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Immunochemotherapy With Rituximab and Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone Significantly Improves Response and Time to
http://www.100md.com 《临床肿瘤学》
     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, Stdtisches 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 Hmatologie/Onkologie, Leipzig

    Department of Hematopathology and Lymph Node Registry Kiel, Kiel, Germany

    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 (IFN). All patients older than 65 years received IFN 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.

    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 (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 maintenance).

    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 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

    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 IFN 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 IFN maintenance received two additional courses of conventional chemotherapy to balance the mobilization scheme (Dexa-BEAM). Subsequently, IFN maintenance was initiated at a dose of 6 x 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 IFN 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 = .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 2 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.

    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.

    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

    Treatment-associated adverse effects predominantly comprised hematotoxicity. The incidence of anemia, thrombocytopenia, and leukocytopenia was not different in the two study arms. In contrast, granulocytopenia occurred more frequently after R-CHOP than after CHOP (83% v 73%, respectively), with severe granulocytopenia in 63% v 53%, respectively (P = .01). However, this difference was of minor clinical relevance, as infectious complications were not observed more frequently in the R-CHOP group (39% v 35%; Table 3a). Nonhematologic toxicity was mild to moderate and was equally distributed in both study arms (Table 3b). Allergic reactions were only observed in the R-CHOP arm (7% v 0%; P < .0001). These reactions occurred predominantly after the first infusion; however, they were of moderate degree and did not require an early cessation of R-CHOP therapy.

    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 IFN 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 IFN 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.

    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.

    Acknowledgment

    The following persons and institutions participated in this study: V. Gro, L. Fischer v Weikersthal, Klinikum St Marien, Amberg; M. Hahn, S. Müller, Hmatologisch-Onkologische Praxis, Ansbach; G. Unverferth, W. Langer, F. Püschel, Kreiskrankenhaus Aurich, Aurich; W.D. Ludwig, H. Harder, Robert Rssle 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. Rhl, G. Mann, Marien-Hospital Bottrop, Bottrop; G. Jordan, A. Pies, Stdtisches Klinkum Braunschweig, Braunschweig; K.H. Pflüger, Th. Wolff, Diakoniekrankenhaus, Bremen; M. Grundeis, Schwerpunktpraxis Onkologie Hmatologie, Chemnitz; M. Lner, Carl-Thiem-Klinikum, Cottbus; J. Pielken, M. Nahler, St Johannes Krankenhaus, Dortmund; M. Gramatzki, Medizinische Klinik III der Universitt, Erlangen; R. Fuchs, S. Wehle-Ilka, J. Wiegand, St-Antonius-Hospital, Eschweiler; H. Nückel, Medizinische Klinik und Poliklinik, Essen; R. Mertelsmann, J. Finke, Medizinische Universittsklinik, Freiburg; T. Reiber, D. Semsek, Praxis für Innere Medizin, Freiburg; L. Trümper, B. Gla, Georg-August-Universitt Gttingen, Gttingen; 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 Universitts-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 Hmatologie/Onkologie, Hechingen; A.D. Ho, E. Leo, Universittsklinik Heidelberg, Heidelberg; H. Dietzfelbinger, Privatklinik Dr R. Schindlbeck, Herrsching; M. Pfreundschuh, Universittsklinik des Saarlandes, Homburg/Saar; K. Hffken, H.J. Fricke, Klinik für Innere Medizin der Friedrich-Schiller-Universitt Jena, Jena; J. Th Fischer, S. Wilhelm, R. Ehrhardt, Stdtisches Klinikum Karlsruhe, Karlsruhe; J. Mezger, G. Gckel, St-Vincentius-Krankenhuser, Karlsruhe; C. Lser, H. Urbanke-Siebert, Rotes Kreuz Krankenhaus, Kassel; Th. Eisenhauer, H. Nolte, Stdtisches Klinikum Kemperhof, Koblenz; V. Diehl, A. Engert, M. Reiser, I. Medizinische Universittsklinik, Kln; S. Schmitz, T. Steinmetz, Internistische Praxis Hmatologie und Onkologie, Kln; M. Planker, M. Busch, M. Hipp, Stdtische Krankenanstalten, Krefeld; M. Stauch, Schwerpunktpraxis Hmatologie und Onkologie, Kronach; G. Kchling, H. Fokken, Kreiskrankenhaus Leer, Leer; L. Mantovani, B. Matthe, Stdt. Klinikum St Georg, Leipzig; G. Liebau, D. Nothnagel, Klinikum Ludwigsburg, Ludwigsburg; M. Uppenkamp, M. Hoffmann, Klinikum der Stadt, Ludwigshafen; E. Kettner, G. Krtki, Stdtisches Klinikum/K.H. Altstadt, Magdeburg; C. Huber, T. Fischer, G. He, III Medizinische Klinik der Universitt, Mainz; N. Schwella, Klinikum der Phillips Universitt, Marburg; A. Pfeiffer, M. Mennicke, Klinikum Memmingen, Memmingen; R. Gtz, P. Jehner, Krankenhaus Bethanien, Moers; C. Lunscken, Hmatologische Praxis, Mülheim Ruhr; R. Forstpointner, Klinikum Grosshadern, München; R. Hartenstein, N. Brack, Stdtisches K.H. München-Harlaching, München; Ch. Peschel, C. v Schilling, Klinikum Rechts der Isar der Technische Universitt, München; D. Schlndorff, J. Walther, U. Seybold, Medizinische Poliklinik Innenstadt, München; W.E. Berdel, Universittsklinikum 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. Ncker, 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, Universittsklinik Regensburg, Regensburg; M. Baldus, Internistische Schwerpunktpraxis, Rüsselsheim; J. Prei, P. Schmidt, Caritas Klinik St Theresia, Saarbrücken; K. Seitz, G. Kfer, Kreiskrankenhaus Sigmaringen, Sigmaringen; S. Martin, Robert-Bosch-Krankenhaus, Stuttgart; E. Heidemann, J. Kaesberger, Diakonissenkrankenhaus, Stuttgart; H. Fiechtner, G. Springer, Praxis für Hmatologie/Onkologie, Stuttgart; M.R. Clemens, Mutterhaus der Borromerinnen, Trier; J. Diers, W. Twiessel, Marienhospital, Vechta; W.W. Reiter, Facharzt für Innere Medizin, Hmatologie und internistische Onkologie, Viersen; N. Frickhofen, H.G. Fuhr, G. Müller, Dr H. Schmidt-Kliniken Wiesbaden, Wiesbaden; Th. Bock, Praxis für Hmatologie/Onkologie, Wittenberge; M. Sandmann, G. Becker, Kliniken St Antonius, Wuppertal; K. Wilms, H. Rückle-Lanz, M. Wilhelm, Medizinische Klinik der Universitt Würzburg, Würzburg.

    NOTES

    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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