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

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1 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.

2 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 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

3 SUMMARY OF FINDINGS: Three systematic reviews, 9-11 five RCTs, nine economic evaluations, and seven evidence-based guidelines 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 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 Some RCTs used the date of start of therapy for survival analyses 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

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

5 Author, Year Study Design Results Interventions: R-CHOP versus CHOP (7 RCTs) *R-CHOP like versus CHOP like (1 RCT) R-CNOP versus CNOP (1 RCT) R-FCM versus FCM (1 RCT) R-CVP versus CVP (1 RCT) R-MCP versus MCP (1 RCT) Adverse events: Fever: OR 4.18 (95% CI 1.55 to 11.28; p<0.001) Leukocytopenia: OR 1.32 (95% CI 1.10 to 1.58; p=0.003) Vidal et al., ,44 Inclusion criteria: RCTs comparing rituximab maintenance therapy with observation or treatment with rituximab at relapse in adult patients with follicular lymphoma Included studies: 5 RCTs (n=1,143) Treatment duration: 8 months to 2 years Median follow-up: 26 to 41 months Patient Population: Follicular lymphoma: Previously untreated (1 RCT) Relapsed or refractory (3 RCTs) Both previously untreated and relapsed/refractory (1 RCT) Overall survival: Overall: HR 0.60 (95% CI 0.45 to 0.79; p=0.0003) Previously untreated: HR 0.68 (95% CI 0.37 to 1.25; p=0.21) Relapsed/refractory: HR 0.58 (95% CI 0.42 to 0.79; p=0.0006) Event-free survival: HR 0.46 (95% CI 0.37 to 0.57; p< ) Progression-free survival: HR 0.53 (95% CI 0.42 to 0.66; p< ) Infections: RR 1.99 (95% CI 1.21 to 3.27; p=0.007) 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: RCTs comparing rituximab maintenance therapy with observation for infections and neutropenia in patients with lymphoma Included studies: 5 RCTs (n=1,060) Treatment duration: 8 months to 2 years Median follow-up: 26 to 42 months Infections: RR 2.82 (95% CI 1.28 to 6.23; p=0.010) Neutropenia: RR 2.39 (95% CI 1.47 to 3.88; p<0.010) Rituximab for Non-Hodgkin s Lymphoma 5

6 Author, Year Study Design Results 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 RCTs 12,13 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

7 Table 2: RCTs Evaluating Rituximab for the Management of Diffuse Large B-Cell Lymphoma Author, Study Design Year Haioun et al., Patient Population: Patients 18 to 60 years with aggressive diffuse large B-cell lymphoma in remission following first-line ACE or ACVBP induction chemotherapy, high-dose chemotherapy, and autologous stem-cell transplantation Interventions: Observation (n=130) versus Rituximab maintenance therapy given weekly for four weeks (n=139) Results Event-free survival: Observation: 71% (95% CI 62% to 78%) Rituximab: 80% (95% CI 72% to 86%) (p=0.099) Vellenga et al., 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 Patient Population: Patients 18 to 65 years with aggressive relapsed or refractory B-cell non-hodgkin s lymphoma (89% diffuse large B-cell lymphoma) *Interventions: Chemotherapy (n=112) versus R-Chemotherapy (n=113) Study Endpoints: Failure-free survival: Time from start of treatment to no response, progression, relapse, or death as a result of any cause Progression free survival: 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 Failure-free survival: Chemotherapy: 24% R-Chemotherapy: 50% (p<0.001) Progression-free survival: Chemotherapy: 31% R-Chemotherapy: 52% (p<0.002) Overall survival: Chemotherapy: 52% R-Chemotherapy: 59% (p=0.15) 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

8 Follicular Lymphoma: Details from three RCTs 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< 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, Year Hochster et al., Study Design Patient Population: Patients with previously untreated stage III and IV indolent lymphoma (91% follicular lymphoma) in remission following CVP chemotherapy Interventions: Observation (n=153) versus Rituximab maintenance therapy given weekly for four weeks every six months for two years (n=158) Study Endpoints: Progression free survival: Progression or death after randomization Overall survival: No definition given Follow-up: 3 years Results Progression-free survival: All patients: Observation: 33% Rituximab: 68% (HR 0.4; 95% CI 0.3 to 0.5; p<0.001) Follicular lymphoma: Observation: 33% Rituximab: 64% (HR 0.4; 95 % CI 0.3 to 0.6; p<0.001) Overall survival: All patients: Observation: 86% Rituximab: 92% (HR 0.6; 95% CI 0.4 to 1.1; p=0.05) Follicular lymphoma: Observation: 86% Rituximab: 91% (HR 0.6; 95% CI 0.4 to 1.2; p=0.08) Rituximab for Non-Hodgkin s Lymphoma 8

9 Author, Study Design Year Salles et al., Patient Population: Patients 18 to 75 years with previously untreated stage II to IV follicular lymphoma Interventions: CHVP+I (n=183) versus R-CHVP+I (n=175) Study Endpoints: Event-free survival: 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 Results Event-free survival: CHVP+I: 37% (95% CI 29% to 44%) R-CHVP+I: 53% (95% CI 45% to 60%) (p=0.001) Overall survival: CHVP+I: 79% (95% CI 72% to 84%) R-CHVP+I: 84% (95% CI 78% to 84%) (p=ns) Marcus et al., Median follow-up: 5 years Patient Population: Patients with previously untreated stage III or IV follicular lymphoma Interventions: CVP (n=162) versus R-CVP (n=159) Primary Endpoint: 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 Median time to treatment failure (months): CVP: 7 (95% CI 6 to 9) R-CVP: 27 (95% CI 25 to 37) (p<0.001) Overall survival at 4 years: CVP: 77% (95% CI 70% to 83%) R-CVP: 83% (95% CI 77% to 89%) (p=0.029) 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

10 Economic evaluations Diffuse Large B-cell Lymphoma: Five cost-effectiveness analyses 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, relapsefree 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 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 costeffective 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, Year Ferrara et al., Perspective & Time Horizon Italian health system Measure of Benefit LYs Gained: CHOP: 2.52 Costs* CHOP (drug): 2,338 CHOP (other): 20,494 ICER Dominant 3 years R-CHOP: 2.70 R-CHOP (drug): 12,424 R-CHOP (other): 9,690 Hornberger et al., United States societal perspective 5 years QALYs Gained: CHOP: 2.11 R-CHOP: 2.77 CHOP (drug): US$3,358 CHOP (other): US$26,685 R-CHOP (drug): US$20,583 R-CHOP (other): US$22,194 US$19,297 Rituximab for Non-Hodgkin s Lymphoma 10

11 Author, Year Perspective & Time Horizon Best et al., French health system Measure of Benefit QALYs Gained: CHOP: 3.59 Costs* CHOP (drug): 4,747 CHOP (other): 24,035 ICER 12, years R-CHOP: 4.66 R-CHOP (drug): 19,111 R-CHOP (other): 22,840 Groot et al., Dutch societal perspective 15 years QALYs Gained: CHOP: 2.98 R-CHOP: 3.87 CHOP (drug): 14,747 CHOP (other): 12,144 R-CHOP (drug): 30,934 R-CHOP (other): 11,817 17,933 Knight et al., Part of United Kingdom NHS R&D HTA Program QALYs Gained: CHOP: 3.77 R-CHOP: 4.58 CHOP (drug): 1,911 CHOP (other): 3,861 R-CHOP (drug): 11,227 R-CHOP (other): 3,228 10, 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 Outpatient nursing Radiotherapy Tests Hospitalization 7,311 6,836 Total 33,088 12,240 FOLLOW-UP R-CHOP (n=72) CHOP (n=67) Oncologists Tests 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

12 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 evaluations 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 firstline 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 costeffective for advanced follicular lymphoma when compared with CVP. Table 6: Cost-Effectiveness Analyses for the use of Rituximab in Patients with Follicular Lymphoma Author, Year Kasteng et al., Perspective & Time Horizon Swedish health system 30 years Measure of Benefit QALYs Gained: Observation: 3.38 Rituximab: 4.29 Costs* Observation (total): 28,156 Rituximab (total): 39,617 ICER 12,584 Hayslip et al., United States health system 5 years QALYs Gained: Observation: NR Rituximab: NR Observation (total): NR Rituximab (total): NR US$19,522 Rituximab for Non-Hodgkin s Lymphoma 12

13 Author, Year Hornberger et al., Perspective & Time Horizon United States societal perspective Measure of Benefit QALYs Gained: CVP: 4.93 Costs* CVP (drug): US$458 CVP (other): US$78,709 ICER US$28, 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 UK 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 ,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 ,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

14 Table 7: Efficacy Endpoints for Clinical Trials Evaluating Therapeutic Agents for the Management of Malignant Lymphomas 8 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 Response duration Patients in complete remission Patients in complete remission or partial remission All Time from documentation of response to relapse or death as a result of lymphoma or acute toxicity of treatment Time from documentation of response to relapse or progression Lymphoma-specific survival Time from date of randomization to death as a result 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

15 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 results 45 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 htis@cadth.ca Tel: Rituximab for Non-Hodgkin s Lymphoma 15

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