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© 2002 American Society for Clinical Oncology Randomized Study to Evaluate the Use of High-Dose Therapy as Part of Primary Treatment for "Aggressive" LymphomaFrom the Departments of Hematology and Oncology, Universitätsklinikum Marburg, Klinikum Nürnberg, Universitätsklinikum Homburg, Universitätsklinikum Jena, Universitätsklinikum Ulm, Klinikum Oldenburg, Universitätsklinikum Hamburg, Thoraxklinik Heidelberg-Rohrbach, Universitätsklinikum Magdeburg, Universitätsklinikum Köln, Zentralklinikum Augsburg, Universitätsklinikum Leipzig, Universitätsklinikum Leipzig, Klinikum Chemnitz, Klinikum Potsdam, Krankenhaus Hamburg-Altona, Universitätsklinikum Münster, Klinikum Kassel, Humboldt-Universität Berlin, Robert-Bosch Krankenhaus Stuttgart, Universitätsklinikum Göttingen, Universitätsklinikum Heidelberg, Universitätsklinikum Kiel, Klinikum Minden, Universitätsklinikum Rostock, Universitätsklinikum Zürich, Klinikum Karlsruhe, Klinikum Hagen, Klinikum Herford, Klinikum Lemgo, Universitätsklinikum Lund, Klinikum Mönchengladbach, Universitätsklinikum Uppsala, Universitätsklinikum Aachen, Diakonissenkrankenhaus Bremen, Klinikum Cottbus, Klinikum Darmstadt, Klinikum Eschweiler, Diakoniekrankenhaus Freiburg, Klinikum Münchberg, Klinikum Schwenningen, Klinikum Schweinfurt, Klinikum Trier, and Klinikum Wolfsburg; the Institute of Medical Statistics, Universität Heidelberg; and the Institute of Hematopathology, Universität Kiel, Germany. Address reprint requests to Ulrich Kaiser, MD, St Bernward Krankenhaus, Klinik für Hämatologie, Onkologie und Immunologie, Treibestrasse 9, D-31134 Hildesheim, Germany; email: pd.dr.u.kaiser{at}bernward-khs.de
PURPOSE: This trial of the German High-Grade Non-Hodgkin’s Lymphoma Study Group compares the use of high-dose therapy (HDT) as part of primary treatment with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus etoposide followed by involved-field (IF) radiotherapy in a randomized, multicenter, phase III study.
PATIENTS AND METHODS: Three hundred twelve patients with "aggressive" non-Hodgkin’s lymphoma aged RESULTS: Among 158 patients randomized to arm B, 103 (65%) received HDT. The complete remission rate at the end of treatment was 62.9% in arm A and 69.9% in arm B. With a median observation time of 45.5 months, overall survival for all 312 patients was 63% after 3 years (63% for arm A, 62% for arm B; P = .68). Event-free survival was 49% for arm A versus 59% for arm B (P = .22). Relapse in arm B was associated with a significantly worse survival rate than relapse in arm A (P < .05). Relapse after HDT occurred early (median interval, 3 months). Six patients developed secondary neoplasia, three in arm A and three in arm B. CONCLUSION: Results of the randomized trial comparing CHOP-like chemotherapy with early HDT do not support the use of HDT with carmustine, etoposide, cytarabine, and melphalan following shortened standard chemotherapy.
WITH CONVENTIONAL chemotherapy, long-term remission can be achieved in approximately 50% of patients with disseminated "aggressive" lymphoma.1 The landmark intergroup study revealed that cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) can still be regarded as the international standard.2 Since the early 1980s, however, data have appeared that indicate that high-dose therapy (HDT) with autologous stem-cell transplantation may be superior to conventional therapy in selected younger patients with aggressive lymphoma. Phase I/II studies, initially performed with autologous bone marrow transplantation, suggested promising results with stable remissions in 70% to 80% of the patients.3 Treatment-related mortality was around 5%. The use of autologous peripheral-blood stem cells and improvements in supportive care have further diminished treatment-related mortality. In patients with relapsed lymphoma, results of the trial conducted by the Parma study group have shown that high-dose chemotherapy in sensitive relapse may be superior to conventional salvage treatment.4 However, in primary aggressive lymphoma, the role of HDT and its optimal timing have still not been determined. In the German High-Grade Lymphoma Study Group, CHOEP (standard CHOP + etoposide) has been established as an effective regimen. In a phase II study recruiting patients from 1982 to 1985, CHOEP followed by involved-field radiation was shown to induce complete remission (CR) rates in 82% of 60 enrolled patients, leading to a 5-year event-free survival rate of 55%.5 In the subsequent phase III study launched in 1986, four cycles of CHOEP were compared with a sequential therapy consisting of an escalating CHOP regimen alternating with ifosfamide, vincristine, etoposide, and prednisone, followed by involved-field radiation in both arms.6 The CR rate was 85%, and event-free survival rates were 59% and 55% after 2 and 5 years, respectively, for both groups without any statistically significant difference underlining the efficacy of the CHOEP regimen. Serum lactate dehydrogenase (LDH) was the strongest prognostic parameter. The 2-year survival rate was 84% for patients with normal LDH versus 55% for patients with elevated LDH (P < .001). These experiences led us to conceive the subsequent trial to determine the value of high-dose chemotherapy followed by autologous stem-cell transplantation. Patients under the age of 61 years with the elevated LDH risk factor were randomized to receive either five courses of CHOEP or three courses of CHOEP followed by high-dose chemotherapy and autologous bone marrow/peripheral stem-cell transplantation. In both arms, patients were to receive involved-field radiotherapy with a total dose of 36 Gy (single dose of 1.8 Gy/d). Here, we report the results of this prospective multicenter study.
Patients Eligible patients had to have a histologic diagnosis of a high-grade (aggressive) lymphoma according to the Kiel classification7 (except for lymphoblastic lymphoma in patients under the age of 35 years; histologic diagnosis had to be confirmed by an expert panel), age 18 to 60 years, stage II to IV disease according to the Ann Arbor classification of malignant lymphomas, and serum LDH level above the normal value. They also had to provide informed consent. Staging included a physical examination, an assessment of laboratory status, a chest x-ray, computed tomography scan of the thorax and abdomen, and a bone marrow biopsy. Lumbar puncture was performed in patients with lymphoblastic or Burkitt’s lymphoma or in case of suspected neurologic involvement. Serum LDH level had to be determined within 3 days before staging; hemolytic anemia had to be excluded. Further investigations (eg, bone scan, endoscopy) were to be performed if deemed necessary by the individual investigator.
Treatment Plan
Stem-Cell Collection Stem cells were collected by bone marrow aspiration according to standard procedure or by separation of peripheral stem cells after prior mobilization with granulocyte colony-stimulating factor in a dosage of 10 µg/kg after treatment cycles 2 or 3. There were no recommendations concerning the source of stem cells. At the time of initiation in 1990, most patients received autologous bone marrow. Since 1994, peripheral stem cells have been the source of choice. No purging procedures were required or recommended.
Evaluation of Response
Study Design
Statistical Analysis Overall survival was the main end point. As described below, 19 patients were excluded after randomization. We believe the exclusion to be justified because (1) the reasons for exclusion had been specified in advance and did not create an arbitrary imbalance and (2) the exclusion reflected clinical reality, as the treatment protocol of this study, particularly HDT, did not apply to these patients. Therefore, all analyses were restricted to the subset of the remaining 312 patients.
Patient Characteristics Between August 1990 and June 1997, 331 patients were registered onto the study. Before the start of therapy or during the first cycle, 19 of the randomized patients were found to violate the entry criteria of the study and were therefore excluded. Of these, 13 patients had been assigned to arm A and six to arm B. The protocol violations were as follows: change of histologic diagnosis by the reference hematopathologist (Hodgkin‘s disease, n = 4; solid tumor, n = 4; low-grade lymphoma, n = 1), diagnosis of a secondary high-grade lymphoma (n = 2), bone marrow infiltration greater than 25% (n = 3), diagnosis of secondary malignancies at the time of randomization (n = 1), age less than 18 years (n = 1), withdrawal of consent immediately after registration (n = 1), proven human immunodeficiency virus infection (n = 1), and treatment according to a leukemia protocol after randomization because of extensive bone marrow infiltration (n = 1). Among the remaining 312 patients, 154 were randomized to arm A and 158 to arm B. Patient characteristics are outlined in Table 1. Median age was 46 years (range, 19 to 60 years) in treatment arm A and 45 years (range, 19-60 years) in arm B. Median age of the whole study population was 46 years.
Patients were retrospectively classified according to the age-adjusted International Prognostic Index.8 In arm A, 26% of the population were grouped as low intermediate, 55% as high intermediate, and 20% as high risk; in arm B, 26% were grouped as low intermediate, 50% as high intermediate, and 24% as high risk (Table 2).
The Revised European-American Lymphoma classification was retrospectively applied to all cases.9 The distribution of the histologic subtypes was as follows (arm A v arm B): 61% versus 58% diffuse large B-cell lymphoma (centroblastic + immunoblastic), 16% versus 9% primary mediastinal large B-cell lymphoma, 10% versus 9% anaplastic large-cell lymphoma, 5% versus 11% lymphoblastic or Burkitt‘s lymphoma, and 4% versus 3% peripheral T-cell lymphoma.
Induction Treatment
Consolidation Treatment
Radiotherapy
Treatment Results Response. For the entire patient population (n = 312), the CR rate at the end of treatment was 66.3% (n = 207) and the PR rate was 16.6% (n = 42). In arm A, the CR rate was 62.9% (n = 97) and the PR rate 22.7% (n = 35); in arm B, the CR rate was 69.9% (n = 110) and the PR rate was 10.7% (n = 17). Survival. The 3-year survival rate was 63% in arm A versus 62% in arm B. The difference was not statistically significant (P = .68, one-tailed log-rank test, Fig 2). The 3-year event-free survival rate was 49% in arm A versus 59% in arm B (Fig 3). The difference was not statistically significant (P = .22, one-tailed log-rank test). Event-free survival and overall survival for patients with high intermediate and high risk factors according to the International Prognostic Index did not reveal statistically significant differences (Figs 4 and 5). After patients with Burkitt’s lymphoma and lymphoblastic lymphoma were excluded, there was still no advantage for the HDT with regard to survival (P = .95) and event-free survival (P = .12). Survival curves for this subgroup of 290 patients is shown in Figs 6 and 7.
Among patients who received HDT, the median time to neutrophil recovery greater than 500/µL was 10 days (range, 5 to 56 days); the median time to platelet recovery 20,000/µL was 11 days (range, 0 to 150 days). Median stay in hospital after HDT was 16.5 days (range, 10 to 78 days). Relapse pattern. Among the 132 patients in arm A who received the whole chemotherapy protocol and reached PR or CR, relapse or disease progression was documented in 61 patients (46%). In 16 (28%) of these patients, relapse or progression occurred exclusively in sites of previous tumor involvement; in 16 (28%) of the patients, it occurred exclusively in previously noninvolved sites; and in 26 (45%) of the patients, it occurred in new and previously involved sites. In three patients, the relapse pattern could not be determined conclusively. In arm B, 28 patients (27%) relapsed among the 103 patients who received the whole treatment plan including HDT. Among these 28 patients, the relapse pattern was as follows: five patients (18%) had a relapse in a previously involved site, 11 patients (39%) had a relapse in a previously uninvolved site, and 12 patients (43%) had relapses in both new and previously involved sites. Relapse after HDT occurred early, with a median interval of 3 months. Median survival after relapse was 7.5 months for patients who relapsed after HDT (n = 28) and 38 months for patients who relapsed after conventional treatment (n = 58). The duration of survival after relapse is shown in Fig 8. The differences between these groups are statistically significant (P = .0022, log-rank test). Salvage HDT after relapse was administered to 26 patients (24 patients who relapsed in arm A and two patients in arm B who relapsed after initial denial of primary HDT). Median survival of patients receiving salvage HDT was 15 months.
Treatment-Related Mortality, Side Effects, and Secondary Neoplasia Thirty-nine patients died during the course of treatment. Thirty-one patients died due to progressive disease. In eight patients (2.6%) who died during treatment, death was judged as possibly treatment related. Patient characteristics are listed in Table 3. Among these eight patients, five died during the first or second cycle of CHOEP, two died within the third cycle of CHOEP, and one patient died after having received five cycles of CHOEP. Six of the eight patients had serum LDH levels that were two times the normal value at diagnosis, which indicates a high tumor load. This led us to implement a cytoreductive treatment with prednisone and vincristine in high-risk patients. No patient died due to HDT, but the 100-day mortality rate after HDT was 5%. All patients died due to disease progression.
Following HDT in treatment arm B, 39% of patients experienced grade 3/4 stomatitis, 27% experienced grade 3/4 infection, and 17% had grade 3/4 diarrhea. In treatment arm A during the corresponding fourth and fifth cycles of CHOEP, no patient experienced grade 3/4 stomatitis or diarrhea, 1% of patients experienced grade 3/4 infection, 73% experienced grade 3/4 leukopenia, and 9% experienced grade 3/4 thrombocytopenia. With a median observation time of 45.6 months, six secondary neoplasias (1.9%) were reported. A case of acute myeloid leukemia (AML) of French-American-British type M2 occurred 8 years after HDT, another patient developed AML of French-American-British type M1 4 years after HDT, a case of AML occurred 3 years after five cycles of CHOEP, and a case of myelodysplasia (refractory anemia with excess blasts in transformation) occurred 1 year after five cycles of CHOEP. One patient developed breast cancer and another patient developed an adenocarcinoma of the bile duct, 2 years after five cycles of CHOEP in both cases.
The aim of this study was to compare HDT as part of the primary treatment to conventional chemotherapy in patients with newly diagnosed, disseminated, aggressive lymphoma and the risk factor of elevated LDH. Thus far, the study has failed to show any benefit of intensive treatment until now in an intent-to-treat evaluation.
In previous studies, CHOEP followed by involved-field radiotherapy was proved to be an effective regimen in the treatment of patients with aggressive lymphoma, and this treatment resulted in stable remission in the majority of patients in this study. It can be administered without major toxicities and with tolerable long-term side effects. The German High-Grade Lymphoma Study Group has conducted a randomized study comparing CHOEP with standard CHOP in 890 patients Why did three cycles of CHOEP followed by BEAM not prove to be superior to five cycles of CHOEP in this patient group? Patients were randomized up front. One third of the patients randomized to treatment arm B did not receive HDT, mainly because of induction failure and patient’s choice. According to the study protocol, the interval between CHOEP cycles was to be 21 days. In fact, the fourth cycle in the conventional treatment arm was given after a median period of 63 days after the first cycle. However, in the high-dose arm, BEAM could only be administered after a median period of 78 days. Patients in the conventional arm therefore received more chemotherapy during that period than patients in the HDT arm. Involved-field radiotherapy was administered in both treatment arms. However, radiotherapy could only be completely administered in 53% of the patients in the high-dose arm compared with 69% in the conventional treatment arm. Major reasons for deletion of radiotherapy were induction failure and hematologic toxicities, predominantly persistent thrombocytopenia. The median interval between the last chemotherapy cycle and radiotherapy was 40 days in arm A; the median interval between HDT and radiotherapy was 59 days in arm B. Therefore, radiotherapy may have been more effective in treatment arm A. These data further illustrate the limited value of administering radiotherapy immediately after HDT. An additional reason why there was no difference in survival between the two treatment groups may be that salvage therapy for patients who relapsed after primary treatment was more effective in patients treated in arm A than in arm B, with increased 2-year survival rates for relapsed patients in arm A (26%) compared with arm B (11%). Twenty-six of the 61 relapsed patients in arm A received salvage high-dose treatment leading to a median survival time of 15 months, whereas relapse after front-line HDT was associated with a median survival time of only 3.8 months. These data suggest that salvage therapy is more effective after conventional therapy than after HDT. Seventy-five percent of the patients were classified as high intermediate or high risk according to the International Prognostic Index. In a subgroup analysis of these patients, there was no difference in event-free survival or overall survival. A number of trials have evaluated HDT as part of front-line therapy. In the LNH87-2 trial of the Groupe d’Etude des Lymphomes de l’Adulte (GELA), patients who had achieved CR after four courses of induction therapy were randomized to receive HDT or conventional consolidation treatment.10 Survival and event-free survival did not reveal any difference, but subgroup analysis demonstrated a benefit in terms of event-free survival and overall survival for high-risk patients.11 The follow-up trial, which evaluated early intensification with BEAM after a shortened induction therapy compared with the conventional GELA arm, demonstrated a benefit for conventionally treated patients.12 The Genova group randomized patients to receive complete conventional therapy versus complete conventional therapy followed by autologous bone marrow transplantation; they did not see any benefit for the high-dose arm.13 The Milan group used a different approach, in which HDT was part of a sequentially escalated treatment regimen.14 With small patient numbers, sequential HDT was superior to conventional treatment with methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin in terms of event-free survival after 7 years. The European Organization for the Research and Treatment of Cancer performed a trial in which patients were randomized after three cycles of a CHOP-like regimen to receive either five more cycles of the same regimen or three more cycles followed by HDT. In contrast to the German trial, 70% of the 311 registered patients belonged to the low or low intermediate risk groups of the International Prognostic Index. Estimated 5-year survival rates did not differ between the two treatment groups.15 Two randomized trials addressed HDT in patients with delayed response after induction therapy.16,17 Both studies included only small patient numbers and failed to show an advantage of HDT for this patient population. When physicians consider the value of up-front high-dose chemotherapy as front-line treatment, the option of salvage HDT has to be taken into account. The PARMA study demonstrated that patients who relapse after conventional treatment can benefit from salvage HDT.4 Our results suggest that patients who relapse after HDT have a worse prognosis than patients who relapse after conventional treatment. In any HDT protocol that is part of primary treatment, this effect has to be considered. This study, as well as previous ones, underscores that outside of clinical trials, there is no indication for up-front HDT. Until now, no prospective randomized trial has proven a survival benefit of high-dose chemotherapy applied after a shortened induction therapy, like the trial outlined above. Trials that have evaluated HDT after a complete course of standard chemotherapy have shown a benefit for a subgroup of patients in retrospective analysis. Is there any role for front-line HDT? A number of clinical trials are presently addressing this issue, including the European MISTRAL trial (Multicenter International Studies on the Treatment of Aggressive Lymphomas) conducted by the Swiss Group for Clinical Cancer Research, which is incorporating the sequential Milan schema, and the German High-Grade Lymphoma Study Group trial, which is evaluating the role of sequential up-front HDT.
Supported by grant no. 70-339 from the Deutsche Krebshilfe. We are indebted to C. Klose, U. Haag, and I. Eschenbach for their excellent assistance and to A. Neubauer and U. Datan for critical revision of the manuscript.
1. Armitage JO: Treatment of non-Hodgkin’s lymphomas. N Engl J Med 328: 1023-1030, 1993
2. 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
3. Nademee A, Schmidt GM, O’Donnell MR, et al: High dose chemoradiotherapy followed by autologous bone marrow transplantation as consolidation therapy during first complete remission in adult patients with poor-risk aggressive lymphoma: A pilot study. Blood 80: 1130-1134, 1992
4. 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 5. Köppler H, Pflüger KH, Eschenbach I, et al: CHOP-VP16 chemotherapy and involved field irradiation for high grade non-Hodgkin’s lymphomas: A phase II multicentre study. Br J Cancer 60: 79-82, 1989[Medline]
6. Köppler H, Pflüger KH, Eschenbach I, et al: Randomised comparison of CHOEP versus alternating hCHOP/IVEP for high-grade non-Hodgkin’s lymphomas: Treatment results and prognostic factor analysis in a multi-centre trial. Ann Oncol 5: 49-55, 1994 7. Stansfeld AG, Diebold J, Noel H, et al: Updated Kiel classification for lymphoma. Lancet 1: 292-293, 1988 (letter)[Medline]
8. 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
9. Harris NL, Jaffe ES, Stein H, et al: A revised European-American classification of lymphoid neoplasms: A proposal from the International Lymphoma Study Group. Blood 84: 1361-1392, 1994
10. Haioun C, Lepage E, Gisselbrecht C, et al: Comparison of autologous bone marrow transplantation with sequential chemotherapy for intermediate-grade and high-grade non-Hodgkin’s lymphoma in first complete remission: A study of 464 patients. J Clin Oncol 12: 2543-2551, 1994
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 LNH-87-2 protocol—A Groupe d’Etude des Lymphomes de l’Adulte study. J Clin Oncol 18: 3025-3030, 2000
12. Gisselbrecht C, Lepage E, Molina T, et al: Shortened first-line high-dose chemotherapy for patients with poor-prognosis aggressive lymphoma. J Clin Oncol 20: 2472-2479, 2002 13. Santini G, Salvagno L, Leoni T, et al: VACOP-B versus VACOP-B plus autologous bone marrow transplantation for advanced diffuse non-Hodgkin’s lymphoma: Results of a prospective trial by the Non-Hodgkin’s Lymphoma Cooperative Study Group. J Clin Oncol 16: 2796-2802, 1998[Abstract]
14. 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 336: 1290-1297, 1997
15. Kluin-Nelemans H, 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, 2001
16. Martelli M, Vignetti M, Zinzanni P, et al: High-dose chemotherapy followed by autologous bone marrow transplantation versus dexamethasone, cisplatin, and cytarabine in aggressive non-Hodgkin’s lymphoma with partial response to front-line chemotherapy: A prospective randomized Italian multicenter study. J Clin Oncol 14: 534-542, 1996
17. Verdonck LF, van Putten WLJ, Hagenbeck 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 Submitted July 16, 2001; accepted July 31, 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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ABSTRACT
INTRODUCTION
60 years with elevated serum lactate dehydrogenase levels were included from 1990 to 1997. Patients with at least a minor response after two cycles of CHOEP (CHOP + etoposide 3 x 100 mg/m2) were to receive three further cycles of CHOEP followed by IF radiotherapy (arm A) or one further cycle of CHOEP followed by autologous stem-cell transplantation and IF radiotherapy (arm B). 
50% in all measurable manifestations and the absence of new lesions. Stable disease was defined as less than PR but no signs of progression. Progressive disease required a greater than 50% increase of any previously identified abnormal node for PR or nonresponders or the appearance of any new lesion during or at the end of therapy. 
