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Randomized Comparison of ACVBP and m-BACOD in the Treatment of Patients With Low-Risk Aggressive Lymphoma: The LNH87-1 Study

From the Centre Henri Becquerel, Rouen; Hôpital Saint-Louis and Hôpital Laënnec, Paris; Centre Hospitalier Régional, Vandoeuvre les Nancy; Centre Hospitalier Régional, Lille; Hôpital Edouard Herriot and Centre Léon Bérard, Lyon; Centre Hospitalier Purpan, Toulouse; Hôpital Hautepierre, Strasbourg; Centre Hospitalier Universitaire, Limoges; Centre Hospitalier Lyon-Sud, Pierre Bénite, France; and Clinique Universitaire de Mont Godinne, Yvoir, Belgium.

Address reprint requests to Hervé Tilly, MD, Centre Henri Becquerel, Rue d’Amiens, 76038 Rouen, France; email herve.tilly{at}rouen fnclcc.fr.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX Study Participants REFERENCES

 
PURPOSE: To compare a short intensified regimen followed by sequential consolidation therapy (doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone [ACVBP]) to the standard regimen of methotrexate, bleomycin, cyclophosphamide, and etoposide (m-BACOD) in patients with low-risk aggressive lymphoma.

PATIENTS AND METHODS: A total of 752 patients with intermediate- or high-grade lymphoma and no adverse prognostic factors (Eastern Cooperative Oncology Group performance status of 2 to 4, two extranodal sites of disease, tumor burden 10 cm in largest dimension, bone marrow or CNS involvement, Burkitt’s or lymphoblastic subtypes) were registered. Of 673 eligible patients, 332 received ACVBP and 341 received m-BACOD.

RESULTS: The complete remission rate was identical (86%) in the two groups. With a median follow-up duration of 7 years, the 5-year failure-free survival (FFS) rate was 65% in the ACVBP group and 61% in the m-BACOD group (P = .16). The 5-year overall survival rate was 75% in the ACVBP group and 73% in the m-BACOD group (P = .47). ACVBP was responsible for more severe and life-threatening infections (P < .01), but m-BACOD caused more pulmonary toxicity (P < .001). The number of treatment-related deaths did not differ between the two regimens. A multivariate analysis indicated that ACVBP was associated with a longer FFS in patients with two or three risk factors of the International Prognostic Index.

CONCLUSION: In this population of patients with low-risk aggressive lymphoma, toxicities of the regimens are different, but the rates of response and survival are identical. The survival advantage of ACVBP over standard regimen in patients with advanced disease is suggested by this analysis but remains to be assessed in prospective studies specifically designed for this purpose.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX Study Participants REFERENCES

 
PROGRESS IN THE treatment of aggressive non-Hodgkin’s lymphoma remains unsatisfactory. It has been established during the recent years that second- and third-generation chemotherapy regimens such as methotrexate, bleomycin, cyclophosphamide, and etoposide (m-BACOD); prednisone, methotrexate, doxorubicin, cyclophosphamide, and etoposide–cytarabine, bleomycin, vincristine, and methotrexate; and methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin were not superior to the standard combination containing cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), which was introduced in the early 1970s.^1-3 The use of intensified regimens with hematopoietic stem-cell rescue as part of the front-line treatment could offer new opportunities to cure younger patients with high-risk disease,^4-6 but the population to which it could be beneficial remains to be determined.

Since 1980, the Groupe d’Etudes des Lymphomes de l’Adulte (GELA) has developed the doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (ACVBP) regimen, which consists of an induction phase of three to four courses of intensified CHOP (with the addition of bleomycin and intrathecal methotrexate) within a short interval, followed by sequential consolidation chemotherapy.^7,8 A large multicenter study published in 1989 demonstrated the feasibility and efficacy of this regimen, but it was not clear whether this treatment was superior to the chemotherapy combinations widely used at that time.⁹ To address this question, in 1987, the GELA began in a phase III study to compare ACVBP plus sequential consolidation with m-BACOD in a population of patients with low-risk aggressive non-Hodgkin’s lymphoma that was not eligible to test more intensive approaches with⁵ or without stem-cell rescue.¹⁰

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX Study Participants REFERENCES

 
In October 1987, the GELA initiated a prospective multicenter study, designated as LNH-87, for patients with aggressive non-Hodgkin’s lymphoma. The study population was stratified in four treatment groups according to age and prognostic factors. Here we report the results of the LNH-87 group 1 trial.

Eligibility Criteria
Newly diagnosed patients between 16 and 69 years of age with intermediate- or high-grade non-Hodgkin’s lymphoma according to the Working Formulation¹¹ were eligible for the present study, providing that they had none of the following adverse prognostic factors: Eastern Cooperative Oncology Group performance status of 2 to 4, two extranodal sites of disease, tumor burden 10 cm in largest dimension, bone marrow or CNS involvement, and Burkitt’s or lymphoblastic histologic subtypes.

Patients were not included if they had a positive serology to human immunodeficiency virus, a concomitant or previous cancer (except in situ cervix carcinoma or skin epithelioma), congestive heart failure, recent myocardial infarction or conduction abnormalities, uncontrolled diabetes mellitus, and liver or kidney failure.

Staging
The extent of the disease was studied by physical examination, computed tomographic scan of chest and abdomen, CSF examination, bone marrow biopsy, and other investigational procedures according to clinical symptoms. The number of extranodal sites and the diameter of the largest tumor mass were determined. Patients’ disease was staged according to the Ann Arbor classification. Performance status was assessed according to the Eastern Cooperative Oncology Group scale (0 to 4).¹² Serum lactate dehydrogenase (LDH) level was expressed as the ratio over the maximum normal value.

Histologic and Immunophenotypic Analysis
A review of histologic documents by three independent pathologists from the GELA was planned in the protocol and conducted in 85% of the enrolled patients. Lymphomas were classified according to the Working Formulation,¹¹ but anaplastic large-cell lymphoma, as defined by the updated Kiel classification,¹³ was added to the categories of this classification.¹⁴ Immunophenotypic studies were performed as previously described.¹⁵

Treatment
After giving informed consent, patients were randomly assigned, through a central procedure, to receive the ACVBP or m-BACOD regimen. The ACVBP regimen consisted of three courses given every 2 weeks of doxorubicin 75 mg/m² on day 1, cyclophosphamide 1,200 mg/m² intravenously on day 1, vindesine 2 mg/m² on days 1 and 5, bleomycin 10 mg on days 1 and 5, prednisone 60 mg/m² orally from day 1 to day 5, and intrathecal methotrexate 15 mg on day 2. When only a partial response was obtained after the third course, a fourth course of ACVBP was administered. Patients with a partial or complete response to this treatment received a sequential consolidation therapy with two courses of intravenous methotrexate 3 g/m² plus leucovorin rescue, two courses of etoposide 300 mg/m² and ifosfamide 1,500 mg/m² with mesna protection, two courses of asparaginase 5,000 U/m², and two courses of cytarabine 100 mg/m² subcutaneously for 4 days, with each consolidation course administered at a 14-day interval.⁹ The m-BACOD regimen was administered as described by Shipp et al,¹⁶ namely, eight cycles with a 3-week interval of doxorubicin 45 mg/m² on day 1, cyclophosphamide 600 mg/m² intravenously on day 1, vincristine 1 mg/m² on day 1, bleomycin 4 mg/m² on day 1, dexamethasone 6 mg/m² orally from day 1 to day 5, and methotrexate 200 mg/m² intravenously on days 8 and 15 followed by leucovorin rescue. In each regimen, no dose adjustment was planned according to hematologic toxicity, but courses were postponed until leukocyte count increased to greater than 2.0 x 10⁹/L and platelet count increased to greater than 100 x 10⁹/L.

Response
Response to treatment was evaluated by repeat staging 3 weeks after the third cycle of chemotherapy and 4 weeks after the therapy ended. Complete remission (CR) was defined by the disappearance of all lesions and the normalization of laboratory abnormalities related to the lymphoma. A decrease of more than 75% of the measurable lesions and normalization of laboratory abnormalities was considered as unconfirmed CR.^9,17,18 Partial response was defined by a 50% to 75% regression of tumor size. All other cases were considered as progressive disease. Patients who had progressive disease at any time were withdrawn from the study and were given other treatment at the discretion of the investigator.

Statistical Methods
Study design. The LNH87-1 was a prospective and randomized study. Randomization was stratified according to the participating centers. The randomization was generated by the GELA program coordinating center, which issued treatment allocation by telephone after confirmation of patient eligibility. Case report forms collected at participating centers were sent to the coordinating center and keyed-in twice for verification. Outliers and erroneous values were checked routinely.

The main objective of the trial was to detect a 10% difference between the ACVBP and m-BACOD regimens on the assumption of an 80% 2-year failure-free survival (FFS) rate in the m-BACOD arm (two-sided test, type I error of .05, type II error of .10). Secondary end points were response to induction, overall survival (OS), and toxicity.

Statistical analyses. The stopping date was December 31, 1997. Patient characteristics, complete remission rates, and frequency of adverse reactions were compared with the ² and Fisher’s exact tests.¹⁹ FFS was measured from the date of randomization to either disease progression, relapse, or death from any cause, or the stopping date. OS was measured from the date of randomization to either death from any cause or the stopping date. When the stopping date was not reached, data were censored at the date of the last follow-up evaluation. The survival functions were estimated by the Kaplan-Meier method²⁰ and compared by log-rank test.²¹ Tests for comparison were regarded as significant if the two-sided P value was less than .05.

Because this trial started 6 years before publication of the International Prognostic Index (IPI) for aggressive lymphoma,²² inclusions could not be defined according to this model. The independent prognostic factors recognized by this model (age, LDH level, performance status, disease stage, and number of extranodal sites) were available in the database. However, because only patients with a performance status of 0 to 1 and 2 extranodal sites were included in the study population, the IPI was not fully applicable. To control for the effects of the applicable IPI factors on outcome caused by sampling fluctuation in the treatment groups, a multivariate survival analysis was performed. A Cox regression model²³ was fitted, including risk factors (LDH > normal v normal; age > 60 v 60; disease stage III/IV v I/II) and treatment arm as explanatory variables. The interactions between risk factors and treatment were also included in the model. SEs were computed with the bootstrap method.²⁴

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX Study Participants REFERENCES

 
Patient Characteristics
Between October 1987 and March 1993, 752 patients were registered for the study. Seventy-nine patients (ACVBP group, n = 40; m-BACOD group, n = 39) were considered ineligible for the following reasons: incorrect histologic diagnosis as determined by central review (n = 52: three carcinoma, six Hodgkin’s disease, eight lymphocytic lymphoma, 26 follicular lymphoma, three lymphoblastic lymphoma, one Burkitt’s lymphoma, and five other lymphoma); positive serology for human immunodeficiency virus (n = 1), CNS involvement (n = 1), bone marrow involvement (n = 1), more than one extranodal site involved (n = 8), tumor mass larger than 10 cm (n = 5), major protocol violation (n = 2), and absence of complete information on staging or response (n = 9). Thus, 673 patients were eligible for analysis: 332 were allocated to ACVBP treatment and 341 to m-BACOD. Their initial characteristics are listed in Table 1.

The theoretical dose-intensity of the two regimens could only be compared for doxorubicin and cyclophosphamide: 37.5 mg/m²/wk and 600 mg/m²/wk for the three cycles of ACVBP and 15 mg/m²/wk and 200 mg/m²/wk for the eight cycles of m-BACOD, respectively. The median received dose of doxorubicin and cyclophosphamide was, respectively, 30 mg/m²/wk and 480 mg/m²/wk (80% of the designed dose) for ACVBP and 13.7 mg/m²/wk and 183 mg/m²/wk (89% of the designed dose) for m-BACOD.

Toxicity
As listed in Table 2, serious toxic reactions were different in each treatment group. The incidence of grade 3 and 4 leukopenia and thrombocytopenia was significantly higher in the ACVBP group (P < .0001), leading to a higher incidence of severe or life-threatening infections (P < .01). On the other hand, pulmonary toxicity occurred in 18.5% of the patients treated with m-BACOD as compared with less than 1% of the patients treated with ACVBP (P < .0001). Half of these pulmonary reactions with m-BACOD were reported as severe, life-threatening, or fatal. The pulmonary toxicity usually occurred after the fourth cycle of m-BACOD (53 of the 63 episodes). This occurrence was not related to main prognostic factors, including age and disease extension. The incidence of treatment-related deaths did not differ significantly in the two groups, with 12 deaths among patients treated with ACVBP (infectious complication, n = 5; pulmonary toxicity, n = 1; cardiac failure, n = 3; cerebral vascular accident, n = 2; and methotrexate overdose, n = 1) and 16 deaths among patients treated with m-BACOD (infectious complication, n = 5; pulmonary toxicity, n = 8; cardiac failure, n = 2; unexplained death, n = 1). Of the eight deaths related to pulmonary toxicity in the m-BACOD group, four occurred in patients less than 60 years of age.

At the time of this analysis, 10 second cancers (including one acute leukemia) had been diagnosed in patients treated with ACVBP and 11 (including two myelodysplastic syndromes) in patients treated with m-BACOD.

Survival
The median follow-up duration was 84 months. As shown in Figs 1 and 2, there was no significant difference in survival between the two treatment groups. The 5-year FFS rate was 65% in the ACVBP group (95% confidence interval, 60% to 70%) and 61% in the m-BACOD group (95% confidence interval, 56% to 66%; P = .16). There were 99 deaths among the patients treated with ACVBP and 111 among those treated with m-BACOD. The 5-year OS rate was 75% in the ACVBP group (95% confidence interval, 70% to 80%) and 73% in the m-BACOD group (95% confidence interval, 68% to 78%; P = .44). There was also no difference between the two groups in an intent-to-treat analysis of the 752 patients registered for the study (P = .47).

View larger version (13K): [in this window] [in a new window]   Fig 1. Estimated FFS according to the treatment group (P = .44).

View larger version (13K): [in this window] [in a new window]   Fig 2. Estimated OS according to treatment group (P = .16).

Multivariate Analysis
Interactions between risk factors of the IPI (age, LDH level, disease stage) and treatment were statistically significant (P = .02). As listed in Table 3, after adjustment for risk factors and interactions, ACVBP demonstrated a significant benefit over m-BACOD in terms of FFS in patients with two or three risk factors and in terms of OS, only in patients with three risk factors.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX Study Participants REFERENCES

In the present study of a selected population of patients with low-risk aggressive lymphoma, there were no significant differences in the rates of CR, FFS, and OS between the two treatment groups.

The serious adverse reactions were different in the two regimens. The 18.5% incidence of pulmonary toxicity with m-BACOD is in accordance with previous publications.^1,28 The toxic reaction has been described to appear after three to eight cycles of m-BACOD. It did not seem predictable by the patient or the disease status and was certainly more related to methotrexate than to bleomycin or other drugs.²⁸ Eight patients in this series died as a consequence of pulmonary toxicity during m-BACOD therapy. It is noteworthy that, although the overall frequency of pulmonary events did not declined with time, six of these deaths occurred during the first 2 years of the trial, and only two deaths occurred after the physicians had been warned of this possible toxicity.

Granulocytopenia was the most important reaction after the induction cycles of ACVBP, with two thirds of the patients experiencing a grade 4 toxicity and 13% having severe, life-threatening, or fatal infection. Growth factor support, which was not used in this trial, has now been introduced after each ACVBP induction cycle.²⁹

The patients in this study could be considered as a low-risk lymphoma population, with 65% with localized disease and more than 75% in the low-risk category of the IPI. As a consequence, the CR rate in the whole study population was 86%, and the 5-year OS was 74%. However, important prognostic factors could still influence the outcome in this population. Patients with localized disease had a 90% CR rate and a 80% 5-year OS rate, which is comparable to the largest series of patients treated with combined modalities.^30,31 Compared with the population included in the Southwest Oncology Group study,³¹ patients with localized disease in this trial seemed to be younger and to have more stage II than stage I disease. However, we cannot exclude the possibility that ACVBP regimen may have a greater toxicity than a more standard approach in the treatment of localized disease stages. This has encouraged the GELA to propose a prospective multicenter study comparing the ACVBP regimen with the standard three cycles of CHOP plus radiotherapy in patients with low-risk localized aggressive lymphoma.

The benefit of more intensive approaches than CHOP-like regimens in aggressive lymphoma is controversial. However, there is some evidence that intensive treatments with^5,6,32 or without³³ stem-cell support may only be of benefit for patients in the higher risk groups. Although results of unplanned analyses should be considered with caution,³⁴ multivariate analysis strongly suggested that ACVBP may improve the outcome of patients with two or three IPI factors. In an attempt to confirm these results, the GELA is currently performing a trial comparing ACVBP with the standard eight cycles of CHOP in patients with high-risk lymphoma who could not benefit from high-dose therapy with stem-cell support.

	APPENDIX Study Participants

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX Study Participants REFERENCES

 
The following clinicians actively participated in the study: C. Allard, G. Alsteens, B. Audhuy, G. Auzanneau, J.C. Barats, E. Baumelou, P. Biron, M. Blanc, J. Bonneterre, R. Bouabdallah, O. Boulat, P. Brice, J. Brière, J. Bury, D. Caillot, D. Canon, B. Christian, J.P. Clauvel, P. Colin, T. Conroy, J.F. Cordier, H. Curé, R. D’Oiron, E. Deconinck, A. Delannoy, A. Devidas, M. Dieras, H. Dombret, C. Doyen, S. Drony, F. Du Bourguet, M.L. Dubreuil, E. Dupuy, E. Duvivier, J.C. Eisenmann, M. Fabbro, P. Fargeot, M.C. Fauchet, C. Fermé, A. Ferrant, M. Ffrench, G. Fillet, M. Flesch, Y. Frilay, J. Gabarre, P. Gabez, J.P. Gaillard, J.A.. Gastaut, J.P. Gayno, C. Gisselbrecht, B. Grosbois, C. Haioun, V. Izrael, P. Jacomy, J. Jaubert, F. Kohser, R. Leblay, F. Lejeune, G. Lepeu, D. Lepillé, A. Le Rol, D. Maraninchi, G. Marit, J.P. Marolleau, C. Martin, M. Marty, F. Mayer, J.L. Michaux, J.M. Micléa, P. Mineur, P. Morel, M. Moriceau, F. Morvan, G. Nédellec, G. Netter-Pinon, E. Oksenhendler, P. Oriol, P.Y. Péaud, M. Perret, B. Pignon, H. Poizot-Martin, J.P. Pollet, E. Pujade-Lauraine, O. Reman, F. Reyes, R. Riou, H. Roché, J.F. Rossi, B. Salles, G. Salles, C. Sarazin, M. Schoenwald, M. Simon, P. Solal-Céligny, A. Stamatoullas, M. Symann, G. Tertian, A. Thyss, G. Tobelem, J. Troncy, A. Van den Bossche, G.L. Vaugier, and B. Velay.

The following pathologists actively participated in the study: M.F. d’Agay, R. Angonin, J. d’Anjou, J. Audouin, F. Berger, S. Boucheron, N. Brousse, P. Brousset, P.A. Bryon, J.P. Carbillet, T. Caulet, D. Cazals, F. Charlotte, L. Charvillat, M. Delos, G. Delsol, J. Diebold, H. Duplay, C. Duval, J.M. Emberger, B. Epardeau, B. Fabiani, P. Felman, Y. Fonck, N. Froment, P. Galian, O. Gasser, P. Gaulard, B. Gosselin, J. Hamels, C. Hopfner, N. Horschowski, E. Labouyrie, B. Lancien, A. Lavergne, C. Lavignac, M. Lecomte-Houke, M.B. Leger-Ravet, R. Loire, R. Marcellin, C. Marty-Double, A. de Mascarel, S. Méhaut, J.P. Merlio, C. Merignargues, J.F. Mosnier, H. Noel, G. Perie, M. Peuchmaur, T. Petrella, M. Pluot, M. Raphael, M.C. Raymond-Gelle, A.M. Roucayrol, S. Thiebaut, D. Wendum, and L. Xerri.

	ACKNOWLEDGMENTS

 
Supported in part by grants from the Délégation à la Recherche Clinique de l’Assistance Publique-Hôpitaux de Paris, the Fondation contre la Leucémie, and the Caisse Nationale d’ Assurance Maladie des Travailleurs Salariés, Paris, France.

We are grateful to Eric Lepage and Jacques Benichou for helpful discussions and comments on the manuscript. We also thank Catherine Balmale for help with data management.

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Submitted June 18, 1999; accepted November 18, 1999.

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