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© 2002 American Society for Clinical Oncology
Autologous Stem-Cell Transplantation as a Component of Initial Treatment for Poor-Risk Patients With Aggressive Non-Hodgkin’s Lymphoma: Resolved Issues Versus Remaining OpportunityJames P. Wilmot Cancer Center, University of Rochester School of Medicine, Rochester, NY HEMATOLOGISTS AND oncologists have traditionally believed that new drugs or treatment strategies that show significant activity in heavily pretreated patients will provide even greater benefit when administered earlier in the course of disease, particularly to newly diagnosed, untreated patients. Better host tolerance and a lower occurrence of drug-resistance factors support the logic of this concept. As described below, high-dose chemotherapy with stem-cell rescue has proven to have important clinical benefit for patients with relapsed aggressive lymphoma. However, to date, it has been difficult to demonstrate that incorporating high-dose chemotherapy with stem-cell rescue into the initial treatment program for untreated patients with aggressive lymphoma has significantly improved the overall survival. The role of autologous bone marrow transplantation (ABMT) in the treatment of patients with aggressive lymphoma has been reviewed.1,2 Initially, bone marrow was the source of the stem cells; later, peripheral-blood stem cells largely replaced bone marrow. The controversy about the benefit of ABMT in relapsed aggressive lymphomas centered around the question of whether the apparent favorable results achieved in single-institution phase II trials represented a true advance for the patients or merely selection of patients with a better prognosis for transplantation. Fortunately, the Parma trial provided a prospective randomized study that clearly demonstrated the superiority of ABMT compared with standard salvage chemotherapy and established salvage ABMT as the standard therapy for all eligible patients with relapsed aggressive lymphoma.3 The improvements in event-free survival and overall survival were not only statistically significant but also clinically important. It is important to remember that the trial enrolled only young patients at first relapse who remained chemosensitive. Although this is the only randomized trial in this patient population, a United States cooperative group phase II trial achieved nearly identical results in a similar patient population.4 Salvage ABMT, as currently utilized, will result in survival of approximately 50% of all patients who actually receive transplants; however, it will only add 10% to the number of newly diagnosed patients with aggressive lymphoma who can be cured with conventional cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy,5 since only a minority of all patients meet all the selection criteria for transplantation. Several studies have now concluded that all patients with aggressive lymphoma do not benefit when stem-cell transplantation is incorporated into their initial treatment strategy compared with patients who are treated with conventional strategy of initial chemotherapy followed by stem-cell transplant at first relapse. This conclusion had been reached by the Groupe Etude Lymphomes Adulte (GELA) LNH-87,6 the Italian Non-Hodgkin’s Lymphoma Cooperative Group,7 as well as the European Organization for Research and Treatment of Cancer Lymphoma Group.8,9 Thus there seems to be no indication to add autologous stem-cell transplantation (ASCT) to the initial combination chemotherapy treatment for all patients with aggressive lymphoma. Fortunately, there is some hope that ASCT might be useful for selected subsets of patients. There is no information from any of the previously mentioned studies to suggest that ASCT adds any benefit to the initial treatment of low-risk patients with aggressive non-Hodgkin’s lymphoma. However, when the International Prognostic Index10 was retrospectively applied to the GELA LNH-87 study, a failure-free and overall survival benefit was demonstrated for the high-/intermediate-risk and high-risk groups.11 A retrospective subset analysis of the Italian trial yielded similar results.7 In this issue of the Journal of Clinical Oncology, Kaiser et al12 report the results of a randomized study conducted by the German High-Grade Non-Hodgkin’s Lymphoma Study Group to evaluate the use of high-dose therapy as part of primary treatment for 312 aggressive lymphoma patients who present with a high lactate dehydrogenase level. All patients received two cycles of a CHOP-like regimen (CHOP plus etoposide [CHOEP]). Patients with at least a minor response received either three more cycles of CHOEP followed by involved-field radiotherapy or one more cycle of CHOEP followed by ASCT with carmustine, etoposide, cytarabine, and melphalan followed by involved-field radiotherapy. Although the event-free survival favors the transplanted group (59% v 49%) after a median follow-up of 45.5 months, the benefit was not statistically significant (P1 = .22). Furthermore, the overall survival curves for the two groups are superimposable. Thus, a high lactate dehydrogenase level alone is not sufficient to define a high-risk patient population with aggressive lymphoma who benefit from initial stem-cell transplant. Furthermore, in a subset analysis, there was no difference in event-free or overall survival for the subset of patients who had high/intermediate or high risk according to the International Prognostic Index. The study by Kaiser et al12 is not without methodologic problems. Patients with stage II disease were entered although it is unclear what justified their inclusion as having a poor prognosis. The initial sample size of the trial is not justified by power calculations in the article. For unclear reasons, the German study group increased accrual from 200 to 300 patients during the study. Presumably, they saw the divergence of the event-free survival and attempted to increase the sample size in order to increase the likelihood of obtaining statistical significance. However, in the end, even the larger sample size was clearly not sufficient. These results must also be interpreted in light of the one-tailed P values that were utilized. Given that several similar trials have actually showed a benefit for the standard treatment arm,13,14 this does not seem appropriate. The authors conclude that the use of high-dose therapy after a shortened course of initial chemotherapy is not indicated. Whether this German study actually represents a shortened course of chemotherapy can be debated. Certainly several attempts have been made to initiate ASCT earlier in the treatment program, ie, before the standard chemotherapy has been completed. The Dutch Organization for Hemato-Oncology in Adults trial13 and the subsequent GELA LNH-93 trial,14 described previously, actually demonstrated a benefit to completion of the conventional chemotherapy when compared with early ASCT. Although six to eight courses of CHOP has been standard practice for many years, it is unclear whether five courses of CHOEP should be considered a short treatment regimen. At this time, should we conclude that high-dose therapy has no role in the initial treatment of patients with aggressive lymphoma? These current data are not inconsistent with the hypothesis that high-/intermediate-risk and high-risk young patients who responded to full-course CHOP chemotherapy would benefit from immediate stem-cell transplantation compared with stem-cell transplantation at relapse. No prospective randomized trials with adequate power to address this question have been reported. To test this hypothesis, the lymphoma committees of the Southwest Oncology Group, Eastern Cooperative Oncology Group, Cancer and Acute Leukemia Group B, and National Cancer Institute of Canada have joined to initiate S9704, a prospective, randomized, phase III comparison of early versus delayed high-dose therapy for patients with high-/intermediate-risk and high-risk diffuse large B-cell lymphoma. Patients will be randomized to receive either standard therapy (eight cycles of CHOP followed by salvage ASCT at relapse) or six cycles of CHOP followed by immediate ASCT. It would seem tragic not to adequately test this hypothesis. The North American hematology, oncology, and transplant communities should rally to support this clinical trial in order to determine whether early transplantation of poor-risk patients represents a significant opportunity to benefit these patients. REFERENCES
1. Shipp MA, Abeloff MD, Antman KH, et al: International consensus conference on high-dose therapy with hematopoietic stem cell transplantation in aggressive non-Hodgkin’s lymphomas: Report of the jury. J Clin Oncol 17: 423-429, 1999 2. Hahn T, Wolff SN, Czuczman MS, et al: The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of diffuse large cell B-cell non-Hodgkin’s lymphoma: An evidence-based review. Biol Blood Bone Marrow Transplant 7: 308-331, 2001[CrossRef][Medline]
3. Philip T, Guglielmi C, Hagenbeek A, et al: Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s lymphoma. N Engl J Med 333: 1540-1545, 1995
4. Stiff PJ, Dahlberg S, Forman SJ, et al: Autologous bone marrow transplantation for patients with relapsed or refractory diffuse aggressive non-Hodgkin’s lymphoma: Value of augmented preparative regimens—A Southwest Oncology Group trial. J Clin Oncol 16: 48-55, 1998
5. Fisher RI, Gaynor ER, Dahlberg S, et al: Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma. N Engl J Med 328: 1002-1006, 1993
6. Haioun C, Lepage E, Gisselbrecht C, et al: Comparison of autologous bone marrow transplantation with sequential chemotherapy for intermediate and high-grade non-Hodgkin’s lymphoma in first complete remission: A study of 464 patients. J Clin Oncol 12: 2543-2551, 1994 7. Santini G, Salvagno L, Leoni P, et al: VACOP-B versus VACOP-B plus autologous bone marrow transplantation for advanced diffuse non-Hodgkin’s lymphoma: Results of a prospective randomized trial by the Non-Hodgkin’s Lymphoma Cooperative Study Group. J Clin Oncol 16: 2796-2802, 1998[Abstract]
8. 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 93: 22-30, 2000
9. Fisher RI: Autologous bone marrow transplantation for aggressive non-Hodgkin’s lymphoma: Lessons learned and challenges remaining. J Natl Cancer Inst 93: 4-5, 2001
10. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project: A predictive model for aggressive non-Hodgkin’s lymphoma. N Engl J Med 329: 987-994, 1993
11. Haioun C, Lepage E, Gisselbrecht C, et al: Survival benefit of high-dose therapy in poor-risk aggressive non-Hodgkin’s lymphoma: Final analysis of the prospective LNH87-2 protocol—A Groupe d’Etude des Lymphomes de l’Adulte Study. J Clin Oncol 18: 3025-3030, 2000
12. 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 20: 4413-4419, 2002
13. Verdonck LF, van Putten WLJ, Hagenbeek A, et al: Comparison of CHOP chemotherapy with autologous bone marrow transplantation for slowly responding patients with aggressive non-Hodgkin’s lymphoma. N Engl J Med 332: 1045-1051, 1995
14. Gisselbrecht C, Lepage E, Molina T, et al: Shortened first-line high-dose chemotherapy for patients with poor-risk aggressive lymphoma. J Clin Oncol 20: 2472-2479, 2002
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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