Intensive Therapy for Aggressive Lymphoma
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《新英格兰医药杂志》
To the Editor: Milpied et al. (March 25 issue)1 provide further information about the benefits of high-dose chemotherapy plus autologous stem-cell support in the initial treatment of aggressive lymphoma. However, almost 50 percent of the patients were at low or low intermediate risk, according to the International Prognostic Index, and it seems that such patients may not benefit from intensive therapy.2
New strategies — for example, high-dose chemotherapy and autologous stem-cell support given initially or at the time of a first relapse, regimens with either higher doses or shorter intervals between cycles,3 and strategies in which monoclonal antibodies are added to older regimens4 — have been shown to improve the results achieved with standard-dose regimens. However, a recent meta-analysis of initial treatment of aggressive lymphoma with high-dose chemotherapy and autologous stem-cell support failed to demonstrate its superiority over standard-dose regimens.5 In our opinion, initial high-dose chemotherapy and autologous stem-cell support should be reserved for use in patients at high intermediate or high risk, preferably in randomized trials, until studies that include some of the new strategies as a control are finished.
David Aguiar Bujanda, M.D.
Uriel Bohn Sarmiento, M.D.
Jose Aguiar Morales, M.D.
Hospital Universitario Gran Canaria Dr. Negrín
35020 Las Palmas de Gran Canaria, Spain
dagubuj@gobiernodecanarias.org
References
Milpied N, Deconinck E, Gaillard F, et al. Initial treatment of aggressive lymphoma with high-dose chemotherapy and autologous stem-cell support. N Engl J Med 2004;350:1287-1295.
Kluin-Nelemans HC, Zagonel V, Anastasopoulou A, et al. Standard chemotherapy with or without high-dose chemotherapy for aggressive non-Hodgkin's lymphoma: randomized phase III EORTC study. J Natl Cancer Inst 2001;93:22-30.
Pfreundschuh M, Trumper L, Kloess M, et al. 2-Weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL. Blood (in press).
Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002;346:235-242.
Strehl J, Mey U, Glasmacher A, et al. High-dose chemotherapy followed by autologous stem cell transplantation as first-line therapy in aggressive non-Hodgkin's lymphoma: a meta-analysis. Haematologica 2003;88:1304-1315.
To the Editor: The elegant article by Milpied et al. relates to a very important issue: the use of high-dose chemotherapy with stem-cell transplantation as first-line therapy in patients with aggressive lymphoma. However, their results may have very limited applicability. As the authors point out, treatment with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) is no longer the standard of care, since other therapies have been found to be superior in terms of event-free and overall survival for patients with aggressive lymphoma.1,2 Moreover, when one of these combinations (doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone) was compared with high-dose therapy, no benefit was observed in the transplantation group.3 First-line high-dose chemotherapy can be, under certain circumstances, inferior to standard therapy for patients with this disease.4 This consideration should not prompt one to question the merit of the work by Milpied et al., but it should alert clinicians to use caution when recommending high-dose chemotherapy as first-line treatment for patients with aggressive lymphoma, since such a regimen should not be considered the standard of care.
Javier Bola?os-Meade, M.D.
University of Maryland Greenebaum Cancer Center
Baltimore, MD 21201
jbola001@umaryland.edu
References
Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002;346:235-242.
Tilly H, Lepage E, Coiffier B, et al. Intensive conventional chemotherapy (ACVBP regimen) compared with standard CHOP for poor-prognosis aggressive non-Hodgkin lymphoma. Blood 2003;102:4284-4289.
Gisselbrecht C, Lepage E, Molina T, et al. Shortened first-line high-dose chemotherapy for patients with poor-prognosis aggressive lymphoma. J Clin Oncol 2002;20:2472-2479.
Kaiser U, Uebelacker I, Abel U, et al. Randomized study to evaluate the use of high-dose therapy as part of primary treatment for "aggressive" lymphoma. J Clin Oncol 2002;20:4413-4419.
To the Editor: Milpied et al. report that intensive chemotherapy with autologous stem-cell support is superior to CHOP as first-line therapy for aggressive lymphoma in young adults with a high intermediate age-adjusted International Prognostic Index. Most of the patients in this study had diffuse large-B-cell lymphoma, but other lymphomas, classified by the authors as "anaplastic," "T-cell lymphoma," and "diffuse, aggressive, unclassifiable," were also included. Because of the clinical and biologic diversity of these subgroups of aggressive lymphoma, it is extremely problematic to evaluate them as a single group and consequently to draw the same conclusions with regard to therapy for all subgroups. Furthermore, the inclusion criteria for this study included stage III or IV or bulky stage II disease. However, according to the baseline characteristics presented in the article, there were 37 patients with stage I or II disease. The standard management of stage I (bulky or nonbulky) diffuse large-B-cell lymphoma is three cycles of CHOP followed by radiotherapy of the involved field.1 For this subgroup, more intensive therapy is not really justified.
Yair Herishanu, M.D.
Tel Aviv Sourasky Medical Center
Tel Aviv 64239, Israel
herishanu@yahoo.com
References
Miller TP, Dahlberg S, Cassady JR, et al. Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin's lymphoma. N Engl J Med 1998;339:21-26.
To the Editor: In the trial reported by Milpied et al., the patients in the two groups received different treatments, and consequently, it is difficult to attribute the improved outcome in the high-dose group to myeloablative therapy itself. Aside from undergoing induction with an unconventional regimen of unknown efficacy (cyclophosphamide, epirubicin, vindesine, and prednisone), these patients received their overall premyeloablative treatment over a much shorter period than did the patients in the CHOP group. Recent data indicate that schedule density can particularly benefit patients with rapid tumor growth, as manifested by elevated lactate dehydrogenase levels (present in 57 percent of the patients in the high-dose group).1,2 Moreover, the third chemotherapy cycle (consisting of methotrexate and cytarabine) included cycle-specific antimetabolites that, in the way they were administered, may also affect rapidly dividing lymphoma cells; analogous regimens are used in protocols for acute leukemia. Twice as many patients in the CHOP group as in the high-dose group did not complete their assigned treatment, supporting the possibility that the chemotherapy in the two groups was unequal.
Athanasios Zomas, M.D.
Anastasia Skandalis, M.D.
G. Gennimatas General Hospital of Athens
11527 Athens, Greece
References
Hasenclever D, Brosteanu O, Gerike T, Loeffler M. Modelling of chemotherapy: the effective dose approach. Ann Hematol 2001;80:Suppl 3:B89-B94.
Pfreundschuh M, Trumper L, Kloess M, et al. 2-Weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL. Blood (in press).
Dr. Milpied replies: Drs. Zomas and Skandalis's remarks are well taken. The aim of our trial was to compare the CHOP regimen with an intensive regimen that should be thought of as an independent entity and not just consolidation bone marrow transplantation during remission. This regimen is comparable to that described by Gianni et al.1 and yields similar results. As for the meta-analysis2 cited by Dr. Aguiar Bujanda and colleagues, only the results of the trial by Gianni et al. and our trial favor high-dose therapy with autologous stem-cell transplantation; in contrast, in the other trials included in that analysis, autologous stem-cell transplantation was used only for consolidation of a response achieved with conventional treatment.
Dr. Herishanu's comments are pertinent. We do not conclude that our high-dose therapy program should be applied to any histologic subtype of aggressive lymphoma. Trials specific to anaplastic T-cell lymphoma are urgently needed. Only one patient with stage I (bulky) disease was included in our trial. The other patients with early-stage disease had bulky stage II disease. In view of recent results,3 we believe that standard treatment with three courses of CHOP and involved-field irradiation for early-stage disease should be considered.
The question raised by Dr. Aguiar Bujanda and colleagues and by Dr. Bola?os-Meade is in line with the issue raised by Dr. Lister in his Perspective article accompanying our report.4 What is the value of high-dose therapy with autologous transplantation as compared with a shortened CHOP regimen or with CHOP plus rituximab? We are starting a prospective trial in which a shortened CHOP regimen with rituximab will be compared with high-dose therapy combined with rituximab. At this time, all we can say is that standard CHOP is no longer the standard of care for adults with aggressive lymphoma and that the exact place of high-dose therapy or of shortened CHOP, with or without rituximab, is an open question.
Noel Milpied, M.D.
Centre Hospitalier Universitaire de Nantes
44035 Nantes CEDEX, France
nmilpied@chu-nantes.fr
References
Gianni AM, Bregni M, Siena S, et al. High-dose chemotherapy and autologous bone marrow transplantation compared with MACOP-B in aggressive B-cell lymphoma. N Engl J Med 1997;336:1290-1297.
Strehl J, Mey U, Glasmacher A, et al. High-dose chemotherapy followed by autologous stem cell transplantation as first-line therapy in aggressive non-Hodgkin's lymphoma: a meta-analysis. Haematologica 2003;88:1304-1315.
Miller TP, Leblanc M, Spier C, Chase E, Fischer RI. CHOP alone compared to CHOP plus radiotherapy for early stage aggressive non-Hodgkin's lymphomas: update of the Southwest Oncology Group (SWOG) randomized trial. Blood 2001;98:724a-724a. abstract.
Lister TA. Who should receive myeloablative therapy for lymphoma? N Engl J Med 2004;350:1277-1278.
New strategies — for example, high-dose chemotherapy and autologous stem-cell support given initially or at the time of a first relapse, regimens with either higher doses or shorter intervals between cycles,3 and strategies in which monoclonal antibodies are added to older regimens4 — have been shown to improve the results achieved with standard-dose regimens. However, a recent meta-analysis of initial treatment of aggressive lymphoma with high-dose chemotherapy and autologous stem-cell support failed to demonstrate its superiority over standard-dose regimens.5 In our opinion, initial high-dose chemotherapy and autologous stem-cell support should be reserved for use in patients at high intermediate or high risk, preferably in randomized trials, until studies that include some of the new strategies as a control are finished.
David Aguiar Bujanda, M.D.
Uriel Bohn Sarmiento, M.D.
Jose Aguiar Morales, M.D.
Hospital Universitario Gran Canaria Dr. Negrín
35020 Las Palmas de Gran Canaria, Spain
dagubuj@gobiernodecanarias.org
References
Milpied N, Deconinck E, Gaillard F, et al. Initial treatment of aggressive lymphoma with high-dose chemotherapy and autologous stem-cell support. N Engl J Med 2004;350:1287-1295.
Kluin-Nelemans HC, Zagonel V, Anastasopoulou A, et al. Standard chemotherapy with or without high-dose chemotherapy for aggressive non-Hodgkin's lymphoma: randomized phase III EORTC study. J Natl Cancer Inst 2001;93:22-30.
Pfreundschuh M, Trumper L, Kloess M, et al. 2-Weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL. Blood (in press).
Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002;346:235-242.
Strehl J, Mey U, Glasmacher A, et al. High-dose chemotherapy followed by autologous stem cell transplantation as first-line therapy in aggressive non-Hodgkin's lymphoma: a meta-analysis. Haematologica 2003;88:1304-1315.
To the Editor: The elegant article by Milpied et al. relates to a very important issue: the use of high-dose chemotherapy with stem-cell transplantation as first-line therapy in patients with aggressive lymphoma. However, their results may have very limited applicability. As the authors point out, treatment with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) is no longer the standard of care, since other therapies have been found to be superior in terms of event-free and overall survival for patients with aggressive lymphoma.1,2 Moreover, when one of these combinations (doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone) was compared with high-dose therapy, no benefit was observed in the transplantation group.3 First-line high-dose chemotherapy can be, under certain circumstances, inferior to standard therapy for patients with this disease.4 This consideration should not prompt one to question the merit of the work by Milpied et al., but it should alert clinicians to use caution when recommending high-dose chemotherapy as first-line treatment for patients with aggressive lymphoma, since such a regimen should not be considered the standard of care.
Javier Bola?os-Meade, M.D.
University of Maryland Greenebaum Cancer Center
Baltimore, MD 21201
jbola001@umaryland.edu
References
Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002;346:235-242.
Tilly H, Lepage E, Coiffier B, et al. Intensive conventional chemotherapy (ACVBP regimen) compared with standard CHOP for poor-prognosis aggressive non-Hodgkin lymphoma. Blood 2003;102:4284-4289.
Gisselbrecht C, Lepage E, Molina T, et al. Shortened first-line high-dose chemotherapy for patients with poor-prognosis aggressive lymphoma. J Clin Oncol 2002;20:2472-2479.
Kaiser U, Uebelacker I, Abel U, et al. Randomized study to evaluate the use of high-dose therapy as part of primary treatment for "aggressive" lymphoma. J Clin Oncol 2002;20:4413-4419.
To the Editor: Milpied et al. report that intensive chemotherapy with autologous stem-cell support is superior to CHOP as first-line therapy for aggressive lymphoma in young adults with a high intermediate age-adjusted International Prognostic Index. Most of the patients in this study had diffuse large-B-cell lymphoma, but other lymphomas, classified by the authors as "anaplastic," "T-cell lymphoma," and "diffuse, aggressive, unclassifiable," were also included. Because of the clinical and biologic diversity of these subgroups of aggressive lymphoma, it is extremely problematic to evaluate them as a single group and consequently to draw the same conclusions with regard to therapy for all subgroups. Furthermore, the inclusion criteria for this study included stage III or IV or bulky stage II disease. However, according to the baseline characteristics presented in the article, there were 37 patients with stage I or II disease. The standard management of stage I (bulky or nonbulky) diffuse large-B-cell lymphoma is three cycles of CHOP followed by radiotherapy of the involved field.1 For this subgroup, more intensive therapy is not really justified.
Yair Herishanu, M.D.
Tel Aviv Sourasky Medical Center
Tel Aviv 64239, Israel
herishanu@yahoo.com
References
Miller TP, Dahlberg S, Cassady JR, et al. Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin's lymphoma. N Engl J Med 1998;339:21-26.
To the Editor: In the trial reported by Milpied et al., the patients in the two groups received different treatments, and consequently, it is difficult to attribute the improved outcome in the high-dose group to myeloablative therapy itself. Aside from undergoing induction with an unconventional regimen of unknown efficacy (cyclophosphamide, epirubicin, vindesine, and prednisone), these patients received their overall premyeloablative treatment over a much shorter period than did the patients in the CHOP group. Recent data indicate that schedule density can particularly benefit patients with rapid tumor growth, as manifested by elevated lactate dehydrogenase levels (present in 57 percent of the patients in the high-dose group).1,2 Moreover, the third chemotherapy cycle (consisting of methotrexate and cytarabine) included cycle-specific antimetabolites that, in the way they were administered, may also affect rapidly dividing lymphoma cells; analogous regimens are used in protocols for acute leukemia. Twice as many patients in the CHOP group as in the high-dose group did not complete their assigned treatment, supporting the possibility that the chemotherapy in the two groups was unequal.
Athanasios Zomas, M.D.
Anastasia Skandalis, M.D.
G. Gennimatas General Hospital of Athens
11527 Athens, Greece
References
Hasenclever D, Brosteanu O, Gerike T, Loeffler M. Modelling of chemotherapy: the effective dose approach. Ann Hematol 2001;80:Suppl 3:B89-B94.
Pfreundschuh M, Trumper L, Kloess M, et al. 2-Weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL. Blood (in press).
Dr. Milpied replies: Drs. Zomas and Skandalis's remarks are well taken. The aim of our trial was to compare the CHOP regimen with an intensive regimen that should be thought of as an independent entity and not just consolidation bone marrow transplantation during remission. This regimen is comparable to that described by Gianni et al.1 and yields similar results. As for the meta-analysis2 cited by Dr. Aguiar Bujanda and colleagues, only the results of the trial by Gianni et al. and our trial favor high-dose therapy with autologous stem-cell transplantation; in contrast, in the other trials included in that analysis, autologous stem-cell transplantation was used only for consolidation of a response achieved with conventional treatment.
Dr. Herishanu's comments are pertinent. We do not conclude that our high-dose therapy program should be applied to any histologic subtype of aggressive lymphoma. Trials specific to anaplastic T-cell lymphoma are urgently needed. Only one patient with stage I (bulky) disease was included in our trial. The other patients with early-stage disease had bulky stage II disease. In view of recent results,3 we believe that standard treatment with three courses of CHOP and involved-field irradiation for early-stage disease should be considered.
The question raised by Dr. Aguiar Bujanda and colleagues and by Dr. Bola?os-Meade is in line with the issue raised by Dr. Lister in his Perspective article accompanying our report.4 What is the value of high-dose therapy with autologous transplantation as compared with a shortened CHOP regimen or with CHOP plus rituximab? We are starting a prospective trial in which a shortened CHOP regimen with rituximab will be compared with high-dose therapy combined with rituximab. At this time, all we can say is that standard CHOP is no longer the standard of care for adults with aggressive lymphoma and that the exact place of high-dose therapy or of shortened CHOP, with or without rituximab, is an open question.
Noel Milpied, M.D.
Centre Hospitalier Universitaire de Nantes
44035 Nantes CEDEX, France
nmilpied@chu-nantes.fr
References
Gianni AM, Bregni M, Siena S, et al. High-dose chemotherapy and autologous bone marrow transplantation compared with MACOP-B in aggressive B-cell lymphoma. N Engl J Med 1997;336:1290-1297.
Strehl J, Mey U, Glasmacher A, et al. High-dose chemotherapy followed by autologous stem cell transplantation as first-line therapy in aggressive non-Hodgkin's lymphoma: a meta-analysis. Haematologica 2003;88:1304-1315.
Miller TP, Leblanc M, Spier C, Chase E, Fischer RI. CHOP alone compared to CHOP plus radiotherapy for early stage aggressive non-Hodgkin's lymphomas: update of the Southwest Oncology Group (SWOG) randomized trial. Blood 2001;98:724a-724a. abstract.
Lister TA. Who should receive myeloablative therapy for lymphoma? N Engl J Med 2004;350:1277-1278.