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Originally published as JCO Early Release 10.1200/JCO.2005.08.133 on January 24 2005 © 2005 American Society of Clinical Oncology. 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)From the Department of Internal Medicine III, Ludwig-Maximilians University; Department of Medical Informatics, Biometrics and Epidemiology (IBE), Ludwig-Maximilians University, Munich; Department of Internal Medicine II, Städtisches Klinikum Braunschweig, Braunschweig; Department of Hematology, University of Essen, Essen; Department of Internal Medicine II, Klinikum Oldenburg, Oldenburg; Department of Hematology and Oncology, Katholisches Krankenhaus, Hagen, Hagen; Department of Hematology and Oncology, University of Marburg, Marburg; Department of Hematology and Oncology, Klinikum Nord, Nuernberg; Department of Internal Medicine II, Carl-Thiem Klinikum, Cottbus; Department of Internal Medicine II, Robert-Bosch-Hospital; Department of Internal Medicine II, Diakonie-Klinikum, Stuttgart; Praxis für Hämatologie/Onkologie, Leipzig; Department of Hematopathology and Lymph Node Registry Kiel, Kiel, Germany Address reprint requests to Wolfgang Hiddemann, MD, PhD, Department of Internal Medicine III of the Ludwig-Maximilians University, Marchioninistrasse 15, 81377 Munich, Germany; e-mail: wolfgang.hiddemann{at}med.uni-muenchen.de
PURPOSE: Mantle cell lymphoma (MCL) is characterized by a poor prognosis with a low to moderate sensitivity to chemotherapy and a median survival of only 3 to 4 years. In an attempt to improve outcome, the German Low Grade Lymphoma Study Group (GLSG) initiated a randomized trial comparing the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) and rituximab (R-CHOP) with CHOP alone as first-line therapy for advanced-stage MCL.
PATIENTS AND METHODS: One hundred twenty-two previously untreated patients with advanced-stage MCL were randomly assigned to six cycles of CHOP (n = 60) or R-CHOP (n = 62). Patients up to 65 years of age achieving a partial or complete remission underwent a second randomization to either myeloablative radiochemotherapy followed by autologous stem-cell transplantation or interferon alfa maintenance (IFN RESULTS: R-CHOP was significantly superior to CHOP in terms of overall response rate (94% v 75%; P = .0054), complete remission rate (34% v 7%; P = .00024), and time to treatment failure (TTF; median, 21 v 14 months; P = .0131). No differences were observed for progression-free survival. Toxicity was acceptable, with no major differences between the two therapeutic groups. CONCLUSION: The combined immunochemotherapy with R-CHOP resulted in a significantly higher response rate and a prolongation of the TTF as compared with chemotherapy alone. Hence, R-CHOP may serve as a new baseline regimen for advanced stage MCL, but needs to be further improved by novel strategies in remission.
Mantle cell lymphoma (MCL) is a relatively rare lymphoma entity accounting for 5% to 10% of all lymphoma cases in North America and Europe.1-3 It represents a major challenge to clinicians and researchers. With a median survival of only 3 to 4 years and a high degree of primary and secondary treatment resistances, MCL remains the lymphoma subtype with the poorest long-term outcome.4,5 In an attempt to overcome these limitations, various drug combinations including alkylating agents, anthracyclines, and purine analogs have been explored. They all failed to substantially improve the long-term perspectives despite achieving overall response rates of approximately 60% to 80%, with complete remissions (CR) in 20% to 30% of cases.6,7 Thus, several new agents, such as flavopiridol, which targets the cyclin D1 pathway, or the proteasome inhibitor bortezomib are currently in the early phase of clinical exploration.8,9 In addition, more aggressive therapeutic approaches implementing high-dose cytarabine, such as the Hyper-CVAD regimen (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone), have been explored in MCL.10 Two other promising treatment modalities have been analyzed in several clinical trials. High-dose therapy followed by autologous stem-cell transplantation (ASCT) has been investigated in various phase II studies, and encouraging results have been reported when applied as consolidation in remission.11-15 This concept was recently tested in a prospective randomized comparison between ASCT and interferon alfa (IFN  ) by the European MCL Network in 122 MCL patients in first remission.16 Patients receiving ASCT had a significantly longer progression-free survival (PFS) in comparison to IFN maintenance. This approach is restricted, however to younger patients and may potentially be hampered by the risk of secondary myelodysplastic syndromes and acute leukemias.17,18 Another encouraging approach is given by the anti-CD20 antibody rituximab. Rituximab is a chimeric murine/human monoclonal antibody that binds the B-cell–specific antigen CD20. In vitro studies demonstrated that rituximab lyses CD20+ cells by complement activation or antibody-dependent cell-mediated cytotoxicity.19,20 The high expression of CD20 makes MCL an attractive target for rituximab treatment, and partial response (PR) rates of approximately 20% to 35% could be achieved by a rituximab monotherapy in relapsed or refractory disease.21-23 Remarkably high responses were reported by a recent phase II study combining the CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone) with rituximab (R-CHOP).24 The German Low Grade Lymphoma Study Group (GLSG) even observed an improved overall survival (OS) in patients with relapsed or refractory MCL who were treated with a combination of rituximab and the FCM regimen (fludarabine, cyclophosphamide, and mitoxantrone) in comparison with FCM alone.25
On the basis of these promising results, the GLSG initiated a randomized trial comparing R-CHOP, with CHOP alone in previously untreated patients with advanced-stage MCL, followed by different strategies of consolidation (myeloablative radiochemotherapy followed by ASCT v IFN
Inclusion Criteria This study was performed as a prospective, randomized, open-label multicenter phase III trial and included previously untreated patients older than 18 years of age with Ann Arbor stage III or IV follicular lymphoma, MCL, or lymphoplasmacytic lymphoma according to the current WHO classification.1 The histologic diagnosis had to be confirmed by a central pathology review at one of six designated pathology reference centers. Patients with stage I or II disease, as well as patients with poor performance status (Eastern Cooperative Oncology Group performance status > 2) were not eligible. In addition, patients with seriously impaired cardiac, pulmonary, hepatic (ALT/AST  3x upper limit of normal, and/or bilirubin 2.0 mg/dL), or renal function (creatinine > 2.0 mg/dL), as well as pregnant or lactating women, were not enrolled. The initial diagnostic work-up comprised the assessment of the extent of the disease, including computed tomography (CT) scans of the neck, chest, and abdomen; abdominal ultrasound; and bone marrow biopsy. Normal organ function was assured by the respective laboratory tests, as well as by echocardiogram and ECG.
Treatment Schedule
In patients up to 65 years of age achieving a CR or PR after induction therapy, a participation in a second randomized trial, comparing the PFS after either myeloablative radiochemotherapy followed by ASCT or IFN
Patients randomly assigned to IFN
Response Criteria and Evaluation Response was defined according to the International Working Group criteria.27 Hence, CR was defined as complete absence of disease manifestations, including bone marrow involvement for at least 4 weeks. PR required at least a 50% reduction of all assessable lymphoma manifestations, without appearance of new lesions for at least 4 weeks. Overall response was defined as the achievement of a PR or a CR. Minimal response (MR) was defined as reduction of all assessable lymphoma manifestations of less than 50%. Stable disease comprised no reduction of assessable lymphoma manifestations; progression was defined as increase in lymphoma-associated symptoms, the appearance of new lymphoma manifestations, or an increase in volume of lymphoma manifestations by more than 25%. Time to treatment failure (TTF) was defined as the interval between initiation of induction therapy until documentation of resistance to induction therapy (MR after six cycles or stable disease after at least two cycles, progression, or death from any cause), or relapse or death from any cause after having achieved a PR or CR. PFS of responders (patients in PR or CR) was defined from the end of successful induction therapy to relapse or death from any cause. Overall survival (OS) was defined as the interval between the start of therapy and death from any cause. The frequency and severity of side effects were recorded according to the WHO classification.28
Trial Design and Statistical Analysis
Secondary analyses were performed on an intention-to-treat basis for the response rates, TTF, PFS, and OS applying the two-sided Fisher's exact text for binary responses, the Kaplan-Meier method, and the log-rank test for time-censored observations. In addition, we carried out an explorative multivariable Cox-regression analysis for PFS. Toxicity was analyzed using the
Trial Conduct
Initially, patients with follicular lymphoma and MCL, as well as those with lymphoplasmacytic lymphoma were included in our trial. In April 2002, the sequential test showed a significantly higher overall response rate after induction therapy with R-CHOP as compared with CHOP. However, subgroup analysis revealed that this advantage was mainly due to the benefit detected in MCL patients. Thus, the GLSG decided to stop random assignment for MCL patients, whereas in patients with follicular and lymphoplasmacytic lymphoma, random assignment was continued in order to detect a difference in TTF, which was defined as the new main study end point. Thus, the emphasis of this analysis is put on the results obtained from patients with MCL.
Patient Characteristics
Treatment Outcome Sixty patients received CHOP chemotherapy alone, whereas 62 patients were randomly assigned to R-CHOP. In the CHOP group, 59 patients were assessable for response, as in one patient, no staging was performed following induction therapy. Following CHOP, an overall response rate of 75% (n = 44), with 7% (n = 4) CR, was observed. In contrast, R-CHOP resulted in an overall response rate of 94% (n = 58; P = .0054); 21 patients (34%) obtained a CR (P = .00024; Table 2).
In addition, R-CHOP was superior to CHOP in terms of the secondary parameter TTF with a median of 21 months versus 14 months after CHOP alone (P = .0131; Fig 2). Of the 27 observed events in the R-CHOP arm, treatment failure was due to failure of induction therapy in four cases, relapse after successful induction therapy in 22 cases, and death in one case. In the CHOP arm, 36 cases of treatment failure were observed. Fifteen cases were due to failure of induction therapy, and 21 relapses after CR or PR were observed. The estimated TTF at 1 year was 84% in the R-CHOP group versus 52% in the CHOP group. Similar to the TTF, the median time to initiation of salvage therapy was significantly longer following R-CHOP, with 25 months as compared with 22 months after CHOP (P = .0262; Fig 3). However, no significant differences in the PFS of responding patients were detectable (P = .31; Fig 4).
After a median follow-up of 18 months, 21 patients died (10 in the R-CHOP and 11 in the CHOP group). In the R-CHOP group versus CHOP group, the leading cause of death was progressive lymphoma (n = 11; four v 7, respectively). Six patients developed infectious complications (four v two, respectively), two patients died following pulmonary embolism (one v one, respectively), and one patient died due to cardiac failure following R-CHOP. In addition, in one CHOP patient, the cause of death is unknown. Accordingly, the 2-year survival probability was 76.6% (median not yet reached), with no differences in the two study arms (P = .93; Fig 5).
Therapy in Remission In patients up to 65 years of age who achieved a CR or PR after induction therapy, a second random assignment, either to myeloablative radiochemotherapy followed by ASCT or to IFN , was offered. Patients older than 65 years of age were treated with IFN maintenance. Thus, 23 patients received myeloablative radiochemotherapy followed by ASCT (14 in the R-CHOP arm and nine after CHOP), 62 patients were treated with IFN (35 R-CHOP and 27 CHOP), and eight patients (two R-CHOP and six CHOP) did not receive any further therapy in remission (Table 1). In addition, in nine patients, the consolidation was not documented. Thus, postinduction therapy was well balanced in both study arms. To investigate the influence of induction therapy (R-CHOP v CHOP), consolidation (ASCT v IFN v none), and the IPI prognostic factors on the PFS, we performed a multivariate Cox regression analysis. This analysis confirmed the LDH ratio and the type of postremission therapy as independent prognostic factors of the PFS. The hazard ratio for the LDH ratio was calculated to 5.7 (P < .0001), and the hazard ratios of ASCT versus IFN versus no postremission therapy were 2.9 and 4.1, respectively (P = .00022). In patients who received ASCT, PFS was not different after R-CHOP as compared with CHOP (four relapses in 14 patients v one relapse in nine patients, respectively; P = .47; median PFS not yet reached). Similarly, no significant differences could be observed in patients who received IFN maintenance (median PFS, 19 v 13 months, respectively; P = .18). However, so far, the number of patients is too low, and the median follow-up is too short to draw definitive conclusions.
Adverse Effects
The current study demonstrates that the combined immunochemotherapy of R-CHOP significantly improves the CR rate (34% v 7%; P = .00024), the overall response rate (94% v 75%; P = .0054), and the TTF (median, 21 v 14 months; P = .0131) as compared with CHOP alone in patients with advanced-stage MCL. In addition, after R-CHOP, patients also experience a significantly longer time period with no further treatment. In both study arms, hematologic toxicity, particularly leukocytopenia, was the predominant treatment-related adverse effect. Although severe grade 3 and 4 granulocytopenia was significantly more frequent following R-CHOP as compared with CHOP (63% v 53%, respectively), this difference was of minor clinical relevance, as no increase in infectious complications could be observed. In addition, allergic reactions occurred significantly more often following rituximab (7% i 0%; P < .0001). These reactions, however, were mostly mild and did not require a cessation of rituximab treatment. Thus, similar to previous studies, the combined application of rituximab and chemotherapy is safe and feasible.24,25,30,31 Promising response rates of combining Rituximab with chemotherapy (R-CHOP) have already been reported in previously untreated patients with MCL, in a recent, nonrandomized phase II study.24 In addition, in another study of The University of Texas M.D. Anderson Cancer Center, encouraging results following the combination of rituximab and Hyper-CVAD have been reported.32 Patients treated with such a combined immunochemotherapy showed a PFS that was comparable to the PFS after high-dose consolidation and ASCT. The GLSG most recently completed a randomized comparison of salvage therapy with FCM with or without rituximab in patients with relapsed MCL.25 Similar to the current trial with CHOP versus R-CHOP, a significantly higher response rate and a longer TTF could be observed after R-FCM as compared with FCM alone. Even more importantly, the OS was significantly prolonged. This finding is in contrast to our current trial as well as to other studies in which no prolongation of the OS or duration of response could be detected.24 This discrepancy might be explained by the relatively small number of MCL patients analyzed in the FCM versus R-FCM trial, or the rather short follow-up in the other studies. Alternatively, the observed difference may also relate to the type of chemotherapy with which rituximab is combined. Hence, a fludarabine-containing combination may be more effective than an anthracycline- or alkylating agent–based regimen, as an in vitro synergism between fludarabine and rituximab has been described.33 This question needs to be addressed in future studies, which should also explore the combination of rituximab and high-dose cytarabine. Encouraging results have recently been achieved in various phase II studies. Lefrere et al showed that more than 80% of patients obtained a CR after a sequential CHOP-DHAP regimen (CHOP plus dexamethasone, high-dose cytarabine, and cisplatin).34 Similarly, high response rates of more than 90% could be demonstrated by the dose-intensified approach of the M.D. Anderson Cancer Center, applying an alternating regimen of Hyper-CVAD with high-dose cytarabine and methotrexate in elderly patients not suitable for stem-cell transplantation.10
The analysis of the current CHOP versus R-CHOP trial confirms that the favorable effect of rituximab is restricted to the period of induction therapy. Hence, no differences in the PFS could be observed after CHOP or R-CHOP therapy, either in patients receiving IFN Another innovative approach is the application of radio (131iodine or 90yttrium)-labeled anti-CD20 antibodies in conventional or myeloablative doses. Different studies achieved remarkably high and long-lasting remissions in relapsed or refractory MCL patients.38,39 Gopal et al investigated the efficacy of the 131iodine-labeled anti-CD20 antibody tositumomab in 16 heavily pretreated patients with MCL, in combination with high-dose chemotherapy followed by ASCT.38 High overall response rates of 100%, with 91% CR and an estimated 3-year OS of 93%, were reported. Promising results have recently also been obtained by the proteasome inhibitor Bortezomib.9 Hence, the spectrum of therapeutic options in MCL has widened substantially within the last few years. This justifies the hope that the long-term outcome of patients suffering from this disease will finally improve. R-CHOP represents an encouraging step forward toward achieving this ultimate goal.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Honoraria: Wolfgang Hiddemann, Roche. Research Funding: Wolfgang Hiddemann, Roche. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and Disclosures of Potential Conflicts of Interest found in Information for Contributors in the front of each issue.
The following persons and institutions participated in this study: V. Groß, L. Fischer v Weikersthal, Klinikum St Marien, Amberg; M. Hahn, S. Müller, Hämatologisch-Onkologische Praxis, Ansbach; G. Unverferth, W. Langer, F. Püschel, Kreiskrankenhaus Aurich, Aurich; W.D. Ludwig, H. Harder, Robert Rössle Klinik, Helios Klinikum Berlin, Berlin; J. Potenberg, E. Aulbert, Evangelisches Waldkrankenhaus Spandau, Berlin; H.J. Weh, B. Angrick, Franziskus Hospital, Bielefeld; G. Dietrich, Krankenhaus Bietigheim, Bietigheim-Bissingen; E. Musch, H. Röhl, G. Mann, Marien-Hospital Bottrop, Bottrop; G. Jordan, A. Pies, Städtisches Klinkum Braunschweig, Braunschweig; K.H. Pflüger, Th. Wolff, Diakoniekrankenhaus, Bremen; M. Grundeis, Schwerpunktpraxis Onkologie Hämatologie, Chemnitz; M. Lößner, Carl-Thiem-Klinikum, Cottbus; J. Pielken, M. Nahler, St Johannes Krankenhaus, Dortmund; M. Gramatzki, Medizinische Klinik III der Universität, Erlangen; R. Fuchs, S. Wehle-Ilka, J. Wiegand, St-Antonius-Hospital, Eschweiler; H. Nückel, Medizinische Klinik und Poliklinik, Essen; R. Mertelsmann, J. Finke, Medizinische Universitätsklinik, Freiburg; T. Reiber, D. Semsek, Praxis für Innere Medizin, Freiburg; L. Trümper, B. Glaß, Georg-August-Universität Göttingen, Göttingen; S. Kraus, I. Hausbrandt, St Salvator Krankenhaus, Halberstadt; N. Schmitz, P. Dreger, Allgemeines Krankenhaus St Georg, Hamburg; D.K. Hossfeld, J. Dierlamm, Medizinische Klinik II Universitäts-Krankenhaus Eppendorf, Hamburg; T.A. Walter, Praxis für Innere Medizin, Hamburg; H.A. Dürk, B. Schmid, S. Weibrecht, St-Marien-Hospital, Hamm; H. Kirchner, M. Sosada, Klinikum Hannover-Siloah, Hannover; F. Henne, Praxis für Hämatologie/Onkologie, Hechingen; A.D. Ho, E. Leo, Universitätsklinik Heidelberg, Heidelberg; H. Dietzfelbinger, Privatklinik Dr R. Schindlbeck, Herrsching; M. Pfreundschuh, Universitätsklinik des Saarlandes, Homburg/Saar; K. Höffken, H.J. Fricke, Klinik für Innere Medizin der Friedrich-Schiller-Universität Jena, Jena; J. Th Fischer, S. Wilhelm, R. Ehrhardt, Städtisches Klinikum Karlsruhe, Karlsruhe; J. Mezger, G. Göckel, St-Vincentius-Krankenhäuser, Karlsruhe; C. Löser, H. Urbanke-Siebert, Rotes Kreuz Krankenhaus, Kassel; Th. Eisenhauer, H. Nolte, Städtisches Klinikum Kemperhof, Koblenz; V. Diehl, A. Engert, M. Reiser, I. Medizinische Universitätsklinik, Köln; S. Schmitz, T. Steinmetz, Internistische Praxis Hämatologie und Onkologie, Köln; M. Planker, M. Busch, M. Hipp, Städtische Krankenanstalten, Krefeld; M. Stauch, Schwerpunktpraxis Hämatologie und Onkologie, Kronach; G. Köchling, H. Fokken, Kreiskrankenhaus Leer, Leer; L. Mantovani, B. Matthe, Städt. Klinikum St Georg, Leipzig; G. Liebau, D. Nothnagel, Klinikum Ludwigsburg, Ludwigsburg; M. Uppenkamp, M. Hoffmann, Klinikum der Stadt, Ludwigshafen; E. Kettner, G. Krötki, Städtisches Klinikum/K.H. Altstadt, Magdeburg; C. Huber, T. Fischer, G. Heß, III Medizinische Klinik der Universität, Mainz; N. Schwella, Klinikum der Phillips Universität, Marburg; A. Pfeiffer, M. Mennicke, Klinikum Memmingen, Memmingen; R. Götz, P. Jehner, Krankenhaus Bethanien, Moers; C. Lunscken, Hämatologische Praxis, Mülheim Ruhr; R. Forstpointner, Klinikum Grosshadern, München; R. Hartenstein, N. Brack, Städtisches K.H. München-Harlaching, München; Ch. Peschel, C. v Schilling, Klinikum Rechts der Isar der Technische Universität, München; D. Schlöndorff, J. Walther, U. Seybold, Medizinische Poliklinik Innenstadt, München; W.E. Berdel, Universitätsklinikum Münster, Münster; W. Ladda, Praxis für Innere Medizin, Neumarkt; S. Fries, Klinikum Nord, Nürnberg; H.J. Illiger, Klinikum Oldenburg, Oldenburg; H.F. Hinrichs, B. Otremba, I. Zirpel, Onkologische Praxis Oldenburg, Oldenburg; H. Keller, H. Leber, D. Nöcker, Brüderkrankenhaus St Josef, Paderborn; P. Weber, S. Perino, Medizinische Klinik des Siloah Krankenhauses, Pforzheim; G. Kautzsch, A. Rupprecht, Sankt-Josefs-Krankenhaus Potsdam, Potsdam; E.D. Kreuser, Krankenhaus Barmherzige Brüder, Regensburg; R. Andreesen, S. Krause, S. Mayer, Universitätsklinik Regensburg, Regensburg; M. Baldus, Internistische Schwerpunktpraxis, Rüsselsheim; J. Preiß, P. Schmidt, Caritas Klinik St Theresia, Saarbrücken; K. Seitz, G. Käfer, Kreiskrankenhaus Sigmaringen, Sigmaringen; S. Martin, Robert-Bosch-Krankenhaus, Stuttgart; E. Heidemann, J. Kaesberger, Diakonissenkrankenhaus, Stuttgart; H. Fiechtner, G. Springer, Praxis für Hämatologie/Onkologie, Stuttgart; M.R. Clemens, Mutterhaus der Borromäerinnen, Trier; J. Diers, W. Twiessel, Marienhospital, Vechta; W.W. Reiter, Facharzt für Innere Medizin, Hämatologie und internistische Onkologie, Viersen; N. Frickhofen, H.G. Fuhr, G. Müller, Dr H. Schmidt-Kliniken Wiesbaden, Wiesbaden; Th. Bock, Praxis für Hämatologie/Onkologie, Wittenberge; M. Sandmann, G. Becker, Kliniken St Antonius, Wuppertal; K. Wilms, H. Rückle-Lanz, M. Wilhelm, Medizinische Klinik der Universität Würzburg, Würzburg.
Supported in part by a grant from the Deutsche Krebshilfe (T14/96/Hi 1, project No.: 70-2208-Hi 2). Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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ABSTRACT
INTRODUCTION
2 test. The significance level was set to .05 for secondary and exploratory analyses. 
