Cologne high-dose sequential chemotherapy in relapsed and refractory Hodgkin lymphoma: results of a large multicenter study of the German Hodgkin Lymphoma Study Group (GHSG)

A. Josting1, C. Rudolph2, M. Mapara3, J.-P. Glossmann1, M. Sienawski, M. Sieber4, H. H. Kirchner5, B. Dörken3, D. K. Hossfeld6, J. Kisro7, B. Metzner8, W. E. Berdel9, V. Diehl1 and A. Engert1

1 First Department of Internal Medicine, University Hospital Cologne; 2 Second Medical Hospital, Carl-Thiem-Hospital Cottbus; 3 University Hospital Charitè Berlin, Section for Hematology/Oncology; 4 Department of Internal Medicine, Städtische Kliniken Gummersbach; 5 Third Medical Department, Clinic for Hematology/Oncology Hannover-Siloah; 6 Section for Hematology/Oncology, University Hospital Hamburg-Eppendorf; 7 Section for Hematology/Oncology, University Hospital Lübeck; 8 Department of Internal Medicine, Klinikum Oldenburg, II; 9 Department of Medicine, Hematology and Oncology, University Hospital Münster Germany

Correspondence to: Dr A. Josting, First Department of Internal Medicine, University Hospital Cologne, Joseph-Stelzmann-Str 9, 50924 Cologne, Germany. Email: andreas.josting{at}uni-koeln.de


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Appendix
 References
 
Background: We designed a dose- and time-intensified high-dose sequential chemotherapy regimen for patients with relapsed and refractory Hodgkin lymphoma (HD).

Patients and methods: Eligibility criteria included age 18–65 years, histologically proven primary progressive (PD) or relapsed HD. Treatment consisted of two cycles DHAP (dexamethasone, high-dose cytarabine, cisplatinum); patients with chemosensitive disease received cyclophosphamide followed by peripheral blood stem cell harvest; methotrexate plus vincristine, etoposide and BEAM plus peripheral blood stem cell transplantation (PBSCT).

Results: A total of 102 patients (median age 34 years, range 18–64) were enrolled. The response rate was 80% (72% complete response, 8% partial response). With a median follow-up of 30 months (range 3–61 months), freedom from second failure (FF2F) and overall survival (OS) were 59% and 78% for all patients, respectively. FF2F and OS for patients with early relapse were 62% and 81%, for late relapse 65% and 81%; for PD 41% and 48%, and for multiple relapse 39% and 48%, respectively. In multivariate analysis response after DHAP (P <0.0001) and duration of first remission (PD and multiple relapse versus early and late relapse; P=0.0127) were prognostic factors for FF2F. Response after DHAP (P <0.0081), duration of first remission (P=0.0017) and anemia (P=0.019) were significant for OS.

Conclusion: Based on the promising results of this study, a prospective randomized European intergroup study was started comparing this intensified regimen with two courses of DHAP followed by BEAM (HD-R2 protocol).

Key words: autologous transplantation, Hodgkin's lymphoma, sequential high-dose chemotherapy


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Appendix
 References
 
High-dose chemotherapy (HDCT) followed by autologous stem cell transplantation (ASCT) has become standard therapy for patients with relapsed and refractory Hodgkin lymphoma (HD). The most compelling evidence for the superiority of HDCT compared with conventional-dose salvage therapy in relapsed HD is based on two randomized trials. The first trial, performed by the British National Lymphoma Investigation (BNLI), compared two to three cycles mini-BEAM (BCNU, etoposide, cytarabine and melphalan) with BEAM and autologous bone marrow transplantation (ABMT) [1Go].

The largest randomized multicenter trial was performed by the German Hodgkin Lymphoma Study Group/European Group for Blood and Marrow Transplantation (GHSG)/(EBMT) to determine the benefit of HDCT in relapsed HD (HD-R1) [2Go]. Patients with relapse after polychemotherapy were randomly assigned to either four cycles of conventional chemotherapy (Dexa-BEAM) or two cycles of Dexa-BEAM followed by HDCT (BEAM) and peripheral blood stem cell transplantation (PBSCT). The final analysis of 144 evaluable patients revealed that chemosensitive patients had superior outcome as measured by freedom from treatment failure (FFTF) (55% versus 34%) when treated with HDCT compared with the conventional treated group. Therefore, two cycles of conventional salvage chemotherapy followed by BEAM is considered standard treatment for these patients by the GHSG and most other groups in this field.

In recent years, sequential high-dose chemotherapy (HDSCT) has been investigated in the treatment of solid tumors, hematologic and lymphoproliferative disorders. Initial results from phase I/II studies indicated that this treatment modality can be safe and effective [3Go–8Go]. Following initial cytoreduction, few non-cross-resistant agents are given at short intervals in accordance with the Norton–Simon hypothesis [9Go]. In general, the transplantation of peripheral blood stem cells (PBSC) and the use of growth factors allow the application of the putatively most effective drugs at the highest possible dose at intervals of 1–3 weeks. HDSCT thereby enables the highest possible dosing over a minimum period of time (dose intensification).

Since HD is a chemosensitive disease, we hypothesized that a more stringent chemotherapy program using HDSCT might improve the treatment results of patients with relapsed/refractory HD. We thus designed a dose- and time-intensified HDSCT regimen after initial cytoreduction with two cycles of DHAP in patients with relapsed and refractory HD. We show that this regimen is feasible, tolerable and highly effective in these poor-risk patients.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Appendix
 References
 
Patient selection
Patients with relapsed or refractory HD were treated in this multicenter phase II study involving 34 centers in Germany (see Appendix). To be eligible, patients between the age of 18 and 65 years had to have biopsy-proven relapsed or refractory HD. Eligibility criteria before study entry included adequate organ function as defined by a creatinine clearance >60 ml/min, serum transaminases less than three times the normal value, bilirubin <2 mg/dl, left ventricular ejection fraction >0.45, forced expiratory volume in the first-second [FEV1] or diffusion capacity of carbon monoxide (DLCO) >60%, Eastern Cooperative Oncology Group (ECOG) performance status ≤2, and white blood cells (WBC) ≥3500/µl, hemoglobin level ≥8 g/dl and platelets ≥100 000/µl. Patients were required to test negative for antibody against human immunodeficiency virus and to be free of active infection. All patients signed consent forms that were based on the Institutional Review Board Guidelines.

All patients had received front-line polychemotherapy with COPP/ABVD (cyclophosphamide, oncovin, procarbazine, prednisone alternating with adriamycin, bleomycin, vinblastine, dacarbazine), ABVD (adriamycin, bleomycin, vinblastine, dacarbazine), BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, oncovin, procarbazine, prednisone) or similar regimens. Primary progressive/refractory disease was defined as disease progression during first-line chemotherapy, or only transient response [complete response (CR) or partial response (PR) lasting ≤90 days] after induction treatment. Progressive disease required the following: (1) ≥25% increase from nadir in the sum of the products of the greatest diameter of any previously identified abnormal node for partial responders or nonresponders; and (2) the appearance of any new lesion during or ≤90 days after the end of therapy. Relapsed HD was defined as a complete disappearance of all detectable clinical and radiographic evidence of disease and the disappearance of all disease-related symptoms for ≥3 months. Early relapse required a complete remission lasting ≥3 months to 12 months. Late relapse was defined as relapse after complete remission lasting ≥12 months.

Study design and treatment procedures
All patients received two cycles of DHAP as initial salvage treatment in order to reduce tumor volume prior to high-dose sequential chemotherapy (HDSCT). DHAP consisted of dexamethasone 40 mg i.v. (day 1–4), cisplatin 100 mg/m2 i.v. given as 24 h continuous infusion (day 1), and cytarabine 2000 mg/m2 i.v. over 3 h 12q (day 2). Hydration (250 ml/h) was started 6–12 h before cisplatin infusion. Corticosteroid eye drops were given topically beginning 12 h before and continuing for 2 days after administration of cytarabine to prevent conjunctivitis. To minimize nausea and vomiting, patients received ondansetrone 8 mg i.v. on days 1 and 2. Twenty-four hours after the last dose of cytarabine, G-CSF (filgrastim) was given at doses of 5 µg/kg/day subcutaneously until leukocytes increased ≥2500/µl for 3 days. The second cycle of DHAP was administered after 14 days providing WBC were >3.000/µl and platelets >75 000/µl.

Patients achieving PR or CR after DHAP received high-dose cyclophosphamide (4000 mg/m2) plus G-CSF (filgrastim) on day 37 followed by PBSC harvest, high-dose methotrexate (8000 mg/m2) plus vincristine 1.4 mg/m2 on day 51, and high-dose etoposide plus G-CSF (filgrastim) on day 58. Finally, a myeloablative treatment (BEAM) with carmustine 300 mg/m2 on day 80, melphalan 140 mg/m2 on day 80, etoposide 150 mg/m2 12q on day 81–84 and cytarabine 200 mg/m2 12q on day 81–84 was given. PBPCs were reinfused and G-CSF (filgrastim) administered until hematological recovery (Table 1).


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Table 1. Cologne high-dose sequential—study design

 
Staging procedures
Before salvage chemotherapy, the extent of disease was assessed by chest X-ray, abdominal ultrasound, computed tomography and bone marrow biopsy. Restaging was performed after two cycles of DHAP. All sites of initial disease were reassessed by adequate methods, including bone marrow biopsy for patients who had bone marrow involvement before salvage therapy. Evaluation of the final response was performed 100 days after PBSCT. Further check-ups were carried out at 3-month intervals during the first year, then at 6-month intervals, and every 12 months after 5 years.

Definition of response
CR was defined as the disappearence of all clinical and radiographic evidence of disease for at least 3 months. PR was defined as a greater than 50% reduction in the product of the largest diameter and its perpendicular of measurable disease lasting >1 month. Any response less than PR was considered as treatment failure.

Statistics
Demographics and disease characteristics were summarized using descriptive statistics. Treatment failure was defined as death from any cause, non-CR and non-PR at the end of therapy (≤3 months) and further relapse, whichever event occurred first.

FF2F was calculated from the date of entry into the protocol to first occurrence of one of the mentioned events or, if none of these occurred, to the date of last information on complete remission. Overall survival (OS) was calculated from the date of entry into the protocol up to the date of death or, if no death occurred, to the last documented information on the patient. OS and FF2F rates were estimated according to the method of Kaplan and Meier [10Go].

The prognostic significance of various factors was tested by multivariate Cox regression analysis for each of the outcome variables (FF2F and OS). The following factors documented before salvage treatment were analysed for their prognostic influence: age (≤40 years versus >40 years), stage at relapse, B symptoms at relapse, duration of first remission (progressive disease, early relapse, late relapse, multiple relapse), primary treatment protocol (BEACOPP versus COPP/ABVD-like regimens), chemosensitivity after two cycles of DHAP and hemoglobin (female ≤10.5 g/dl versus >10.5 g/dl, male ≤12.0 g/dl versus >12 g/dl). Candidate factors were examined by stepwise procedures. Removal and entry levels of significance were 0.1 and 0.05, respectively. No adjustment was made for multiple comparison; all P values were two-sided. All statistical analysis was performed using SPSS 10.0. (SPSS Inc., Chicago, IL).


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Appendix
 References
 
Patient characteristics
Patient characteristics are listed in Table 2. One hundred and two patients were included in this study. The median age at study entry was 34 years (range 18–64 years). Fourty-four patients (43%) had late relapse, 29 patients (29%) early relapse, 17 patients (17%) primary progressive/refractory disease and 12 (12%) patients had multiple relapse. Most of the patients (62%) had extensive disease (stage III/IV) at relapse. B symptoms at relapse were present in 36 patients (34%). In 79 patients (77%) hemoglobin was less than 12 g/dl in male patients or less than 10.5 g/dl in female patients. Front-line chemotherapy consisted of COPP/ABVD in 51 patients (50%), BEACOPP baseline in 24 (24%), ABVD in 13 (13%), BEACOPP escalated in eight (8%), BEACOPP-14 in two (1%), and other regimens in four patients (4%). Patients with primary progressive disease were pretreated with ABVD (n=5), COPP/ABVD (n=5) or BEACOPP baseline (n=7). Sixty-one of the patients (60%) had been treated with combined chemoradiotherapy during first-line therapy. Relapse or progression was proven by biopsy in all patients.


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Table 2.

 
Toxicity of DHAP
A total of 201 courses were administered in 102 patients. The main toxicity of DHAP was myelosuppression with leukocytes of less than 1000/µl (median duration 1.1 days; range 0–6 days,) and thrombocytopenia of less than 25 000/µl (median duration 1.4 days; range 0–11 days) in 43% and 48% of all courses, respectively. The mean number of platelet transfusions was 0.4 (range 0–4). The mean number of red blood cell (RBC) units transfused was 0.5 (range 0–4). In 18 courses patients developed fever (mean 0.3 days; range 0–8 days). WHO grade 3 and grade 4 nausea/vomiting occurred in 24% and 2% of all courses, respectively. Two patients developed WHO grade 3 toxicity and one patient developed polyneuropathy WHO grade 3. No patient died due to treatment related toxicity.

Toxicity of the sequential high-dose chemotherapy
The main toxicity of the sequential HDCT was myelosuppression with leukocytes ≤1000/µl after cyclophosphamide for a median duration of 4.4 days (range 0–13 days), after methotrexate (MTX) for 0.3 days (0–4 days), after etoposide for 6.4 days (0–13 days) and after BEAM for 9.4 days (5–19 days). Thrombocytopenia of less than 25 000/µl was observed after cyclophosphamide for 3.0 days (0–20 days), after MTX for 0.6 day (0–8 days), after etoposide for 4.6 days (0–15 days) and after BEAM for 16.6 days (11–26 days).

The mean number of RBC-transfusions was 2.3 after cyclophosphamide (range 0–11), 0.6 after MTX (0–4), 2.6 after etoposide (range 0–10) and 3.6 after BEAM (0–14). The mean number of platelet transfusions was 1.3 after cyclophosphamide (range 0–11), 0.1 after MTX (0–5), 2.0 after etoposide (0–10) and 4.7 after BEAM (0–22). Results are summarized in Table 3.


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Table 3. Cologne high-dose sequential—hematologic toxicity

 
WHO grade 3 or 4 mucositis was observed in eight patients (10%) after MTX, 13 patients (16%) after etoposide and in 58 patients (76%) after BEAM. Two patients died during HDSCT. One patient died in septic shock during neutropenia after cyclophospamide (multiresistant Staphylococcus aureus infection) and one patient during neutropenia after BEAM (Candida septicemia). These results are summarized in Table 4.


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Table 4. Cologne high-dose sequential—non-hematologic toxicity

 
Response rates
Response rates are listed in Tables 5 and 6. The overall response rate for all patients after two cycles DHAP was 88% (21% CR and 67% PR). The results were comparable in patients with late relapse (RR 91%, CR 26%, PR 65%), early relapse (RR 93%, CR 17%, PR 76%) and multiple relapse (RR 92%, CR 23%, PR 69%). In contrast, the response rate in patients with progressive/relapsed HD was only 65% (CR 12%, PR 53%). Prognostic factors predicting response to DHAP included remission status (relapsed HD versus progressive HD) and stage at relapse (stage I/II versus stage III/IV) [11Go].


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Table 5. Response after two cycles DHAP

 

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Table 6. Response at the final evaluation

 
The final evaluation included patients who failed after two cycles of DHAP, as well as patients who completed the whole treatment protocol (restaging 100 days after PBSCT). The response rate at the final evaluation was 80% for all patients (72% CR and 8% PR). Patients with relapsed HD responded in 83% (75% CR and 8% PR) in contrast to 59% in patients with primary progressive HD (53% CR and 6% PR).

Survival and causes of death
With a median observation time of 30 months (range 3–61 months), the actuarial FF2F and OS for all patients after initiation of salvage therapy were 59% and 78% for all patients, respectively (Figure 1). FF2F and OS for patients with early relapse were 62% and 81%, for late relapse 65% and 81%, for progressive disease 41% and 48% and for multiple relapse 39% and 48%, respectively (Figures 2 and 2).



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Figure 1. Overall survival (OS) and freedom from second failure (FF2F) for all patients (n=102).

 


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Figure 2. Freedom from second failure according to the duration of first remission.

 


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Figure 3. Overall survival according to the duration of first remission.

 
There are currently 76/102 patients alive (75%). Twenty-three patients (22%) died as a result of disease progression and two patients died in septic shock during neutropenia (see toxicity of the sequential HDCT). One patient developed a secondary myelodysplastic syndrome (MDS). This 49-year-old male patient was pretreated with seven cycles BEACOPP escalated. He did not respond after two cycles of DHAP and was then treated with Dexa-BEAM and BEAM plus PBSCT. Four months after BEAM, an MDS (RAEB-t) was diagnosed.

Prognostic factors
Prognostic factors for FF2F and OS were assessed by univariate Kaplan–Meier analysis and by multivariate Cox regression analysis. Both, backward and forward selection methods resulted in an identical selection of significant factors. Univariate and multivariate regression results are displayed in Table 7.


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Table 7. Results of the uni- and multivariate analysis

 
In the multivariate analysis, stage at relapse (stage I/II versus III/IV, P=0.0358), duration of first remission (progressive disease and multiple relapse versus early and late relapse, P=0.0051), and chemosensitivity after two cycles of DHAP (P <0.0001) were significant factors for FF2F. Response after DHAP (P=0.0081), duration of first remission (P=0.0017) and anemia at relapse (P=0.019) were identified as prognostic factors for OS.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Appendix
 References
 
The following findings emerge from this multicenter phase II study. (1) DHAP is an effective salvage chemotherapy regimen with low toxicity prior to sequential HDCT in patients with refractory and relapsed HD. (2) The complete program is feasible with an acceptable acute toxicity rate. (3) The regimen is effective with an overall response rate of 80% and an OS of 78% after a median follow-up of 30 months. (4) There is no outcome difference between early or late relapsed HD. (5) In multivariate analysis response after two cycles of DHAP (P < 0.0001) and duration of first remission (PD and multiple relapse versus early and late relapse; P=0.0127) were prognostic factors for FF2F. Response after DHAP (P <0.0081), duration of first remission (P=0.0017) and anemia (P=0.019) were identified as prognostic factors for OS.

There are a number of studies evaluating high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) in patients with relapsed or refractory Hodgkin lymphoma [12Go–20Go]. This strategy has been shown to produce long-term disease-free survival in selected patients, mainly those with chemosensitive relapse [12Go–20Go]. Based on the results of two randomized trials, HDCT and ASCT are being considered as standard treatment for patients with Hodgkin lymphoma failing first-line chemotherapy [1Go, 2Go].

The high relapse rates observed in most trials using a single HDCT, however, suggest that this strategy might not be sufficiently effective against non-proliferative cells. Therefore, in accordance with the Norton–Simon hypothesis [9Go], sequential high-dose chemotherapy regimens have been introduced in the treatment of solid tumors and lymphoproliferative disorders [3Go–8Go]. After initial cytoreduction, single-agent non-cross-resistant drugs are given at short intervals. In general, the transplantation of PBSC and the use of growth factors allow the application of the putatively most effective drugs at the highest possible doses at intervals of 1–3 weeks. Sequential high-dose chemotherapy thereby enables the highest possible dosing over a minimum period of time (dose intensification).

In an effort to reconcile tumor cell resistance, Gianni et al. [3Go] reported the use of a sequential HDCT regimen in 25 patients with poor risk relapsed and refractory HD. All patients had either refractory disease, were partial responders or in early relapse. Their treament program consisted of rapid sequential administration of high-dose cyclophosphamide, high-dose methotrexate, high-dose etoposide and total body irradiation (TBI) plus high-dose melphalan. At 6-years follow-up, the proportion of patients remaining event-free was 78% for those with a short initial complete remission and 31% for patients with refractory disease after initial mechlorethamine, vincristine procarbazine and prednisone (MOPP)/ABVD.

Several studies have been performed with conventional salvage regimens prior to the administration of HDCT [21Go–30Go]. Although, response rate and toxicity profile of conventional salvage chemotherapy are different, detailed analyses comparing various regimens are difficult due to the heterogenous patient population treated. Dexa-BEAM used as a conventional salvage chemotherapy in former GHSG trials was associated with prolonged myelosuppression and a treatment-related mortality rate of 4%–8% [2Go, 24Go]. Although there is a lack of randomized studies comparing different salvage chemotherapies, we used the DHAP regimen as conventional salvage chemotherapy in the present study. In a prior analysis we reported that DHAP induced high response rates with low toxicities in patients with HL, allowing the majority of patients to proceed to the final myeloablative regimen [11Go].

In the present study 102 patients with relapsed or refractory Hodgkin's disease (HD) were treated with DHAP plus G-CSF to shorten the intervals between each cycle. The median time between the first and second cycle of DHAP was 16 days (range 12–31 days). This represents a dose-escalation by a factor of 1.8 compared with DHAP given at 28-day intervals. The response rate after two cyles of DHAP was 89% (21% CR, 68% PR) and thus at least comparable to results observed with other salvage regimens [11Go, 19Go, 21Go–28Go]. The toxicity profile was excellent with WHO grade 4 leucocytopenia and thrombocytopenia occuring in 43% and 48% with a mean duration of 1.1 days and 1.4 days, respectively. Neither severe infections nor treatment-related deaths occured.

The second part of the treatment program consisted of high-dose cyclophosphamide at a dose of 4000 mg/m2. This drug does not have a strong proliferation-dependent cytotoxicity and, thus, will also kill tumor cells which are out of the cell cycle [31Go]. MTX 8000 mg/m2 and vincristine (VCR) 1.4 mg/m2) are class II specific anticancer agents with an expected optimal activity when given after cyclophosphamide. Importantly, MTX and VCR are non-marrow toxic drugs and obviate the risk of a second myelosuppressive treatment during early recovery of the marrow after cyclophosphamide [31Go]. Etoposide at 2000 mg/m2 as the final course prior to myelosuppressive therapy with BEAM is a highly active cytotoxic drug in lymphoma patients with moderate toxicity when given as a single agent at high doses. The conditioning regimen used was BEAM at standard doses.

Despite possible concern of additive toxicity, the four-step high-dose sequential program proved to be well tolerated in this multicenter study including 102 patients. The observed CR (72%) and overall RR (80%) demonstrated that this regimen is highly effective in HD patients failing primary therapy. In addition, patients with early and late relapse had a similiar outcome (FF2F and OS for patients with early relapse, 62% and 81%; for late relapse, 65% and 81%) suggesting that one of the most important prognostic factor in these patients might be overcome with further dose intensification. In a retrospective comparison with an earlier analysis of the GHSG database on 422 relapsed patients, these results are clearly superior to those observed for patients with early and, in particular, those with primary progressive disease [32Go].

In conclusion, this new three-phase treatment regimen is well tolerated and feasible in patients with relapsed and primary progressive HD. These data suggests a high efficacy in relapsed HD patients, warranting further randomized studies. As a direct consequence of the present study, the GHSG, EBMT, EORTC and the GEL/TAMO developed a large intergroup study (HDR-2) in which relapsed HD patients responding to two cycles DHAP are randomized to receive either BEAM followed by PBSCT (arm A of the study) or high-dose cyclophosphamide, followed by high-dose MTX and vincristine, followed by high-dose etoposide and a final myeloablative course with BEAM (arm B of the study).


    Appendix
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Appendix
 References
 
The following centers participated in this study: Prof. Dr Diehl, Klinik I für Innere Medizin, Universität zu Köln; Prof. Dr Dörken, Abteilung für Hämatologie, Onkologie und Tumorimmunologie, Max-Delbrück-Centrum für Molekulare Medizin Berlin; Dr Rudolph, II. Medizinische Klinik, Carl-Thiem-Klinikum, Cottbus; Prof. Dr Hossfeld, Abteilung Onkologie und Hämatologie, Medizinische Klinik, Universitätskrankenhaus Hamburg-Eppendorf; PD Dr Kirchner, Klinik für Hämatologie und Onkologie, Medizinische Klinik III, Klinikum Hannover – Siloah; Prof. Dr Wagner, Medizinische Klinik I, Medizinische Universität zu Lübeck; Prof. Dr Berdel, Medizinische Klinik und Poliklinik A, Westfälische Wilhelms-Universitäsklinik Münster; Prof. Dr Illiger, Klinik für Innere Medizin II, Städtische Kliniken Oldenburg; Prof. Dr Fischer, II. Medizinische Klinik, Städtisches Klinikum Karlsruhe; Prof. Dr Heit, Medizinische Klinik, Evangelisches Krankenhaus Essen-Werden; Dr Böck, Gemeinschaftspraxis für Hämatologie und Onkologie, Offenbach; Dr Grote-Metke, Evangelisches Krankenhaus Hamm; Dr Abedinpour, Städtisches Krankenhaus München-Schwabing; Prof. Dr Reiss, Med. Klinik I, Klinik Maria Hilf, Krankenhaus Franziskushaus, Mönchengladbach; Prof. Dr Heidemann, Medizinische Klinik Abteilung 2, Diakonissenkrankenhaus Stuttgart; Prof. Dr Benöhr, Medizinische Klinik I, Bürgerhospital Stuttgart; Prof. Dr Dührsen, Abteilung für Hämatologie, Universitätsklinik Essen; Prof. Dr Trümper, Abt. für Hämatologie/Onkologie, Universitätsklinik Göttingen; Prof. Dr Schmiegel, Knappschaftskrankenhaus Bochum-Langendreer, Medizinische; Universitätsklinik Bochum; PD Dr Ko, Medizinische Klinik und Poliklinik, Universitätsklinik Bonn; Dr Nahler, Medizinische Klinik II, St. Johannishospital Dortmund; Prof. Dr Knuth, II. Medizinische Klinik, Krankenhaus Nordwest Frankfurt; Prof. Dr Doberauer, Medizinische Klinik, Robert Koch Krankenhaus Hannover; Prof. Dr Fauser, Klinik für Knochenmarktransplantation und Hämatologie/Onkologie, Idar-Oberstein; PD Dr Uppenkamp, Medizinische Klinik A, Klinikum Ludwigshafen; Prof. Dr Franke, Abteilung für Hämatologie und Onkologie, Universitätsklinik Magdeburg; Dr von Schilling, III. Medizinische Klinik und Poliklinik, Klinikum rechts der Isar der Technischen Universität München; Prof. Pralle, Medizinische Klinik IV, Universitätsklinik Gießen; Prof. Dr Schmoll, Klinik für Innere Medizin IV, Martin-Luther-Universität Halle; Prof. Dr Ganser, Medizinische Klinik und Poliklinik, Medizinische Hochschule Hannover; Prof. Dr Ho, Medizinische Klinik und Poliklinik V, Universitätsklinik Heidelberg; Prof. Dr Pfreundschuh, Abteilung für Innere Medizin I, Universitätsklinik Homburg; Prof. Dr Hiddemann, Medizinische Klinik und Poliklinik III, Universitätsklinik München-Großhadern; PD Dr Frickhofen, Innere Medizin III, Dr Horst-Schmidt-Kliniken Wiesbaden.

Received for publication April 27, 2004. Revision received July 15, 2004. Accepted for publication July 16, 2004.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Appendix
 References
 
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