus CVP
alone). There was a higher incidence of serious neutropenia during treatment with R-CVP (24%)
compared with CVP (14%) (statistical significance not calculated). However this did not result in
a higher rate of infections (rates not reported). There were no treatment-related deaths.

Table 3: RCTs Evaluating Rituximab for the Management of Follicular Lymphoma

  Author,                               Study Design                                 Results
    Year
 Hochster et                    Patient Population:                        Progression-free survival:
 al., 200914     Patients with previously untreated stage III and IV                All patients:
                  indolent lymphoma (91% follicular lymphoma) in                 Observation: 33%
                      remission following CVP chemotherapy                        Rituximab: 68%
                                                                       (HR 0.4; 95% CI 0.3 to 0.5; p<0.001)
                                  Interventions:                               Follicular lymphoma:
                               Observation (n=153)                               Observation: 33%
                                       versus                                     Rituximab: 64%
                  Rituximab maintenance therapy given weekly for       (HR 0.4; 95 % CI 0.3 to 0.6; p<0.001)
                     four weeks every six months for two years
                                      (n=158)                                   Overall survival:
                                                                                   All patients:
                                Study Endpoints:                                Observation: 86%
                             Progression free survival:                          Rituximab: 92%
                      Progression or death after randomization         (HR 0.6; 95% CI 0.4 to 1.1; p=0.05)
                                  Overall survival:                           Follicular lymphoma:
                                No definition given                             Observation: 86%
                                                                                 Rituximab: 91%
                                         Follow-up:                    (HR 0.6; 95% CI 0.4 to 1.2; p=0.08)
                                          3 years




 Rituximab for Non-Hodgkin’s Lymphoma                                                                    8
  Author,                                Study Design                                    Results
     Year
 Salles et al.,                  Patient Population:                           Event-free survival:
   200815          Patients 18 to 75 years with previously untreated      CHVP+I: 37% (95% CI 29% to 44%)
                           stage II to IV follicular lymphoma              R-CHVP+I: 53% (95% CI 45% to
                                                                                       60%)
                                     Interventions:                                  (p=0.001)
                                    CHVP+I (n=183)
                                         versus                                   Overall survival:
                                   R-CHVP+I (n=175)                       CHVP+I: 79% (95% CI 72% to 84%)
                                                                           R-CHVP+I: 84% (95% CI 78% to
                                    Study Endpoints:                                   84%)
                                    Event-free survival:                              (p=NS)
                  Time from randomization to disease progression,
                   relapse, initiation of a new alternative treatment,
                                 or death from any cause
                                     Overall survival:
                  Time from randomization to death from any cause

                                   Median follow-up:
                                        5 years

  Marcus et                      Patient Population:                        Median time to treatment failure
  al., 200816      Patients with previously untreated stage III or IV                 (months):
                                  follicular lymphoma                           CVP: 7 (95% CI 6 to 9)
                                                                             R-CVP: 27 (95% CI 25 to 37)
                                     Interventions:                                   (p<0.001)
                                      CVP (n=162)
                                         versus                               Overall survival at 4 years:
                                     R-CVP (n=159)                          CVP: 77% (95% CI 70% to 83%)
                                                                           R-CVP: 83% (95% CI 77% to 89%)
                                 Primary Endpoint:                                     (p=0.029)
                              Time to treatment failure:
                      Time between randomization and disease
                   progression, relapse after response, initiation of
                   new antilymphoma treatment, stable disease, or
                                death from any cause

                               Secondary Endpoints:
                   Overall survival at 4 years, time to progression,
                  response rates, duration of response, time to next
                    antilymphoma treatment or death, disease-free
                            survival (definitions not given)

                                   Median follow-up:
                                      53 months

CHVP+I=cyclophosphamide, doxorubicin, etoposide, and prednisone plus interferon; CI=confidence interval;
CVP=cyclophosphamide, vincristine, and prednisone; HR= hazard ratio; NS=non-significant; R-=rituximab plus
specific chemotherapy regimen




  Rituximab for Non-Hodgkin’s Lymphoma                                                                       9
Economic evaluations

Diffuse Large B-cell Lymphoma:

Five cost-effectiveness analyses17-21 in diffuse large B-cell lymphoma were identified. Results
are summarized in Table 4. Each economic model calculated an incremental cost-effectiveness
ratio (ICER) based on the additional cost per the additional benefit associated with R-CHOP
therapy. The measure of benefit was life-years (LYs) or quality-adjusted life years (QALYs)
gained.

Ferrara et al. examined the cost-effectiveness of the addition of rituximab to CHOP for the
management of patients aged 18 to 60 years with previously untreated diffuse large B-cell
lymphoma.17 Estimates for clinical effectiveness were obtained from a single RCT.40 Results
showed that the higher costs associated with the addition of rituximab were offset by savings as
a result of lower requirements for salvage therapy. Based on a favorable ICER, R-CHOP was
defined as the dominant treatment. Sensitivity analyses for variations in response rate, relapse-
free survival, and overall survival supported the cost-effectiveness of the addition of rituximab.
The authors concluded that R-CHOP was a cost-effective alternative to CHOP for patients
under the age of 60 years with diffuse large B-cell lymphoma.

Four cost-effectiveness analyses examined the addition of rituximab to CHOP in patients with
previously untreated large B-cell lymphoma over the age of 60 years.18-21 Each economic model
used survival estimates from a single RCT.33 The ICERs from all four studies indicate that R-
CHOP is cost-effective compared with CHOP alone for patients with untreated diffuse large B-
cell lymphoma over the age of 60 years. Knight et al. and Groot et al. also showed that R-CHOP
was cost-effective in patients under the age of 60 years with ICERs of £7,533 and €13,983,
respectively. Sensitivity analyses undertaken in all four models showed these results to be
robust. Overall, these results indicated that rituximab used in combination with CHOP is a cost-
effective treatment for first-line treatment of diffuse large B-cell lymphoma.

Table 4: Cost-Effectiveness Analyses for Rituximab in Combination with Chemotherapy
         for Patients with Previously Untreated Diffuse Large B-Cell Lymphoma

  Author,       Perspective             Measure of            Costs*               ICER
   Year            & Time                Benefit
                   Horizon
 Ferrara et     Italian health      LYs Gained:         CHOP (drug): €2,338      Dominant
 al., 200817        system          CHOP: 2.52         CHOP (other): €20,494

                   3 years                            R-CHOP (drug): €12,424
                                   R-CHOP: 2.70       R-CHOP (other): €9,690

 Hornberger     United States      QALYs Gained:       CHOP (drug): US$3,358     US$19,297
   et al.,         societal         CHOP: 2.11        CHOP (other): US$26,685
   200518        perspective
                                                     R-CHOP (drug): US$20,583
                   5 years         R-CHOP: 2.77      R-CHOP (other): US$22,194




 Rituximab for Non-Hodgkin’s Lymphoma                                                           10
   Author,      Perspective              Measure of                Costs*                     ICER
    Year           & Time                 Benefit
                  Horizon
 Best et al.,   French health       QALYs Gained:          CHOP (drug): €4,747              €12,259
  200519           system            CHOP: 3.59           CHOP (other): €24,035

                   15 years                              R-CHOP (drug): €19,111
                                    R-CHOP: 4.66         R-CHOP (other): €22,840

   Groot et          Dutch          QALYs Gained:         CHOP (drug): €14,747              €17,933
  al., 200520       societal         CHOP: 2.98           CHOP (other): €12,144
                  perspective
                                                         R-CHOP (drug): €30,934
                   15 years         R-CHOP: 3.87         R-CHOP (other): €11,817

   Knight et    Part of United      QALYs Gained:          CHOP (drug): £1,911              £10,596
  al., 200421     Kingdom            CHOP: 3.77            CHOP (other): £3,861
                 NHS R&D
                HTA Program                              R-CHOP (drug): £11,227
                                    R-CHOP: 4.58         R-CHOP (other): £3,228
                   15 years
CHOP=cyclophosphamide, doxorubicin, vincristine, and prednisone; ICER=incremental cost-effectiveness ratio; LYs=
life years; NHS HTA= National Health Service Research and Development Health Technology Assessment;
QALYs=quality-adjusted life years; R-CHOP=rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone
*Other costs include those for drug administration, adverse effects, post-treatment cancer surveillance, salvage
therapy (intensive chemotherapy only), and palliative care for patients who fail to respond to CHOP or R-CHOP.

Lee et al. conducted a microcosting study to estimate and compare the costs associated with R-
CHOP and CHOP when used for diffuse large B-cell lymphoma from a Canadian cancer care
perspective.22 A retrospective analysis was conducted primarily using local data from the Tom
Baker Cancer Center in Calgary, Alberta to determine costs for patients receiving R-CHOP
between February 2001 and July 2004 or CHOP between January 1998 and July 2004 (Table
5).

Table 5: Mean Cost Per Patient for First-Line Treatment with R-CHOP or CHOP (2004 C$)22

        TREATMENT                              R-CHOP (n=84)                     CHOP (n=78)
            Drugs                                 23,164                            3,408
          Oncologists                               625                              552
       Outpatient nursing                           975                              627
         Radiotherapy                               580                              455
            Tests                                   431                              363
        Hospitalization                            7,311                            6,836
             Total                                33,088                           12,240
         FOLLOW-UP                             R-CHOP (n=72)                     CHOP (n=67)
          Oncologists                               100                              259
            Tests                                   785                              753
        Hospitalization                            2,330                            7,917
             Total                                 3,215                            8,929
CHOP=cyclophosphamide, doxorubicin, vincristine, and prednisone; R-CHOP=rituximab-cyclophosphamide,
doxorubicin, vincristine, and prednisone




  Rituximab for Non-Hodgkin’s Lymphoma                                                                       11
These results indicated that for first-line treatment, drug cost was the largest contributor to total
cost, followed by hospitalization cost. Although the cost for patients receiving R-CHOP was
higher during treatment, CHOP patients cost nearly three times as much as R-CHOP patients
during the follow-up phase. This was mainly due to the higher hospitalization cost of CHOP
patients during this phase. For treatments subsequent to first-line treatment, no significant cost
differences were found between R-CHOP and CHOP patients. Hospitalization and
transplantation costs were the two largest constituents of total costs subsequent to first-line
treatment.

Follicular Lymphoma:

Three economic evaluations23-25 examining the cost-effectiveness of rituximab for different
indications in patients with follicular lymphoma were identified. Results are presented in Table 6.
Each economic model calculated an ICER based on the additional cost of therapy with rituximab
per QALY gained. Sensitivity analyses undertaken in all three models showed results to be
robust.

Two economic evaluations examined the cost-effectiveness of maintenance rituximab (given
every three months for two years) when compared with observation for the management of
patients with relapsed or refractory follicular lymphoma in remission following treatment with R-
CHOP or CHOP.23,24 Estimates of clinical effectiveness were obtained from one RCT.38 Both
trials showed that rituximab maintenance treatment for patients with relapsed or refractory
follicular lymphoma is cost-effective when compared with observation.

Hornberger et al. examined the cost-effectiveness of the addition of rituximab to CVP as first-
line treatment for the management of patients with advanced follicular lymphoma.25 Clinical
effectiveness data were derived from one RCT.35 The authors concluded that R-CVP was cost-
effective for advanced follicular lymphoma when compared with CVP.

Table 6: Cost-Effectiveness Analyses for the use of Rituximab in Patients with Follicular
         Lymphoma

  Author,       Perspective             Measure of              Costs*                 ICER
   Year           & Time                 Benefit
                 Horizon
 Kasteng et      Swedish           QALYs Gained:                                      €12,584
 al., 200823       health         Observation: 3.38   Observation (total): €28,156
                  system
                                   Rituximab: 4.29     Rituximab (total): €39,617
                  30 years

 Hayslip et     United States       QALYs Gained:                                    US$19,522
 al., 200824       health          Observation: NR      Observation (total): NR
                   system
                                    Rituximab: NR        Rituximab (total): NR
                   5 years




 Rituximab for Non-Hodgkin’s Lymphoma                                                               12
   Author,       Perspective             Measure of                    Costs*                    ICER
    Year            & Time                Benefit
                   Horizon
 Hornberger      United States       QALYs Gained:                                            US$28,565
   et al.,          societal           CVP: 4.93              CVP (drug): US$458
   200825         perspective                                CVP (other): US$78,709

                   30 years              R-CVP: 5.85        R-CVP (drug): US$24,536
                                                            R-CVP (other): US$81,071
CVP=cyclophosphamide, vincristine, and prednisone; ICER=incremental cost-effectiveness ratio; NR=not reported;
QALYs=quality-adjusted life years; R-CVP=rituximab-cyclophosphamide, vincristine, and prednisone
*Other costs include those for drug administration, adverse effects, post-treatment cancer surveillance, salvage
therapy (intensive chemotherapy only), and palliative care for patients who fail to respond to therapy.

Guidelines and recommendations

Evidence-based guidelines from Cancer Care Ontario,26 the National Comprehensive Cancer
Network (NCCN) in the United States,27 the Italian Society of Hematology,28,29 and the National
Institute for Health and Clinical Excellence (NICE) in the UK30-32 were identified for the use of
rituximab in patients with Non-Hodgkin’s lymphoma. In general, the guidelines make the
following recommendations:

Diffuse Large B-cell Lymphoma:

    •   Rituximab should be used in combination with chemotherapy for the management of
        patients with previously untreated stage III or IV diffuse large B-cell lymphoma.26,27,29,30
    •   Salvage chemotherapy with or without rituximab can be used for patients with relapsed
        or refractory stage III or IV diffuse large B-cell lymphoma.26,27,29,30
    •   There is currently insufficient evidence to support the use of rituximab as maintenance
        therapy in patients with diffuse large B-cell lymphoma who have completed initial
        chemotherapy with or without rituximab.26,29

Follicular Lymphoma:

    •   Rituximab should be used with or without chemotherapy for the induction of remission in
        patients with previously untreated stage III or IV follicular lymphoma.26-28,32
    •   Rituximab can be used with or without chemotherapy for the induction of remission in
        patients with relapsed or refractory stage III or IV follicular lymphoma.26-28,31
    •   Rituximab can be used for maintenance therapy in patients with stage III or IV follicular
        lymphoma.26,27,31

No guidelines were identified regarding the date to use for time zero in clinical trials evaluating
survival following treatment with rituximab. However, general recommendations for the
standardization of efficacy endpoints including the measurement of survival in clinical trials have
been developed from an International Harmonization Project initiated by the German
Competence Network Malignant Lymphoma (Table 7).8




  Rituximab for Non-Hodgkin’s Lymphoma                                                                             13
Table 7: Efficacy Endpoints for Clinical Trials Evaluating Therapeutic Agents for the
         Management of Malignant Lymphomas8

            Endpoint                     Patients                                Definition

 Primary
     Overall survival                     All             Time from randomization to death as a result of any
                                                                               cause
 Progression-free survival                All             Time from randomization to disease progression or
                                                                   death as a result of any cause
 Secondary
    Event-free survival                   All            Time from randomization to treatment failure (e.g. due
                                                            to disease progression or discontinuation due to
                                                          toxicity or patient preference) or death as a result of
                                                                                 any cause
    Time to progression                   All            Time from randomization to progression or death as a
                                                                            result of lymphoma
   Disease-free survival             Patients in          Time from documentation of response to relapse or
                                  complete remission        death as a result of lymphoma or acute toxicity of
                                                                                 treatment
     Response duration                Patients in         Time from documentation of response to relapse or
                                  complete remission                            progression
                                  or partial remission
    Lymphoma-specific                      All           Time from date of randomization to death as a result
          survival                                                           of lymphoma
   Time to next treatment                 All            Time from end of primary treatment to new treatment
RCT=randomized controlled trial

Limitations

    •   Trials included in the systematic reviews were heterogeneous with respect to patient
        population (type of lymphoma), previous therapy (previously untreated patients or
        patients with relapsed/refractory disease), induction regimens, and maintenance therapy
        schedules.
    •   Many of the trials lacked details on methods for allocation concealment of treatment and
        none of the trials were blinded which may have introduced selection bias.
    •   Few trials evaluated the effectiveness of rituximab as second-line therapy in patients
        with relapsed or refractory diffuse large B-cell lymphoma or for maintenance therapy in
        patients with diffuse large B-cell lymphoma.
    •   Although all cost-effectiveness studies indicated that rituximab may be a cost-effective
        option for the management of diffuse large B-cell lymphoma or follicular lymphoma,
        indirect costs (e.g., lost productivity, days lost from work) were not considered and these
        results may not be generalizable to publicly funded healthcare systems in Canada.
    •   There are no evidence-based guidelines for which schedules or combinations are most
        effective when using rituximab for the induction of remission or maintenance therapy.




  Rituximab for Non-Hodgkin’s Lymphoma                                                                        14
CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING:

In summary, there is clear evidence to support the addition of rituximab to chemotherapy in
patients with previously untreated diffuse large B-cell lymphoma and patients with previously
untreated or relapsed/refractory follicular lymphoma. Although trials have indicated higher rates
of leukocytopenia and neutropenia when rituximab is used for induction therapy, this does not
appear to lead to higher rates of infection or treatment-related deaths when compared to
chemotherapy alone. In addition, there is evidence that maintenance treatment of up to two
years with rituximab prolongs remission and increases overall survival in patients with follicular
lymphoma following different induction regimens. However, significantly higher rates of
infections have been observed when rituximab is used for maintenance therapy in patients with
follicular lymphoma.

Several economic evaluations have suggested that rituximab is a cost-effective option in the
United States and Europe for the induction of remission in patients with previously untreated
diffuse large B-cell lymphoma or follicular lymphoma and for maintenance therapy in patients
with follicular lymphoma. A Canadian costing study indicated that treatment with rituximab
reduces follow-up hospitalization costs in patients with previously untreated diffuse large B-cell
lymphoma. Furthermore, unpublished results45 suggest that rituximab may also be cost-effective
from the perspective of the Canadian healthcare system when used for maintenance therapy in
patients with follicular lymphoma.

Based on the available evidence, current guidelines recommend rituximab for the first-line
treatment of patients with previously untreated diffuse large B-cell lymphoma or follicular
lymphoma. The guidelines also recommend rituximab for second-line treatment in patients with
relapsed or refractory follicular lymphoma and as maintenance therapy for patients with follicular
lymphoma. Further trials are needed to investigate the role of rituximab for second-line therapy
in patients with relapsed or refractory diffuse large B-cell lymphoma or as maintenance therapy
in patients with diffuse large B-cell lymphoma. Although Health Canada has approved rituximab
in combination with specific chemotherapy regimens (CHOP for diffuse large B-cell lymphoma
and CVP for follicular lymphoma),6 evidence-based guidelines for the optimal chemotherapy
regimen to combine with rituximab, or the schedule and duration for maintenance therapy have
yet to be established. Recommendations have been developed to standardize measurements of
survival, usually from the date of randomization, in clinical trials evaluating therapeutic agents
for the management of malignant lymphomas.

Until further information is available, the strengths and limitations of the available evidence,
clinical experience, and institution-specific budgets should be considered when making policy
decisions regarding the use of rituximab in patients with non-Hodgkin’s lymphoma.


PREPARED BY:
Sarah Ndegwa, BScPharm, Research Officer
Carolyn Spry, BSc, MLIS, Information Specialist
Health Technology Inquiry Service
Email: htis@cadth.ca
Tel: 1-866-898-8439




 Rituximab for Non-Hodgkin’s Lymphoma                                                              15
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 Rituximab for Non-Hodgkin’s Lymphoma                                                           18
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 Rituximab for Non-Hodgkin’s Lymphoma                                                            19
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 Rituximab for Non-Hodgkin’s Lymphoma                                                        20

								
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