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) 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)

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)

  1. Wolfgang Hiddemann
  1. 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
  1. 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
 
Next Section

Abstract

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 (IFNα). All patients older than 65 years received IFNα maintenance.

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.

Previous SectionNext Section

INTRODUCTION

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 (IFNα) 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 IFNα 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 IFNα maintenance).

Previous SectionNext Section

PATIENTS AND METHODS

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 ≥ 3× 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

Patients were randomly assigned either to the CHOP regimen alone or to R-CHOP. Randomization was carried out centrally and was stratified according to histology (follicular lymphoma v MCL v lymphoplasmacytic lymphoma), age (< 60 v ≥ 60 years), and number of risk factors (Two or fewer v three or more, except for age) defined by the International Prognostic Index (IPI).26 The CHOP combination comprised cyclophosphamide 750 mg/m2 intravenously (IV), day 1; doxorubicin 50 mg/m2 IV, day 1; vincristine 1.4 mg/m2 (maximum 2 mg) IV, day 1; and prednisone 100 mg/m2 PO, days 1 to 5. Treatment cycles were repeated every 3 weeks for a total of six cycles. Patients who were randomly assigned to the R-CHOP arm received rituximab 375 mg/m2 after prophylactic application of antipyretic and antihistamine premedication on day 0 of the respective CHOP course.

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 IFNα maintenance, was offered. This second random assignment was stratified according to the type of induction chemotherapy. Patients in the ASCT arm received intensified stem-cell mobilization chemotherapy (Dexa-BEAM: dexamethasone, BCNU, etoposide, cytarabine, melphalan) 4 to 8 weeks after completion of induction therapy. Subsequent high-dose therapy, which was performed within the following 2 months, consisted of total body irradiation (TBI; 12 Gy on days −6 to −4) and high-dose cyclophosphamide (60 mg/kg body weight IV, days −3 and −2). The previously harvested peripheral blood stem cells were reinfused on day 0.

Patients randomly assigned to IFNα maintenance received two additional courses of conventional chemotherapy to balance the mobilization scheme (Dexa-BEAM). Subsequently, IFNα maintenance was initiated at a dose of 6 × 106 U subcutaneously three times weekly within 4 weeks after the last cycle of therapy, and continued until progression or until the occurrence of intolerable side effects. All patients older than 65 years of age received IFNα maintenance.

Response Criteria and Evaluation

Response to therapy was assessed after every two cycles of induction therapy and 4 weeks after the completion of the last cycle. Response evaluation included a physical examination, a CBC, a serum biochemistry profile, an ultrasound of the abdomen, and CT scans of previously involved areas. In patients with initial bone marrow involvement, a bone marrow biopsy was performed. Follow-up was performed every three months in both study arms by the above mentioned analyses, except for CT scans of previously involved areas which were repeated every six months.

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

Both the overall response as well as the CR rate were primary end points of this trial. These parameters were monitored by truncated one-sided sequential probability ratio tests in order to allow a stop of random assignment as soon as a significant difference was detected between the two study arms.29 To adjust for multiple testing and to maintain the global significance level α = .05, the significance level for the overall response rate was set to .04, and for the CR rate, to .01. Assuming an overall response rate of 85% following CHOP, an improvement to 95% after R-CHOP was expected. For the rate of CRs, an improvement of 20% to 40% was considered a clinically relevant goal. Both tests were adjusted to a power of 95% for the expected improvement.

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 χ2 test. The significance level was set to .05 for secondary and exploratory analyses.

Trial Conduct

The study was carried out in accordance with the Declaration of Helsinki. All patients gave their written informed consent after having been informed about the purpose and investigational nature of the trial. Before initiation, the study received approval by the responsible ethical committee.

Previous SectionNext Section

RESULTS

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

Between May 2000 and July 2002, 128 patients with previously untreated advanced-stage MCL from 79 clinical institutions were centrally randomly assigned either to CHOP or R-CHOP. The trial profile is shown in Figure 1. At the time of this analysis, 122 of these patients were assessable. Seventy-nine percent of patients presented with Ann Arbor stage IV disease, 28% had an elevated serum lactate dehydrogenase (LDH) level, and 37% reported “B” symptoms. Of the 121 patients assessable for the IPI, 24% had a low-risk IPI; 40%, a low-intermediate–risk IPI; 27%, a high-intermediate–risk IPI; and 8%, a high-risk IPI. The patients' characteristics are comparable in the two study arms and are summarized in Table 1.

Fig 1.
View larger version:
Fig 1.

Trial profile. CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; R-CHOP, rituximab and CHOP.

View this table:
Table 1.

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).

View this table:
Table 2.

Response to Induction Therapy After CHOP and R-CHOP

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).

Fig 2.
View larger version:
Fig 2.

Time to treatment failure (TTF) after initiation of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) and rituximab and CHOP (R-CHOP). Patients assigned to R-CHOP experienced a significantly longer TTF (P = .0131) In parentheses, number of censored patients/total number of patients.

Fig 3.
View larger version:
Fig 3.

Median time to initiation of salvage therapy following cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) and rituximab and CHOP (R-CHOP). Patients assigned to R-CHOP experienced a significantly longer time to salvage therapy (P = .0262).

Fig 4.
View larger version:
Fig 4.

Progression-free survival after cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) and rituximab and CHOP (R-CHOP). No significant differences were observed between the two treatment arms (P = .31).

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).

Fig 5.
View larger version:
Fig 5.

Overall survival after initiation of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) and rituximab and CHOP (R-CHOP). No significant differences were observed between the two treatment arms (P = .93).

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 IFNα, was offered. Patients older than 65 years of age were treated with IFNα 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 IFNα (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 IFNα 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 IFNα 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 IFNα 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.

Previous SectionNext Section

DISCUSSION

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 IFNα maintenance or in patients undergoing myeloablative radiochemotherapy. These results also emphasize that MCL remains a therapeutic challenge with a high degree of inherent treatment resistance that is still poorly understood. MCL clearly differs from follicular lymphoma, in which the addition of rituximab to chemotherapy not only improved the initial response rate, but also prolonged the PFS as well as the OS.25,30 Hence, MCL remains a major challenge and requires additional therapeutic options to translate the high remission rate achieved by the combination of rituximab and chemotherapy into a longer PFS and OS. One approach may be consolidation with myeloablative radiochemotherapy followed by ASCT in first remission. In a recently completed randomized trial by the European MCL Network, ASCT significantly improved the PFS as compared with IFNα maintenance.16 Based on the finding that the quality of remission before stem-cell transplantation has an important impact on the patients' outcome,14,35 it is possible that R-CHOP induction therapy may provide an improved basis for intensified consolidation. Other approaches aim at improving the outcome of ASCT by exploring more effective purging procedures.36,37

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.

Previous SectionNext Section

Authors' Disclosures of Potential Conflicts of Interest

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.

Previous SectionNext Section

Acknowledgments

The following persons and institutions participated in this study: V. Groβ, 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. Löβner, 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. Glaβ, 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. Heβ, 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. Preiβ, 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.

Previous SectionNext Section

Footnotes

  • 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.

  • Received August 25, 2004.
  • Accepted December 9, 2004.
Previous Section
 

REFERENCES

  1. ↵
    Jaffe ES, Harris NL, Stein H, et al: World Health Organization Classification of Tumours: Tumours of the Haemopoitic and Lymphoid Tissues. IARC Press, Lyon, France, 2001
  2. Meusers P, Hense J, Brittinger G: Mantle cell lymphoma: Diagnostic criteria, clinical aspects and therapeutic problems. Leukemia 11:S60-S64, 1997 (suppl 2)
  3. ↵
    Weisenburger DD, Armitage JO: Mantle cell lymphoma: An entity comes of age. Blood 87:4483-4494, 1996
    FREE Full Text
  4. ↵
    Hiddemann W, Dreyling MH, Tiemann M, et al: Mantle cell lymphomas. Haematologica 84:93-95, 1999
    CrossRefMedline
  5. ↵
    Weisenburger DD, Vose JM, Greiner TC, et al: Mantle cell lymphoma: A clinicopathologic study of 68 cases from the Nebraska Lymphoma Study Group. Am J Hematol 64:190-196, 2000
    CrossRefMedline
  6. ↵
    Zucca E, Roggero E, Pinotti G, et al: Patterns of survival in mantle cell lymphoma. Ann Oncol 6:257-262, 1995
    Abstract/FREE Full Text
  7. ↵
    Vandenberghe E, De Wolf-Peeters C, Vaughan Hudson G, et al: The clinical outcome of 65 cases of mantle cell lymphoma initially treated with non-intensive therapy by the British National Lymphoma Investigation Group. Br J Haematol 99:842-847, 1997
    CrossRefMedline
  8. ↵
    Kouroukis CT, Belch A, Crump M, et al: Flavopiridol in untreated or relapsed mantle-cell lymphoma: Results of a phase II study of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 21:1740-1745, 2003
    Abstract/FREE Full Text
  9. ↵
    Goy A, Younes A, McLaughlin P, et al: Phase II study of proteasome inhibitor bortezomib in relapsed or refractory B-cell non-Hodgkin’s lymphoma. J Clin Oncol 23:10.1200/JCO.2005.03.108
  10. ↵
    Romaguera JE, Khouri IF, Kantarjian HM, et al: Untreated aggressive mantle cell lymphoma: Results with intensive chemotherapy without stem cell transplant in elderly patients. Leuk Lymphoma 39:77-85, 2000
    Medline
  11. ↵
    Stewart DA, Vose JM, Weisenburger DD, et al: The role of high-dose therapy and autologous hematopoietic stem cell transplantation for mantle cell lymphoma. Ann Oncol 6:263-266, 1995
    Abstract/FREE Full Text
  12. Decaudin D, Brousse N, Brice P, et al: Efficacy of autologous stem cell transplantation in mantle cell lymphoma: A 3-year follow-up study. Bone Marrow Transplant 25:251-256, 2000
    CrossRefMedline
  13. Kroger N, Hoffknecht M, Dreger P, et al: Long-term disease-free survival of patients with advanced mantle-cell lymphoma following high-dose chemotherapy. Bone Marrow Transplant 21:55-57, 1998
    CrossRefMedline
  14. ↵
    Vandenberghe E, Ruiz de Elvira C, Loberiza FR, et al: Outcome of autologous transplantation for mantle cell lymphoma: A study by the European Blood and Bone Marrow Transplant and Autologous Blood and Marrow Transplant Registries. Br J Haematol 120:793-800, 2003
    CrossRefMedline
  15. ↵
    Dreger P, Martin S, Kuse R, et al: The impact of autologous stem cell transplantation on the prognosis of mantle cell lymphoma: A joint analysis of two prospective studies with 46 patients. Hematol J 1:87-94, 2000
    CrossRefMedline
  16. ↵
    Hiddemann W, Dreyling MH, Pfreundschuh M, et al: Myeloablative Radiochemotherapy followed by autologous Blood stem cell transplantation leads to a significant prolongation of the event-free survival in patients with mantle cell lymphoma (MCL): Results of a prospective randomized European Intergroup study. Blood 98:861a, 2001 (abstr 3572)
  17. ↵
    Lenz G, Dreyling M, Schiegnitz E, et al: Moderate increase of secondary hematologic malignancies following myeloablative radiochemotherapy and autologous stem cell transplantation in patients with indolent lymphoma: Results of a prospective randomized trial of the German Low Grade Lymphoma Study Group. J Clin Oncol 22:4926-4933, 2004
    Abstract/FREE Full Text
  18. ↵
    Micallef IN, Lillington DM, Apostolidis J, et al: Therapy-related myelodysplasia and secondary acute myelogenous leukemia after high-dose therapy with autologous hematopoietic progenitor-cell support for lymphoid malignancies. J Clin Oncol 18:947-955, 2000
    Abstract/FREE Full Text
  19. ↵
    Smith MR: Rituximab (monoclonal anti-CD20 antibody): mechanisms of action and resistance. Oncogene 22:7359-7368, 2003
    CrossRefMedline
  20. ↵
    Manches O, Lui G, Chaperot L, et al: In vitro mechanisms of action of rituximab on primary non-Hodgkin lymphomas. Blood 101:949-954, 2003
    Abstract/FREE Full Text
  21. ↵
    Ghielmini M, Schmitz Hsu S-F, Cogliatti S, et al: Effect of standard or prolonged treatment with single agent rituximab in patients with mantle cell lymphoma: A randomized trial of the SAKK. Hematol J 4:263, 2003 (abstr 881)
    CrossRefMedline
  22. Foran JM, Cunningham D, Coiffier B, et al: Treatment of mantle-cell lymphoma with Rituximab (chimeric monoclonal anti-CD20 antibody): Analysis of factors associated with response. Ann Oncol 11:117-121, 2000
    FREE Full Text
  23. ↵
    Tobinai K: Monoclonal antibody therapy for B-cell lymphoma: Clinical trials of an anti-CD20 monoclonal antibody for B-cell lymphoma in Japan. Int J Hematol 76:411-419, 2002
    Medline
  24. ↵
    Howard OM, Gribben JG, Neuberg DS, et al: Rituximab and CHOP induction therapy for newly diagnosed mantle-cell lymphoma: Molecular complete responses are not predictive of progression-free survival. J Clin Oncol 20:1288-1294, 2002
    Abstract/FREE Full Text
  25. ↵
    Forstpointner R, Dreyling MH, Repp R, et al: The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared to FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: Results of a prospective randomized study of the German Low Grade Lymphoma Study Group. Blood 104:3064-3071, 2004
    Abstract/FREE Full Text
  26. ↵
    A predictive model for aggressive non-Hodgkin's lymphoma: The International Non-Hodgkin's Lymphoma Prognostic Factors Project. N Engl J Med 329:987-994, 1993
    CrossRefMedline
  27. ↵
    Cheson BD, Bennett JM, Kopecky KJ, et al: Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol 21:4642-4649, 2003
    Abstract/FREE Full Text
  28. ↵
    World Health Organization: A handbook for reporting results of cancer treatment. World Health Organization, Geneva, Switzerland, WHO Publication 38, 1979
  29. ↵
    Whitehead J: The Design and Analysis of Sequential Clinical Trials (ed 2), Horwood, Chichester, United Kingdom, 1992
  30. ↵
    Hiddemann W, Dreyling MH, Forstpointner R, et al: Combined immuno-chemotherapy (R-CHOP) significantly improves time to treatment failure in first-line therapy of follicular lymphoma: Results of a prospective randomized Trial of the German low-Grade lymphoma Study Group (GLSG). Blood 102:104, 2003 (abstr 352)
  31. ↵
    Venugopal P, Wooldridge J, Yunus F, et al: Chemoimmunotherapy with combination of rituximab, GMCSF and CHOP in patients with previously untreated aggressive non Hodgkin's lymphoma. Blood 102:4930, 2003 (abstr)
  32. ↵
    Romaguera J, Cabanillas F, Dang N, et al: Mantle cell lymphoma (MCL): Update on results after R-HCVAD without stem cell transplantation(SCT). Ann Oncol 13:8, 2002 (abstr)
    FREE Full Text
  33. ↵
    Di Gaetano N, Xiao Y, Erba E, et al: Synergism between fludarabine and rituximab revealed in a follicular lymphoma cell line resistant to the cytotoxic activity of either drug alone. Br J Haematol 114:800-809, 2001
    CrossRefMedline
  34. ↵
    Lefrere F, Delmer A, Suzan F, et al: Sequential chemotherapy by CHOP and DHAP regimens followed by high-dose therapy with stem cell transplantation induces a high rate of complete response and improves event-free survival in mantle cell lymphoma: A prospective study. Leukemia 16:587-593, 2002
    CrossRefMedline
  35. ↵
    Andersen NS, Pedersen L, Elonen E, et al: Primary treatment with autologous stem cell transplantation in mantle cell lymphoma: Outcome related to remission pretransplant. Eur J Haematol 71:73-80, 2003
    CrossRefMedline
  36. ↵
    Gianni AM, Magni M, Martelli M, et al: Long-term remission in mantle cell lymphoma following high-dose sequential chemotherapy and in vivo rituximab-purged stem cell autografting (R-HDS regimen). Blood 102:749-755, 2003
    Abstract/FREE Full Text
  37. ↵
    Magni M, Di Nicola M, Devizzi L, et al: Successful in vivo purging of CD34-containing peripheral blood harvests in mantle cell and indolent lymphoma: Evidence for a role of both chemotherapy and rituximab infusion. Blood 96:864-869, 2000
    Abstract/FREE Full Text
  38. ↵
    Gopal AK, Rajendran JG, Petersdorf SH, et al: High-dose chemo-radioimmunotherapy with autologous stem cell support for relapsed mantle cell lymphoma. Blood 99:3158-3162, 2002
    Abstract/FREE Full Text
  39. ↵
    Younes A, Pro B, Delpassand E, et al: A phase II study of 90yttrium-ibritumomab (Zevalin) for the treatment of patients with relapsed and refractory mantle cell lymphoma (MCL). Blood 102:1476, 2003 (abstr)
| Table of Contents

This Article

  1. Published online before print January 24, 2005, doi: 10.1200/JCO.2005.08.133 JCO vol. 23 no. 9 1984-1992
  1. Abstract
  2. » Full Text
  3. PDF

Classifications

Navigate This Article

Current Issue

  1. July 20, 2013, 31 (21)
  1. Alert me to new issues of JCO
    • Advertisement
    • Advertisement
    • Advertisement