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Journal of Clinical Oncology, Vol 22, No 24 (December 15), 2004: pp. 4926-4933
© 2004 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2004.06.016
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Moderate Increase of Secondary Hematologic Malignancies After 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

Georg Lenz, Martin Dreyling, Eva Schiegnitz, Torsten Haferlach, Joerg Hasford, Michael Unterhalt, Wolfgang Hiddemann

From the Departments of Internal Medicine III and Medical Informatics, Biometrics and Epidemiology (IBE), Ludwig-Maximilians University, Munich, Germany

Address reprint requests to Georg Lenz, MD, University Hospital Grosshadern, Department of Internal Medicine III, Ludwig-Maximilians-University, Marchioninistrasse 15, 81377 Munich, Germany; e-mail: georg.lenz{at}med3.med.uni-muenchen.de


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix
 Authors' Disclosures of...
 REFERENCES
 
PURPOSE: An increased risk of therapy-related myelodysplastic syndrome (t-MDS) and acute myeloid leukemia (t-AML) after high-dose therapy and autologous stem-cell transplantation (ASCT) for malignant lymphoma has been described by several studies, reporting a highly variable incidence ranging from 1% to 12%. To assess this risk more precisely, the German Low Grade Lymphoma Study Group investigated the incidence of t-MDS/t-AML after ASCT on the basis of a randomized comparison of ASCT versus interferon alfa (IFN-{alpha}) maintenance in indolent lymphoma.

PATIENTS AND METHODS: Between 1996 and 2002, 440 patients with indolent lymphoma were randomly assigned after a cyclophosphamide, doxorubicin, vincristine, and prednisone–like induction therapy regimen to myeloablative radiochemotherapy followed by ASCT or IFN-{alpha}. The incidence of secondary hematologic malignancies was determined by standardized follow-up of all study patients. Bone marrow samples from patients with proven or suspected t-MDS/t-AML were centrally reviewed.

RESULTS: After a median follow-up of 44 months, 431 patients were assessable. Five of 195 patients developed a secondary hematologic malignancy after ASCT. Two of these patients developed a secondary AML. Accordingly, the estimated 5-year risk for secondary hematologic neoplasias after ASCT was 3.8%. In contrast, in the IFN-{alpha} arm, the 5-year risk of hematologic neoplasias was 0.0% (P = .0248).

CONCLUSION: The data of this randomized trial demonstrate an increased risk of secondary hematologic malignancies after myeloablative radiochemotherapy and ASCT compared with conventional chemotherapy. However, as ASCT significantly improves progression-free survival, it is currently not evident to what extent the higher rate of t-MDS/t-AML will diminish the benefit of ASCT in indolent lymphoma.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix
 Authors' Disclosures of...
 REFERENCES
 
Myeloablative chemo- or radiochemotherapy followed by autologous stem-cell transplantation (ASCT) is increasingly applied in the treatment of patients with malignant lymphomas. ASCT has been accepted as the treatment of choice in patients with relapsed aggressive lymphoma.1 In addition, it is frequently applied as consolidation therapy in indolent lymphoma both in first- or second-line treatment. This approach is supported by promising results of several phase II studies2,3 and two recently completed randomized trials of the German Low Grade Lymphoma Study Group and the Groupe d'Etudes des Lymphomes de l'Adulte.4,5 These studies showed a significantly longer progression-free (PFS) or overall survival after ASCT as compared with conventional chemotherapy when applied in first remission of follicular lymphoma. Comparable results were also reported from a similarly designed trial of the European Mantle-Cell Lymphoma Network in mantle-cell lymphoma.6

These highly encouraging results are hampered by the potentially increased risk of therapy-related myelodysplastic syndrome (t-MDS) or acute myeloid leukemia (t-AML) after ASCT, as suggested by several retrospective evaluations.7-10 In these studies, the incidence of secondary hematologic malignancies varied substantially. Hence, Micallef et al7 reported an incidence of 12% for t-MDS/t-AML after a median follow-up of 6 years, whereas other studies described a lower frequency of 1% to 3%.8,9 All of these studies were retrospective and included patients with different lymphoma subentities. In addition, intensity, duration, and number of chemotherapeutic regimens applied before ASCT varied to a large degree. These and other factors, such as age or the application of total-body irradiation (TBI) as part of the conditioning regimen, are known to influence the risk of developing secondary hematologic neoplasias after ASCT.7,9-12 Additionally, no randomized comparison with patients receiving standard-dose chemotherapy is currently available, as t-MDS and t-AML are well-known long-term complications after conventional-dose chemotherapy as well.13,14 The exact frequency of t-MDS/t-AML after ASCT remains therefore uncertain and needs to be determined more precisely on the basis of a prospective randomized evaluation of ASCT versus conventional chemotherapy.

Such an analysis was performed by the German Low Grade Lymphoma Study Group in a randomized comparison of myeloablative radiochemotherapy followed by ASCT to interferon alfa (IFN-{alpha}) maintenance after initial cytoreductive chemotherapy in patients with indolent lymphoma. The incidence of secondary hematologic malignancies in both study arms was evaluated by standardized follow-up data and detailed questionnaires.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 Appendix
 Authors' Disclosures of...
 REFERENCES
 
Inclusion Criteria
Eligible patients included previously untreated patients up to 60 years of age (65 years for patients with mantle-cell lymphoma) with advanced Ann Arbor stage III and IV follicular lymphoma, mantle-cell lymphoma, marginal zone lymphoma, or lymphoplasmacytic lymphoma according to the current WHO classification.15 The histologic classification was confirmed by a central pathology review. The study protocol was approved by the local ethics committees of the participating centers, and all patients had given an informed consent before enrollment in accordance with the Declaration of Helsinki.

Treatment Schedule
Patients were initially randomly assigned to different induction chemotherapy regimens and received either cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP; cyclophosphamide 750 mg/m2 administered intravenously [IV] on day 1, doxorubicin 50 mg/m2 IV on day 1, vincristine 1.4 mg/m2 [maximum 2 mg] IV on day 1, and prednisone 100 mg/m2 orally [PO] on days 1 through 5) or mitoxantrone, chlorambucil, and prednisone (MCP; mitoxantrone 8 mg/m2 IV on days 1 and 2, chlorambucil 3 x 3 mg/m2 PO on days 1 to 5, and prednisone 25 mg/m2 PO on days 1 to 5). Since May 2000, patients were randomly assigned either to CHOP or to the combination of CHOP and the anti-CD20 antibody rituximab (375 mg/m2). All patients achieving at least a partial remission after induction therapy were centrally randomly assigned to myeloablative radiochemotherapy followed by ASCT or to IFN-{alpha} maintenance. Patients achieving a complete remission after four cycles of initial cytoreductive chemotherapy proceeded immediately to consolidation therapy; all other patients received six cycles of induction therapy (Fig 1).



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  		Fig 1. Study profile of the German Low Grade Lymphoma Study Group trial. CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; PR, partial response; CR, complete response; Dexa-BEAM, dexamethasone, carmustine, melphalan, etoposide, cytarabine, and granulocyte colony-stimulating factor; TBI, total-body irradiation; ASCT, autologous stem-cell transplantation.

 
Patients in the ASCT arm received intensified mobilization chemotherapy with dexamethasone 3 x 8 mg PO on days 1 through 10, carmustine 60 mg/m2 IV on day 2, melphalan 20 mg/m2 IV on day 3, etoposide 75 mg/m2 IV on days 4 to 7, cytarabine 2 x 100 mg/m2 IV on days 4 to 7, and granulocyte colony-stimulating factor initiated day 11) for subsequent stem cell collection. Conditioning high-dose therapy was performed within 2 months of mobilization and consisted of TBI (12 Gy on days –6 to –4) and high-dose cyclophosphamide (60 mg/kg of body weight administered IV on days –3 and –2). The previously collected peripheral-blood stem cells were reinfused on day 0.

Patients randomly assigned to IFN-{alpha} maintenance received two additional courses of conventional chemotherapy to balance the mobilization scheme (dexamethasone, carmustine, melphalan, etoposide, cytarabine, and granulocyte colony-stimulating factor). Subsequently, IFN-{alpha} was applied at 5 x 106 U administered subcutaneously three times weekly until progression or the occurrence of intolerable side effects (Fig 1).

Diagnosis of t-MDS and t-AML
Standardized follow-up was performed every 3 months after ASCT or IFN-{alpha} and induced the assessment of the remission status by ultrasound and computed tomography scans as well as a differential CBC count. In addition, the participating centers received a detailed questionnaire concerning the development of secondary malignancies.

t-MDS and t-AML were diagnosed according to the current WHO classification.15 Bone marrow aspirates of all patients with suspected t-MDS or t-AML, as well as aspirates from patients with persistent abnormal blood counts, were centrally reviewed in a blinded fashion to confirm or reject the diagnosis.

Statistics
The main parameter was the time from initiation of consolidation therapy until the diagnosis of a secondary malignancy. This parameter was monitored prospectively as a secondary end point of a randomized comparison of myeloablative radiochemotherapy and ASCT and IFN-{alpha} in which the primary efficacy end point was PFS. All randomly assigned patients were included in the analysis if ASCT was successfully completed or IFN-{alpha} maintenance was initiated. Evaluation was performed as treated according to common practice for safety assessments.

Point estimates for the cumulative risk of developing a secondary malignancy were calculated using the Kaplan-Meier method. Patients without secondary neoplasia were censored at the date of last follow-up. Because, according to the protocol, ASCT was applied as salvage therapy in a proportion of patients who experienced relapse in the IFN-{alpha} arm, these patients were censored at the date of transplantation. In addition to the Kaplan-Meier estimates, the cumulative incidence of secondary neoplasias was calculated as described previously,16 considering death as a competing event. The influence of continuous covariates on the risk of secondary neoplasias was analyzed by the Cox regression model.

PFS was defined as the time from the end of successful induction therapy until relapse or death. PFS was analyzed using the Kaplan-Meier method. Patients without event were censored at the date of the last follow-up. 95% CIs for the PFS and the risk of secondary neoplasias were calculated according to Greenwood's formula. Group comparisons for the risk of secondary neoplasias and for the PFS were conducted by means of the two-sided log-rank test. The significance level was set to alpha = 0.05. All statistical calculations were performed with the SAS system (version 8.02; SAS Institute, Cary, NC).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 Appendix
 Authors' Disclosures of...
 REFERENCES
 
Patient Characteristics
Four hundred forty consecutive patients treated either with myeloablative radiochemotherapy followed by ASCT or IFN-{alpha} were included in this analysis. Three patients in the ASCT group and six in the interferon arm were excluded, as the original diagnosis was not confirmed in the pathology review. Of the 431 assessable patients, 195 received ASCT and 236 received IFN-{alpha} maintenance. The number of included patients in the two study arms differs slightly, because in the ASCT study group, a sufficient number of stem cells could not be collected in all patients, and ASCT was refused in some cases. The vast majority of patients were diagnosed with follicular lymphoma (75%), 17% had mantle-cell lymphoma, 2% had marginal-zone lymphoma, and 7% had a lymphoplasmacytic lymphoma. Clinical characteristics of patients in the two study arms were comparable and are summarized in Table 1.


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  		Table 1. Patient Characteristics

 
PFS
To assess the impact of ASCT versus IFN-{alpha} maintenance in indolent lymphoma, we analyzed the PFS in the two cohorts. In patients receiving ASCT, the PFS was 83.7% after 2 years (95% CI, 78.4% to 88.9%) and 60.2% after 5 years (95% CI, 51.1% to 69.3%) in comparison to only 56.8% (95% CI, 50.3% to 63.2%) after 2 years and 31.6% (95% CI, 24.5% to 38.8%) after 5 years in the IFN-{alpha} study arm, respectively (P < .0001; two-sided log-rank test).

Incidence and Onset of Secondary Hematologic Neoplasias
At a median follow-up of 44 months (45 months for patients treated with myeloablative radiochemotherapy followed by ASCT and 44 months in the IFN-{alpha} maintenance arm), five secondary hematologic neoplasias were observed and confirmed by the central cytological review. The characteristics of patients developing t-MDS or t-AML are summarized in Table 2.


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  		Table 2. Clinical Characteristics of Patients Developing Therapy-Related Myelodysplastic Syndrome or Therapy-Related AML

 
In the ASCT arm, five cases of t-MDS were detected, resulting in an estimated 5-year risk of secondary hematologic neoplasias of 3.8% (95% CI, 0.4% to 7.3%). All cases presented with pancytopenia. Two of these patients proceeded into a secondary AML, from which they died shortly after diagnosis. One patient with t-MDS received an allogeneic transplantation as salvage treatment and is currently in ongoing complete remission, whereas the other two patients are still alive with stable blood counts. In addition, in another patient of the ASCT group, a t-MDS was diagnosed by bone marrow biopsy. However, the central hematology review detected myelodysplastic features in a previous bone marrow biopsy before myeloablative radiochemotherapy. Consequently, we did not include this case in our analysis.

In contrast, the estimated 5-year risk for secondary hematologic neoplasias in the IFN-{alpha} study arm was 0.0%, as no patient in the IFN-{alpha} group developed a t-MDS (one patient in the IFN-{alpha} study arm who developed a t-MDS was censored, as he received a secondary ASCT as salvage therapy). Thus the estimated 5-year risk for t-MDS was significantly higher in the ASCT cohort as compared with the IFN-{alpha} group (P = .0248, two-sided log-rank test; Fig 2). In addition, we analyzed the estimated 5-year cumulative incidence rate of t-MDS or t-AML considering death as a competing event. The estimated 5-year incidence rate was 3.5% in the ASCT study arm and 0.0% in the IFN-{alpha} group, respectively.



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  		Fig 2. Cumulative risk of therapy-related myelodysplastic syndrome or therapy-related acute myeloid leukemia after myeloablative radiochemotherapy followed by autologous stem-cell transplantation (ASCT) or interferon (IFN) alfa maintenance.

 
The median time to development of t-MDS and t-AML was 38 months (range, 13 to 56 months) after diagnosis of non-Hodgkin's lymphoma and 30 months (range, 9 to 51 months) after initiation of myeloablative radiochemotherapy followed by ASCT. The median latency after start of consolidation was slightly shorter for t-MDS (30 months; range, 9 to 51 months) in comparison to t-AML (42 months; range, 40 to 44 months).

Initial Chemotherapy and Risk for t-MDS or t-AML
To assess the impact of the conventional chemotherapy, we analyzed the incidence of secondary hematologic neoplasias according to the respective induction therapy. Sixty-eight patients received the CHOP-like regimen MCP, and 362 patients received CHOP. In 68 of the CHOP patients, the anti-CD20 antibody rituximab was additionally applied. Only three of 362 patients in the CHOP group developed a secondary hematologic malignancy. In contrast, three of 68 patients developed a t-MDS or t-AML after MCP induction therapy. As in this analysis, patients in the IFN study arm were not censored because of secondary ASCT as salvage therapy, and six cases of secondary t-MDS were observed. Accordingly, the estimated 5-year risk for secondary hematologic neoplasias was 5.1% (95% CI, 0.0% to 10.7%) after MCP. Because the MCP study arm was closed in 1998, patients receiving MCP had a longer median follow-up as compared with the total group of patients receiving CHOP. Thus we compared the MCP group with patients receiving CHOP in the same time period with a similar median follow-up (61 months for MCP, 62 months for CHOP). In this CHOP cohort, only one of 104 patients developed a secondary hematologic malignancy, and the estimated 5-year risk was 1.3% (95% CI, 0.0% to 3.7%). However, this difference was not significant, possibly because of the small number of assessable patients (P = .1449; Fig 3). In subsequent analyses, age, sex, and histology (mantle-cell lymphoma v follicular lymphoma) were not associated with an increased risk of a secondary MDS or AML.



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  		Fig 3. Cumulative risk of therapy-related myelodysplastic syndrome or therapy-related acute myeloid leukemia after mitoxantrone, chlorambucil, and prednisone (MCP) and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP).

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
Appendix
 Authors' Disclosures of...
 REFERENCES
 
The current study clearly demonstrates that the application of myeloablative radiochemotherapy followed by ASCT is associated with an increased risk of secondary hematologic malignancies. After a median follow-up of 44 months, five of 195 patients developed a t-MDS/t-AML after ASCT in first remission. The estimated 5-year cumulative risk of patients receiving ASCT was 3.8%, in comparison with 0.0% after IFN-{alpha} (P = .0248). Thus the frequency of t-MDS and t-AML at 4 years is in the range of 1% and 3.0%, as reported in recent studies.8,9 However, it is much lower than suggested in a previously reported retrospective evaluation, which claimed an incidence of 12% after a median follow-up of 6 years,7 and lower than in the randomized GOELAMS trial, which reported a rather high incidence of secondary tumors after a median follow-up of 56 months in patients with follicular lymphoma after ASCT.17 In addition, the PFS for patients receiving ASCT was significantly better as compared with those receiving IFN-{alpha} (60.2% v 31.6% after 5 years; P < .0001), clearly indicating the superiority of ASCT. Thus currently there is no evidence that the moderate increase in the incidence of secondary t-MDS or t-AML will substantially diminish the long-term benefit of myeloablative radiochemotherapy and ASCT.

The role of TBI as part of the conditioning regimen is not yet fully elucidated. In different retrospective studies of lymphoma patients receiving ASCT, multivariate analyses suggested TBI to be associated with an increased risk of secondary hematologic malignancies.10,12,18 In contrast, in a recently published case-control study of 56 t-MDS/t-AML patients, TBI at doses of 12 Gy did not increase the risk of t-MDS or t-AML.19

The data of the current study also suggest that the risk of t-MDS after ASCT has to be evaluated in the context of the preceding antilymphoma chemotherapy. Hence 5.1% of patients receiving MCP developed a secondary hematologic neoplasia, in comparison with only 1.3% of patients receiving CHOP. Possibly because of the rather small number of only 68 patients receiving MCP, this difference was not significant. However, an increased risk of secondary hematologic malignancies has been described after treatment with chlorambucil or its derivates by other investigators. Two retrospective evaluations described an increased risk for the development of secondary leukemia after therapy with prednimustine, a 21-prednisolone ester of chlorambucil. In patients with advanced breast cancer, a cumulative risk for therapy-related leukemia of 25% at 37 months was reported after a combination of prednimustine, methotrexate, fluorouracil, mitoxantrone, and tamoxifen. Similarly, in a cohort study of 2-year survivors of malignant lymphomas, an increased incidence of secondary acute nonlymphocytic leukemia was associated with the application of prednimustine.20,21 Similarly, mitoxantrone has been suggested to be associated with an increased risk of secondary hematologic neoplasias. Two recent studies in breast cancer claimed an increased risk of t-MDS/t-AML after mitoxantrone-based chemotherapy.22,23 In contrast, our current study does not confirm such a high rate of secondary neoplasias, especially because no t-MDS/t-AML could be observed in the MCP/IFN-{alpha} arm. However, it is tempting to speculate that the combination of TBI and alkylating substances or anthracyclines might especially contribute to the rather high incidence of t-MDS/t-AML after high-dose consolidation.

The treatment of secondary hematologic neoplasias remains unsatisfactory, with allogeneic transplantation being the only potentially curative approach.24,25 One patient in our cohort with t-MDS underwent allogeneic transplantation and is currently in complete remission. Two patients who developed secondary AML died shortly after diagnosis. The other two patients are still alive with stable blood counts.

In conclusion, the data of our randomized trial demonstrate a statistically significant increased risk of secondary hematologic malignancies after myeloablative radiochemotherapy followed by ASCT compared with conventional chemotherapy in patients with indolent lymphoma. Patients receiving the combination of TBI and alkylating agents seem to have an especially increased risk for developing a secondary hematologic neoplasia. Despite this moderately higher rate, the PFS in patients receiving ASCT was significantly superior as compared with those receiving conventional chemotherapy. Thus at this time there is no evidence that the risk of secondary malignancies after ASCT might substantially diminish the long-term benefits of this therapeutic approach, which provides the perspective for a significantly prolonged PFS and potentially overall survival as compared with conventional therapy in the vast majority of patients.


   Appendix
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix
Authors' Disclosures of...
 REFERENCES
 
The following persons and institutions participated in this study: M. Hahn, S. Müller, Praxis für Hämatologie/Onkologie, Ansbach; J. Gensicke, P. Dravoj, Stadtkrankenhaus Arolsen, Arolsen; G. Schlimok, M. Sandherr, Zentralklinikum Augsburg, Augsburg; G. Unverferth, W. Langer, F. Püschel, Kreiskrankenhaus Aurich, Aurich; R. Paliege, P. Majunke, Kreiskrankenhaus Bad Hersfeld, Bad Hersfeld; W. Schultze, H. Fuss, P. Frenzel, Humaine Klinikum Bad Saarow, Bad Saarow; D. Hennesser, Vinzenz-Pallotti Hospital, Bergisch Gladbach; B. Dörken, G. Massenkeil, Charité/Virchow-Klinikum, Berlin; K. Possinger, O. Sezer, Universitätsklinikum Charité/Campus Mitte, Berlin; W.D. Ludwig, H. Harder, Robert Rössle Klinik, Berlin; H.J. Weh, B. Angrick, Franziskus Hospital, Bielefeld; W. Schmiegel, U. Graeven, Medizinische Universitätsklinik und Knappschafts-Krankenhaus, Bochum; H. Vetter, S. Fronhoffs, Universitätsklinikum Bonn, Bonn; E. Musch, H. Röhl, G Mann, Marien-Hospital Bottrop, Bottrop; B. Wörmann, G. Jordan, A. Pies, Städtisches Klinkum Braunschweig, Braunschweig; M. Adler, Hämatologische Praxis, Braunschweig; H. Hotz, F. Marquard, Allgemeines Krankenhaus Celle, Celle; F. Fiedler, A. Hänel, Klinikum Chemnitz, Krankenhaus Küchwald, Chemnitz; R. Lohmann, Krankenhaus Coesfeld, Coesfeld; M. Lößner, Carl-Thiem-Klinikum, Cottbus; U. v Grünhagen, Onkologische Schwerpunktpraxis, Cottbus; D. Fritze, A. Rost, H. Schuppert, Klinikum Darmstadt, Darmstadt; F.W. Kleinsorge, Internistische Praxis, Detmold; T.U. Hausamen, W Freund, Städtisches Krankenhaus Dortmund, Dortmund; M. Schäfers, K. Quabeck, Internistische Praxis, Duisburg; W. Lange, Johanniter-Krankenhaus Rheinhausen, Duisburg; R. Haas, Universitätsklinik Düsseldorf, Düsseldorf; M. Gramatzki, Universitätsklinikum Erlangen, Erlangen; M. Eckart, Praxis für Hämatologie/Onkologie, Erlangen; R. Fuchs, S. Wehle-Ilka, J. Wiegand, St-Antonius-Hospital, Eschweiler; U. Dührsen, H. Nückel, Medizinische Klinik und Poliklinik, Essen; S. Seeber, M.R. Nowrosian, Westdeutsches Tumorzentrum, Essen; U. v Verschuer, R. Rudolph, Hämatologische Praxis, Essen; J.G. Saal, D. Hartwigsen, U. Strack, St-Franziskus-Hospital, Flensburg; A. Machraoui, T. Koch, Diakonissenkrankenhaus Flensburg, Flensburg; T. Reiber, D. Semsek, Praxis für Innere Medizin, Freiburg; A. Ochs, U. Brand, Evangelisches Diakoniekrankenhaus, Freiburg; R. Mertelsmann, J. Finke, Medizinische Universitätsklinik, Freiburg; G. Heil, E. Stelzer, Klinikum Gera, Gera; G. Schliesser, Hämatologische Praxis, Giessen; L. Trümper, B. Glaß, Universitätsklinikum Göttingen, Göttingen; H. Eimermacher, Katholisches Krankenhaus, Hagen; S. Kraus, I. Hausbrandt, St Salvator Krankenhaus, Halberstadt; H.J. Hurtz, R. Rohrberg, R. Behrends, Schwerpunktpraxis, Halle/Saale; N Schmitz, P Dreger, Allgemeines Krankenhaus St. Georg, Hamburg; A.R. Zander, N. Kröger, H. Renges, S. Hegewisch-Becker, Universitäts-Krankenhaus Eppendorf, Hamburg; K. Verpoort, W. Zeller, Onkologische Schwerpunktpraxis, Hamburg; H. Schmidt, Kreiskrankenhaus Hameln, Hameln; A. Ganser, D. Peest, Medizinische Hochschule Hannover, Hannover; R. Mao, Hämatologische Praxis, Hannover; R. Voigtmann, E. Schilling, Marienhospital Herne, Herne; H. Dietzfelbinger, Privatklinik Dr R. Schindlbeck, Herrsching; M. Prisch, M. Bach, St-Elisabeth-Hospital, Herten; U. Basler, B. Sievers, Städtisches Krankenhaus Hildesheim, Hildesheim; D. Urbanitz, T.F. Heide, U. Kaiser, St Bernward-Krankenhaus, Hildesheim; W. Freier, Onkologische Schwerpunktpraxis, Hildesheim; M. Pfreundschuh, Universitätsklinik des Saarlandes, Homburg/Saar; A.A. Fauser, M. Kiehl, Klinik für KMT, Hämatologie/Onkologie, Idar-Oberstein; K. Höffken, H.J. Fricke, Universitätsklinikum Jena, Jena; J. Th. Fischer, S. Wilhelm, R. Ehrhardt, Städtisches Klinikum Karlsruhe, Karlsruhe; J Mezger, G. Göckel, St-Vincentius-Krankenhäuser, Karlsruhe; W.D. Hirschmann, E.U. Steinhauer, Städtische Kliniken Kassel, Kassel; M. Kneba, Universitätsklinikum Kiel, Kiel; I. Meuthen, G. Kunstmann, H. Spangenberger, Krankenhaus Holweide, Köln; V. Diehl, A. Engert, M. Reiser, Universitätsklinikum Köln, Köln; S. Schmitz, T. Steinmetz, Internistische Praxis, Köln; M. Planker, M. Busch, M. Hipp, Städtische Krankenanstalten, Krefeld; B. Tschechne, Hämatologisch-Onkologische Praxis, Lehrte; D. Niederwieser, W. Pönisch, Universitätklinikum Leipzig, Leipzig; A. Aldaoud, A. Schwarzer, Gemeinschaftspraxis, Leipzig; L. Mantovani, B. Matthe, Städtisches Klinikum St Georg, Leipzig; H.P. Lohrmann, H. Middeke, Klinikum Lippe-Lemgo, Lemgo; L. Heidenreich, K.A. Jost, Dreifaltigkeitshospital, Lippstadt; F. Bergmann, Evangelisches Krankenhaus Lippstadt, Lippstadt; S. Fetscher, Städtisches Krankenhaus Süd, Lübeck; M. Uppenkamp, M. Hoffmann, Klinikum der Stadt, Ludwigshafen; H. Weiss, St-Marien-Krankenhaus, Ludwigshafen; M. Wiermann, Universitätsklinikum Magdeburg, Magdeburg; C. Huber, T. Fischer, G. Heß, Universitätsklinikum Mainz, Mainz; R. Hehlmann, E. Lengfelder, I. Kottke, III. Medizinische Klinik Mannheim, Mannheim; A. Neubauer, N. Schwella, Universitätsklinikum Marburg, Marburg; M. Schwonzen, H. Spangenberger, St-Walburga-Krankenhaus, Meschede; H. Bodenstein, H.H. Wöltjen, Klinikum Minden, Minden; H.E. Reis, D. Kohl, D. Berkovic, Kliniken Maria Hilf, Mönchengladbach; C. Lunscken, Hämatologische Praxis, Mülheim a.d. Ruhr; C. Peschel, C. v Schilling, Klinikum Rechts der Isar der Technischen Universität, München; P.C. Scriba, B. Emmerich, Medizinische Klinik Innenstadt der Universität, München; R. Forstpointner, V.B. Nerovcic, Klinikum Grosshadern der Ludwig-Maximilians University, München; R. Hartenstein, N. Brack, Städtisches Krankenhaus München-Harlaching, München; D. Schlöndorff, J. Walther, U. Seybold, Klinikum Innenstadt, München; W.E. Berdel, Universitätsklinikum Münster, Münster; R. Kriebel-Schmitt, V. Burstedde, B. Berning, Schwerpunktpraxis für Hämatologie/Onkologie, Münster; J. Wehmeyer, C. Lerchenmüller, Onkologische Schwerpunktpraxis, Münster; H. Rühle, N. Grobe, F. Jungmichel, Klinikum Neubrandenburg, Neubrandenburg; W. Maurer, A. v Bierbrauer, Städtisches Krankenhaus, Neunkirchen; P. Ehscheidt, St-Elisabeth-Krankenhaus, Neuwied; B. Krämer, W. Linke, Kreiskrankenhaus Nordhorn, Nordhorn; H. Wandt, J. Wortmann, Klinikum Nord, Nürnberg; H.J. Illiger, B. Metzner, Klinikum Oldenburg, Oldenburg; L. Theilmann, B. Sandritter, Städtisches Klinikum Pforzheim, Pforzheim; R. Pasold, F. Rothmann, A. Haas, Ernst-Von-Bergmann-Klinik, Potsdam; G. Kautzsch, A. Rupprecht, St Josefs-Krankenhaus Potsdam, Potsdam; R. Andreesen, S. Krause, S. Mayer, Universitätsklinikum Regensburg, Regensburg; E. Günther, Kreiskrankenhaus Reutlingen, Reutlingen; W. Bootsveld, Jakobi-Krankenhaus, Rheine; H. Huff, B. Schönberger, G. Puchtler, Klinikum Rosenheim, Rosenheim; P. Ketterer, O. Anders, Klinikum Südstadt, Rostock; M. Freund, Universitätsklinikum Rostock, Rostock; M. Baldus, Internistische Schwerpunktpraxis, Rüsselsheim; J. Preiß, P. Schmidt, Caritas Klinik St Theresia, Saarbrücken; J. Schimke, G. Jacobs, H. Daus, Praxis für Hämatologie/Onkologie, Saarbrücken; R. Subert, D. Häling, C. Schult, Medizinisches Zentrum der Landeshauptstadt, Schwerin; E. Jähde, Evangelisches Jung-Stilling Krankenhaus, Siegen; W. Gassmann, T. Gaska, St.-Marien-Krankenhaus Siegen, Siegen; HR Ochs, G. Schütte, Marienkrankenhaus Soest, Soest; W. Aulitzky, S. Martin, Robert-Bosch-Krankenhaus, Stuttgart; E. Höring, M. v Ehr, M. Respondek, Praxis für Hämatologie/Onkologie, Stuttgart; H.G. Mergenthaler, Bürgerhospital, Stuttgart; E. Heidemann, J. Kaesberger, Diakonissenkrankenhaus, Stuttgart; H.G. Biedermann, W. Larisch, Kreiskrankenhaus Traunstein, Traunstein; C.B. Kölbel, K.J. Weber, H. Kirchen, Krankenhaus der Barmherzigen Brüder, Trier; M.R. Clemens, Mutterhaus der Borromäerinnen, Trier; M. Grundheber, Praxis für Hämatologie/Onkologie, Trier; H. Döhner, M. Bentz, Universitätsklinikum Ulm, Ulm; W. Brugger, I. Funke, Medizinische Klinik Villingen-Schwenningen, Villingen; L. Labedzki, H.J. Bias, Kreiskrankenhaus Waldbröl, Waldbröl; N. Frickhofen, H.G. Fuhr, G. Müller, Dr.-H.-Schmidt-Kliniken Wiesbaden, Wiesbaden; K.M. Josten, Deutsche Klinik für Diagnostik, Wiesbaden; A. Köhler, Deutsche Klinik für Diagnostik, Wiesbaden; U. Rasenack, A. Körfer, Stadtkrankenhaus Wolfsburg, Wolfsburg; M. Sandmann, G. Becker, Kliniken St Antonius, Wuppertal; C. Maintz, Praxis für Hämatologie/Onkologie, Würselen; K. Wilms, H. Rückle-Lanz, M. Wilhelm, U. Gunzer, Universitätsklinikum, Würzburg; G. Schott, Heinrich-Braun-Krankenhaus Zwickau, Zwickau, Germany.


   Authors' Disclosures of Potential Conflicts of Interest
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix
 Authors' Disclosures of...
REFERENCES
 
The authors indicated no potential conflicts of interest.


   NOTES
 
Supported as part of the Competence Network Malignant Lymphoma (BMBF grant No. 01 GI 9994).

Presented in part at the 45th Annual Meeting of the American Society of Hematology, San Diego, CA, December 6-9, 2003.

Authors' disclosures of potential conflicts of interest are found at the end of this article.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix
 Authors' Disclosures of...
 REFERENCES
 
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Submitted June 2, 2004; accepted September 21, 2004.


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