- Email: [email protected]
Highlights of the 2008 International Conference on Malignant Lymphoma
Editorial Bruce D. Cheson, MD Lombardi Cancer Center Georgetown University Hospital Washington, DC
Clinical Lymphoma & Myeloma Vol. 8, No. 4, 205-208, 2008 DOI: 10.3816/CLM.2008.n.028
Highlights of the 2008 International Conference on Malignant Lymphoma The recent International Conference on Malignant Lymphoma (ICML) brought together more than 3000 attendees with a clinical or laboratory interest in the various malignant lymphomas. A number of presentations reflected the international collaborations that are becoming so critical. Nancy Harris presented the deliberations of the working groups that have revised the World Health Organization Classification, which will be published in September.1 A number of new entities were proposed, while several controversial features were retained, such as the grading system for follicular lymphomas (FLs). The Lunenburg Consortium proposed an integration of molecular and genetic studies into the International Prognostic Index (IPI),2 while Federico and colleagues attempted to improve on the prognostic strength of the IPI, recognizing the importance of tumor bulk, which was not included in the initial recommendations.3 Workshops on lymphoma in underdeveloped countries and further attempts to standardize [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) in Hodgkin lymphoma (HL) were also featured. Several themes were prominent during the meeting, including recognition of the fiftieth anniversary of the discovery of Burkitt lymphoma, which featured a description of the history and biology by Ian Magrath and data on the Hoelzer regimen and dose-adjusted R-EPOCH (rituximab with etoposide/prednisone/vincristine/ cyclophosphamide/doxorubicin), both of which appear to advance the treatment of this now highly curable aggressive lymphoma. In recent years, important observations have been made in our understanding of the biology and molecular genetics of diffuse large B-cell lymphoma (DLBCL). Several laboratories have demonstrated different signatures that correlate with outcome, including the germinal B-cell and activated B-cell types originally described by Rosenwald and colleagues.4 Expression of a number of genes also appears to correlate with response and outcome: Mounier et al showed that rituximab improved the outcome of patients whose lymphoma was positive for Bcl-2 overexpression, but with less of an effect in Bcl-2–negative tumors, and in those with high numbers of tumor-associated macrophages.5,6 In a trial led by the Eastern Cooperative Oncology Group, Winter et al showed that, among Bcl-6–positive cases, the addition of rituximab to CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) had no effect on outcome, which was very different than was observed with the Bcl6–negative cases.7 Indeed, Bcl-6 loses its prognostic significance when rituximab is added to the regimen. These data were updated and expanded at the ICML to include the investigation of p21, a
cyclin-dependent kinase inhibitor that is a downstream effector of p53. Patients whose DLBCL was positive for p21 derived benefit from rituximab, in contrast with the negative tumors. The most favorable group included patients with Bcl-2–negative/p21-positive tumors, while the converse was associated with the poorest outcome. Other combinations were intermediate.8 Based on observations such as these, the Lunenburg Consortium was organized to create a clinico-biologic prognostic index for DLBCL. A controversial topic has been the role of radiation therapy in the management of patients with the DLBCL variant, primary mediastinal B-cell non-Hodgkin lymphoma (NHL). Dunleavy and colleagues presented important data with R-EPOCH and no radiation, with a 100% response rate, including 92% complete remissions, and at a median follow-up of 3.1 years, the overall survival (OS) was 100% with an 84% event-free survival.9 Despite the successes with DLBCL, mantle cell lymphoma (MCL) continues to provide challenges. This heterogeneous disorder (or disorders) remains incurable; nonetheless, the prognosis has likely been underestimated in most of the recent literature. Whereas the published data suggest a median survival of 3-4 years, more current results suggest values 2-3 times as long. An explanation for this discrepancy is not apparent as the therapeutic advances have been modest. CHOP or similar regimens remain a poor standard, and the initial excellent results with hyperCVAD (cyclophosphamide/vincristine/doxorubicin/dexamethasone) were not confirmed by a Southwest Oncology Group phase II clinical trial.10,11 Of note is the controversy regarding the role of rituximab in this disorder. Whereas this antibody when added to chemotherapy clearly improves survival of certain subsets of patients with follicular and low-grade, and diffuse large B-cell NHL, the benefits in MCL are not readily apparent. The initial data from Howard and colleagues showed impressive complete and overall response rates with rituximab with CHOP (R-CHOP), but with a disappointing time to progression of only about 18 months.12 The German Low-Grade Lymphoma Study Group randomized previously untreated patients to CHOP or R-CHOP, with a secondary randomization to one of several interferon or transplantation-based regimens, based on patient age. R-CHOP resulted in a higher complete and overall response rate, but with no effect on progression-free survival (PFS) or OS.13 The same cooperative group compared fludarabine/cyclophosphamide/mitoxantrone (FCM) with or without rituximab in patients with relapsed and refractory disease and showed a survival benefit from the antibody.14 When they evaluated the role of
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Highlights of the 2008 International Conference on Malignant Lymphoma rituximab maintenance in these patients, the antibody achieved a prolonged response duration; a significant survival advantage was not yet apparent. This controversy was further sustained by the report at ICML by Herold et al from another German Lymphoma Study group who randomized patients between mitoxantrone/ chloramabucil/prednisolone (MCP) and rituximab with MCP, with no apparent benefit from the antibody.15 Similarly, Zelenetz and colleagues from Memorial Sloan-Kettering Cancer Center, using historical comparisons, failed to support and benefit from rituximab.16 In contrast, Khouri and colleagues, using historical controls, suggested that adding high doses of rituximab to autologous stem cell transplantation might improve the outcome of patients with MCL, especially when the transplantation was performed in first remission.17 One of the most attractive therapeutic options for patients with FL has been anti-idiotype vaccines, based largely on the data from Ron Levy of Stanford University. Patients who experienced a cellular and humoral response to the vaccine had a longer PFS than those who did not.18 These data led to 3 prospective randomized trials. At the ICML, Dr. Levy presented the first of these, which, unfortunately, failed to demonstrate benefit from adding the vaccine to patients treated with CVP (cyclophosphamide/vincristine/ prednisone).19 This negative outcome was supported by the results of a trial conducted by the Favrille Corporation in which patients received rituximab induction followed by the vaccine or placebo, with similarly disappointing results. In the absence of effective therapies, criteria to measure response are irrelevant. However, the increasing number of effective therapies has necessitated standardized, accurate measures of response assessment. In 1999, the International Working Group Criteria became the standard for clinical trials.20 Since that time, and with extensive use of these guidelines, it became apparent that modifications were required. The strongest support for these revisions was the increased availability of FDG-PET. At the ICML 3 years ago, the International Harmonization Project convened to revise the response criteria, which were published in 2007.21 These guidelines provided recommendations for the use of FDG-PET in clinical trials. At the 2008 ICML, several abstracts in DLBCL and Hodgkin lymphoma demonstrated that PET could limit the number of patients who were treated with radiation. Despite the enthusiasm for this technology, a number of discussions provided needed balance for a technology for which the amount of available information far outweighs its demonstrable benefits. At a point-counter-point, Drs. Cheson and Stroobants provided 2 sides to the use of PET.22,23 Whereas PET increases the number of lesions identified compared with computed tomography (CT), the number of patients whose stage is altered is in the range of 10%30%, but fewer still have their therapy changed on the basis of this information, and there are no data that outcome is improved. Although PET after ≥ 1 cycles of therapy predicts outcome, no data demonstrate that changing therapy on the basis of this information prolongs survival. In DLBCL and HL, a posttreatment PET might distinguish patients who are cured at that point from those who might need additional therapy; however, a follow-up CT might provide comparable information. Finally, the available data do not support routine surveillance PET scans. Jerusalem et
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al reported on 36 patients who underwent PET posttreatment and every 4-6 months thereafter.24 Of the 5 positive studies, one was in a patient with known active disease, and 2 in patients who had already developed disease-related symptoms, with 6 false-positive studies. More recently, Zinzani and colleagues25 showed that the risk of relapse for DLBCL and HL was too low after a year to justify scanning all patients, and for indolent lymphomas, it is less important to identify relapse earlier than clinically apparent. In an abstract from Mocikova et al at the ICML,26 the lack of benefit from surveillance scans was confirmed. Nevertheless, the promise of PET will hopefully be realized in the large number of ongoing or planned risk-directed studies which will hopefully result in reduced treatment for lower-risk patients and a better outcome for patients with more advanced and resistant disease. Therapeutic advances, based largely on the availability of new and effective agents such as rituximab and radioimmunotherapy, have clearly prolonged the survival of patients with follicular and large-cell NHL. Nevertheless, many patients fail initial therapy or relapse, and new agents are needed. Even in HL, where 85% can be cured with initial chemotherapy alone or with radiation, those who are not cured cannot always be successfully salvaged, even with stem cell transplantation. Sandra Horning’s presentation at the ICML clearly demonstrated that the outcome of patients who relapse within a year of stem cell transplantation is dismal.27 These patients are suitable candidates for new drug studies, rather than traditional, ineffective agents. Thus, considerable attention was focused on new agents in lymphoma. Bendamustine is a unique drug that has been in clinical use for over 30 years in the German Democratic Republic but is just being studied in other parts of the world. Studies from the United States confirmed responses of over 70% in rituximabrefractory follicular and low-grade NHL and over 90% when combined with rituximab in patients with relapsed, nonrefractory disease.28,29 The immunomodulatory drug lenalidomide has also shown promise and is being combined with other agents. Of interest were agents that were directed at cell signaling pathways, including temsirolimus and everolimus, which are active in MCL and other histologies as well. Tonic Bcr signaling appears to be important for lymphoma survival, and the pathways can be inhibited by spleen tyrosine kinase (SYK) inhibitors, such as fostamatinib, an oral agent with activity in DLBCL and chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia.30 Further study is clearly warranted. The histone deacetylase inhibitors target cellular epigenetic mechanisms and a number of these are in the clinic (vorinostat) or in trials (romidepsin, MGCD0103) with promising activity in nonHodgkin and Hodgkin lymphomas. Impaired apoptosis appears to be important in lymphomagenesis, and an increasing menu of small molecules that target the intrinsic or extrinsic pathways of apoptosis are in clinical trials, such as oblimersen, obatoclax, AT-101, ABT263, anti-TRAIL, and YM155. Considerable interest has also focused on new biologic agents. The efficacy and tolerability of rituximab has led to the development of at least a half dozen human or humanized anti-CD20s, which either bind to a different epitope or have differences in antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, induction of apoptosis, or target binding. Whether any of these features will result in improved activity compared
Bruce D. Cheson with rituximab or activity in the setting of rituximab resistance remains to be demonstrated. Preliminary data with GA101 and veltuzumab presented at the ICML, should stimulate interest in their further development.31 The Cancer and Leukemia Group B has taken an approach in patients with low or intermediate FL IPI to use combinations of targeted agents as the initial treatment. Dr. Leonard presented the initial study of rituximab plus galiximab, which resulted in high response rates in the lower-risk patients; a rituximab-plus-epratuzumab trial is ongoing.32 Byrd et al presented data on the combination of lumiliximab, a primatized anti-CD23 monoclonal antibody (MoAb), with the FCR regimen (fludarabine/cyclophosphamide/rituximab) in CLL. A suggestion of an improved complete remission rate when compared with historical data with FCR alone led to the international LUCID trial, which will be completed in the near future and will define the role for this new antibody in the management of these patients.33 Antibodydrug conjugates are also being studied, such as SGN-35, a conjugate of the anti-CD30 MoAb and aurostatin, a tubulin poison. Initial impressive results in HL will hopefully be reproduced in an ongoing confirmatory trial. The ICML clearly demonstrated the important advances that have been made in our understanding of the biology and genetics of lymphoid malignancies, their classification, determining prognosis, new treatment approaches, and methods of assessing response. Incorporating the various components of this expanding body of knowledge into novel treatment strategies will certainly lead to an improved outcome for patients with malignant lymphomas.
Bruce D. Cheson, MD 1. Harris NL, Swerdlow S, Campo E, et al. The World Health Organization (WHO) classification of lymphoid neoplasms: what's new? Ann Oncol 2008; 19(suppl 4):iv119 (Abstract 112). 2. The Lunenburg Lymphoma Biomarker Consortium (LLBC). First results of an international study to establish a new clinico-biological prognostic index for diffuse large B-cell lymphoma (DLBCL). Ann Oncol 2008; 19(suppl 4):iv100 (Abstract 054bis). 3. Federico M, Bellei M, Marcheselli L, et al. F2 Prognostic Index. Ann Oncol 2008; 19(suppl 4):iv101 (Abstract 058). 4. Rosenwald A, Wright G, Chan WC, et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large B-cell lymphoma. N Engl J Med 2002; 346:1937-47. 5. Mounier N, Briere J, Gisselbrecht C, et al. Rituximab plus CHOP (R-CHOP) overcomes bcl-2--associated resistance to chemotherapy in elderly patients with diffuse large B-cell lymphoma (DLBCL). Blood 2003; 101:4279-84. 6. Canioni D, Salles G, Mounier N, et al. High numbers of tumor-associated macrophages have an adverse prognostic value that can be circumvented by rituximab in patients with follicular lymphoma enrolled onto the GELA-GOELAMS FL-2000 trial. J Clin Oncol 2008; 26:440-6. 7. Winter JN, Weller EA, Horning SJ, et al. Prognostic significance of Bcl-6 protein expression in DLBCL treated with CHOP of R-CHOP: a prospective correlative study. Blood 2006; 107:4207-13. 8. Winter JN, Zhang L, Li S, et al. P21, BCL-2, and the IPI, but not Bcl-6, predict clinical outcome in DLBCL treated with rituximab(R)CHOP: long-term followup from E4494. Ann Oncol 2008; 19(suppl 4):iv99 (Abstract 051). 9. Dunleavy K, Pittaluga S, Janik J, et al. The addition of rituximab to dise-adjusted (DA)-EPOCH obviates the need for radiation in the treatment of primary mediastinal large B-cell lymphoma (PMBL): a prospective study of 58 patients. Ann Oncol 2008; 19(suppl 4):iv96 (Abstract 43). 10. Romaguera JE, Favad L, Rodriguez MA, et al. High rate of durable remissions after treatment of newly diagnosed aggressive mantle-cell
11. 12.
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18. 19.
20. 21. 22. 23. 24. 25. 26. 27. 28.
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lymphoma with rituximab plus hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine. J Clin Oncol 2005; 23:7013-23. Epner E, Unger J, Miller T, et al. A multi-center trial of hyperCVAD+rituxan in patients with newly diagnosed mantle cell lymphoma. Blood 2007; 110:121a (Abstract 387). Howard OM, Gribben JG, Neuberg DS, et al. Rituximab and CHOP induction therapy for newly diagnosed mantle-cell lymphoma: molecular complete responses are not predictive of progression-free survival. J Clin Oncol 2002; 20:1288-94. Lenz G, Dreyling M, Hoster E, et al. Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone significantly improves response and time to treatment failure, but not long-term outcome in patients with previously untreated mantle cell lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG). J Clin Oncol 2005; 23:1984-92. Forstpointner R, Unterhalt M, Dreyling M, et al. Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG). Blood 2006; 108:4003-8. Herold M, Haas A, Doerken B, et al. Immunochemotherapy (R-MCP) in advanced mantle cell lymphoma is not superior to chemotherapy (MCP) alone - 50 months update of the OSHO phase III study (OSHO#39). Ann Oncol 2008; 19(suppl 4):iv85 (Abstract 012). Zelenetz AD, Persky D, Rice RD, et al. Results of sequential chemotherapy followed by high dose therapy and autologous stem cell rescue for mantle cell lymphoma: role of rituximab and functional imaging. Ann Oncol 2008; 19(suppl 4):iv85 (Abstract 013). Khouri IF, Tam CS, Ledesma C, et al. Non-myeloablative allogeneic stem cell transplantation (NST) vs. autologous transplantation (ASCT) in patients with mantle cell lymphoma (MCL). Ann Oncol 2008; 19(suppl 4):iv86 (Abstract 014). Hsu FJ, Caspar C, Czerwinski D, et al. Tumor-specific idiotype vaccines in the treatment of patients with B-cell lymphoma - long term results of a clinical trial. Blood 1997; 89:3129-35. Levy R, Robertson M, Leonard J, et al. Results of a phase 3 trial evaluating safety and efficacy of specific immunotherapy, recombinant idiotype (ID) conjugated to KLH (ID-KLH) with GM-CSF, compared to nonspecific immunotherapy, KLH with GM-CSF, in patients with follicular non-Hodgkin's lymphoma (FNHL). Ann Oncol 2008; 19(suppl 4): iv102 (Abstract 57). Cheson BD, Horning SJ, Coiffier B, et al. Report of an International Workshop to standardize response criteria for non-Hodgkin's lymphomas. J Clin Oncol 1999; 17:1244-53. Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol 2007; 25:579-86. Stroobants S. Has PET changed the approach to lymphoma patients? (PROS). Ann Oncol 2008; 19(suppl 4):iv122 (Abstract 120). Cheson BD. Has PET changed the approach to lymphoma patients? (COS). Ann Oncol 2008; 19(suppl 4):iv122 (Abstract 121). Jerusalem G, Beguin Y, Fassotte MF, et al. Early detection of relapse by whole-body positron emission tomography in the follow-up of patients with Hodgkin's disease. Ann Oncol 2003; 14:123-30. Zinzani PL, Stefoni V, Ambrosini V, et al. FDG-PET in the serial assessment of patients with lymphoma in complete remission. Blood 2007; 110:71a (Abstract 216). Mocikova H, Obrtlikova P, Vackova B, et al. FDG-PET during followup in patients with Hodgkin lymphoma after first line therapy. Ann Oncol 2008; 19(suppl 4):iv123 (Abstract 124). Horning SJ, Fanale M, deVos S, et al. Defining a population of Hodgkin lymphoma patients for novel therapeutics: an international effort. Ann Oncol 2008; 19(suppl 4):iv120 (Abstract 118). Friedberg JW, Cohen P, Chen L, et al. Bendamustine in patients with rituximab refractory and alkylator-refractory, indolent and transformed non-Hodgkin's lymphoma: Results from a phase II multicenter singleagent study. J Clin Oncol 2008; 28:204-10. Robinson KS, Williams ME, van der Jagt RH, et al. Bendamustine plus rituximab in patients with relapsed indolent B-cell and mantle cell nonHodgkin's lymphoma: a phase II multicenter study. J Clin Oncol 2008. In press. Friedberg J, Sharman J, Schaefer-Cutillo J, et al. Tamatinib fosdium
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Highlights of the 2008 International Conference on Malignant Lymphoma (TAMF), an oral SYK inhibitor, has significant clinical activity in B-cell non-Hodgkin's lymphoma (NHL). Ann Oncol 2008; 19(suppl 4):iv116 (Abstract 102). 31. Umana P, Moessner E, Grau R, et al. GA101, a novel therapeutic type II CD20 antibody with outstanding anti-tumor efficacy in non-Hodgkin lymphoma xenograft models and superior B cell depletion. Ann Oncol 2008; 19(suppl 4):iv115 (Abstract 098). 32. Czuczman MS, Johnson J, Jung S, et al. A phase II trial of extended
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induction galiximab ([G] anti-CD80 monoclonal antibody) plus rituximab in previously untreated follicular lymphoma (FL): initial report of CALGB 50402. Ann Oncol 2008; 19(suppl 4):iv130 (Abstract 143). 33. Byrd J, Castro J, Flinn I, et al. Lumiliximab in combination with FCR for the treatment of relapsed chronic lymphocytic leukemia (CLL): results from a phase I/II multicenter study. Ann Oncol 2008; 19(suppl 4):iv130 (Abstract 145).
Clinical Lymphoma & Myeloma Vol. 8, No. 4, 205-208, 2008 DOI: 10.3816/CLM.2008.n.028
Highlights of the 2008 International Conference on Malignant Lymphoma The recent International Conference on Malignant Lymphoma (ICML) brought together more than 3000 attendees with a clinical or laboratory interest in the various malignant lymphomas. A number of presentations reflected the international collaborations that are becoming so critical. Nancy Harris presented the deliberations of the working groups that have revised the World Health Organization Classification, which will be published in September.1 A number of new entities were proposed, while several controversial features were retained, such as the grading system for follicular lymphomas (FLs). The Lunenburg Consortium proposed an integration of molecular and genetic studies into the International Prognostic Index (IPI),2 while Federico and colleagues attempted to improve on the prognostic strength of the IPI, recognizing the importance of tumor bulk, which was not included in the initial recommendations.3 Workshops on lymphoma in underdeveloped countries and further attempts to standardize [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) in Hodgkin lymphoma (HL) were also featured. Several themes were prominent during the meeting, including recognition of the fiftieth anniversary of the discovery of Burkitt lymphoma, which featured a description of the history and biology by Ian Magrath and data on the Hoelzer regimen and dose-adjusted R-EPOCH (rituximab with etoposide/prednisone/vincristine/ cyclophosphamide/doxorubicin), both of which appear to advance the treatment of this now highly curable aggressive lymphoma. In recent years, important observations have been made in our understanding of the biology and molecular genetics of diffuse large B-cell lymphoma (DLBCL). Several laboratories have demonstrated different signatures that correlate with outcome, including the germinal B-cell and activated B-cell types originally described by Rosenwald and colleagues.4 Expression of a number of genes also appears to correlate with response and outcome: Mounier et al showed that rituximab improved the outcome of patients whose lymphoma was positive for Bcl-2 overexpression, but with less of an effect in Bcl-2–negative tumors, and in those with high numbers of tumor-associated macrophages.5,6 In a trial led by the Eastern Cooperative Oncology Group, Winter et al showed that, among Bcl-6–positive cases, the addition of rituximab to CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) had no effect on outcome, which was very different than was observed with the Bcl6–negative cases.7 Indeed, Bcl-6 loses its prognostic significance when rituximab is added to the regimen. These data were updated and expanded at the ICML to include the investigation of p21, a
cyclin-dependent kinase inhibitor that is a downstream effector of p53. Patients whose DLBCL was positive for p21 derived benefit from rituximab, in contrast with the negative tumors. The most favorable group included patients with Bcl-2–negative/p21-positive tumors, while the converse was associated with the poorest outcome. Other combinations were intermediate.8 Based on observations such as these, the Lunenburg Consortium was organized to create a clinico-biologic prognostic index for DLBCL. A controversial topic has been the role of radiation therapy in the management of patients with the DLBCL variant, primary mediastinal B-cell non-Hodgkin lymphoma (NHL). Dunleavy and colleagues presented important data with R-EPOCH and no radiation, with a 100% response rate, including 92% complete remissions, and at a median follow-up of 3.1 years, the overall survival (OS) was 100% with an 84% event-free survival.9 Despite the successes with DLBCL, mantle cell lymphoma (MCL) continues to provide challenges. This heterogeneous disorder (or disorders) remains incurable; nonetheless, the prognosis has likely been underestimated in most of the recent literature. Whereas the published data suggest a median survival of 3-4 years, more current results suggest values 2-3 times as long. An explanation for this discrepancy is not apparent as the therapeutic advances have been modest. CHOP or similar regimens remain a poor standard, and the initial excellent results with hyperCVAD (cyclophosphamide/vincristine/doxorubicin/dexamethasone) were not confirmed by a Southwest Oncology Group phase II clinical trial.10,11 Of note is the controversy regarding the role of rituximab in this disorder. Whereas this antibody when added to chemotherapy clearly improves survival of certain subsets of patients with follicular and low-grade, and diffuse large B-cell NHL, the benefits in MCL are not readily apparent. The initial data from Howard and colleagues showed impressive complete and overall response rates with rituximab with CHOP (R-CHOP), but with a disappointing time to progression of only about 18 months.12 The German Low-Grade Lymphoma Study Group randomized previously untreated patients to CHOP or R-CHOP, with a secondary randomization to one of several interferon or transplantation-based regimens, based on patient age. R-CHOP resulted in a higher complete and overall response rate, but with no effect on progression-free survival (PFS) or OS.13 The same cooperative group compared fludarabine/cyclophosphamide/mitoxantrone (FCM) with or without rituximab in patients with relapsed and refractory disease and showed a survival benefit from the antibody.14 When they evaluated the role of
Clinical Lymphoma & Myeloma August 2008
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Highlights of the 2008 International Conference on Malignant Lymphoma rituximab maintenance in these patients, the antibody achieved a prolonged response duration; a significant survival advantage was not yet apparent. This controversy was further sustained by the report at ICML by Herold et al from another German Lymphoma Study group who randomized patients between mitoxantrone/ chloramabucil/prednisolone (MCP) and rituximab with MCP, with no apparent benefit from the antibody.15 Similarly, Zelenetz and colleagues from Memorial Sloan-Kettering Cancer Center, using historical comparisons, failed to support and benefit from rituximab.16 In contrast, Khouri and colleagues, using historical controls, suggested that adding high doses of rituximab to autologous stem cell transplantation might improve the outcome of patients with MCL, especially when the transplantation was performed in first remission.17 One of the most attractive therapeutic options for patients with FL has been anti-idiotype vaccines, based largely on the data from Ron Levy of Stanford University. Patients who experienced a cellular and humoral response to the vaccine had a longer PFS than those who did not.18 These data led to 3 prospective randomized trials. At the ICML, Dr. Levy presented the first of these, which, unfortunately, failed to demonstrate benefit from adding the vaccine to patients treated with CVP (cyclophosphamide/vincristine/ prednisone).19 This negative outcome was supported by the results of a trial conducted by the Favrille Corporation in which patients received rituximab induction followed by the vaccine or placebo, with similarly disappointing results. In the absence of effective therapies, criteria to measure response are irrelevant. However, the increasing number of effective therapies has necessitated standardized, accurate measures of response assessment. In 1999, the International Working Group Criteria became the standard for clinical trials.20 Since that time, and with extensive use of these guidelines, it became apparent that modifications were required. The strongest support for these revisions was the increased availability of FDG-PET. At the ICML 3 years ago, the International Harmonization Project convened to revise the response criteria, which were published in 2007.21 These guidelines provided recommendations for the use of FDG-PET in clinical trials. At the 2008 ICML, several abstracts in DLBCL and Hodgkin lymphoma demonstrated that PET could limit the number of patients who were treated with radiation. Despite the enthusiasm for this technology, a number of discussions provided needed balance for a technology for which the amount of available information far outweighs its demonstrable benefits. At a point-counter-point, Drs. Cheson and Stroobants provided 2 sides to the use of PET.22,23 Whereas PET increases the number of lesions identified compared with computed tomography (CT), the number of patients whose stage is altered is in the range of 10%30%, but fewer still have their therapy changed on the basis of this information, and there are no data that outcome is improved. Although PET after ≥ 1 cycles of therapy predicts outcome, no data demonstrate that changing therapy on the basis of this information prolongs survival. In DLBCL and HL, a posttreatment PET might distinguish patients who are cured at that point from those who might need additional therapy; however, a follow-up CT might provide comparable information. Finally, the available data do not support routine surveillance PET scans. Jerusalem et
206
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al reported on 36 patients who underwent PET posttreatment and every 4-6 months thereafter.24 Of the 5 positive studies, one was in a patient with known active disease, and 2 in patients who had already developed disease-related symptoms, with 6 false-positive studies. More recently, Zinzani and colleagues25 showed that the risk of relapse for DLBCL and HL was too low after a year to justify scanning all patients, and for indolent lymphomas, it is less important to identify relapse earlier than clinically apparent. In an abstract from Mocikova et al at the ICML,26 the lack of benefit from surveillance scans was confirmed. Nevertheless, the promise of PET will hopefully be realized in the large number of ongoing or planned risk-directed studies which will hopefully result in reduced treatment for lower-risk patients and a better outcome for patients with more advanced and resistant disease. Therapeutic advances, based largely on the availability of new and effective agents such as rituximab and radioimmunotherapy, have clearly prolonged the survival of patients with follicular and large-cell NHL. Nevertheless, many patients fail initial therapy or relapse, and new agents are needed. Even in HL, where 85% can be cured with initial chemotherapy alone or with radiation, those who are not cured cannot always be successfully salvaged, even with stem cell transplantation. Sandra Horning’s presentation at the ICML clearly demonstrated that the outcome of patients who relapse within a year of stem cell transplantation is dismal.27 These patients are suitable candidates for new drug studies, rather than traditional, ineffective agents. Thus, considerable attention was focused on new agents in lymphoma. Bendamustine is a unique drug that has been in clinical use for over 30 years in the German Democratic Republic but is just being studied in other parts of the world. Studies from the United States confirmed responses of over 70% in rituximabrefractory follicular and low-grade NHL and over 90% when combined with rituximab in patients with relapsed, nonrefractory disease.28,29 The immunomodulatory drug lenalidomide has also shown promise and is being combined with other agents. Of interest were agents that were directed at cell signaling pathways, including temsirolimus and everolimus, which are active in MCL and other histologies as well. Tonic Bcr signaling appears to be important for lymphoma survival, and the pathways can be inhibited by spleen tyrosine kinase (SYK) inhibitors, such as fostamatinib, an oral agent with activity in DLBCL and chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia.30 Further study is clearly warranted. The histone deacetylase inhibitors target cellular epigenetic mechanisms and a number of these are in the clinic (vorinostat) or in trials (romidepsin, MGCD0103) with promising activity in nonHodgkin and Hodgkin lymphomas. Impaired apoptosis appears to be important in lymphomagenesis, and an increasing menu of small molecules that target the intrinsic or extrinsic pathways of apoptosis are in clinical trials, such as oblimersen, obatoclax, AT-101, ABT263, anti-TRAIL, and YM155. Considerable interest has also focused on new biologic agents. The efficacy and tolerability of rituximab has led to the development of at least a half dozen human or humanized anti-CD20s, which either bind to a different epitope or have differences in antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, induction of apoptosis, or target binding. Whether any of these features will result in improved activity compared
Bruce D. Cheson with rituximab or activity in the setting of rituximab resistance remains to be demonstrated. Preliminary data with GA101 and veltuzumab presented at the ICML, should stimulate interest in their further development.31 The Cancer and Leukemia Group B has taken an approach in patients with low or intermediate FL IPI to use combinations of targeted agents as the initial treatment. Dr. Leonard presented the initial study of rituximab plus galiximab, which resulted in high response rates in the lower-risk patients; a rituximab-plus-epratuzumab trial is ongoing.32 Byrd et al presented data on the combination of lumiliximab, a primatized anti-CD23 monoclonal antibody (MoAb), with the FCR regimen (fludarabine/cyclophosphamide/rituximab) in CLL. A suggestion of an improved complete remission rate when compared with historical data with FCR alone led to the international LUCID trial, which will be completed in the near future and will define the role for this new antibody in the management of these patients.33 Antibodydrug conjugates are also being studied, such as SGN-35, a conjugate of the anti-CD30 MoAb and aurostatin, a tubulin poison. Initial impressive results in HL will hopefully be reproduced in an ongoing confirmatory trial. The ICML clearly demonstrated the important advances that have been made in our understanding of the biology and genetics of lymphoid malignancies, their classification, determining prognosis, new treatment approaches, and methods of assessing response. Incorporating the various components of this expanding body of knowledge into novel treatment strategies will certainly lead to an improved outcome for patients with malignant lymphomas.
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induction galiximab ([G] anti-CD80 monoclonal antibody) plus rituximab in previously untreated follicular lymphoma (FL): initial report of CALGB 50402. Ann Oncol 2008; 19(suppl 4):iv130 (Abstract 143). 33. Byrd J, Castro J, Flinn I, et al. Lumiliximab in combination with FCR for the treatment of relapsed chronic lymphocytic leukemia (CLL): results from a phase I/II multicenter study. Ann Oncol 2008; 19(suppl 4):iv130 (Abstract 145).