Abbreviations - Kompetenznetz Maligne Lymphome

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Italian Lymphoma Intergroup (Intergruppo Italiano Linfomi). IMISE. Institute ... OSHO. Eastern German Study Group for Haematology and Oncology ( Ostdeutsche.
Competence Network Malignant Lymphomas

Annual Report 2003

Funding Period June 2002 – April 2003

For further information please contact: Prof. Dr. Volker Diehl (Speaker of the network) Klinik I für Innere Medizin der Universität zu Köln Joseph-Stelzmann-Str. 9, D-50924 Köln Phone: +49 (0) 221-478-4400 • Fax: +49 (0) 221-478-5455 Email: [email protected]

or PD Dr. Annegret Herrmann-Frank (CEO) Zentrale - Kompetenznetz Maligne Lymphome Klinikum der Universität zu Köln Joseph-Stelzmann-Str. 9, D-50924 Köln Phone: +49 (0) 221-478-7400 • Fax: +49 (0) 221-478-7406 Email: [email protected]

or Project leaders of the network (Corresponding addresses: see Chapter 4, Progress reports)

Annual Report Competence Network Malignant Lymphomas 2003

Abbreviations

Abbreviations AIHA

Autoimmune haemolytic anaemia

AILD

Angioimmunoblastisches T-Zell-Lymphom

AML

Acute myeloic leukaemia

AMCL

Acute myeloblast cell leukemia

AOK

Statutory health insurance institution (Allgemeine Ortskrankenkasse)

BMBF

Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung)

BMGS

Federal Ministry of Health and Social Security (Bundesministerium für Gesundheit und Soziale Sicherung)

B-NHL

B-cell lymphoma

cDNA

Complementary desoxyribonucleic acid

CHMG

Cochrane Haematological Malignancies Group

CHOEP

Chemotherapy regimen (cyclophosphamide, doxorubicin, vincristine, etoposide and prednisone

CHOP

Chemotherapy regimen (cyclophosphamide, doxorubicin, vincristine, prednisone)

CLL

Chronic lymphocytic leukemia

CMS

Content management system

CNS

Central nervous system

CRF

Case report form

CTA

Cancer-testis antigen

DGHO

German Society of Haematology and Oncology (Deutsche Gesellschaft für Hämatologie und Onkologie)

DGIM

German Society of Internal Medicine (Deutsche Gesellschaft für Innere Medizin)

DLH

German Leukemia and Lymphoma Patients’ Association (Deutsche Leukämieund Lymphom Hilfe)

DNA

Desoxyribonucleic acid

DNS

Domain name system

DSHNHL

German High-Grade Non-Hodgkin’s Lymphoma Study Group (Deutsche Studiengruppe Hochmaligne Non-Hodgkin Lymphome)

DSMM

German Study Group Multiple Myeloma (Deutsche Studiengruppe Multiple Myeloma)

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Abbreviations

GMMG

German Multiple Studiengruppe)

Myeloma

Study

Group

EBM

Evidence-based medicine

EBMT

European Group for Blood and Marrow Transplantation

e. V.

Registered association (eingetragener Verein)

EORTC

European Organisation for Research and Treatment of Cancer

EPCOL

European Platform for the Conquest of Lymphomas

EU

European Union

GCLLSG

German CLL Study Group (Deutsche CLL Studiengruppe)

G-CSF

Granulocyte-colony stimulating factor

GCP

Good clinical practice

GHSG

German Hodgkin’s Lymphoma Study Group (Deutsche Hodgkin Lymphom Studiengruppe)

GLSG

German Low-Grade Non-Hodgkin’s Lymphoma Studiengruppe Niedrigmaligne Lymphome)

GSGL

German Study Group Gastro-intestinal Lymphoma (Deutsche Studiengruppe Gastrointestinale Lymphome)

HD

Hodgkin’s disease

HLA

Human leukocyte antigen

ICD

International Classification of Diseases

ICH

International Conference on Harmonisation

IP

Internet protocol

IPI

International Prognostic Index

IIL

Italian Lymphoma Intergroup (Intergruppo Italiano Linfomi)

IMISE

Institute of Medical Informatics, Statistics and Epidemiology, University of Leipzig

ISDN

Integrated services digital network

IT

Information technology

LDH

Lactate dehydrogenase

LPHD

Lymphocyte predominant Hodgkin's disease

MCL

Mantle cell lymphoma

MHC

Major Histocompatibility Complex

Annual Report Competence Network Malignant Lymphomas 2003

(Deutsche

Study

Multiple

Myeloma

Group (Deutsche

3

Abbreviations

MM

Multiple myeloma

MINT

Mabthera International Trial

MLL

Mixed lineage leukaemia

MSI

Microsatellite instability

NHL

Non-Hodgkin’s lymphoma

NLL

North German Leukemia and Lymphoma Study Group (Norddeutsche Leukämieund Lymphomstudie)

NRW

North Rhine-Westphalia

OSHO

Eastern German Study Group for Haematology and Oncology (Ostdeutsche Studiengruppe für Hämatologie und Onkologie)

ProMISe

Project Manager Internet Server

PLL

Prolymphocytic leukaemia

PT-LPD

Post-Transplantation Lymphoproliferative Disorder Study Group

QM

Quality management

RCT

Randomised clinical trials

RT-PCR

Reverse transcriptase polymerase chain reaction

SOP

Standard operating procedures

SP

Subproject

SQL

Structured Query Language

SR

Systematic review

TMF

Telematics Platform for Medical Research Networks

T-NHL

T-cell lymphoma

TOP

Therapy optimisation protocol

UHC

University Hospital Cologne

WG-QM

Working group on quality management (AG Qualitätsmanagement)

WHO

World Health Organisation

WWW

World Wide Web

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1 Introduction

1 Introduction The present report covers the period from June 2002 to May 2003. Due to the midterm evaluation in June 2002, the Competence Network Malignant Lymphomas received funding for further two years. The first funding period of most of the subprojects (SP) was finished in the end of 2002, thus the second funding period will comprise the period up to 2004. Currently enclosed in the network are the following subprojects:

Information and IT-based Communication

Quality Management

New Therapies

SP1

Central Office

SP2

Telematics & Quality Management

SP3

Pathology

SP4

Radiotherapy

SP5

Network of Private Practices

SP6

Survey of Lymphoma Health Care

SP12

Epidemiology (new)

SP8

EBM/Cochrane

SP9

High Dose Therapy

SP10

Long Term Effects

SP11

Vaccine Therapy

SP13

Biologic Risk Factors (new)

The former subprojects “Health economics” (SP7) and EBM/Meta-analysis (SP8a) finished their work in the end of the first funding period; SP9 (High dose therapy) will be closed in June 2003. Two new subprojects were included: SP13 (Epidemiology) resulted out of a former cooperation with SP6 (Survey of lymphoma health care), while SP13 forms the bridge between the work of the pathologists and the clinical study groups by building up an optimised infrastructure for the collection and further investigation of fresh tumour tissue. In the following chapters, we give a survey of the overall network activities of the Competence Network Malignant Lymphomas, followed by the reports of the subprojects. Finally the reader will find a summary describing the objectives of the network for the next two years.

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2 Organisation and management of the network

2 Organisation and management of the network 2.1 Association of new study groups The Competence Network wants to be an open platform for all groups working in research and treatment of lymphoma. Founded by the three major German lymphoma study groups for Hodgkin disease (GHSG) and for high and low malignant NHL (GLSG, DSHNHL), three further clinical study groups were associated in the first funding period: the German CLL Study Group (GCLLSG), the Study Group for Gastrointestinal Lymphoma (GSLG) and the Eastern German Study Group for Haematology and Oncology (OSHO). In between, the CLL group has achieved the status of a full member of the network (see below). One important criterion for the affiliation of study groups to the network is that all their subgroups apply for a common membership. In this way, competing studies exerting the same design or very similar ones may be avoided in the future. Recently, the Competence Network succeeded in convincing the German study groups working on multiple myeloma, DSMM (Chairman: H. Einsele) and GMMG (Chairman: H. Goldschmidt), to join forces and to apply for a common membership. Moreover, the application of the study group(s) dealing with CNS lymphoma is expected within the next months.

2.2 The legal structure For the future, the network aims to constitute itself in form of a registered association. To date, the rules (Satzung), which were introduced in early 2000, are still valid. Nevertheless, the affiliation of new study groups required some changes. Since the GCLLSG became a full member of the network in 2003, the chairman (M. Hallek, Munich) became a member of the board of directors. The members of the network approved the necessary changes in the rules. The general intention is to implement a legal form, which allows the membership of all groups involved in lymphoma research and associated health care including lay people.

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3 Network activities

3 Network activities 3.1 Sustainability Within the last year, two initiatives have been started to ensure the maintenance of the medical/scientific projects of the network:

3.1.1 Network “Molecular Mechanisms in Malignant Lymphoma” The lymphoma study groups and the reference centres for lymph node pathology submitted a joint grant application to the “Deutsche Krebshilfe”. The proposal is focused on gene expression in malignant lymphomas. The aim is the prognostic validation of gene expression data in malignant lymphomas by comparing gene expression data with those from classical cytogenetics or clinical studies. Samples of tumour tissue will be utilized as well as sera from lymphoma patients. The infrastructure built up by subproject 13 of the Competence Network will guarantee the further collection and storage of tumour tissue. Data will be integrated in the already existing database of the pathologists’ subproject (SP3). The project has been approved for funding for initially 3 years and will start its work in the second half of 2003. Chairmen of this initiative are L. Trümper (Göttingen) and H. Stein (Berlin).

3.1.2 „European Platform for the Conquest of Lymphomas“ (EPCOL) Within the 6th Framework Programme of the European Community for Research, the Competence Network submitted a proposal for a so-called Network of Excellence. Together with clinical lymphoma study and research groups of 14 European countries, the network aims to coordinate lymphoma research and treatment within Europe and to increase the knowledge of ongoing and upcoming lymphoma studies. Nine task forces have been proposed, e.g. for the initiation and coordination of European wide clinical studies, for radiotherapy and for pathology as well as for clinically related basic research. By analogy with the Competence Network, further task forces were proposed in the field of quality management, telematics and epidemiology & prevention. Coordinators of the network are M. Pfreundschuh (Homburg/Saar) and A. Herrmann-Frank (Cologne). A decision about funding is expected in autumn 2003. The overall strategy to maintain the network beyond the BMBF grant period is to transform it into a registered association, which offers a membership with equal rights to all groups involved in lymphoma research and therapy, to partners from patient initiatives and from the health care system, and to the pharmaceutical industry. Several efforts have been undertaken to prepare this step:

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A task force „Future of the Competence Network” has been founded. Here, the general aims should be formulated and a concept for the structure of the future association is to be developed.



A first contact has been established with a public relations agency. The agency has received information about the structure of the network, the participants and cooperation partners, of the past activities and the current ideas for the future. In collaboration with the members of the Competence Network, they will develop a concept for public relations including fundraising possibilities.

3.2 Public relations and information service Public relations and information service are important aspects of the Central Office’s tasks and therefore are described in more detail in the progress report of subproject 1. Here, only a summary of the main activities is given.

3.2.1 Symposia & meetings The Competence Network organised the following meetings or sessions: Annual meeting of the network, patients’ symposia, symposia on the occasion of the annual meetings of the “Deutsche Gesellschaft für Hämatologie und Onkologie” (DGHO) and the “Deutsche Gesellschaft für Innere Medizin” (DGIM), and presentations at the European Congress of Haematology. Implementation of EU directive 2001/20/EC The Directive 2001/20/EC of the European Parliament and of the Council on the “approximation of laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use” has to be transformed into national law by the European Member States in 2003. The directive does not differentiate between regulatory clinical studies for drug approval and investigator-initiated therapy optimisation protocols (TOPs), which poses a threat to the latter. The clinical studies of the Competence Network Malignant Lymphomas are TOPs and are publicly funded. Therefore they would lack the necessary funds to comply with a strict transformation of the directive into national law. To address this problem, the Coordinating Centre for Clinical Trials Cologne together with the Competence Network organised a symposium on the “problems and changes for investigator-initiated and publicly funded clinical trials due to the implementation of the EU directive 2001/20/EC into the German laws” in February 2003. The network’s public relations manager prepared the press kit for this symposium.

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3.2.2 Newsletter Twice per year, the network publishes a newsletter. A modified layout was developed and three further issues have appeared. The newsletter provides information on the network’s activities, e.g. current projects or new study protocols, and serves as a forum for patients’ associations.

3.2.3 Flyer A new flyer describing the network, its projects and participants has been published in March 2003 and broadly distributed. In order to present the network on an international level, an English version of the flyer has been published as well.

3.2.4 Exhibitions An information booth to present the network in the exhibition area of scientific meetings and events for patients or the general public was designed and produced in spring 2003. During the reported time frame, the network presented itself at eight such events. In order to inform about clinical research and to improve the acceptance of clinical trials in the general public, a life-size board game was designed and produced. It has been used successfully for the first time at the “Lange Nacht der Wissenschaften” in Berlin in June 2003.

3.2.5 Homepage The Central Office initiated a restructuring and actualisation of the information portal’s contents with the technical restructuring realised in close collaboration with subproject 2. The new homepage will be launched in summer 2003. Due to recommendations of patients’ representatives, the contents of the patients’ section of the current homepage were integrated into the scientific pages. A new topic “Information on Malignant Lymphomas” now covers everything from the basics of the disease to expert information in a gradual information flow. Subprojects, working groups and study groups will be presented in a standardised way with mandatory contents. To ensure the quality and timeliness of information, online-editors of every subproject, working group and study group have been recruited and trained in the use of the network’s content management system. On the new homepage, documents for every ongoing clinical trial of the study groups will be available for download: Synopsis, flow-sheet and informed consent materials are accessible by everyone; protocols are password-protected. Since May 2003 access to the password protected study protocols and ethics approvals has been facilitated by means of an online registration form and a common login for all study groups.

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3.3 Quality management The improvement of quality in all aspects of lymphoma treatment is an aim spanning all activities of the Competence Network. The technical aspect of quality management is an important task of subproject 2 and therefore is described in more detail in the progress report of this project. Here, only superordinate efforts are mentioned.

3.3.1 Working group “Quality Management” Most clinical studies performed in the network are quality assurance protocols, i.e. trials for the optimisation of therapy, rather than new drug approvals. Therefore, it is the aim to interpret the guidelines for good clinical practice (GCP in the International Conference on Harmonization (ICH) Guidelines) and put them into defined terms for this kind of protocols. The working group “Quality Management” (WG-QM) develops a suitable system of Standard Operating Procedures (SOPs) for study centres. To support the harmonisation of quality standards beyond the Competence Network Malignant Lymphomas, a cooperation with the Competence Network Paediatric Oncology and Haematology has been initiated in 2003. The aim of this cooperation is to co-develop parts of the SOP-system. Besides the SOP-system the WG-QM develops appropriate methods for quality assurance and its review process in the study groups. Furthermore, the Competence Network aims towards harmonisation of case report forms (CRFs) and clinical definitions. A first phase of CRF harmonisation with focus on term definitions was finished in 2002 and a second phase focussing on the CRF layout started. Also in 2002, the harmonisation of clinical definitions has been expanded into an international cooperation of scientists working on malignant lymphoma with Bruce Cheson (USA) and the WG-QM (Beate Pfistner, Cologne) as coordinators. Finally, the WG-QM together with the EORTC (Belgium) coordinates the European quality management group of the EPCOL application (see 3.1.2). The European quality management group aims towards harmonisation of quality standards with special regard to European trial joint ventures (for details see SP2).

3.3.2 Informed consent project In a cooperative project funded by the Telematics Platform for Medical Research Networks (TMF), the scientific coordinator of the network (subproject 1), the data security expert of subproject 6 and a project manager of the Coordinating Centre for Clinical Trials Cologne analysed the data protection requirements for the informed consent process. The project was realised in two phases. In the first phase (07/2002 - 11/2002), a review of current informed consent material, the respective laws, the GCP guideline and recommendations of ethics committees led to the compilation of a list of required items and an evaluation of the available informed consent material. In the second phase (11/2002 - 03/2003), the items were rated

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according to their importance, evaluated by a lawyer and expanded into models for generic informed consent solutions. The project ended with the handing over of the final report to the coordinating council of the TMF in March 2003. The report comprises the commented item-list, a condensed checklist for day-to-day use and the legal expert opinion among other things. A discussion of the results with the data protection authorities and the association of ethics committees as well as the publication of the report are in preparation.

3.3.3 Consultation service The study groups of the Competence Network offer a consultation service for medical specialists and patients. In cooperation with the Central Office all relevant contact information were collected and published in form of flyer, which has been widely distributed to hospitals and practices and to patients as well. While the Central Office addresses general questions about malignant lymphoma and clinical studies, experts in the study centres answer all questions concerning their respective field of knowledge.

3.3.4 Project for support of non-university hospitals in medical documentation In early 2002, a joint project between the Competence Network Malignant Lymphomas and the pharmaceutical industry has been initiated in order to improve the medical documentation of clinical study data in non-university hospitals. Documentation is performed by the network assistants and two additional study nurses remunerated by industry. Within the past year, the network has gained great acceptance and the number of participating hospitals raised to 39. To date, 11 trials out of four study groups (GHSG, DSHNHL, GLSG, GCLLSG) are documented. The supported hospitals are required to participate in at least two trials. The supporting industry partners have also positively evaluated the project. Currently, the conditions for further funding up to the end of the second funding period are negotiated. Please find further details in the progress report of the Central Office.

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3.4 Activities of the clinical study groups The Competence Network Malignant Lymphomas is based on the German lymphoma study groups and their activities. Integrated into the network are the following study groups: GHSG1, DSHNHL2, GLSG3, GCLLSG4, GSGL5 and OSHO6. In addition, PT-LPD7 and Radio immunotherapy in Malignant Lymphoma are associated with the network. Currently the German study groups working on multiple myeloma DSMM8 (Chairman: H. Einsele) and GMMG9 (Chairman: H. Goldschmidt) join the network. Below, the activities of the main study groups are briefly summarised to document their importance not only for the Competence Network Malignant Lymphomas, but also for the clinical research in the area of lymphomas in general:

3.4.1 GHSG After 5 years of recruitment the GHSG closed their fourth generation of clinical studies (HD1012) in January 2003. In the same month the fifth generation (HD13-15) started. In HD10 (limited stages) 1223 patients with Hodgkin’s disease, in HD11 (intermediate stages) 1422 patients and in HD12 (advanced stages) 1597 patients were treated. The final evaluation of the trials is expected to take place in about four years. The main goal of the new studies HD13 and HD15 is the reduction of toxicity and side effects of the treatment, while at the same time maintaining the good results of the previous studies. For HD14 the goal is to improve the event-free survival from 80% to over 90%. More than 400 centres in Germany and other European countries participate in the trials. Since January 2003, approximately 80 patients per month entered the HD13-15 trials. Besides HD13-15, the LPHD-observation study and the HDR2-trial for relapsed Hodgkin lymphomas are still ongoing. Overall, more than 9.000 patients are included in the database of the GHSG.

3.4.2 DSHNHL The DSHNHL currently offers four phase III-clinical trials for patients with aggressive

1

German Hodgkin Lymphoma Study Group German High-Grade Non-Hodgkin’s Lymphoma Study Group 3 German Low-Grade Non-Hodgkin’s Lymphoma Study Group 4 German CLL Study Group 5 German Study Group Gastro-intestinal Lymphoma 6 Eastern German Study Group for Haematology and Oncology 7 Post-Transplantation Lymphoproliferative Disorder Study Group 8 German Study Group Multiple Myeloma 9 German Multiple Myeloma Study Group 2

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lymphomas. About 200 clinical centres participate in the 1999-1 trial (Ricover 60) for elderly patients (>750 patients) and the 1999-2 trial (HiCHOEP) for young low-risk patients (>330 patients already recruited). Due to an increased rate of infections compared to the previous study (NHL-B) the G-CSF application in both protocols was changed back to the old standard in May 2003. In the Mabthera international trial (MINT, young low-risk patients, 254 patients from Germany) 36 German centres participate. The new 2002-1 trial (Mega-CHOEP PIII) started in March 2003. It is open for young high-risk patients (≤60 years, age-adjusted IPI ≥2), comparing a high-dose chemotherapy including a threefold stem cell support with an intensive Chemotherapy without stem cell support. Furthermore, the addition of rituximab is evaluated in both arms. Another new study for patients with peripheral T-cell lymphomas or AILD (2003-1; CHOP-Campath, phase II) is planned to open in July 2003.

3.4.3 GLSG During the last year, a number of therapy optimisation protocols of the GLSG have achieved a statistical significance due to the enhanced patient recruitment supported by the Competence Network Malignant Lymphomas. Initial therapy of indolent lymphoma (R-CHOP vs. CHOP): In patients with follicular lymphoma, there was no difference in complete and overall response whereas a significant difference in favour of the combined immuno-chemotherapy was detected in the subset of patients with mantle cell lymphoma. Relapsed follicular and mantle cell lymphomas (R-FCM vs. FCM): For both lymphoma subtypes, the addition of rituximab to a fludarabine containing chemotherapy resulted in significantly improved remission rates, progression-free survival (follicular lymphoma) and overall survival (MCL). In addition to these protocols, a number of phase II studies were activated to evaluate innovative treatment options, e.g.:

combined

immuno-chemotherapy

(BMR)

in

relapsed

indolent

lymphoma,

new

chemotherapy combination (GO) in relapsed indolent lymphoma or allogeneic stem cell transplantation with dose-reduced conditioning regimen. Currently, more than 2000 lymphoma patients are registered in the central GLSG database with a regularly updated follow-up provided by approximately 350 clinical institutions from all over Germany.

3.4.4 GCLLSG For the first line therapy of CLL-patients, the GCLLSG offers a variety of clinical trials (CLL1, CLL4, CLL5) designed for different age groups (≤65; >65) and stages of the disease (Binet A/B, symptoms). Over 1200 patients have been included in the first line studies so far. Besides the first line studies, the GCLLSG offers trials for relapsed CLL (CLL2H, CLL3C, CLL3R, CLL3X, CLL6) and the closely related entities AIHA, PLL and Morbus Waldenström (AIHA1, PLL1, TPLL1, WM1). In addition, a few selected patients (first line and relapse) are treated in studies,

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which try to evaluate the role of stem cell transplantation in the therapy of CLL (CLL3-protocols). A set of new clinical trials is planned for autumn 2003, e. g. the CLL7 trial will replace CLL1. Overall, more than 1.600 patients are included in the database of the GCLLSG and around 390 centres participate in the current trials.

3.4.5 OSHO The “Ostdeutsche Studiengruppe Hämatologie und Onkologie” (OSHO) is active in a broad spectrum of haematology and oncology clinical trials with only a fraction of them being in the area of malignant lymphomas. The ongoing phase III-study OSHO #39 evaluates the role of the antibody rituximab in the treatment of advanced indolent and mantle-cell lymphomas in addition to chemotherapy. So far, over 350 patients have been included in this study, which is expected to close within the next few months with first results available at the beginning of 2004. Other efforts of the OSHO include phase II-trials to improve the treatment of mediastinal large B-cell lymphomas (OSHO #49, 20 patients) and the chemotherapy of relapsed indolent and mantlecell lymphomas (OSHO #42, 20 patients). Altogether, the OSHO is active in seven phase I/II lymphoma studies and one phase III-trial with around 30 participating centres. Further studies are in preparation including a new phase III-trial to replace OSHO #39.

3.5 Recent publications of the clinical study groups 3.5.1 GHSG •

Glossmann, J.P., Josting, A., Pfistner, B., Paulus, U., Engert, A.: A randomized trial of chemotherapy with carmustine, etoposide, cytarabine, and melphalan (BEAM) plus peripheral stem cell transplantation (PBSCT) vs single-agent high-dose chemotherapy followed by BEAM plus PBSCT in patients with relapsed Hodgkin's disease (HD-R2). Ann Haematol 2002, 81 (8): 424-429



Schmitz, N., Pfistner, B., Sextro, M., Sieber, M., Carella, A.M., Haenel, M., Boissevain, F., Zschaber, R., Muller, P., Kirchner, H., Lohri, A., Decker, S., Koch, B., Hasenclever, D., Goldstone, A.H., Diehl, V.: Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin's disease: a randomised trial. Lancet 2002, 359 (9323): 2065-2071



Weihrauch, M.R., Re, D., Bischoff, S., Dietlein, M., Scheidhauer, K., Krug, B., Textoris, F., Ansen, S., Franklin, J., Bohlen, H., Wolf, J., Schicha, H., Diehl, V., Tesch, H.: Whole-body positron emission tomography using 18F-fluorodeoxyglucose for initial staging of patients with Hodgkin's disease. Ann Haematol 2002, 81 (1): 20-25



Rehwald U, Schulz H, Reiser M, Sieber M, Staak JO, Morschhauser F, Driessen C, Rudiger T, Muller-Hermelink K, Diehl V, Engert A; German Hodgkin Lymphoma Study Group (GHSG). Treatment of relapsed CD20+ Hodgkin lymphoma with the monoclonal antibody rituximab is effective and well tolerated: results of a phase 2 trial of the German Hodgkin Lymphoma Study Group. Blood 2003, 101 (2): 420-424

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Sieber M, Bredenfeld H, Josting A, Reineke T, Rueffer U, Koch T, Naumann R, Boissevain F, Koch P, Worst P, Soekler M, Eich H, Muller-Hermelink HK, Franklin J, Paulus U, Wolf J, Engert A, Diehl V; German Hodgkin's Lymphoma Study Group. 14-day variant of the bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone regimen in advanced-stage Hodgkin's lymphoma: results of a pilot study of the German Hodgkin's Lymphoma Study Group. J Clin Oncol 2003, 21 (9): 1734-1739



Diehl, V., Franklin, J., Pfreundschuh, M., Lathan, B., Paulus, U., Hasenclever, D., Duehmke, E., Georgii, A., Mueller-Hermelink, H.K., Loeffler: M.: Dose escalated BEACOPP chemotherapy for advanced stage Hodgkin's disease: final results of the German Hodgkin's lymphoma Study Group randomized trial. N Engl J Med 2003, 348 (24): 2386-2395



Engert A., Schiller P., Josting A., Herrmann R., Koch P., Sieber M., Boissevain F., de Wit M., Stein H., Dühmke E., Willich N., Müller R.-P., Schmidt B. F., Renner H., MüllerHermelink H. K., Pfistner B., Wolf J., Hasenclever D., Löffler M., Diehl V. for the German Hodgkin's Study Group (GHSG): Involved field (IF) radiotherapy is equally effective and less toxic as compared with extended field (EF) radiotherapy after 4 cycles of chemotherapy in patients with early-stage unfavourable Hodgkin's lymphoma - Results of the HD8 trial of the German Hodgkin Study Group (GHSG). Submitted.

3.5.2 DSHNHL •

Wunderlich A, Kloess M, Reiser M, Rudolph C, Truemper L, Bittner S, Schmalenberg H, Schmits R, Pfreundschuh M on behalf of the German High-Grade NHL Study Group:Practicability and acute haematologic toxicity of 2- and 3-weekly CHOP and CHOEP chemotherapy for aggressive non-Hodgkin’s lymphoma: results from the NHL-B trial of the German High-Grade Non-Hodgkin’s Lymphoma Study Group (DSHNHL). Annals of Oncology 2003, 14: 881-893

3.5.3 GLSG •

Hiddemann W, Dreyling M, Unterhalt M: Rituximab plus chemotherapy in follicular and mantle cell lymphomas. Semin Oncol 2003, 81 (Suppl 2), 16-20



Hiddemann W, Dreyling M: Mantle Cell Lymphoma: Therapeutic strategies are different from CLL. Curr Treat Options Oncol 2003, 4(3): 219-26



M Dreyling, Unterhalt U, Hiddemann W: Role of monoclonal antibodies in the treatment of follicular and mantle cell lymphoma. Haematology J 2003, 4 (Suppl. 3): 191-194



Forstpointner R, Dreyling M, Repp R, Hermann S., Hänel A, Metzner B, Pott C, Hartmann F, Rothmann F, Rohrberg R, Böck H-P, Wandt H, Unterhalt M, Hiddemann W: The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared to FCM alone in patients with relapsed and refractory follicular and manttle cell lymphomas – results of a prospective randomized study of the German Low Grade Lymphoma Study Group. Submitted.

3.5.4 GCLLSG •

Schulz H., Klein S. K., Rehwald U., Reiser M., Hinke A., Knauf W. U., Aulitzky W. E., Hensel M., Herold M., Huhn D., Hallek M., Diehl V., Engert A.; German CLL Study Group: Phase 2 study of a combined immunochemotherapy using rituximab and fludarabine in patients with chronic lymphocytic leukemia. Blood. 2002, 100(9): 3115-20.

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3 Network activities



Schmitt B., Wendtner C.-M., Bergmann M., Busch R., Franke A., Pasold R., Schlag R., Hopfinger G., Hiddemann W., Emmerich B., Hallek M.: Fludarabine combination therapy for the treatment of chronic lymphocytic leukemia. Clin Lymphoma. 2002, 3(1): 26-35.



Wendtner C.-M., Ritgen M., Schweighofer C. D., Fingerle-Rowson G. Campe H., Jäger G. Schmitt B., Busch R., Diem H., Engert A., Stilgenbauer S., Döhner H., Kneba M., Emmerich B., Hallek M. and the German CLL Study Group (GCLLSG): High efficacy but considerable toxicity of alemtuzumab (MabCampath) consolidation therapy in CLL patients responding to fludarabine or fludarabine/cyclophosphamide – results of randomized phase III trial of the GCLLSG. Submitted.

3.5.5 OSHO •

Herold M, G Dölken, F Fiedler, A Franke, M Freund, W Helbig, R Pasold: Randomized phase III study for the treatment of advanced indolent non-Hodgkin's lymphomas (NHL) and mantle cell lymphoma: chemotherapy versus chemotherapy plus rituximab. Ann Haematol 2003, 82: 77-79.

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5. Summary and perspectives

5. Summary and perspectives 5.1 General objectives 5.1.1 Consolidation and extension of the network As outlined in chapter 3.1, the Competence Network has undertaken several efforts to sustain part of its medical/scientific projects. The newly founded network “Molecular Mechanisms in Malignant Lymphoma”, which is a collaboration of pathologists, clinicians and basic researchers, is a typical example how the idea of multidisciplinarity established in the Competence Network is transferred to other activities. In the Competence Network itself, a close interaction with the network of Pathologists (SP3) and subproject 13, which provides the infrastructure for a nation wide tumour tissue collection, exists. With the “European Platform for the Conquest of Lymphomas“ (EPCOL), the Competence Network followed the vote of the midterm report’s reviewers to “go international”. In the future “Network of Excellence” EPCOL also the ideas of accelerating the information transfer and establishing a high-level quality management have been taken up, supplemented by the European-wide coordination of clinical studies. The participation of 14 European countries in this proposed network shows the interest and needs of other European countries for this kind of network structures. For the application, the existing infrastructure of the Central Office was utilised. To date it is discussed whether the existing infrastructure of the current Competence Network can be partially integrated into the EPCOL. A decision about funding is expected in autumn 2003. A further step to maintain the network beyond the BMBF grant period is its transformation into a registered association. To this end, the task force ”Future of the Competence Network” has been initiated. The following activities have been scheduled up to the end of 2003: •

One of the first results of this task force was the decision to open the Competence Network to all partners in lymphoma treatment and research including patients and their advocates, the partners from the health care system and industry. Currently, a proposal for a structure is developed that aims to take into account the interest and needs of these different groups. After general acceptance of this proposal by all future partners, legal support will be requested to formulate the rules for a registered association.



A public relations agency is currently developing a concept for the future Competence Network’s public relations including fundraising possibilities. This concept is strongly dependent on which groups in which form will be part of the future network. Thus both activities – finding a new structure and developing a fundraising/sponsoring concept – have to be brought in line. The current time schedule assumes the founding of an association at the end of 2003 or early 2004.

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5.1.2 Quality management – Data protection and security Over the last months the data protection concept of the pathologists’ network (SP3) was evaluated by the responsible data protection authority of Berlin and duly accepted. However, the data-protection authority of North Rhine-Westphalia (NRW), which due to the fact that the Central Office in Cologne coordinates the Competence Network on the whole participated in the evaluation process, raised some concerns. Currently, data protection issues concerning the study groups are evaluated when a trial protocol is submitted to its primary (master) ethics commission. But to date, no data protection concept that covers all subprojects of the network exists. Recently the Telematics Platform for Medical Research Networks (TMF) has published a general data safety and protection concept for two distinct medical research networks. The concept lists all known requirements, describes the two developed structures and guides through the implementing steps. Based on the instructions, a similar concept will be developed for the Competence Network within the next months. A working group, which comprises members from all lymphoma study groups integrated in the network and from all subprojects with data protection and/or security issues, will meet for the first time in July 2003 to discuss the problems and upcoming activities. In a cooperative project funded by the TMF, the data protection requirements for the informed consent process were analysed. The final report comprises a commented item-list, a condensed checklist for day-to-day use and a legal expert opinion. Discussions of the results with the data protection authorities and the association of ethics committees are in preparation. The results will also provide a basis for the planned data safety and protection concept of the Competence Network.

5.2 Specific objectives 5.2.1 Information service and IT infrastructure (SP1-4) Symposia (SP1): As in the past years, the network will present itself in various forms at medical/scientific meetings, e.g. symposia, posters and exhibition booths. For the first time, the Central Office presented the network internationally at the European Haematology Association (EHA) congress 2003 in Lyon (France). For the rest of the funding period, it is also planned to attend the Annual Meeting of the American Society of Haematology (ASH). Moreover, the presence at patients’ congresses will be increased. For the first time, the Competence Network and the North Rhine-Westphalia NHL self-help group will jointly organize the NHL patients’ congress in October 2003. More than 400 visitors are expected. Homepage (SP1 and SP2): By definition, the homepage is a dynamic structure and will be developed and expanded continuously. The replacement of the current homepage with a more Annual Report Competence Network Malignant Lymphomas 2003

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structured version has been scheduled for summer 2003. To improve the network’s international acceptance, the introductory parts of the homepage will then be available in English, the translation of other parts, however, will be one of the major tasks for the next year. With the relaunch of the homepage, a special service for self-help groups will be provided: The groups will be able to present themselves on the pages of the Competence Network. Over the next years it is also planned to expand the homepage into a comprehensive information and communication portal with support for different communities (personnel of the clinical trials, doctors, scientists, patients etc.) including standard portal functionalities (e.g. email client, user homepages, groupware, public key infrastructure) and ongoing specific information services and applications (e.g. therapy management tools, material databases, databases for histological pictures). IT security management (SP2): Parallel to the development of the data protection concept (see 5.1), the study centres in Cologne, Leipzig, and Munich have to elaborate their local IT-security concepts according to the model of the network’s communication centre in Leipzig. The achieved security level will be confirmed and certified by a third party, in order to document the security reliability of the network. Networks of pathologists (SP3) and radiotherapists (SP4): Establishing the online and offline discussion of lymphoma cases will be in the focus of SP3. The development of the off-line discussion system requires the acquisition of very large images files, which cover the whole tissue section at high resolution. A transmission of the very large data files to all reference centres is not possible. To make the images of the whole tissue sections available for all reference pathologists, only the requested portion of a slide will be transmitted thus enabling rapid high quality transfer of extreme large images via Internet. The major task in the network of radiotherapists (SP4) will be the expansion and evaluation of the integrated communication system. Moreover, the central technical service has to be adapted to increasing requests and usage.

5.2.2 Quality management (SP2, SP5, SP6, SP8, SP12) SP2 and WG-QM: The task of the IT-based quality management will be the functional extension of the “SOP-Creator” (for SOP administration and handling) as well as the realisation of a data dictionary, which provides a consistent term basis for different document types in the context of clinical trials. The objective of the working group Quality Management is to complete the SOP system and to harmonise and implement quality management measures in the study centres, followed by the gradual introduction of the corresponding IT tools (i.e. SOP-Creator, data dictionary) into the management process of clinical trials. Network of private practices (SP5): The main goal of SP5 will be to increase the number of private practices taking part in the data acquisition. In order to have common guidelines for the Annual Report Competence Network Malignant Lymphomas 2003

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members of the network, a concept for a handbook on the diagnosis, therapy and aftercare of lymphoma patients (“Kompetenzguide”) will be elaborated. Survey of health care and epidemiology (SP6 and SP12): Within the so-called „Lymphoma Project“ in Cologne and Saarland (SP6), further lymphoma cases diagnosed up to December 2002 will be recruited. Following closure of the database, the final analysis will be performed including the evaluation of clinical pathways. The collected health insurance data will permit a determination of health care costs of the incident cases. After completion of a comprehensive pilot study, the second phase of SP12 has started in March 2003. The project tries to answer the questions whether or not the patients treated in therapy optimisation protocols (TOPs) are representative for all patients; and whether or not results obtained in TOPs actually extend to patients treated otherwise by linking epidemiological data with the central documentation of multi-centre clinical TOPs. Cochrane Haematological Malignancies Group (SP8): This subproject plans to publish 7 new systematic reviews. The trial research coordinator will develop the CHMG specialised trials register as a research tool of excellence. Moreover, a 'virtual library' for haematological malignancies will be set up in partnership with the German Central Medical Library (ZbMed). In a joint project funded by the “Deutsche Krebshilfe”, a CHMG consumer network will be established.

5.2.3 New therapies (SP10, 11, 13) Long-term effects (SP10): The systematic screening for secondary haematological neoplasias will be extended to patients with aggressive lymphomas, CLL, and multiple myelomas, based on the data of the different clinical study centres. To provide a reliable clinical follow-up of the patients after high-dose therapy, the local database will be transformed into a web-based information platform of up to 300 patients’ samples. Vaccine therapy (SP11): The identification of T-cell epitopes of lymphoma-associated cancer testis antigens (CTA) will continue. The demonstration of the natural processing and the more detailed analysis of the MHC restrictions of identified candidates should be accomplished by the end of 2003. Moreover, a mammalian expression system will be utilised; assuring that the identification of eucaryotically expressed lymphoma antigens can be accomplished by the end of the second funding period. Biologic risk factors (SP13): This subproject aims to build up the infrastructure for the collection and storage of fresh tumour tissue, which will be further investigated within a recently founded joint network (Molecular mechanisms of malignant lymphomas) funded by the “Deutsche Krebshilfe”.

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6 Addresses of board members

6 Addresses of board members 6.1 Board of directors (Engerer Vorstand) Prof. Dr. Volker Diehl (Speaker) Klinikum der Universität zu Köln Joseph-Stelzmann-Str. 9 D-50924 Köln Tel.: +49 (0)221-4784400 Fax: +49 (0)221-4785455 e-mail: [email protected] Prof. Dr. Wolfgang Hiddemann (Vice speaker) Klinikum Großhadern Medizinische Klinik III Marchioninistr. 15 D-81377 München Tel.: +49 (0)89-70952550 Fax: +49 (0)89-70958875 e-mail: [email protected] Prof. Dr. Michael Pfreundschuh (Vice speaker) Universitätskliniken des Saarlandes Innere Medizin I Kirrberger Straße D-66421 Homburg/Saar Tel.: +49 (0)6841-162-3002 Fax: +49 (0)6841-162-3101 e-mail: [email protected] Prof. Dr. Michael Hallek Klinikum Großhadern Medizinische Klinik III Marchioninistr. 15 D-81377 München Tel.: +49 (0)89-70951 Fax: +49 (0)89-21806797 e-mail: [email protected] Prof. Dr. Markus Löffler Universität Leipzig Institut für Medizinische Informatik, Statistik und Epidemiologie Liebigstr. 27 D-04103 Leipzig Tel.: +49 (0)341-9716100 Fax: +49 (0)341-9716109 e-mail: [email protected]

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6 Addresses of board members

Prof. Dr. Rolf-Peter Müller Universität zu Köln Klinik u. Poliklinik für Strahlentherapie Joseph-Stelzmann-Str. 9 D-50924 Köln Tel.: +49 (0)221-4785450 Fax: +49 (0)221-4786158 e-mail: [email protected] PD Dr. Stephan Schmitz Schwerpunktpraxis für Hämatologie und Onkologie Sachsenring 69 D-50677 Köln Tel.: +49 (0)221-9318220 Fax: +49 (0)221-9318229 e-mail: [email protected] Prof. Dr. Harald Stein Universitätsklinikum Benjamin Franklin Institut für Pathologie Hindenburgdamm 30 D-12200 Berlin Tel.: +49 (0)30-84452295 Fax: +49 (0)30-84454473 e-mail: [email protected] Prof. Dr. Lorenz Trümper Georg-August-Universität Zentrum Innere Medizin Hämatologie und Onkologie Robert-Koch-Str. 40 D-37075 Göttingen Tel.: +49 (0)551-398535 Fax: +49 (0)551-398587 e-mail: [email protected]

6.2 Extended board (Erweiterter Vorstand) Dr. Jürgen Bausch Kassenärztliche Vereinigung Hessen Georg-Voigt-Str. 15 D-60325 Frankfurt Tel.: +49 (0)69-79502512 Fax: +49 (0)69-79502590 Dr. Erich Enghofer MedacSchering Onkologie GmbH Nördliche Auffahrtsallee 44 D-80638 München Tel.: +49 (0)89-74514410 Fax: +49 (0)89-74514440 e-mail: [email protected]

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Prof. Dr. Robert Fischer Universität zu Köln Institut für Pathologie Joseph-Stelzmann-Straße 9 D-50924 Köln Tel.: +49 (0)221-4786371 Fax: +49 (0)221-4786360 PD Dr. Michael Herold Klinikum Erfurt GmbH 2. Medizinische Klinik Nordhäuser Str. 74 D-99089 Erfurt Tel.: +49 (0)361-7813502 Fax: +49 (0)361-7814803 e-mail: [email protected] Dr. Ulrike Holtkamp Deutsche Leukämie- und Lymphom-Hilfe e.V. Thomas-Mann-Str. 40 D-53111 Bonn Tel.: +49 (0)228-3 90 44-0 Fax: +49 (0)228-3 90 44-22 e-mail: [email protected] Dr. Peter Koch Universitätsklinik Münster Medizinische Klinik A Hämatologie/Onkologie Albert-Schweitzer-Str. 33 D-48149 Münster Tel.: +49 (0)251-8347593 Fax: +49 (0)251-8347592 e-mail: [email protected] Dr. Birgit Weihrauch Ministerium für Frauen, Jugend, Familie und Gesundheit NRW Fürstenwall 25 D-40219 Düsseldorf Tel.: +49 (0)211-8553557 Fax: +49 (0)211-8553239 e-mail: [email protected]

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