Evidence-based Series 6-8 Version 2.2005: TO BE UPDATED Rituximab in Lymphoma and Chronic Lymphocytic Leukemia Members of the Hematology Disease Site Group A Quality Initiative of the Program in Evidence-based Care (PEBC), Cancer Care Ontario (CCO) Evidence-based Series 6-8 was reviewed in 2012 and the Hematology Disease Site Group (DSG) made a decision to UPDATE it on May 24, 2012. See Section 4: Document Review Summary and Tool for details. The reviewed EBS report consists of: Section 1: Clinical Practice Guideline (TO BE UPDATED) Section 2: Systematic Review Section 3: EBS Development Methods and External Review Process and Results Section 4: Document Review Summary and Tool and is available on the CCO Web site (http://www.cancercare.on.ca) PEBC Hematology DSG page at: https://www.cancercare.on.ca/toolbox/qualityguidelines/diseasesite/hema-ebs/ Release Date: June 12, 2012 For information about this document, the PEBC and/or the most current version of all reports, please visit the CCO Web site at http://www.cancercare.on.ca/ or contact the PEBC office at: Phone: 905-527-4322 ext. 42822 Fax: 905-526-6775 E-mail: ccopgi@mcmaster.ca Guideline Citation (Vancouver Style): Members of the Hematology Disease Site Group. Rituximab in lymphoma and chronic lymphocytic leukemia. Toronto (ON): Cancer Care Ontario; 2012 Jun 12 [To be updated]. Program in Evidence-based Care Evidence-Based Series No.: 6-8 Version 2.2005 To Be Updated.
Evidence-based Series 6-8 Version 2.2005: TO BE UPDATED Rituximab in Lymphoma and Chronic Lymphocytic Leukemia Guideline Report History GUIDELINE VERSION Search Dates SYSTEMATIC REVIEW Data PUBLICATIONS NOTES AND KEY CHANGES Evidence Summary 1999 1966-1999 Full Report Web publication NA Original version 2 December 2006 1966-2006 Full Report Web publication This document replaced the evidence summary that was completed in 1999 Updated search March 2012 2006-2012 New data found in Section 4: Document Review Summary and Tool 2006 recommendations require an UPDATE
Evidence-based Series 6-8 Version 2.2005: Section 1 Rituximab in Lymphoma and Chronic Lymphocytic Leukemia: A Clinical Practice Guideline K. Imrie, M.C. Cheung, A.E. Haynes, A. Stevens, R. Meyer, and the members of the Hematology Disease Site Group A Quality Initiative of the Program in Evidence-based Care (PEBC), Cancer Care Ontario (CCO) Current Report Date: December 1, 2006 The 2006 guideline recommendations requires an UPDATE This means that the DSG/GDG will rewrite the guideline at the earliest opportunity. Until then the recommendations remain of some use in clinical decision making. Please see Section 4: Document Review Summary and Tool for a summary of updated evidence published between 2006 and 2012. Questions Lymphoma 1. In patients with lymphoma of any type or stage, is rituximab used alone or in combination with chemotherapy more effective than non rituximab-containing regimens for improving overall survival, disease control (as assessed by measures such as progression-free survival, event-free survival, time-to-treatment failure, or response duration), response rate, or quality of life? 2. What is the toxicity associated with the use of rituximab used alone or in combination with chemotherapy compared with non rituximab-containing regimens? 3. Which patients with lymphoma are more or less likely to benefit from treatment with rituximab compared with those treated with non rituximab-containing regimens? Chronic Lymphocytic Leukemia 1. What beneficial outcomes are associated with the use of rituximab for the treatment of patients with chronic lymphocytic leukemia (CLL)? Outcomes of interest are overall PRACTICE GUIDELINE: 1
survival, disease control (as assessed by measures such as progression-free survival, event-free survival, time-to-treatment failure, or response duration), and response rate. 2. What is the toxicity associated with the use of rituximab? 3. Which patients are more or less likely to benefit from treatment with rituximab? Target Population Lymphoma These recommendations apply to adult patients with lymphoma of any type, at any stage, and any histology. Chronic Lymphocytic Leukemia These recommendations apply to adult patients with CLL at any stage. Recommendations Lymphoma Previously untreated patients with diffuse large B-cell lymphoma (DLBCL), or a variant of DLBCL (such as mediastinal sclerosing B-cell lymphoma, T-cell rich B-cell lymphoma, Burkitt-like lymphoma, or intravascular lymphoma), who are candidates for treatment with curative intent and will receive cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), should receive this therapy in combination with rituximab. This grouping includes patients with untreated DLBCL that has transformed from follicular or other indolent lymphoma. There is insufficient evidence at this time to support or refute treatment with a rituximabcontaining chemotherapy regimen in patients who have been previously treated for diffuse DLBCL or a variant of DLBCL. There is insufficient evidence to support combining rituximab with chemotherapy when treating patients with human immunodeficiency virus (HIV)-related lymphoma. These patients may be at an increased risk for life-threatening infections when rituximab is combined with CHOP. Previously untreated patients with follicular or other indolent B-cell histology lymphoma (such as mantle cell lymphoma, marginal zone lymphoma, and lymphoplasmacytoid lymphoma), excluding small lymphocytic lymphoma (SLL), who are appropriate candidates for chemotherapy, should receive this chemotherapy in combination with rituximab. For patients with follicular lymphoma or other indolent B-cell lymphomas who respond to treatment with combination chemotherapy and/or rituximab, this treatment should be followed by the use of maintenance rituximab. For previously treated patients with follicular or other indolent B-cell histology lymphoma (such as mantle cell lymphoma, marginal zone lymphoma, and lymphoplasmacytoid lymphoma), excluding SLL: Patients who have not previously received rituximab and who are appropriate candidates for chemotherapy should receive this chemotherapy in combination with rituximab. Patients who have previously received rituximab (including combination rituximabchemotherapy, rituximab monotherapy, or maintenance rituximab) and who have achieved a response of at least one year s duration to the last rituximab administration and who are appropriate candidates for chemotherapy should receive this chemotherapy in combination with rituximab. Chronic Lymphocytic Leukemia There is insufficient evidence at this time to support or refute the use of single-agent rituximab or a rituximab-containing chemotherapy regimen in patients with CLL. PRACTICE GUIDELINE: 2
Qualifying Statements Rituximab has a favourable single-agent toxicity profile. The addition of rituximab to chemotherapeutic regimens such as cyclophosphamide, vincristine, and prednisone (CVP), CHOP, and fludarabine, cyclophosphamide, and mitoxantrone (FCM) does not appear to significantly alter the toxicity of these regimens in lymphoma. Rituximab should be administered at a dose of 375 mg/m 2 and given at the beginning of each treatment cycle of chemotherapy. There is significant variability in the published administration schedules for rituximab maintenance. The DSG felt that the regimen studied by the EORTC/Intergroup (rituximab 375mg/m 2 every 3 months until relapse or 2 years) was a reasonable and convenient option. Maintenance rituximab should be initiated within 8 weeks of completion of the induction regimen. Prolonged rituximab therapy may be associated with hypogammaglobulinemia. Immunoglobulin quantitation was a common monitoring strategy in the pivotal clinical trials and should be considered for patients receiving maintenance therapy. In the absence of randomized data evaluating the role of rituximab re-treatment, the recommendation that rituximab be reused in combination with chemotherapy is based on the consensus opinion of the Hematology Disease Site Group. There is a rapid availability of new data regarding the role of rituximab in treating these diseases. Practitioners and patients are advised to review the Web site of Cancer Care Ontario s Program in Evidence-based Care (PEBC) to learn the status of this practice guideline. Key Evidence Lymphoma A total of 22 randomized controlled trials were identified: 9 trials assessed patients with aggressive histology and 13 assessed patients with indolent histology. Three trials in aggressive histology were published in article form, as were seven trials in indolent histology; all remaining reports were preliminary publications in abstract form. The Hematology DSG was compelled by these data despite the limitation of their being primarily in abstract form. In one randomized trial comparing CHOP plus rituximab (CHOP-rituximab) with CHOP alone in previously untreated patients with DLBCL (aged 60 to 80 years), complete response, disease control (event-free survival), and overall survival were superior in patients allocated to receive CHOP-rituximab. In another randomized (reported in abstract form) comparing CHOP-14 (administered every 14 days) plus rituximab with CHOP-14 alone in patients aged 65 and older with DLBCL, mantle cell lymphoma, or grade III follicular lymphoma, disease control (event-free survival) and overall survival were again superior in the R-CHOP-14 group. A third randomized trial in elderly patients (age 61 to 80 years) with DLBCL similarly randomized patients to R-CHOP-14 vs. CHOP-14 and demonstrated improved disease control (freedom from treatment failure). No difference in overall survival has been detected in the preliminary analysis of this trial (presented in abstract form). In one randomized trial comparing CHOP-rituximab with CHOP alone (reported in abstract form), in previously untreated patients with DLBCL (age 60 years and greater), disease control (time-to-treatment failure) was superior in patients allocated to receive CHOPrituximab. No difference between randomized groups in overall survival was detected. In that trial, patients responding to induction therapy underwent a second randomization to receive maintenance therapy with rituximab or observation. Disease control (time-to- PRACTICE GUIDELINE: 3
treatment failure) was superior in patients allocated to receive rituximab; no difference between randomized groups in overall survival was detected. In one randomized trial of younger patients (age 60 and younger) with low-risk DLBCL (reported in abstract form), patients received CHOP-like chemotherapy with or without rituximab. Disease control (time-to-treatment failure), and overall survival were superior in patients that received rituximab in addition to chemotherapy compared to patients that received chemotherapy alone. In a randomized trial of CHOP-rituximab compared with CHOP alone in patients with previously untreated human immunodeficiency virus (HIV)-related lymphoma, no overall survival benefit was derived from the addition of rituximab therapy. Although there was a trend to improvement in the primary outcome of response rate for R-CHOP, this benefit was offset by a statistically significant increased risk of treatment-related infectious death. In three trials comparing chemotherapy with or without rituximab in previously untreated patients with advanced-stage follicular lymphoma, disease control (time-to-treatment failure, time to progression, or two-year event-free survival) was superior in patients allocated to receive rituximab. An overall survival benefit was demonstrated with rituximab-based therapy in one full publication report, despite a brief median follow-up period of only 18 months. In another study, a strong trend to improved overall survival in the rituximab arm has been reported. An aggregate-data meta-analysis including these data has also confirmed an overall survival benefit in patients treated with rituximab and chemotherapy. In one trial comparing FCM to FCM-R in previously treated patients with indolent lymphomas, response rate, disease control (progression-free survival) and overall survival were superior in patients allocated to receive FCM-R. In another trial comparing CHOP to CHOP-R in patients with follicular lymphoma relapsed or resistant to a maximum of two nonanthracycline regimens, complete response and disease control (three-year progressionfree survival) were superior in patients allocated to receive CHOP-R compared to patients that received CHOP alone. In both trials, patients responding to induction therapy underwent a second randomization to receive maintenance therapy with rituximab or observation. Disease control (response duration or progression-free survival) was superior in patients allocated to receive maintenance rituximab; overall survival was not reported in the abstract reports of these studies. In one randomized trial comparing maintenance rituximab to observation in patients with untreated indolent lymphoma who initially responded to CVP induction, disease control (progression-free survival) and overall survival were superior in patients allocated to receive rituximab maintenance. There were no trials that compared chemotherapy to the same chemotherapy plus rituximab in patients who had previously received rituximab and achieved a response duration of at least one year. Two randomized trials comparing chemotherapy plus rituximab to chemotherapy alone in patients previously treated with rituximab alone showed improvement in survival or progression-free survival. One randomized trial that compared maintenance rituximab to re-treatment with rituximab at disease progression following induction treatment with rituximab monotherapy, reported a response rate for re-treatment that was comparable to first-line treatment. No important additional hematologic or non-hematologic toxicities were observed when rituximab was combined with chemotherapy. Chronic Lymphocytic Leukemia No randomized controlled trials were located. PRACTICE GUIDELINE: 4
Related Guidelines PEBC Evidence-Based Series: #6-1: Fludarabine in Intermediate and High-Risk Chronic Lymphocytic Leukemia. #6-7: The Use of Chemotherapy and Growth Factors in Older Patients with Newly Diagnosed, Advanced-Stage, Aggressive Histology Non-Hodgkin's Lymphoma. Funding The PEBC is supported by Cancer Care Ontario and the Ontario Ministry of Health and Long-Term Care. All work produced by the PEBC is editorially independent from its funding agencies. Copyright This guideline is copyrighted by Cancer Care Ontario; the guideline and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization. Disclaimer Care has been taken in the preparation of the information contained in this document. Nonetheless, any person seeking to apply or consult the practice guideline is expected to use independent medical judgment in the context of individual clinical circumstances or seek out the supervision of a qualified clinician. Cancer Care Ontario makes no representation or guarantees of any kind whatsoever regarding their content or use or application and disclaims any responsibility for their application or use in any way. Contact Information For further information about this series, please contact: Dr. K. Imrie, Co-Chair, Hematology Disease Site Group, Toronto-Sunnybrook Regional Cancer Centre, 2075 Bayview Avenue, Toronto, Ontario, M4N 3M5; TEL (416) 480-4757; FAX (416) 480-6002; or Dr. C.T. Kouroukis, Co-Chair, Hematology Disease Site Group, Juravinski Cancer Centre, 699 Concession Street, Hamilton, Ontario, L8V 5C2; TEL (905) 387-9711 ext. 62484; FAX (905) 575-6340. For information about the PEBC and the most current version of all reports, please visit the CCO Web site at http://www.cancercare.on.ca/ or contact the PEBC office at: Phone: 905-525-9140, ext. 22055 Fax: 905-522-768 PRACTICE GUIDELINE: 5
Evidence-based Series 6-8 Version 2.2005: Section 2 Rituximab in Lymphoma and Chronic Lymphocytic Leukemia: A Systematic Review K. Imrie, M.C. Cheung, A.E. Haynes, A. Stevens, R. Meyer, and the members of the Hematology Disease Site Group A Quality Initiative of the Program in Evidence-based Care (PEBC), Cancer Care Ontario (CCO) Developed by the Hematology Disease Site Group Original Report Date: February 17, 2005 Current Report Date: December 1, 2006 This evidence-based series replaces an evidence summary completed March 15, 1999 and published as: Imrie K, Esmail R, Buckstein R, Berinstein N, Meyer R, and the Hematology Disease Site Group. Use of rituximab in the treatment of lymphoma: an evidence summary. Curr Oncol. 1999;6(4):228-35. QUESTIONS Lymphoma 1. In patients with lymphoma of any type or stage, is rituximab used alone or in combination with chemotherapy more effective than non rituximab-containing regimens for improving overall survival, disease control (as assessed by measures such as progression-free survival, event-free survival, time-to-treatment failure, or response duration), response rate, or quality of life? 2. What is the toxicity associated with the use of rituximab used alone or in combination with chemotherapy compared with non rituximab-containing regimens? 3. Which patients with lymphoma are more or less likely to benefit from treatment with rituximab compared with those treated with non rituximab-containing regimens? Chronic Lymphocytic Leukemia 1. What beneficial outcomes are associated with the use of rituximab for the treatment of patients with chronic lymphocytic leukemia (CLL)? Outcomes of interest are overall survival, disease control (as assessed by measures such as progression-free survival, event-free survival, time-to-treatment failure, or response duration), and response rate. 2. What is the toxicity associated with the use of rituximab? 3. Which patients are more or less likely to benefit from treatment with rituximab? SYSTEMATIC REVIEW page 1
INTRODUCTION Each year, over 2400 patients in Ontario are diagnosed with lymphoma. Follicular lymphoma, the most common subtype, is incurable with conventional therapy. Patients often respond well to initial therapy with oral alkylator chemotherapy, which is associated with minimal adverse effects. Later in the course of the disease, however, treatment involves more toxic intravenous chemotherapy, generally with a progressively shorter duration of response. The median survival in patients with advanced stage disease is seven to ten years from the time of diagnosis. Monoclonal-antibody therapy is a novel treatment approach being applied to lymphomas and other cancers. Rituximab is the first such agent to be approved for use by the U.S. Food and Drug Administration (FDA) and was approved in Canada in March 2000. However, this agent is expensive and has rare life-threatening, infusion-related toxicity. Phase II trials published in the late 1990 s reported significant clinical activity and a favourable toxicity profile for this agent when used alone (e.g., McLaughlin et al. [1]). When evidence of the single-agent activity of rituximab in lymphoma became available in 1998, the Hematology Disease Site Group (DSG) of Cancer Care Ontario's (CCO) Program in Evidence-Based Care (PEBC) identified rituximab as a high priority. The DSG developed and regularly updated an evidence summary report (ES #6-8) (2). The evidence summary identified rituximab as an agent with very manageable toxicity that should be available for selected patients with lymphoma and facilitated the implementation of an Ontario Ministry of Health and Long-Term Care policy making rituximab widely available as a third-line therapy to patients who had indolent lymphoma other than CLL. The evidence summary was modified in 2000 after the publication of a randomized trial reported that the addition of rituximab to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) improved survival in older patients with DLBCL. In the modified summary, and in an associated practice guideline assessing the treatment for older patients with aggressive histology lymphoma (PEBC Evidence-based Series #6-7), a recommendation was made that rituximab in combination with CHOP be considered standard therapy for those patients when the goal of therapy was to achieve an optimum state of disease control and to prolong survival. This evidence summary and the associated practice guideline facilitated a change in the Ontario funding policy to provide rituximab to patients aged 60 years and greater with previously untreated de novo DLBCL. The funding policy implementation in January 2001 was within one month of the presentation of the new data in abstract form. Presentations at the December 2003 ASH meeting motivated the Hematology DSG to conduct a third overall review of the available evidence. The DSG anticipated that this review could lead to new recommendations that would warrant the development of a practice guideline (as opposed to an evidence summary). Anticipating that these new recommendations would have important implications for the Ontario Ministry of Health and Long-Term Care s cancerrelated New Drug Funding Program, the DSG requested that the Policy Advisory Committee (PAC) of CCO review a draft version of a practice guideline evaluating rituximab, prior to the completion of the full Practice Guideline Development Cycle (3). This evidence-based series replaces the original evidence summary. The treatment of patients with CLL with rituximab is also formally addressed in this evidence-based series. METHODS This systematic review was developed by Cancer Care Ontario s Program in Evidencebased Care (PEBC). Evidence was selected and reviewed by two members of the PEBC, one external reviewer, and methodologists. This systematic review is a convenient and up-to-date source of the best available evidence on the use of rituximab when treating patients with lymphoma and CLL. The body of evidence in this review is primarily comprised of mature randomized controlled trial data. That evidence forms the basis of a clinical practice guideline developed by the Hematology Disease SYSTEMATIC REVIEW page 2
Site Group. The systematic review and companion practice guideline are intended to promote evidence-based practice in Ontario, Canada. The PEBC is editorially independent of Cancer Care Ontario and the Ontario Ministry of Health and Long-Term Care. Literature Search Strategy Lymphoma MEDLINE (Ovid) (1966 through February Week one [February 15], 2006), EMBASE (1980 through Week 6 [February 15] 2006), and the Cochrane Library (2006, Issue 1) databases were searched. In MEDLINE, "Exp lymphoma/" (Medical subject heading [MeSH]) was combined with "exp lymphoma, large-cell/" (MeSH), "lymphoma.mp." (textword), and each of the following phrases used as text words: "rituxan.mp.", "rituximab.mp.", "ritux:.mp.", "idec.mp." combined with "c2b8.mp." or "c2b?.mp.", "anti-cd20.mp.", "anticd-20.mp.", "anticd20.mp.", "mabthera.mp.", and "rituxin.mp.". These terms were then combined with the search terms for the following publication types and study designs: practice guidelines, systematic reviews, meta-analyses, reviews, randomized controlled trials, controlled clinical trials, and clinical trials. Searches in the other bibliographic databases were similar. The MEDLINE search focused on retrieving randomized controlled trials. In addition, conference proceedings of ASH (1998-2005) and the American Society of Clinical Oncology (ASCO; 1997-2005) were searched for abstracts of relevant trials. Personal files were also consulted. Relevant bibliographic citations were selected by two reviewers. All the evidence was reviewed by two reviewers. Chronic Lymphocytic Leukemia MEDLINE (Ovid) (1966 through February Week one [February 15], 2006), EMBASE (1980 through Week 6 [February 15] 2006), and the Cochrane Library (Ovid) (2006, Issue 1; the Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews were searched) databases were searched. In MEDLINE, "Leukemia, lymphocytic/" (MeSH) was combined with "exp leukemia, lymphocytic, chronic/" (MeSH), "chronic lymphocytic leukemia.mp." (textword), "chronic lymphocytic leukaemia.mp.", "CLL.mp.", and each of the following phrases used as textwords: "rituxan.mp.", "rituximab.mp.", "ritux:.mp.", "idec.mp." combined with "c2b8.mp." or "c2b?.mp.", "anti-cd20.mp.", "anticd-20.mp.", "anticd20.mp.", and "mabthera.mp.". Searches in the other bibliographic databases were similar. In addition, conference proceedings of ASH (1996-2005) and ASCO (1995-2005) were searched for abstracts of relevant trials. The Canadian Medical Association Infobase (http://mdm.ca/cpgsnew/cpgs/index.asp) and the National Guidelines Clearinghouse (http://www.guideline.gov/index.asp) were also searched for existing evidence-based practice guidelines. Personal files were also reviewed. Relevant bibliographic citations were selected by two reviewers in the original literature search (to December 2003). Evidence was reviewed by two reviewers. Study Selection Criteria Inclusion Criteria Lymphoma Articles were selected for inclusion in this systematic review of the evidence if they were fully published reports or published abstracts in the English language of: 1. Randomized controlled trials (RCTs), systematic reviews, meta-analyses, or evidencebased practice guidelines; 2. Studies that include adult patients with lymphoma of any type, at any stage, and any histology; SYSTEMATIC REVIEW page 3
3. Studies comparing rituximab alone with non-rituximab regimens or comparing rituximab combination therapy with non-rituximab regimens; and, 4. Studies evaluating one or more of the following outcomes: overall survival, disease control (progression-free survival, event-free survival, time-to-treatment failure, or response duration), response rate, quality of life, or toxicity. Chronic lymphocytic leukemia Articles were selected for inclusion in this systematic review of the evidence if they were fully published reports or published abstracts in the English language of: 1. Primary studies of any design type, systematic reviews, meta-analyses, or evidencebased clinical practice guidelines; 2. Studies that include patients with CLL or small lymphocytic lymphoma (SLL). For studies including patients with various histologic subtypes of lymphoproliferative disorders, outcomes of patients with CLL must be identified separately; 3. Studies evaluating rituximab alone or in combination with other agents; and, 4. Studies evaluating at least one of the following outcomes were reported: overall survival, disease control (progression-free survival, time-to-treatment failure, event-free survival, or response duration), or toxicity. If response rate is reported, at least one of the above outcomes must also be reported to be included. Exclusion Criteria Lymphoma Letters, comments, books, notes, and editorial publication types were not considered. Chronic lymphocytic leukemia The following were not considered: 1. Letters, comments, and editorial publication types. 2. Reports evaluating patients undergoing stem cell transplantation. 3. Studies with fewer than 10 patients. Article Selection Lymphoma Citations in the original literature search were reviewed by two reviewers for inclusion. Citations were not blinded for author, journal name, institution, or results. Each citation was scored as: Yes (inclusion criteria were met, no exclusion criteria were met), No (one or more exclusion criteria were met), or Maybe (unclear from the citation if article meets any criteria). The full-length article was retrieved if the citation was scored yes or maybe by at least one reviewer, and inclusion and exclusion criteria were applied to the full article, if necessary. Interobserver kappa coefficients were calculated using GraphPad QuickCalcs (GraphPad Software, Inc.: http://graphpad.com/quickcalcs/kappa1.cfm). Chronic lymphocytic leukemia Citations in the original literature search were reviewed by two reviewers for inclusion. Citations were not blinded for author, journal name, institution, or results. Each citation was scored as: Yes (inclusion criteria were met, no exclusion criteria were met), No (one or more exclusion criteria were met), or Maybe (unclear from the citation if article meets any criteria). The full-length article was retrieved if the citation was scored yes or maybe by at least one reviewer, and inclusion and exclusion criteria were applied to the full article, if necessary. Interobserver kappa coefficients were calculated using GraphPad QuickCalcs (GraphPad Software, Inc.: http://graphpad.com/quickcalcs/kappa1.cfm). SYSTEMATIC REVIEW page 4
Synthesizing the Evidence Lymphoma The DSG identified that a meta-analysis of the published evidence for this topic is a high priority. However, sufficient information to allow for a meta-analysis is currently unavailable in the published abstracts. We will consider conducting a meta-analysis in a future update of this guideline using Review Manager 4.2 (RevMan Analyses [4]), which is available through the Cochrane Collaboration. Chronic Lymphocytic Leukemia Data appropriate for meta-analysis were not identified. RESULTS Literature Search Results Systematic Reviews No practice guidelines have been developed to specifically address the use of rituximab in lymphoma. However, the Italian Societies of Hematology recently devised guidelines for the management of nodal indolent lymphomas (follicular and small lymphocytic) in which the role of rituximab was discussed (5). After conducting a systematic review of the literature, an Expert Panel (composed of eight senior hematologists) graded the evidence and formulated treatment recommendations. Consensus was achieved using iterative group techniques (nominal and Delphi methodologies). The literature review was purposefully inclusive and updated to March 2005. The guideline statements relevant to rituximab are discussed in the indolent lymphoma outcomes sections below. Although the guideline statements were designed to be applicable to both follicular and SLL patients, the majority of studies reviewed were in patients with follicular lymphoma, and the authors did not present evidence that would justify an extrapolation of the recommendations to patients with SLL. A meta-analysis of RCTs comparing chemotherapy with or without rituximab in patients with previously untreated or relapsed indolent lymphomas has recently been presented in abstract form (6). The meta-analysis was based on aggregate data and was completed according to the Cochrane group methodology. The preliminary analysis provides a pooledanalysis of five RCTs to determine the survival benefit associated with added rituximab. Two additional systematic reviews have been identified that address the role of rituximab in lymphoma (7,8). The first, reported by Knight et al (7), examined the clinical and cost effectiveness of adding rituximab to CHOP chemotherapy for adult patients with DLBCL. The authors did not search the proceedings of ASCO or ASH, and the literature was last searched in September 2002. As a result, the systematic review contains only one trial of CHOP compared to CHOP-R. The Hematology DSG s literature search for this systematic review identified four additional trials of CHOP compared to CHOP-R and one other trial of CHOP or CHOP-like regimens compared to the same regimens with rituximab. The second systematic review, reported by Wake et al (8), examined the role of rituximab monotherapy as third-line treatment for refractory or recurrent stage III or IV follicular NHL. The authors intended to search conference proceedings for abstracts of relevant trials, however due to time constraints were unable. The literature search was last performed in September 2000. Due to the fact that both systematic reviews contained literature searches that were three (7) and five (8) years out of date, and the fact that neither included the proceedings of ASCO or ASH in the literature search, the Hematology DSG did not include either systematic review in its discussion of the evidence. Lymphoma Twenty-three trials were identified that met the inclusion criteria (9-38). One citation was identified as relevant but was not retrievable (9). Many of the 22 retrievable trials were reported SYSTEMATIC REVIEW page 5
in more than one publication. For those trials, only the most recent abstract report was referenced. Abstracts of trials for which full publications were available were not referenced, except when the abstract report contained more recent information or data not available in the full publication. All full publications were referenced. The 22 trials were comprised of nine full papers and 15 abstract reports. One full paper reported by Mounier et al (10), was a subsequent publication of Coiffier et al (11) and is not discussed further as the authors did not report any additional data. One full paper reported by Ghielmini et al (39) combined results from earlier publications (34,35) to determine factors that predict for response to rituximab maintenance after induction with rituximab monotherapy. One abstract reported by Van Oers et al (38) was presented at the 2005 ASH Annual Meeting, where additional data on overall survival were reported. The European Organisation for Research and Treatment of Cancer (EORTC) has made the overall survival data from that presentation available on their website, which has been referenced in this systematic review (40). Thirteen trials (four assessing patients with DLBCL and nine assessing patients with follicular or other indolent-histology lymphoma) compared chemotherapy plus rituximab with identical chemotherapy without rituximab; in one of those trials, a third randomized group was included to assess treatment with rituximab without chemotherapy. Six trials (one assessing patients with DLBCL and five assessing patients with follicular or other indolent-histology lymphoma) evaluated the role of maintenance therapy. Chronic Lymphocytic Leukemia Thirty publications of 27 trials (16 full papers and 14 abstracts) met the inclusion criteria. Ten trials evaluated rituximab as monotherapy (41-51), and, in 14, rituximab was tested in combination with other agents (52-68). In one case, an abstract and a full report provided information for the same trial (48,49). One randomized phase II trial assessed fludarabine plus rituximab and fludarabine followed by rituximab (52). Two studies included historical cohort comparisons (61,69); one study (69) was another reporting of an included trial (52). One phase II study had only enough patient data for evaluating toxicity (51). The remaining studies were phase I (67), pilot studies (62,65), phase I/II (45,46), and single-arm phase II studies. Outcomes Lymphoma Aggressive histology lymphoma Nine trials evaluated the role of rituximab in aggressive lymphoma. Table 1 summarizes the response rate, disease control, and overall survival data. Study quality Six of the trials were published in abstract form only (13-16,19,20) and could not be properly evaluated for study quality. Therefore, only three full publications were evaluated for RCT quality. Coiffier et al (11,12) reported the results of a randomized trial of chemotherapy with rituximab versus chemotherapy alone in previously untreated patients with DLBCL who were 60 to 80 years of age. The study scored two points on the Jadad quality scale. Concealment of allocation was not reported. The primary endpoint of the trial was event-free survival, with the authors estimating that three-year event-free survival would be 30% for the control arm. The trial was designed to detect a 15% increase in three-year event-free survival for the chemotherapy and rituximab arm with a significance level of p=0.05 and a power of 80%. Secondary endpoints were tumour response, overall survival, progression-free survival, disease-free survival, and toxicity. The data were analysed based on an intent-to-treat approach. One patient withdrew consent and was not included in the analysis. The trial was supported by grants from the pharmaceutical industry, and some of the authors had received research funding or had filled a consultant or advisory role. Kaplan et al (17) reported the SYSTEMATIC REVIEW page 6
results of a randomized trial of CHOP versus CHOP plus rituximab (CHOP-R). Patients were centrally randomized 2:1 to CHOP-R or CHOP. Concealment of allocation was not reported. The trial was designed to detect an increase in complete response rate from 50% in the CHOP arm to 75% in the CHOP-R arm at p=0.05 (one-sided) with a power of 81%. Secondary endpoints included time-to-progression, progression-free survival, and overall survival. Fortyseven patients in the CHOP-R arm and 28 patients in the CHOP alone arm prematurely discontinued treatment due to an adverse event, disease progression, or death. However, the authors did analyse the data using an intent-to-treat approach. The trial was supported in part by grants from the pharmaceutical industry. Details of treatment regimens for the five trials are found in Appendix 1. van Heeckeren et al (18) reported a small single-centre study comparing two B-cell purging strategies in patients with various B-cell lymphomas undergoing high-dose chemotherapy and autologous stem cell transplantation. Concealment of allocation was not reported. The study was powered to detect a 50% improvement in neutrophil recovery at 10 days post-transplantation with the rituximab-based purging strategy (two-sided significance of 0.05 and power of 92%). Secondary endpoints included event-free survival and overall survival. Of 34 patients randomized, 7 were removed from the studies due to failure of the purging strategy or mobilisation, disease progression prior to mobilisation, or contraindication to transplantation. The analysis was not completed with an intention-to-treat approach. Table 1. Randomized controlled trials evaluating chemotherapy plus rituximab versus non-rituximab regimens in aggressive histology lymphoma. Author, study Coiffier (11), Full Feugier (12), Full, update Sonneveld (14), abst Pfreundschuh (15), abst N rand Patients Treatment A Follow-up time of study 399 Untreated DLBCL CD, age 60-80y 632 {Untreated} G DLBCL, age 60y 250 Untreated DLBCL, mantle cell lymphoma, FL grade III, intermediate/high -risk IPI, age 65 1300 Untreated KL DLBCL, age 61-80y Pfreundschuh 824 Untreated (16), abst DLBCL, IPI 0-1, age 18-60y CHOP-R vs. Median 24 CHOP E mo CHOP-R vs. CHOP E MR vs. Observation for responders R-CHOP-14 vs. CHOP-14 R-CHOP-14 vs. CHOP-14 Median 5y RR B 76% vs. 63%; p=0.005 (CR+CRu) Median 2.7y 77% vs. 76% H ; p=0.76 N/A Disease OS B Comment control B 2y EFS: 57% vs. 38%, p<0.001 F At 2y: 70% vs. 57%, p=0.007 F ITT analysis with all randomized pts 5y EFS: 5y: 58% vs 47% vs 29% 45% p=.00002 p=.0073 TTF p=0.25 FI Eval: 540 pts superior in for induction; R-CHOP FI ; 348 pts for p=0.025 maintenance. TTF superior for MR p=0.01 Habermann (13), abst Induction randomization Median 4 mo J NR EFS superior in R-CHOP- 14 I ; p-value NR Median 26 mo CT M + R vs. Median 24 CT M mo NR 85% vs. 65%; p<0.005 (CR) FFTF superior in R-CHOP- 14 FI ; p=0.000025 2y TTF: 79.9% vs. 60.8%; p=0.000000 007 F p=0.67 OS superior in R-CHOP- 14 I ; p-value NR At 26 mo: 74% vs. 78%; p=0.13 95% vs. 86%; p=0.0002 F Eval: 171 at first interim analysis Eval: 828 pts Eval: 823 pts SYSTEMATIC REVIEW page 7
Kaplan (17), Full Van Heeckeren (18), Full Pohlman (19), abst Maintenance therapy Habermann (13), abst Maintenance randomization Haioun (20), abst 150 N Untreated HIV lymphoma (aggressive B- cell) 34 B-cell NHL high-risk, relapsed, or transformed disease undergoing HDC and ASCT (aggressive histology, n=17; indolent histology, n=10) 76 B-cell NHL eligible for ASCT 632 {Untreated} G DLBCL, age 60y 269 DLBCL, 2 mo post-asct (+HDC), age <60y CHOP-R (+R maint for pts with CR or PR) vs. CHOP E Median 137 wk In vivo purge Median 796 N/A with pre-daymobilisation rituximab vs. ex vivo CD34+ cell enrichment using immunomagnetic beads E Premobilisation rituximab vs. no rituximab premobilisation CHOP-R vs. CHOP E MR vs. Observation for responders Median 39 mo 57.6% vs. 47.0%; p=0.147 (CR+CRu) N/A Median 2.7y 77% vs. 76% H ; p=0.76 N/A Median PFS: 45 vs. 38 wk (p=0.67) 2y EFS: 81% vs. 76% p=0.66) Median: 139 vs. 110 wk (p=0.76) 3 y OS: 67% vs 100% p=0.16) Age range: 26 to 73y Eval: 27 pts No No Eval: 55 difference in difference PFS at 39 in OS at 39 mo (p-value mo (pvalue NR) NR) TTF superior in R-CHOP FI ; p=0.025 TTF superior for MR p=0.01 R vs. obs post ASCT L Median 3y N/A 3y EFS: 80% vs. 72% (p=0.10) p=0.25 FI p=0.67 NR Eval: 540 pts for induction; 348 pts for maintenance. high risk pts (aaipi 2 or 3) Note: aaipi=adverse age-adjusted International Prognostic Index factors; abst=abstract; ASCT=autologous stem cell transplantation; CHOP=cyclophosphamide, doxorubicin, vincristine, and prednisone; CHOP-14=CHOP administered every 14 days; CR=complete response; CRu=unconfirmed CR; CT=chemotherapy; DLBCL=diffuse large B-cell lymphoma; EFS=event-free survival; eval=evaluable; HDC=high-dose consolidative chemotherapy; HIV=human immunodeficiency virus; ITT=intention-to-treat; maint=maintenance; mo=month; MR=maintenance rituximab; N=number; N/A=not applicable; NR=not reported; NS=not significant; obs=observation; OS=overall survival; PFS=progression-free survival; pts=patients; rand=randomized; R=rituximab; RR=response rate; TTF=time-totreatment failure; FFTF=freedom from treatment failure; vs.=versus; wk=week; y=year. A Treatment details are provided in Appendix 1. B Data provided in order of intervention versus control. C Of patients with central pathologic review (n=385), 87% had confirmed DLBCL. D Some patients with T-cell lymphoma (exclusion criterion) were discovered on central pathologic review. E No difference between groups for baseline/clinical characteristics. F Log-rank. G Information provided in study protocol (Protocol ID E-4494, date last modified 2002-03-01; National Cancer Institute Clinical Trials, http://www.cancer.gov/search/viewclinicaltrials.aspx?cdrid=65935&version=healthprofessional &protocolsearchid=1000667). H Overall RR; no definition provided. I Data in each arm not provided. J Median time off protocol. K Authors did not indicate whether groups similar at baseline. L 1300 patients recruited. Authors did not indicate number of patients randomized. M CT included CHOP-21, CHOEP-21, MACOP-B, or PMitCEBO; doses and schedules not reported. N Randomized in 2:1 ratio in favour of rituximab. SYSTEMATIC REVIEW page 8
Study results Coiffier et al (11) have published the results of a randomized trial comparing CHOP-R with CHOP alone in 399 patients with DLBCL, ages 60 to 80 years. The rituximab dose was 375 mg/m 2 and was given on day one of each treatment. The complete response (CR) rate and two-year event-free and overall survivals were superior in patients allocated to receive CHOP-R (Table 1). In patients receiving CHOP-R, the adjusted risk ratio (RR) for death, disease progression, or other events was 0.55 (95% confidence interval [CI], 0.41 to 0.75), and the adjusted RR for all-cause death was 0.53 (95% CI, 0.37 to 0.77); analyses were adjusted for prognostic factors. Feugier et al (12) provided updated results with a median follow-up of 5 years. Both five-year overall survival and event-free survival were significantly higher in the rituximab arm compared to the control arm (Table 1). Habermann et al (13) reported the results of a randomized trial comparing CHOP-R with CHOP alone in 632 patients with DLBCL, ages 60 years and greater. The rituximab dose was 375 mg/m 2, but the schedule differed from that of Coiffier et al (11): rituximab was given on day - 7 and -3 before cycle 1 and two days before cycles 3, 5, and 7. Responding patients underwent a second randomization to receive maintenance therapy with rituximab (four weekly doses every six months for four courses) or to observation. The abstract publication included an analysis of 540 patients for the induction question. The results are shown in Table 1. With respect to the induction question, time-to-treatment failure was superior (p=0.025) in patients allocated to receive rituximab; no differences in response rate or overall survival were detected. Sonneveld et al (14) reported (in abstract form) the results of a randomized trial of an intensified CHOP regimen administered every 14 days (CHOP-14) with or without rituximab in elderly patients ( 65) with intermediate or high-risk DLBCL, mantle cell lymphoma, or grade III follicular lymphoma. At the time of the first interim analysis, 171 patients were evaluable. Although there was no difference in complete response rates between the two treatment arms, patients who received rituximab with CHOP-14 had significantly improved event-free and overall survival durations (p-values not reported). Median follow-up reported in the preliminary analysis is brief (4 months), and further analyses are pending to justify stopping the trial. Pfreundschuh et al (15) reported (in abstract form) the results of a 2x2 factorial randomized trial comparing (1) CHOP-14 with or without rituximab and (2) 6 versus 8 cycles of chemotherapy in elderly patients (age 61-80 years) with stage I-IV DLBCL. Radiotherapy was planned for initial bulk or extranodal disease. There were 828 patients evaluable at the time of the first interim analysis. Freedom from treatment failure was significantly better in patients who received R-CHOP-14 compared to CHOP-14 alone (p=0.000025). No benefit was derived from additional chemotherapy cycles (6 vs. 8 cycles, p=0.23). With preliminary follow-up of only 26 months, an overall survival benefit has not been demonstrated with the addition of rituximab therapy (p=0.13). Pfreundschuh et al (16) reported (in abstract form) the results of a randomized trial comparing chemotherapy with CHOP, CHOP+etoposide (CHOEP), methotrexate-leucovorindoxorubicin-cyclophosphamide-vincristine-bleomycin-prednisone (MACOP-B), or prednisolonemitoxantrone-cyclophosphamide-etoposide-bleomycin-vincristine (PMitCEBO) to chemotherapy with rituximab in 824 previously untreated patients with DLBCL who were 60 years of age or younger. Rituximab was given at a dose of 375 mg/m 2 on day one of each three week cycle. Complete response rate (p<0.005), two-year time-to-treatment failure (p=0.000000007), and two-year overall survival (p=0.0002) were superior for patients that received chemotherapy plus rituximab compared to patients that received chemotherapy alone (Table 1). Kaplan et al (17) have published the results of a randomized trial comparing CHOP-R with CHOP alone in 150 patients with HIV-related, aggressive-histology B-cell lymphoma. Rituximab was given on day 1 of each cycle (CHOP was given day 3) and maintenance rituximab was given to patients in the CHOP-R arm that had complete or partial responses. No differences in the complete response rate, time-to-progression, progression-free survival, or SYSTEMATIC REVIEW page 9
overall survival were detected between the two arms (Table 1). More patients receiving CHOP- R died of an infectious complication compared to CHOP alone (14% versus [vs.] 2 percent, respectively; p=0.02). van Heeckeren et al (18) published the results of a small randomized trial comparing two B-cell purging protocols in patients with high-risk, relapsed, or transformed B-cell NHL undergoing high-dose chemotherapy and autologous stem cell transplantation. Patients were randomized to either an in vivo purging strategy with rituximab administered prior to stem-cell mobilisation versus an ex vivo strategy in which CD34+ stem cells were positively selected. Thirty-four patients underwent randomization; of 27 evaluable patients, 17 had aggressivehistology lymphomas. Although the study was powered to detect differences in myeloid recovery after transplantation, EFS and OS outcomes were also reported as secondary outcomes. No differences in these latter outcomes were detected between the two purging strategies. Pohlman et al (19) also reported (in abstract form) a randomized trial in B-cell lymphoma patients eligible for high-dose chemotherapy and autologous stem cell transplantation. Patients were randomized to receive mobilisation chemotherapy with or without rituximab prior to mobilisation. Of 76 patients enrolled, 55 were evaluable. Progression-free and overall survival were secondary outcomes, and were not found to be significantly different between the mobilisation strategies (p-values not reported). Maintenance rituximab in aggressive histology lymphoma As described above, Habermann et al (13) reported the results of a randomized trial in elderly patients (age 60) with DLBCL comparing (1) CHOP-R versus CHOP alone for induction therapy (first randomization) and (2) rituximab versus observation for maintenance therapy in responders (second randomization). Maintenance rituximab was administered as four weekly doses every six months for four courses. The abstract publication included an analysis of 348 patients for the maintenance question. Time-to-treatment failure was superior (p=0.01) in patients allocated to receive rituximab; however, no difference in overall survival was detected. In a subset analysis to control for interaction between the induction and maintenance randomizations, patients who received CHOP induction had a superior time-to-treatment failure (p=0.0001) when maintenance rituximab was administered compared to observation. In patients allocated to CHOP-R induction, no difference in time-to treatment failure was detected (p=0.83). Therefore, the benefit of rituximab maintenance appears to be limited to patients who did not receive immunotherapy with initial induction. Haioun et al (20) reported the results of a randomized trial comparing maintenance therapy with rituximab with observation in high-risk DLBCL patients (2-3 age-adjusted International Prognostic Index factors) who had responded to high-dose chemotherapy followed by autologous stem cell transplantation. An initial randomization to non rituximab-containing induction chemotherapy preceded the high-dose strategy. Among the 331 patients who received high-dose chemotherapy, 269 were randomized to MR or observation. The dose of rituximab was 375 mg/m 2, with four weekly doses given beginning two months posttransplantation. No difference in three-year event-free survival was detected; results of overall survival were not reported in the publication of this abstract (Table 1). Indolent histology lymphoma Thirteen randomized trials evaluated the role of rituximab in indolent lymphoma. Seven trials are available as full publications (21,29,30,34-37); the remaining trials are available as preliminary reports or in abstract form only. Nine trials compared a chemotherapy regimen plus rituximab with the same regimen without rituximab, and five trials evaluated the role of maintenance therapy. Five studies included only patients with follicular lymphoma, another five studies included patients with follicular and other indolent histologies, two studies included only SYSTEMATIC REVIEW page 10