All - Relapsed - All-Rez BFM 2002

ALL-REZ BFM 2002
Protocol for the Treatment of Children with

Relapsed Acute Lymphoblastic Leukemia
Treatment Optimization Study using Chemotherapy and Radiotherapy
by the Society of Pediatric Oncology and Hematology (GOPH)
Version: 25/06/2003
Principal Investigator: G. Henze

Co-principal Investigator: R. Fengler
Study Coordinator: A. von Stackelberg
Documentation: A. Kretschmann
Address of the study center:
Klinik für Pädiatrie m.S. Onkologie/Hämatologie

Charité – Universitätsmedizin Berlin, CVK
Augustenburger Platz 1, D - 13353 Berlin
Germany
Tel: +49-(0)-30-450-566 354

Fax: +49-(0)-30-450-566 901
email: allrez@charite.de
ALL-REZ BFM 2002 II Protocol version: 25.06.2003
Privileged information for investigational use only
This protocol was designed by the members of the ALL-REZ BFM study committee (principal
investigator: Prof. Dr. med. Dr. h.c. G. Henze, Charité Berlin). The content of this protocol is
confidential and must not be disseminated in either oral or written form without the permission of the
principal investigator.
ALL-REZ BFM 2002 III Protocol version: 25.06.2003
Main investigators
Principal investigator Prof. Dr. med. Dr. h.c. Günter Henze 1

Tel: + 49(0) 30/450 566 032
Email: guenter.henze@charite.de
Co-principal investigator Dr. med. Rüdiger Fengler 1

Tel: + 49(0) 30/ 450 566 011
Email: ruediger.fengler@charite.de
Study coordinator Dr. med. Arend von Stackelberg

Tel: + 49(0) 30/ 450 566 354
Email: arend.stackelberg@charite.de
Documentation Andrea Kretschmann 1

Tel: + 49(0) 30/ 450 566 354
Email: allrez@charite.de
Radiation therapy Dr. med. M. Albrecht 2

Tel: + 49(0) 30/ 3976 3611
Email: u.ruehl@khf.de
Bone marrow transplant coordinator Prof Dr. T. Klingebiel 3

Tel: + 49(0) 69/ 6301 5094
Email: tklingebiel@zki.uni-frankfur.de
1
ALL-REZ Studienzentrale
Charité – Universitätsmedizin Berlin, CVK
Augustenburger Platz 1, D – 13353 Berlin
Germany
Tel: + 49(0) 30/ 450 566 354; Fax: + 49(0) 30/450 566 901; Email: allrez@charite.de
2
Klinikum im Friedrichshain
Klinik für Strahlentherapie/Radioonkologie
Standort Moabit-Turmstraße
Turmstr. 21, D- 10559 Berlin
Germany
Telefon: + 49(0) 30/ 3976 – 3611; Telefax: + 49(0) 30/ 3976 – 3609
3
Universitäts – Kinderklinik, Hämatologie/Onkologie

Theodor-Stern-Kai 7
60590 Frankfurt
Germany
Telefon: + 49(0) 69/ 6301 5094; Telefax: + 49(0) 69/ 6301 6700
ALL-REZ BFM 2002 IV Protocol version: 25.06.2003
Members of the study committee
Name Email
Dr. med. M. Albrecht u.ruehl@khf.de
Prof. Dr. med. J.D. Beck joern.beck@kinder.imed.unierlangen.de
Prof. Dr. med. U. Bode bode@ukb.uni-bonn.de
Dr. med. W. Dörffel wdoerffel@berlin.helios-kliniken.de
Dr. med. W. Ebell wolfram.ebel@charite.de
Dr. med. R. Fengler ruediger.fengler@charite.de
Prof. Dr. med. H. Gadner gadner@ccri.univie.ac.at
Prof. Dr. med. U. Göbel KK04AMBZ@uni-duesseldorf.de
Prof. Dr. med. G. Henze guenter.henze@charite.de
Frau Prof. Dr. med. G. Janka janka@uke.uni-hamburg.de
Prof. Dr. med. T. Klingebiel tklingebiel@zki.uni-frankfurt.de
PD Dr. med. E. Koscielniak cws.study@olgahospital.s.shuttle.de
Dr. med. G. Mann mann@ccri.univie.ac.at
Prof. Dr. med. S. Müller-Weihrich smq@lrz.tu-muenchen.de
PD Dr. med. Ch. Peters peters@ccri.univie.ac.at
Prof. Dr. med. J. Ritter ritterj@uni-muenster.de
Prof. Dr. med. M. Schrappe schrappe.martin@mh-hannover.de

ALL-REZ BFM 2002 V Protocol version: 25.06.2003
Reference laboratories
Test Phone/Fax Address
Contact
Cytomorphology, ALL-REZ Studienzentrale,
cytochemistry, treatment Charité CVK
response Klinik für Pädiatrie m.S.
Tel: +49 (0) 30 450 566 354 Onkoligie/Hämatologie
Dr. A.v. Stackelberg Fax: +49 (0) 30 450 566 901 Augustenburger Platz 2,
D – 13353 Berlin
Laboratory Tel: +49 (0) 30 450 566 050 Germany
Fax: +49 (0) 30 450 566 903
Molecular Genetics, ALL-REZ Studienzentrale,
Cytogenetics Charité CVK
Dr. Dr. K. Seeger Tel: +49 (0) 30 450 566 088 Klinik für Pädiatrie m.S.
Fax:+49 (0) 30 450 566 946 Onkoligie/Hämatologie
Augustenburger Platz 2,
D – 13353 Berlin, Germany
MRD - Testing ALL-REZ Studienzentrale,
C. Eckert Tel: +49 (0) 30 450 566 088 Charité CVK
Fax: +49 (0) 30 450 566 946 Klinik für Pädiatrie m.S.
Onkoligie/Hämatologie
Augustenburger Platz 2,
D – 13353 Berlin, Germany
Immunology Immunol. Zellmarkerlabor,
Prof. Dr. WD. Ludwig Tel: +49 (0) 30 9417 1362 Charité, Campus Berlin-Buch
Fax: +49 (0) 30 9417 1308 Robert Rössle Klinik – MDC
Lindenberger Weg 80,
D – 13122 Berlin – Buch,
Germany
MRD Testing after bone
marrow transplantation MRD-/Chimärismuslabor,
Klinik für Kinderheilkunde und
PD Dr. P. Bader Tel: +49(0) 7071 29-83809 Jugendmedizin
Fax: +49(0) 7071 29-5365 Hoppe-Seyler-Straße 1
D – 72076 Tübingen, Germany
ALL-REZ BFM 2002 VI Protocol version: 25.06.2003
Signatures
_____________________________________________ Berlin, 10.02.2003

Prof. Dr. med. Dr. h.c. G. Henze
Principal Investigator
_____________________________________________ Berlin, 10.02.2003

Dr. med. R. Fengler
Co-Investigator
_____________________________________________ Berlin, 10.02.2003

Dr. med. A.v. Stackelberg
Study Coordinator
ALL-REZ BFM 2002 VII Protocol version: 25.06.2003
Abstract
The protocol ALL-REZ BFM 2002 aims at the optimization of treatment for children with
relapsed acute lymphoblastic leukemia. It is designed as a prospective controlled randomized
multi-center study. The participating centers include all hospitals treating children with relapsed
acute lymphoblastic leukemia in Germany and Austria as well as some centers in Switzerland.
The study is based on the results of five consecutive trials performed by the ALL-REZ BFM study
group since 1983. Thus the study meets the criteria of evidence-based therapy, which has been
developed over nearly 20 years. Multi-agent chemotherapy in short intensive courses, which are
separated by treatment-free intervals, has proved to be a successful form of induction and
consolidation therapy. It is followed by preventative (or therapeutic) cranial irradiation and
continuation therapy. A number of risk factors, particularly the time of relapse, site of relapse, and
the ALL immunophenotype, allow the stratification of patients into a group that has an acceptable
prognosis after treatment with chemotherapy alone and a second group that has a high risk of
subsequent recurrence following the achievement of a second remission. The latter group requires
further intensification of consolidation therapy by allogenic stem cell transplantation (SCT). To
date, the indication for SCT has remained unclear for a large and heterogeneous group of patients
with an intermediate prognosis. During the precursor study ALL-REZ BFM 96, however, the
amount of minimal residual disease (MRD) determined quantitatively with clonal molecular
markers after the second induction therapy element was shown to be a highly significant predictor
of relapse-free survival.
The primary objective of study ALL-REZ BFM 2002 is the randomized comparison of a lower
dosed and less intensive, but continuous consolidation therapy with conventional therapy
administered in treatment blocks. Outcome measures are the reduction of MRD, event-free and
overall survival, and the toxicity associated with each treatment strategy.
The secondary objectives include an improvement of the prognosis in the intermediate risk group
using the stratification in treatment arms with and without allogenic SCT based on the MRD result
after the second treatment element of induction therapy. An additional aim is to improve the
remission induction rate in all groups by increasing the treatment intensity during induction. This
is achieved by shortening the intervals between treatment blocks in keeping with the principles of
guiding therapy as defined in the protocol. A series of biological companion studies aims to
advance our understanding of the disorder and to establish novel prognostic factors that will allow
a risk-adapted therapy.
The accrual of the study is planned for 5 years during which approximately 450 patients will be
enrolled.
Time line
Begin of the ALL-REZ BFM Pilot 02 01.01.2002
End of the pilot study 31.07.2003
Begin of the main study ALL-REZ BFM 2002 01.08.2003
End of patient accrual 31.07.2007
End of the treatment phase 31.07.2008
End of the study 31.07.2012
ALL-REZ BFM 2002 1 Protocol version: 25.06.2003
Table of Contents
1 GENERAL REMARKS ...................................................................................................... 6
1.1 Abbreviations ................................................................................................................ 7
2 INTRODUCTION ............................................................................................................... 8
2.1 Design and results of previous studies .......................................................................... 9
2.1.1 Results of studies ALL-REZ BFM 83-90................................................................................... 9
2.1.2 Results of randomizations ........................................................................................................ 11
2.1.3 Prognostic Factors .................................................................................................................... 11
2.2 Study ALL-REZ BFM 95/96 ...................................................................................... 14
2.2.1 Definition of risk groups (S groups)......................................................................................... 14
2.2.2 Study design ............................................................................................................................. 14
2.2.3 Results for the overall study population and for subgroups ..................................................... 15
2.2.4 The randomized use of filgrastim (G-CSF) .............................................................................. 16
2.2.5 Pilot Studies P99 and P01......................................................................................................... 17
2.3 Extramedullary relapse................................................................................................ 18
2.3.1 Isolated CNS relapse ................................................................................................................ 18
2.3.2 Isolated Testicular relapse ........................................................................................................ 19
2.4 Stem Cell Transplantation........................................................................................... 19
2.5 Results of other studies ............................................................................................... 22
3 AIMS AND RATIONALE OF THE STUDY .................................................................. 23
3.1 Conclusions from previous studies.............................................................................. 23
3.1.1 Chemotherapy .......................................................................................................................... 23
3.1.2 Principal treatment guidelines .................................................................................................. 23
3.1.3 Strategic groups and indications for transplantation................................................................. 23
3.1.4 Minimal Residual Disease........................................................................................................ 23
3.2 Aims of study ALL-REZ BFM 2002 .......................................................................... 23
3.3 Comparison of treatment blocks with continuous chemotherapy ............................... 24
3.3.1 Protocol II – IDA...................................................................................................................... 25
3.3.2 R Blocks ................................................................................................................................... 25
3.3.3 Comparison of cumulative drug doses ..................................................................................... 26
3.3.4 Toxicity .................................................................................................................................... 26
3.3.5 Randomization.......................................................................................................................... 26
3.3.6 Monitoring................................................................................................................................ 26
3.4 Stratification according to MRD after the second treatment element ......................... 27
3.5 Increased treatment intensity during initial therapy as a result of shorter intervals
between the initial treatment blocks............................................................................ 28
3.6 Improvement of the remission induction rate in strategic group S4 ........................... 28
3.7 Standardization and monitoring of treatment of L-asparaginase ............................... 29
3.8 Additional aims and modifications.............................................................................. 29
3.8.1 Simplification of continuation therapy – the use of 6-mercaptopurine and oral methotrexate . 29
3.8.2 Autologous SCT for an isolated CNS relapse with unfavorable prognosis .............................. 29
3.8.3 Experimental treatment approaches for high risk groups ......................................................... 30
3.8.3.1 STI571 for BCR-ABL-positive patients................................................................................... 30
3.8.3.2 Re-intensification for S3/4 patients with a positive MRD result prior to SCT ......................... 31
3.9 Scientific companion studies....................................................................................... 31
3.9.1 Prognostic relevance of MRD at additional time points........................................................... 31
3.9.2 Prognostic relevance of MRD prior to SCT ............................................................................. 32
3.9.3 Monitoring of L-asparaginase activity...................................................................................... 32
3.10 Summary of rationale – risk-benefit analysis.............................................................. 32
4 STUDY DESIGN .............................................................................................................. 36
4.1 Features of the study ................................................................................................... 36
4.2 Study Organization...................................................................................................... 36
4.3 Inclusion and exclusion criteria................................................................................... 36
4.4 Duration of study participation ................................................................................... 37

4.5 Recommendations for cases with a subsequent relapse .............................................. 37
4.6 Registration and randomization .................................................................................. 37
4.7 Definition of risk groups ............................................................................................. 38
4.7.1 Treatment group S1 .................................................................................................................. 38
4.8 Treatment Plan ............................................................................................................ 39
4.8.1 Treatment plan.......................................................................................................................... 40
4.8.2 Treatment plan for group S1..................................................................................................... 41
4.9 Radiation Therapy ....................................................................................................... 42
4.9.1 Bone marrow relapse................................................................................................................ 42
4.9.2 CNS relapse.............................................................................................................................. 42
4.9.3 Testicular relapse...................................................................................................................... 43
4.9.4 Radiation technique and dose ................................................................................................... 43
4.10 Other forms of local therapy ....................................................................................... 43
4.10.1 Intrathecal chemotherapy ......................................................................................................... 43
4.10.2 Orchiectomy ............................................................................................................................. 44
4.11 Stem cell transplantation ............................................................................................. 44
4.11.1 Definition of stem cell donor types .......................................................................................... 44
4.11.2 Indications ................................................................................................................................ 44
4.11.3 HLA Typing ............................................................................................................................. 45
4.11.4 Transplantation protocol........................................................................................................... 46
4.11.5 Documentation ......................................................................................................................... 48
4.12 Continuation therapy ................................................................................................... 48
4.12.1 Reinduction pulses with etopside ............................................................................................. 48
5 TREATMENT ELEMENTS ............................................................................................. 49
5.1 Cytoreductive prephase ............................................................................................... 49
5.2 Intrathecal chemotherapy ............................................................................................ 49
5.3 Block F1 ...................................................................................................................... 50
5.4 Block F2 ...................................................................................................................... 50
5.5 R2-Block ..................................................................................................................... 50
5.6 R1-Block ..................................................................................................................... 51
5.7 Protocol II-IDA ........................................................................................................... 52
6 DRUGS.............................................................................................................................. 53
6.1 Instructions for the administration of chemotherapeutic agents.................................. 53
6.1.1 L-asparaginase.......................................................................................................................... 53
6.1.2 Cyclophosphamide ................................................................................................................... 53
6.1.3 Cytarabine ................................................................................................................................ 53
6.1.4 Daunorubicin ............................................................................................................................ 54
6.1.5 Dexamethasone ........................................................................................................................ 54
6.1.6 Etoposide.................................................................................................................................. 54
6.1.7 Idarubicin ................................................................................................................................. 54
6.1.8 Ifosfamide................................................................................................................................. 54
6.1.9 Methotrexate............................................................................................................................. 54
6.1.10 Folinic acid rescue.................................................................................................................... 54
6.1.11 6-Mercaptopurine ..................................................................................................................... 55
6.1.12 Prednisone ................................................................................................................................ 55
6.1.13 6-Thioguanine .......................................................................................................................... 55
6.1.14 Vincristine ................................................................................................................................ 55
6.1.15 Vindesine.................................................................................................................................. 55
6.2 Mechanisms of action and side effects........................................................................ 55
6.2.1 L-asparaginase.......................................................................................................................... 55
6.2.2 Cyclophosphamide ................................................................................................................... 56
6.2.3 Cytarabine ................................................................................................................................ 56

6.2.4 Daunorubicin ............................................................................................................................ 56
6.2.5 Dexamethasone ........................................................................................................................ 57
6.2.6 Etoposide.................................................................................................................................. 58
6.2.7 Idarubicin ................................................................................................................................. 58
6.2.8 Ifosfamide................................................................................................................................. 58
6.2.9 Methotrexate............................................................................................................................. 58
6.2.10 Mercaptopurine ........................................................................................................................ 58
6.2.11 Prednisone ................................................................................................................................ 59
6.2.12 6-Thioguanine .......................................................................................................................... 59
6.2.13 Vincristine ................................................................................................................................ 59
6.2.14 Vindesine.................................................................................................................................. 59
7 GUIDELINES FOR THE ADMINISTRATION OF PROTOCOL THERAPY............... 60
7.1 General principles ....................................................................................................... 60
7.2 F blocks ....................................................................................................................... 60
7.3 First block R2 .............................................................................................................. 60
7.4 First block R1 .............................................................................................................. 60
7.5 Subsequent treatment blocks R1 and R2..................................................................... 61
7.6 Protocol II-IDA ........................................................................................................... 61
7.7 Reduction of the treatment intensity based on toxicity ............................................... 61
7.8 Continuation therapy ................................................................................................... 62
7.8.1 Reinduction Pulses ................................................................................................................... 63
8 SUPPORTIVE CARE ....................................................................................................... 64
8.1 Emergencies ................................................................................................................ 64
8.1.1 Acute tumour lysis syndrome ................................................................................................... 64
8.1.2 Impaired elimination of methotrexate ...................................................................................... 64
8.1.3 Extravasation of anthracyclines or vinca alkaloids................................................................... 64
8.2 Prophylactic measures................................................................................................. 65
8.3 Anti-emetic treatment.................................................................................................. 65
8.4 Interventional supportive therapy................................................................................ 65
8.4.1 Mucosal Lesions....................................................................................................................... 65
8.4.2 Febrile Neutropenia .................................................................................................................. 66
8.4.3 GCSF........................................................................................................................................ 66
8.4.4 Transfusion of blood products.................................................................................................. 66
9 DIAGNOSTIC TESTS ...................................................................................................... 67
9.1 Definitions................................................................................................................... 67
9.1.1 Site of Relapse.......................................................................................................................... 67
9.1.2 Response to therapy and course................................................................................................ 67
9.1.3 Subsequent Relapse .................................................................................................................. 68
9.2 Initial diagnostic tests at relapse of ALL..................................................................... 68
9.2.1 Bone Marrow............................................................................................................................ 68
9.2.2 CNS .......................................................................................................................................... 70
9.2.3 Testis ........................................................................................................................................ 70
9.2.4 Other forms of relapse .............................................................................................................. 70
9.3 Diagnostic tests during the course of treatment .......................................................... 70
9.3.1 Response to therapy.................................................................................................................. 70
9.3.2 Infectious Diseases ................................................................................................................... 71
9.3.3 HLA Typing ............................................................................................................................. 72
9.3.4 Diagnostic tests during continuation therapy ........................................................................... 72
9.3.5 Diagnostic tests at the end of therapy ....................................................................................... 72
9.3.6 Follow-up investigations, detections of late effects.................................................................. 72
9.4 Minimal Residual Disease (MRD) .............................................................................. 72
9.5 Time points for the collection of samples ................................................................... 73
9.6 Shipment of samples ................................................................................................... 73
9.7 Reference Institutions.................................................................................................. 73
9.8 Addresses of laboratories ............................................................................................ 73
9.8.1 Molecular biology and diagnosis of MRD ............................................................................... 73
9.8.2 MRD Diagnostic following SCT.............................................................................................. 74

9.8.3 Immunology ............................................................................................................................. 74
9.9 Scientific Companion Studies ..................................................................................... 75
9.9.1 MRD diagnosis by flow cytometry .......................................................................................... 75
9.9.2 Spectral karotyping (SKY) ....................................................................................................... 75
9.9.3 mRNA expression arrays/microchip analysis........................................................................... 75
9.9.4 In vitro resistance to apoptosis-inducing agents ....................................................................... 75
10 PATIENT SAFETY ......................................................................................... 76
10.1 Adverse Events............................................................................................................ 76
10.1.1 Documentation and evaluation of adverse events..................................................................... 76
10.2 Severe adverse events.................................................................................................. 76
10.2.1 Documentation and reporting of severe adverse events ........................................................... 76
11 EVALUATION CRITERIA AND STATISTICAL ANALYSIS.................... 77
11.1 Definitions................................................................................................................... 77
11.2 Criteria for the evaluation of the study results ............................................................ 77
11.3 Statistical methods....................................................................................................... 78
11.4 Estimation of accrual................................................................................................... 79
11.5 Stoppage criteria.......................................................................................................... 79
11.6 Documentation and Randomization ............................................................................ 80
11.7 Definition and report of adverse events ...................................................................... 80
11.8 Quality Assurance ....................................................................................................... 80
12 ETHICS............................................................................................................ 82
12.1 Declaration of Helsinki ............................................................................................... 82
12.2 Research Ethics Board ................................................................................................ 82
12.3 Disclosure and consent to participation in the study ................................................... 82
12.4 Use, storage and transmission of data ......................................................................... 82
12.5 Pertinent laws and administrative guidelines .............................................................. 82
12.6 Process for Protocol Amendments .............................................................................. 83
13 REFERENCES................................................................................................. 84
14 APPENDICES.................................................................................................. 90
APPENDIX 1: DISCLOSURE AND CONSENT......................................................................91

Guidelines for disclosure and consent to treatment .......................................................................... 92
Summary of disclosure session ......................................................................................................... 94
Patient information and consent to treatment .................................................................................... 96
Consent to forwarding and processing of personal data ................................................................. 100
APPENDIX 2: DOCUMENTATION OF TREATMENT BLOCKS..........................................102

DOCUMENTATION OF BLOCKS ........................................................................................103
Block F1 ........................................................................................................................................... 103
Block F2 ........................................................................................................................................... 104
Block R2........................................................................................................................................... 105
Block R1........................................................................................................................................... 106
Protokoll II-IDA................................................................................................................................. 107
ORDER SETS ......................................................................................................................108

Block F1 ........................................................................................................................................... 109
Block F2 ........................................................................................................................................... 110
Block R2........................................................................................................................................... 111
Block R1........................................................................................................................................... 112
Protokoll II-IDA (Part 1).................................................................................................................... 113
Protokoll II-IDA (Part 2).................................................................................................................... 114
Infusion orders for methotrexat (1 g/m2/36h) ................................................................................... 115
Infusion orders for cytarabine during block F2................................................................................. 116
Infusion orders for cytarabine during block R1 ................................................................................ 117
Infusion orders for ifosfamide during block R2 ................................................................................ 118
Infusion orders for cyclophosphamide during protocol II-IDA.......................................................... 119
Folinic acid rescue for methotrexat (1 g/m2/36h) ............................................................................. 120
APPENDIX 3: DATA COLLECTION FORMS.......................................................................121

Registration form for patients with relapsed ALL............................................................................. 122
Report of a subsequent event.......................................................................................................... 123
Report of a severe adverse event.................................................................................................... 124
Toxcity form - arm A (protocol II-IDA) and arm B (R blocks) ........................................................... 125
Documentation of the course of therapy.......................................................................................... 126
Checklist (required documentation) ................................................................................................. 127
Documentation of late effects .......................................................................................................... 128
Monitoring of late effects.................................................................................................................. 129
APPENDIX 4: REQUISITIONS ............................................................................................130

Cytology, molecular studies, MRD................................................................................................... 131
Immunophenotyping ........................................................................................................................ 132
Chimerism and MRD studies following SCT.................................................................................... 134
ETHICS REVIEW .................................................................................................................136

ALL-REZ 2002- LIST OF PARTICIPATING CENTERS .......................................................138
1 GENERAL REMARKS
The concept of this treatment protocol was approved by the members of the study committee in
February 2001 and presented to the plenary session of the BFM study group in September 2001. The
pilot phase with the objective to prove the feasibility of the protocol therapy ran from January 2002 to
July 2003. The main study began on 1st August 2003. It is anticipated to conclude on 30th July 2008.
The specific type and combination of therapeutic instructions described in this protocol do not
represent the recommendation of a universally accepted form of treatment. Rather, these instructions
represent guidelines that are part of a study aimed at the optimization of therapy. For ethical and legal
reasons, therefore, it is not permissible to treat patients according to this protocol in centers that do not
participate in the study and thus do not meet the requirements of documentation and ongoing feedback
with the study center. Patients and/or their legal guardians have to be informed accordingly.
The highest degree of diligence was used during the preparation of this protocol. Nevertheless, errors
cannot be completely ruled out. Therefore, it is important to point out that the treating physician
ultimately is responsible for the treatment. The principal investigator does not assume any legal
responsibility for consequences that may result from the implementation of recommendations made in
this protocol. Registered trademarks were identified. However, it cannot be concluded from the
absence of such identification that a registered trademark does not apply.
The aids for data documentation, which are provided in this protocol such as the documentation of
treatment blocks and order sets for infusions, are merely recommendations. It is, for example,
impossible to summarize the entire information that is pertinent to a particular treatment block in a
legible form on a single page. Each participating center, therefore, may design its own aids for the
documentation as it considers them appropriate. The study center accepts any form of documentation
that shows the same information in unequivocal fashion and allows a review of the diagnosis,
treatment and course.
The study center offers an extensive spectrum of additional services. They include the central review
of bone marrow and peripheral blood smears, CSF cytospin and tumor touch preparations. All patient
data collected during the study will be carefully documented and reviewed at regular intervals. All
centers participating in this study have access to consultation for any diagnostic and therapeutic issue.
Typically, a response will be provided within 24 hours. In the case of severe adverse effects of therapy
the study center will contact the treating center immediately.
The services provided by the study center also include a consultation regarding the indication for stem
cell transplantation (SCT) in individual patients. Due to the ongoing feedback with other transplant
centers the recommendations reflect the most up-to-date practice of stem cell transplantation. Upon
request the study center is also willing to assist with the referral of patients to transplant centers. Bone
marrow transplant beds are also available at the study center.
1.1 Abbreviations
6-MP 6-mercaptopurine
6-TG 6-thioguanine
ALL acute lymphoblastic leukemia
ARA cytosine arabinoside
Asp asparaginase
BFM Berlin-Frankfurt-Münster
CCG Children's Cancer Group
CML chronic myeloid leukemia
CPM cyclophosphamide
C(C)R complete (continuous) remission
DNR daunorubicin
Dexa dexamethasone
EFS event-free survival
HD high-dose
G-CSF granulocyte-colony stimulating factor
HLA human leukocyte antigen
IDA idarubicin
IFO ifosfamide
i.t. intrathecal
i.v. intravenous
MFD matched family donor
MRC Medical Research Council
MRD minimal residual disease
MSD matched sibling donor
MTX methotrexate
MUD matched unrelated donor
p probability
PBC peripheral blood cell count
PEG polyethylene glycol
POG Pediatric Oncology Group
PPG poor prognosis group
Pred prednisone
REZ relapse
SCT, SZT stem cell transplantation
SRV survival
U unit(s)
VCR vincristine
VDS vindesine
CNS central nervous system
2 INTRODUCTION
The Berlin-Freiburg-Münster (BFM) study group has evaluated approaches to the treatment of
children with a relapse (REZ) of acute lymphoblastic leukemia (ALL) in multi-center studies since
1983. The study group comprises more than 100 centers in Germany, Austria and Switzerland. It can
be assumed that almost all children with relapsed ALL in Germany and Austria are enrolled.
Compared to the primary disease, the probability of cure is significantly lower for children with a
relapse. The overall probability of survival after 5 years is approximately 35%. The primary objective
of the ALL-REZ BFM studies, therefore, is to improve the chance of cure for these children. Proven
therapeutic interventions include chemotherapy, radiation therapy and stem cell transplantation (SCT).
In addition, companion research studies aim to advance our insight into this disorder. The results of
the ALL-REZ BFM relapse studies have to be viewed together with the results of the treatment studies
for primary ALL. Since the primary ALL-BFM studies have achieved a continual improvement of
results and a decreased rate of recurrence, we anticipate that a decreasing number of patients will be
available for the relapse studies and that the cases of leukemia will be more resistant as a result of the
more intensive risk-adapted primary therapy (Schrappe et al., 2000). The number of patients treated on
the pilot and main studies over the years as well as the number of patients with protocol violations is
shown in fig. 1.
Fig. 1: Number of registrations of a first relapse by year and treatment strategy
140
120
number of violation
100
80
60
treatment
40
treatment violation
20
pilot study
0 main study
83 85 87 89 91 93 95 97 99
year of relapse
2.1 Design and results of previous studies
2.1.1 Results of studies ALL-REZ BFM 83-90

The risk-adapted treatment concept of the first four ALL relapse studies, ALL-REZ BFM 83, 85, 87
and 90, was based on the stratification of patients into three strategic groups. This stratification used
the time and site of relapse as prognostic factors and reflected the state of the field at the beginning of
the 1980s. In strategic group A patients with an early bone marrow relapse were treated with nine
blocks of chemotherapy. In strategic group B patients with a late bone marrow relapse received eight
blocks of chemotherapy. Strategic group C, comprising patients with an isolated extramedullary
relapse, initially received four blocks - and since study ALL-REZ BFM 86 a total of six blocks - of
chemotherapy. Two different combinations of cytotoxic drugs, block R1 and R2, were used in an
alternating fashion. In strategic group A of study 83 the induction protocol E and in studies 85 and 87
two additional blocks of induction therapy, protocol F, were used (fig. 2, p.10). All blocks contained
intermediate-dose or high-dose methotrexate. The cumulative anthracyline dose was 200 mg/m2 and
150mg/m2 daunorubicin, respectively (Henze et al., 1994a; Henze et al., 1991).
Study 90 evaluated the efficacy of the newly designed treatment block R3 in comparison to historical
controls. This treatment block contained high-dose cytarabine and etoposide as essential elements and
was used in alternating fashion together with the conventional treatment blocks R1 and R2. At present,
with a 10-year follow up, block R3 has not resulted in a detectable improvement of results (fig. 4,
p.11).
Only patients for whom the protocol therapy was expected to be efficacious were included in study 90.
Children with a particularly unfavorable prognosis (poor prognosis group, PPG), i.e. patients with a
very early bone marrow relapse or with a (even extramedullary) relapse of a T-ALL were no longer
part of the main study but instead were treated according to pilot protocols.
In all studies mentioned above the phase of intensive chemotherapy in blocks was followed by
radiation therapy. In case of a testicular or CNS relapse the involved compartment was irradiated.
During the course of studies 85/87 preventative cranial irradiation proved important for the
improvement of relapse-free survival in patients with a bone marrow relapse even in the absence of
CNS involvement (Buhrer et al., 1994). Since study 90 all patients with a bone marrow relapse have
been treated with cranial irradiation at a dose of 12Gy.
After the completion of the intensive phase of therapy, patients in groups A/B received 24 months and
patients in group C 12 months of continuation therapy with 6-thioguanine (6-TG p.o., daily) and
methotrexate (MTX i.v., q 14 days).
Since 1983, stem cell transplantation (SCT) has been increasingly used to maintain a remission. The
improvement of relapse-free survival by allogeneic SCT, however, was accompanied by increased
morbidity and mortality so that this procedure was primarily reserved for children with a particularly
unfavorable prognosis (Borgmann et al., 1997; Borgmann et al., 1995a; Dopfer et al., 1991). The
indication for allogeneic SCT was particularly unclear and was not standardized in the group of
children with an intermediate prognosis. The overall results of studies 83 to 90 are shown in fig.3
(p.10). Due to the exclusion of the PPG from study 90, patients with a corresponding risk profile were
also excluded from the analysis of other studies to allow a comparison. A largely consistent event-free
survival of 30-40% is apparent without further significant improvement during the course of these
studies.
Fig. 2: Studydesign ALL-REZ BFM 83 to 90
ALL- group week 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27
REZ A C E R1 R2 R1 R2 R1 R2 R1 R2 D 24
BFM
B C R1 R2 R1 R2 R1 R2 R1 R2 D 24
83
C C R1 R2 R1 R2 D12
group week 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29
A R C F R1 R2 R1 R2 R1 R2 R1 R2 D24
85/
87 B (R) C R1 R2 R1 R2 R1 R2 R1 R2 D 24
C (R) C R1 R2 R1 R2 R1 R2 D12
group week 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29
90 A/B R C R1 R2 R3 R1 R2 R3 R1 R2 R3 D24
C R C R1 R2 R3 R1 R2 R3 D12
C, cytoreductive pre-phase; D 24 / 12 , continuationtherapy 24 / 12 month; R, randomization; , radiation

therapy; E / R1 / R2 / R3 / F (= F1 / F2), Polychemotherapie-Blöcke.
Fig. 3: Event-free survival of protocol patients, studies ALL-REZ BFM83-95, PPG excluded; status 09/01
1,0
,8
pEFS
,6
,4
,2
0,0
0 5 10 15
Years
________
83: n= 65; cens.= 20; pEFS= .30 ± .06
__ __ __
85: n= 101; cens.= 36; pEFS= .35 ± .05
_____
87: n= 151; cens.= 57; pEFS= .38 ± .04
__ _ __ _
90: n= 374; cens.= 136; pEFS= .36 ± .03
__ _ _ __
95/96 n= 408; cens.= 253; pEFS= .47 ± .03
p = 0.017
2.1.2 Results of randomizations

In study 85 the treatment with high-dose methotrexate at a dose of 1g/m2/36 hours (with two doses of
leucovorin) was randomized with high-dose methotrexate at 12g/m2/4 hours (with 12 doses of
leucovorin). The randomization was terminated early because no advantage but instead a trend toward
more frequent subsequent relapse was detected in the arm using the higher methotrexate dose (Henze
et al., 1991). Study 89 randomized the sequence of high-dose methotrexate and high-dose Ara-C
during protocol F. A difference between the arms using methotrexate vs. Ara-C as the first element
could not be demonstrated. In study 90 a randomized comparison of high-dose methotrexate at a dose
of 5g/m2/24 hours (with three doses of leucovorin) vs. 1g/m2/36 hours was performed. No difference
of EFS or subsequent extramedullary relapse could be detected between both groups at a median
follow up of 8.6 years (fig.5), (Henze et al.,1994b). Based on these results a methotrexate dose of
1g/m2 infused over 36 hours will be used in treatment blocks F1, R1 and R2 with two doses of
leucovorin.
Fig. 4: Historical comparison of block therapy with Fig. 5: Randomization of MTX 1 g/m² vs. 5 g/m²,
(study 90) vs. without R3 (studies 83-87), PPG PPG excluded, SCT censored, ALL-REZ BFM 90;
excluded, SCT censored status 09/01
1,0 1,0
,8 pEFS ,8
,6 ,6
pEFS
,4 ,4
,2 ,2
0,0
0,0
0 2 4 6 8 10
0 2 4 6 8 10
years
years
n= 374; cens.= 187; pEFS= .38 ± .03 5 g/m²: n= 128; cens.= 65; pEFS= .40 ± .05
____
with R3:
without R3: n= 317; cens.= 133; pEFS= .33 ± .03 1 g/m²: n= 141; cens.= 71; pEFS= .38 ± .05
______
p= 0.47 p= 0.96
2.1.3 Prognostic Factors

Several prognostic factors could be established as the basis for a risk-adapted stratification in studies
83 to 90. The time (fig.6, p.12) and the site of relapse (fig.7, p.12) were used for stratification into
groups A, B and C. It was demonstrated that patients with a combined bone marrow relapse had a
better prognosis than patients with an isolated bone marrow relapse (Buhrer et al., 1993). Children
with a relapse of a T-ALL had a significantly lower event-free survival than those with a relapse of a
B precursor ALL (fig.8, p.12), (Henze, 1997). In addition, male gender and older age at the diagnosis
of primary ALL were found to be prognostically unfavorable parameters in children with a CNS
relapse (Stackelberg, et al. 1999). Patients with BCR-ABL-positive leukemia have an unfavorable
prognosis at relapse. The expression of BCR-ABL has independent prognostic relevance despite its
association with known adverse prognostic factors (fig. 10, p.13), (Beyermann et al., 1997). The
cryptic translocation t(12;21) and its molecular correlate TEL-AML1 represent the most common
chromosomal aberration in children with relapsed ALL with a frequency of approximately 20%. This
translocation is associated with favorable prognostic factors such as a long duration of first remission
and a low peripheral blast count at the diagnosis of relapse. Although TEL-AML1 is a favorable
prognostic parameter in a univariate analysis (fig.11, p.13) (Seeger et al., 1998), a trend but no
significant independent prognostic value is evident in a multivariate and matched-pair analysis,
respectively (Seeger et al., 2001).
Fig. 6: Event-free survival dependent on time of Fig. 7: EFS dependent on site of relapse, studies 83-96,
relapse, studies 83-96, SCT censored; status 09/01 SCT censored (isol. EM, isolated extramedullary; comb.,
combined bone marrow; isol. BM, isolated bone marrow)
1,0 1,0
,8 ,8
,6 ,6
pEFS
pEFS
,4 ,4
,2 ,2
0,0 0,0
0 2 4 6 8 10 0 2 4 6 8 10
years years
late: n = 669; cens. = 394; pEFS = .45 ± .02 isol.EM: n = 233; cens.= 139; pEFS= .52 ± .04
__ __
early: n = 421; cens. = 206; pEFS = .26 ± .03 comb.: n = 300; cens.= 164; pEFS= .44 ± .03
____
very early: n = 217; cens. = 67; pEFS = .15 ± .03 isol.BM: n = 774; cens.= 364; pEFS= .23 ± .02
______
p < 0.001 p < 0.001
Fig. 8: Event-free survival dependent on immunopheno- Fig. 9: Event-free survival dependent on the interval
type, studies 83-96, SCT censored; status 09/01 between the first two treatment elements; ALL-REZ BFM
90, all documented patients; status 09/01
1,0 1,0
,8 ,8
,6 ,6
pEFS
pEFS
,4 ,4
,2 ,2
0,0 0,0
0 2 4 6 8 10 0 2 4 6 8 10
years years
non-T: n = 669; cens.= 394; pEFS= .45 ± .02

______
<21 days: n= 94; cens.= 45; pEFS=.48±.05
n = 217; cens.= 67; pEFS= .34 ± .02
__ __ _
T: 21 -25 days: n=129; cens.= 48; pEFS=.37±.04
____
>25 days: n= 78; cens.= 22; pEFS=.27±.05
p < 0.001 p < 0.01
The prognostic impact of treatment intensity during the phase of therapy in blocks was first evaluated
in study ALL-REZ BFM 90. Patients with shorter intervals between the initial treatment blocks had a
more favorable event-free survival (fig.9) (Hartmann et al., 1995).
Fig. 10: Event-free survival dependent on the expression Fig. 11: Event-free survival dependent on expression of
of BCR-ABL, studies 83-96, SCT censored; status 09/01 TEL-AML1, studies 83-96, SCT censored; Stand 09/01
1,0 1,0
,8 ,8
pEFS
,6 pEFS
,6
,4 ,4
,2 ,2
0,0 0,0
0 2 4 6 8 10 0 2 4 6 8 10
Years Years
BCR-ABL-: n = 546; zens = 318; pEFS= .37 ± .03 TEL-AML1+: n = 70; zens.= 57; pEFS=.68 ±.08
______
n = 715; zens.= 331; pEFS= .34 ± .02 n=903; zens.= 415; pEFS=.33 ±.02
____
no data: no data:
BCR-ABL+: n = 46; zens.= 18; pEFS= .16 ± .09 TEL-AML1-: n=306; zens.=136; pEFS=.29 ±.04
__ __
p < 0.001 p < 0.001

2.2 Study ALL-REZ BFM 95/96
2.2.1 Definition of risk groups (S groups)

The strategic groups S1 to S4 were developed as novel risk groups that were based on known
prognostic factors such as time and site of relapse as well as the blast immunophenotype (table 8.,
p.38). The retrospective application of these criteria to previous studies showed that group 1 had a
satisfactory prognosis with chemotherapy alone. Thus further intensification of therapy did not appear
warranted. In contrast, patients in group S3 and S4 had an event-free survival of less than 5% after
chemotherapy with an extraordinarily low remission induction rate in group S4. For these groups the
intensification of therapy - after a complete remission was achieved - was absolutely mandatory. This
goal was addressed by introducing mandatory stem cell transplantation. The largest and heterogenous
group S2 showed an intermediate prognosis with chemotherapy alone. In this group the clarification of
the indication for potential SCT using additional risk factors was important. The inclusion of patients
with an early and very early isolated extramedullary relapse in this group resulted in an increase of
treatment intensity for this subset of patients compared to previous studies (fig.12).
Fig. 12: Event-free survival dependent on the strategic Fig. 13: Event-free survival dependent on the strategic
group,studies95/96, SCT censored; status 09/01 group, study 95/96, and SCT; status 09/01
1,0 1,0
,8 ,8
,6 ,6
pEFS
pEFS
,4 ,4
,2 ,2
0,0 0,0
0 2 4 6 8 10 0 1 2 3 4 5 6
years years
pEFS = .75 ± .06 n = 29; cens. = 24; pEFS = .79 ± .09

______
S1: n = 51; cens. = 40;
pEFS = .38 ± .02 n = 325; cens. = 206; pEFS = .48 ± .04
__ __
S2: n = 577; cens. = 277;
pEFS = .02 ± .02 n = 69; cens. = 26; pEFS = .25 ± .06
____
S3: n = 153; cens. = 46;
pEFS = .04 ± .02 n = 106; cens. = 20; pEFS = .19 ± .04
__ _ __
S4: n = 252; cens. = 60;
p < 0.001 p < 0.001
2.2.2 Study design

The design of study ALL-REZ BFM 95/96 is depicted in fig.14 (p.15). Study 95 is the pilot study of
study 96. The only difference between both studies is the randomized use of G-CSF in study 96
whereas treatment with G-CSF was assigned by the study center in study 95. Except for the
randomized question the results of both studies were combined.
Patients in group S1 continued to receive 6 R-blocks in addition to induction therapy with blocks F1
and F2. Local radiation therapy and 12 months of continuation therapy followed. For this group the
aim was to reproduce the favorable result of a greater than 70% EFS.
Patients in group S2 received 8 alternating blocks R1 and R2 after the induction blocks F1 and F2.
This was followed by cranial irradiation for all patients with CNS or bone marrow involvement and by
24 months of continuation therapy. The latter included reinduction pulses with VP16. After a complete
remission was achieved stem cell transplantation could be performed as treatment alternative
depending on the availability of a suitable donor and on the subgroup within S2 (for definitions see
tab. 3, p.21).
Similarly, patients in group S3 received induction therapy with F blocks followed by a series of
alternating R blocks. After a complete remission was achieved mandatory SCT followed.
Additionally, the use of G-CSF during the intervals between the first four treatment blocks was
randomized for patients in group S2 and S3. The aim was to evaluate if G-CSF resulted in the
intensification of induction therapy and, as a consequence, the improvement of remission induction
rate and survival.
Patients in group S4 were treated with a novel induction block I followed by S blocks. The design of
these blocks focused on a somewhat reduced treatment intensity and improved therapeutic control.
The aim was to reduce the comparatively high treatment-related mortality and induction death rate
observed in the previous studies. These blocks used idarubicin, etoposide and thiotepa, cytotoxic
agents that had shown activity in vitro against highly drug-resistant leukemic cells. After the
achievement of a complete remission prompt SCT was recommended since an early subsequent
relapse had to be anticipated.
Fig. 14: Design of study ALL-REZ BFM 95/96

group week 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29
S1 C F1 F2 R1 R2 R1 R2 R1 R2 D 12
S2 R C F1 G? F2 G? R1 G? R2 R1 R2 R1 R2 R1 R2 D 24V
S3 R C F1 G? F2 G? R1 G? R2 stemm cell transplantation
S4 I G S G S G S G stemm cell transplantation
C, cytoreductive pre-phase; D12, continuation therapy 12 months; D24V, continuation therapy 24 months
with VP16 reinduction pulses; R, randomization; , radiation therapy; R1 / R2 / F1 / F2, chemotherapy
blocks
2.2.3 Results for the overall study population and for subgroups
With a study duration of 6 years and 2 months and a median follow up of 2.7 years (5.5 years for study
95, 2.0 years for study 96) the .47±.03 pEFS of study 95/96 is a significant improvement over the
preceding studies (fig.3, p.10). When the criteria underlying the strategic groups S1 to S4 are
retrospectively applied to the previous studies, it is evident that the satisfactory result of group S1
could be reproduced. In group S3 and S4 the event-free survival plateaued at 25% and 19%,
respectively. This result, however, does not represent a significant improvement compared to previous
studies when transplantation is taken into account. Moreover, the trend of the remission induction rate
in group S4 is significantly worse compared with studies 85 and 87 (induction therapy with protocol
F1 and F2). The rate of induction deaths could not be reduced (table 1, p.16). Patients in group S3 and
S4 who were transplanted in CR had an event-free survival of 40%. All patients who were not
transplanted early despite achieving a CR had a subsequent event (fig.15, p.16).
The event-free survival of group S2 was significantly better than in previous studies (fig.16, p.16).
Tab. 1: Results of induction therapy in group S4 dependent on treatment protocol; PPG included
ALL-REZ BFM 85 / 87 90 (PPG) 95/96

N % N % N %
Protocol patients 54 100 131 100 106 100
death during induction 3 6 12 9 12 11
non-response 12 22 37 28 38 36
complete remission* 39 72 82 63 56 53
• studies 85/87 vs. 95/96: p = 0.03
Fig. 15: Event-free survival of patients in group S3 and S4 Fig 16: EFS of patients in group S2; studies 95/96 vs. 83-
(after achieving a CR) with vs. Without SCT; studies 90; PPG excluded; status 09/01
95/96; status 09/01
1,0 1,0
,8 ,8
,6 ,6
pEFS
pEFS
,4 ,4
,2 ,2
0,0 0,0
0 1 2 3 4 5 6 0 2 4 6 8 10
years years
n = 71; cens. = 31; pEFS = .41 ± .06 n = 313; cens. = 204; pEFS = .49 ± .04
__ __
SZT: 95/96:
______
no SZT: 83-90:
p = 0.013
2.2.4 The randomized use of filgrastim (G-CSF)

The randomized use of G-CSF (filgrastim) in group S2 and S3 was completed according to schedule in
January 2001. The randomization rate was greater than 80%. The proportion of deviations from the
randomized treatment was significantly higher in the group randomized to the arm without G-CSF.
Preliminary results show that the intervals between the initial treatment blocks were significantly
shorter in the G-CSF arm (fig.20, p.17). The majority of patients, however, continued their treatment
according to the time points specified in the treatment overview even though this continuation may
have violated the principles for the administration of therapy as defined by the protocol. As a
consequence, the full extent to which treatment intensity during induction could have been increased
in each arm was not realized. The event-free survival does not show a significant difference between
both arms whether analyzed by ‘intention to treat’ (fig.18, p.17) or ‘treatment received’ (fig.17, p.17).
An increase of the initial treatment intensity due to more stringent principles for the administration of
chemotherapy cannot be proved in comparison to historical controls because of differences in the
study design. As in study 90, however, a prognostic impact of the interval between the first two
treatment elements (F1 and F2) was demonstrated, which was independent of the use of G-CSF
(fig.19, p.17). Preliminary toxicity data (documented according to modified WHO criteria) did not
show a difference between both arms.
Fig. 17: G-CSF randomization: analysis by treatment Fig. 18: G-CSF randomization: intention-to-treat analy-
received ; status 09/01 sis; status 09/01
1,0 1,0
,8 ,8
,6 ,6
pEFS
pEFS
,4 ,4
,2 ,2
0,0 0,0
0 1 2 3 4 5 0 1 2 3 4 5
years
years
__ __
G-CSF-:
n = 108; cens. = 58; pEFS = 40 ± .08 n = 118; cens. = 63; pEFS = .41 ± .07
______
G-CSF+:
p = 0.30
Fig. 19: Event-free survival dependent on the interval Fig. 20: Intervals between the first 4 blocks of therapy
between the first two treatment elements F1/F2; ALL-REZ treatmentarms with and without G-CSF; ALL-REZ BFM
BFM 95/96, strategie group S2 95/96, strategie group S2/S3 with documentation of
intervals
1,0 F1/F2 F2/R1 R1/R2

30
,8
25
,6
pEFS
D
,4 a 20
y
s
,2
15 G-CSF
0,0
without
0 1 2 3 4 5
10 with
years N = 38 50 38 48 37 42
P= 0.049 0.11 0.025

interval:
≤ 14 days: n= 114; cens.= 75; pEFS= .50 ±.07
______
n= 126; cens.= 70; pEFS= .44 ±.06

__ __ _
> 14 days:
p = 0.02
2.2.5 Pilot Studies P99 and P01

After the decreased remission induction rate of group S4 - compared to previous studies - became
apparent, a pilot study was started July 1999 to evaluate a modified protocol II in this group. The first
part of this design corresponded to protocol II-IDA. The second part, however, was equivalent to a
CWS relapse protocol with two doses of cyclophosphamide at 1.5g/m2 and 4 doses VP16 at 150mg/m2
(CV). Additional blocks included modified blocks R3 (R3m) with high-dose cytarabine (HD-Ara-C)
and VP16. After a CR was achieved mandatory SCT was planned. With this strategy, 43% of 14
patients with a first relapse achieved a remission (table 2, p.18). All patients, who achieved a CR, did
so by day 15 or 33 of protocol II IDA-CV. An additional benefit of element of HD-CPM/VP16 could
not be demonstrated.
Study P01 piloted arm A of the current study, ALL-REZ BFM 2002, in group S4. Induction therapy
with blocks F1 and F2 was followed by consolidation therapy using protocol II-IDA and bone marrow
transplantation if a CR was achieved. 73% of patients achieved a CR using this strategy (table 2, p.18).
Tab. 2: Results of Pilot Studies P99 und P01
ALL-REZ BFM P99 P01

N % N %
Protocol patients 14 100 15 100
death in induction 2 14 - -
non-response 6 43 4 27
CR 6 43 11 73
treatment-related death 1 7 1 7
relapse 4 29 1 7
second malignancy 1 7 -
CCR - - 9 60
2.3 Extramedullary relapse

Children with a combined relapse receive the same local therapy as children with an isolated
extramedullary relapse. The more favorable prognosis in comparison to an isolated bone marrow
relapse suggests that the recurrence results from the reseeding of the bone marrow by the
extramedullary compartment. The blasts appear less drug-resistant than those of an isolated bone
marrow relapse. According to the ALL-REZ BFM studies, children with an isolated extramedullary
relapse have been treated with intensive multi-agent chemotherapy similar to children with a systemic
relapse. The duration of treatment, however, has been shorter than that for children with a bone
marrow relapse. Retrospective analyses demonstrated a significant prognostic difference depending on
the time of relapse. When the strategic groups S1 to S4 were introduced, children with an early and
very early isolated extramedullary relapse were placed in group S2. As a consequence, therapy for
these patients was significantly prolonged and intensified compared to previous studies.
Isolated extramedullary relapse usually occurs in the CNS or testis, i.e. in organs that show a
functional barrier toward the blood circulation and thus to a degree are protected from systemically
administered cytotoxic agents. Rarely, other sites of relapse such as skin, kidney, ovary or bone were
observed. Since a barrier towards systemic chemotherapy is not assumed to exist at these sites of
relapse, specific local therapy was usually not given.
2.3.1 Isolated CNS relapse

Children with an isolated CNS relapse received cranial or craniospinal irradiation. The dose depended
on age and previous radiation exposure. A cumulative dose of 40Gy was not to be exceeded. Children
over the age of 2 years with a previous radiation exposure of < 18Gy received cranial radiation with
18Gy. Craniospinal irradiation was an alternative to cranial irradiation that was used in specific
centers. Retrospectively, an advantage of this intensified treatment cannot be demonstrated.
In contrast to other manifestations, sex and age at diagnosis of primary ALL proved to be significant
prognostic factors in children with an isolated CNS relapse (fig. 21 and fig.22, p.19), (Stackelberg et
al., 1999). In a multivariate Cox regression analysis, an early time point of relapse, male sex, older age
at the time of diagnosis of primary ALL and T-cell immunophenotype were significant and
independent prognostic factors.
Fig 21: EFS of children with an isolated CNS relapse Fig 22: EFS of children with an isolated CNS relapse
(early or very early, S2) dependent on sex; ALL-REZ BFM (early or very early, S2) dependent on age at initial
83 - 96; status 09/01 diagnosis of ALL-REZ BFM 83 - 96; status 09/01
1,0 1,0
,8 ,8
pEFS
pEFS
,6 ,6
,4 ,4
,2 ,2
0,0 0,0
0 2 4 6 8 10 0 2 4 6 8 10
Years Years
__ __
Girls: < 6 Years:
n = 74; cens. = 26; pEFS = 29 ± .06 ≥ 6 Years: n = 41; cens. = 11; pEFS = .17 ± .07
______
Boys:
p < 0.001 p < 0.001
2.3.2 Isolated Testicular relapse

Isolated testicular relapse usually occurs later than isolated CNS relapse. Two thirds of children in
strategic group S1 with a late isolated extramedullary relapse have a testicular recurrence.
Local therapy for an involved testis consisted of orchiectomy or local irradiation with 24Gy. Since a
residual endocrine function is not expected following this irradiation dose, the surgical removal and
implantation of prostheses were recommended. A contralateral testis that by biopsy was shown to be
not involved was irradiated with only 15 Gy. In most cases this approach preserved sufficient residual
endocrine function to allow the spontaneous onset of puberty (Wolfrom et al., 1997).
Only the immunophenotype of the blasts could be identified as additional prognostic factor for early
and very early testicular relapse. An unfavorable prognosis was associated with testicular relapse of T-
ALL.
2.4 Stem Cell Transplantation

Stem cell transplantation is an alternative intensification of treatment for patients with an unfavorable
prognosis once a complete remission is achieved. Past experience shows that allogeneic stem cell
transplantation provides a better relapse-free survival than chemo/radiotherapy alone, but is associated
with a higher treatment-related morbidity and mortality. Since the inception of the ALL-REZ BFM
studies a stem cell transplant (SCT) from an HLA- identical sibling (matched family donor, MFD) was
usually performed in patients with a bone marrow relapse who had a suitable sibling donor (Dopfer et
al., 1991). For extramedullary relapse, however, the indication was significantly restricted since the
graft-versus-leukemia (GvL) effect, which is credited for the relapse-free survival, appears to have at
best a limited if any effect on extramedullary disease (Borgman et al, 1995a). In the 1990s a series of
patients was treated with myeloablative high-dose therapy and autologous SCT. Since an improvement
of event-free and relapse-free survival could not be achieved, this conventional approach to autologous
SCT was not further pursued (table 4, p.21 and fig.25, p21) (Borgmann et al., 1995b).
50 Fig. 23: Proportion of patients

in the ALL-REZ BFM studies
undergoing stemm cell
40 transplantation (SCT) after
% achieving a complete
therapy remission; patients treated
30 according to protocol in the
chemo. pilot and main studies are
included.
20 MSD-SCT
(MSD, matched sibling donor;
MUD-SCT MUD, matched unrelated donor)
10
autologous SCT
0 haploidentical SCT
83 85 87 90 95 96
ALL-REZ BFM
Since the early 1990s SCT from an HLA-identical unrelated donor (matched unrelated donor, MUD)
has become increasingly available. Presently a suitable donor can be identified for approximately 75%
of all patients within three months. Stem cell transplantation from an unrelated donor has a
significantly higher treatment-related mortality and morbidity due to T-cell depletion and graft versus
host disease than SCT from a related donor. Therefore, it was usually performed only in patients with
a particularly unfavorable prognosis (fig.25, p.21).
In some regards ALL-REZ BFM 95/96 clearly defined the indication for allogeneic SCT based on the
risk group. Examples are the mandatory stem cell transplantation for group S3 and S4 and the lack of
an indication for group S1. In the large and heterogeneous group S2, however, the indication for SCT
from an unrelated donor was not clearly defined (fig.26, p.21). Time and site of relapse, initial blast
count, expression of BCR-ABL and cytologic response to treatment proved to be relevant prognostic
factors within strategic group S2 (Beyermann et al., 1997; Buehrer et al., 1996). The cryptic
translocation t(12;21) (TEL-AML1) was shown to be a parameter that correlates with favorable
prognostic factors but at this point - with a short follow-up - does not have independent prognostic
relevance (Seeger et al., 1998; Seeger et al., 2001).
Based on these risk factors the further stratification of group S2 into subgroups S2A to S2D was
introduced by the study committee and the Pediatric Working Group for Bone Marrow and Peripheral
Blood Stem Cell Transplantation (Paed-AG-KBT) as a guideline regarding the indication for SCT
(fig.24, p.21 and table 3, p.21). The following recommendations were made.
S2A chemotherapy, optional MFD-SCT
S2B MFD-SCT, chemotherapy vs. high-resolution MUD-SCT
S2C MFD-SCT, MUD-SCT, haplo-identical or autologous SCT
S2D chemotherapy, possibly autologous SCT
The results of SCT in patients of group S2 are shown in table 4 and fig 26.
Fig. 24: Event-free survival of S2 subgroups A-D, studies 83- Tab. 3: Definition of subgroups S2 A-D
96, SCT censored; status 09/01
1,0
Site isol. comb. isol.
BM KM extramed.
,8
Time late late early early/
very early
pEFS
,6 < 1/µl PBC A A B D

1 - < 10.000/µl B
≥ 10.000/µl C
,4 BCR/ABL + C C C
,2
0,0
0 2 4 6 8 10
years
pEFS = .53 ± .04
______
S2A: n = 221; cens. = 140;
pEFS = .36 ± .03
__ __
S2B: n = 401; cens. = 218;
pEFS = .24 ± .06
____
S2C: n = 153; cens. = 92;
pEFS = .39 ± .04
__ _ __
S2D: n = 184; cens. = 93;
p < 0.001
Tab. 4: Results in group S3/S4 and S2 after SCT, studies 90-96; status 09/01
strategic group S3 / S4 S2
SCT MFD MUD autologous MFD MUD autologous
N % N % N % N % N % N %
Total 49 100 57 100 16 100 54 100 24 100 13 100
treatment-related mortality 7 14 12 21 - - 1 2 11 46 - -
second malignancy 1 2 2 4 - - - - 1 4 - -
Relapse 21 43 18 32 13 81 17 32 3 13 10 77
CCR 20 41 25 44 3 19 36 67 9 38 3 23
MFD, HLA-matched family donor; MUD, HLA- matched unrelated donor
Fig. 25: Event-free survival of groups S3/S4 after stem Fig. 26: Event-free survival of group S2 after stem cell
cell transplantation, studies 90-96; status 09/01 transplantation, studies 90-96; status 09/01
1,0 1,0
,8 ,8
,6
pEFS
,6
pEFS
,4 ,4
,2
,2
0,0
0,0
0 2 4 6 8
0 2 4 6 8
years years
MFD-SZT: n = 49; cens. = 20; pEFS = .37 ± .08 n = 54; cens. = 36; pEFS = .63 ± .07
______
MUD-SZT: n = 57; cens. = 25; pEFS = .41 ± .07 n = 24; cens. = 9; pEFS = .35 ± .11
__ __
____
autolog:
p = 0.19 p < 0.001
2.5 Results of other studies

The treatment of children with relapsed ALL has not been the focus of prospective multi-center
studies to the same degree as the treatment of primary ALL. Frequently patients were treated on small
pilot or phase I/II studies without centralized collection of data. This situation is reflected by
publications that describe the results of a study but not the treatment protocols that were used.
Differences in the intensity and efficacy of the primary therapy as well as different definitions and risk
factors make a comparison of these studies difficult.
The Pediatric Oncology Group (POG) uses risk-adapted multi-agent chemotherapy and radiation
therapy in children with relapsed ALL. Compared to ALL-REZ BFM therapy treatment is less intense
but more continuous with fewer treatment-free intervals. The result of this strategy is comparable to
that of the ALL-REZ BFM group (Buchanan 1990, Buchanan et al., 2000, Sadovitz et al., 1993;
Wofford et al., 1992). POG achieved outstanding results in the treatment of children with an isolated
CNS relapse (Ritchey et al., 1999; Winick et al., 1993). Study ALL-REZ BFM 2002 adopts the
concept of a more continuous therapy for a prospective evaluation in comparison to therapy using
treatment blocks.
The British MRC-UKALL group published results of an initially heterogeneous treatment of children
with relapsed ALL (Wheeler et al., 1998). Subsequently a chemotherapeutic concept of multi-agent
blocks similar to that of the ALL-REZ BFM group was pursued (Lawson et al., 2000). Regarding the
indication for transplantation the British group arrived at similar results. In particular these also
included the finding that an advantage for allogeneic SCT could not be demonstrated in intermediate
risk patients and that the indication required further clarification based on controlled prospective trials
or additional prognostic factors (Wheeler et al., 1998).
The study group of the Scandinavian countries (NOPHO) also published comparable results for an
overall heterogeneous treatment of children with relapsed ALL that was determined by the time of
relapse (Schroeder et al., 1995). In a retrospective analysis SCT from a related donor yielded
significantly better results than chemotherapy/radiotherapy alone in children with an early bone
marrow relapse. In patients with a late bone marrow relapse such a difference could not be detected
(Schroeder et al., 1999).
The Children’s Cancer Group (CCG) published the results of a large number of patients with relapsed
ALL. A detailed description of the therapy used, however, was not provided (Gaynon et al, 1998). The
group at St. Jude’s Children’s Research Hospital published remarkable treatment results for children
with bone marrow and CNS relapse of ALL in a comparatively small cohort of patients (Pui et al.,
1988; Ribeiro et al., 1995; Rivera et al., 1996).
Children with relapsed ALL are receiving increasing attention as a group. These patients pose a
particular challenge to pediatric oncologists with a resistant form of leukemia that requires intensive
chemotherapy/radiotherapy and - in some cases - additional intensification by stem cell
transplantation. The group encompasses subgroups, such as children with a CNS or testicular relapse,
that present specific challenges and small case numbers. In order to be able to conduct prospective
randomized studies for such subgroups in a reasonable time frame, a cooperative approach at least
within Europe is necessary.
3 AIMS AND RATIONALE OF THE STUDY
3.1 Conclusions from previous studies
3.1.1 Chemotherapy
The results of the ALL-REZ BFM studies hold up favorably in an international comparison. The
principle of treatment consists of intensive multi-agent chemotherapy, which is organized in treatment
blocks during induction and consolidation therapy. This treatment phase is followed either by
conventional continuation therapy with or without VP16 reinduction pulses (for patients with a good
or intermediate prognosis after chemotherapy alone) or, alternatively, by stem cell transplantation (for
patients with an intermediate or unfavorable prognosis). This principle remains unchanged. Induction
and consolidation therapy using the blocks I and S in strategic group S4 resulted in a lower remission
induction rate compared to the historical controls of the precursor studies. The highest remission
induction rates were achieved with blocks F1 and F2 in studies ALL-REZ BFM 85 and 87. As a
consequence the current study will use a uniform induction therapy with blocks F1 and F2 for group
S4 as well.
Treatment with L-asparaginase was heterogeneous in the preceding studies. Depending on preexisting
sensitization to conventional E. coli L-asparaginase, PEG-L-asparaginase was used as a first line or
second line treatment. Studies of L- asparaginase activity in the serum were performed at doses
between 500 and 1000 units/m2. In case of allergy Erwinia L-asparaginase was used as an alternative.
Since study ALL-REZ BFM 96 did not detect a difference of event-free survival between the arms
with and without G-CSF, the current study will no longer employ G-CSF with the goal of intensifying
therapy. Instead, G-CSF will only be used with a classical supportive care indication in patients who
experience particularly frequent complications and - as a result - long delays of therapy.
3.1.2 Principal treatment guidelines

The intervals between the initial treatment blocks R1, R2, and R3 in study ALL-REZ BFM 90 and
between induction blocks F1 and F2 in study ALL-REZ BFM 95/96, respectively, were shown to have
prognostic significance (Hartmann et al, 1995). Based on the clinical data available to date the
consistent administration of the initial part of therapy continues to appear essential.
3.1.3 Strategic groups and indications for transplantation

Study ALL-REZ BFM 95/96 confirmed the value of strategic groups S1 to S4. This stratification very
clearly distinguishes patient groups based on their probability of survival and thus defines a group that
principally does not need stem cell transplantation (S1) and another that virtually always requires stem
cell transplantation to maintain a remission (S3/4). Within the large and heterogeneous strategic group
S2 the use of additional prognostic factors resulted in the delineation of subgroups (S2A to S2D) that
are helpful for the determination of the indication for allogeneic bone marrow transplantation.
3.1.4 Minimal Residual Disease

The detection of minimal residual disease (MRD) after the second treatment element (F2) proved to be
a significant parameter to predict subsequent relapse in strategic group S2 (fig. 27, p.28). The current
study evaluates the stratification of patients with a positive MRD result (MRD > 10-3) into a treatment
arm with mandatory SCT and of patients with a negative MRD result (MRD < 10-3) into an arm with
further multi-agent chemotherapy plus continuation therapy.
3.2 Aims of study ALL-REZ BFM 2002

The aim of the study is to improve the prognosis of children with relapsed ALL using a newly
designed chemotherapy and radiation therapy approach, which is based on the experience of the
preceding BFM relapse studies, as well as the targeted use of stem cell transplantation. An additional
aim is to advance our insight into this disease. The specific aims of study ALL-REZ BFM 2002 are as
follows.
• To determine in a prospective randomized comparison whether treatment in blocks (R
blocks) vs. continuous chemotherapy (protocol II-IDA) during consolidation therapy is
more efficacious in maintaining a complete remission and in reducing minimal residual
disease; to compare the toxicities of both strategies. Outcomes measures are the
probability of event-free and overall survival, treatment related mortality, toxicity
(assessed according to modified WHO criteria), and the level of minimal residual disease
at specified time points.
• To determine - in a comparison with historical controls - if the stratification of patients in
group S2 based on the MRD result after the second treatment element (F2) into a
subgroup with and another without allogeneic SCT from an HLA-identical unrelated
donor results in an increase of event-free survival for the entire group or for the
subgroups. Outcomes measures are the probability of event-free and overall survival and
treatment-related mortality.
• To determine - in a comparison with historical controls - if the standardization of
induction therapy through a shortening of intervals between the treatment blocks (in
accordance with the guidelines for administering therapy) improves the remission
induction rate. Outcomes are event-free and overall survival as well as the length of the
intervals between blocks.
• To improve the remission induction rate in strategic group S4 using a modified
induction/consolidation therapy.
• To standardize the treatment with L-asparaginase using the routine monitoring of L-
asparaginase activity.
3.3 Comparison of treatment blocks with continuous chemotherapy

Since 1983 the induction and consolidation chemotherapy of the ALL-REZ BFM protocols has been
based on highly dosed blocks of multi-agent chemotherapy that are followed by treatment-free
intervals allowing the regeneration of bone marrow function (Henze et al, 1994a, Henze et al. 1991).
Preceding therapeutic attempts had simply repeated the primary therapy (Creutzig and Schellong,
1980). The principle of a continuous multi-agent chemotherapy for several weeks (protocol I) proved
successful during the primary therapy of ALL. Particularly the introduction of protocol II as re-
intensification of ALL-BFM therapy both for standard and high risk patients resulted in a significant
reduction of the relapse rate (Henze et al., 1990; Nachman et al., 1997, Riehm et al 1987, Schrappe et
al., 2000). In addition, studies by the Pediatric Oncology Group (POG) suggest that lower dosed but
continuous chemotherapy is efficacious in the treatment of children with relapsed ALL (Buchanan et
al., 1991; Buchanan et al., 2000; Ritchey et al., 1999). The cumulative doses of most cytotoxic agents
are markedly lower than those used during the R blocks (see chapter 3.3.3). In the absence of
complications the protocol stipulates hospitalization only for the course of cyclophosphamide. In
contrast, five to six days of in-patient therapy are mandatory during any R block. The feasibility and
efficacy of a modified protocol II was evaluated in pilot protocols P99 and P01.
Using the quantitative monitoring of MRD, the anti-leukemic efficacy of treatment elements can be
further evaluated as a reduction of MRD even after a cytologic remission is achieved. A prospective
randomized comparison will determine if treatment using the known R blocks vs. continuous
chemotherapy using a modified protocol II (Prot-II-IDA) during consolidation is better suited to
reduce MRD and to maintain a complete remission.
3.3.1 Protocol II – IDA

Several modifications of the protocol II used during ALL-BFM primary therapy have been introduced.
Use of L-asparaginase: in the absence of hypersensitivity reactions four doses of 10,000 units/m2 of
native E.coli L-asparaginase are administered at five-day intervals. Alternatively, two doses of PEG-
L-asparaginase at 1,000 units/m2 at an interval of 10 days or ten doses of Erwinia L-asparginase at a
dose of 10,000 units/m2 at an interval of 48 hours are used.
Instead of four doses of adriamycin at 30 mg/m2, four doses of idarubicin at 6 mg/m2 are administered.
In in vitro drug resistance tests idarubicin proved particularly efficacious to induce apoptosis in the
blasts of relapsed ALL when compared to other anthracyclines (Prokop, personal communication).
Idarubicin is ascribed a lower degree of cardiotoxicity than daunorubicin (Berman, 1993, Villani et al.,
1989). Moreover, a higher degree of CSF penetration was demonstrated (Reid et al, 1990). The
efficacy and tolerability of idarubicin was demonstrated in pilot study ALL REZ BFM 90. A
randomized comparison of idarubicin vs. daunorubicin was performed by CCG and initially showed a
better anti-leukemic efficacy of idarubicin. Long term results, however, failed to demonstrate a
significant difference between both anthracyclines (Feig et al., 1996). Using a idarubicin to
daunorubicin dose ratio of 1 to 6, the relapse protocol including all R blocks reaches a cumulative
anthracycline dose of maximal 214 mg/m2. This dose appears acceptable given a typical previous
anthracycline exposure of 240 mg/m2 during primary ALL-BFM therapy and the slower
administration of the drug with lower peak levels.
Compared to the conventional protocol II, the dexamethasone dose will be decreased from 10mg/m2 to
6mg/m2 in order to avoid toxicity and treatment delays. Further, protocol II-IDA will start immediately
with dexamethasome /VCR/IDA omitting the one-week dexamethasone pre-phase. As consequence,
the schedules of protocol II-IDA in treatment arm A and of the three R blocks in arm B are
synchronized and both arms are comparable.
3.3.2 R Blocks
The treatment arm using R blocks is largely equivalent to the previously used standard therapy.
Compared with the design of study ALL-REZ BFM 96 the following modifications of the R blocks are
introduced.
Following induction blocks F1/2, block R2 is used first followed by R1. With the administration of
eight R blocks in group S2 the cumulative anthracycline dose remains unchanged and merely the
sequence of blocks is altered with the following rationale: the interval between diagnosis and the first
dose of antracycline is shortened; a better comparability to the antracycline-containing protocol II-IDA
is achieved.
According to the new sequence protocol II-IDA is followed by block R1 without daunomycin. Thus
the cumulative dose of anthracyclines is reduced by 35mg/m2 in this arm and the further sequence of R
blocks is synchronized in both arms.
3.3.3 Comparison of cumulative drug doses

The cumulative doses are significantly higher in arm B (R2/R1/R2) than in arm A (protocol II-IDA).
For L-asparaginase the cumulative dose ratio between both arms differs depending on the preparation.
Only the dose of antracycline used in protocol II-IDA is significantly higher than that used in arm B
(assuming 6 fold ratio of equivalent doses of idarubicin vs daunorubicin, table 5)
Tab. 5: Cumulative drug doses of treatment element II-IDA vs. R2/R1/R2
treatment protocol R2/R1/R2
drug II-IDA
dexamethasone [mg/m²] 100 300
vincristine [mg/m²] 6 3
vindesine [mg/m²] - 6
idarubicine [mg/m²] 24 -
daunorubicine [mg/m²] - 70
anthracyclin-equivalent [mg/m²] 144 70
E. Coli L-asparaginase [U/m²] 40.000 30.000
cyclophosphamide [mg/m²] 1000 -
ifosfamide [mg/m²] - 4000
cytarabine [mg/m²] 600 4000
methotrexate i.v. [mg/m²] - 3000
6-TG/6-MP [mg/m²] 840 1500
pred/MTX/ARA-C i.th. (n) 3 3
3.3.4 Toxicity
In addition to anti-leukemic efficacy both strategies will be compared with regard to toxicity. In arm A
toxicity will be documented from the start of protocol II-IDA until the start of the second part (day 1-
28) and from the start of the second part (day 29) until the start of the subsequent R block. In arm B
the toxicity of the first three R blocks will be documented at the start of each subsequent R block. The
form enclosed in the appendix (p125) and the criteria recommended by the WHO will be used to
document toxicity.
3.3.5 Randomization
Enrollment in the arm containing protocol II-IDA (arm A) vs. R blocks (arm B) is determined by
randomization. The randomization is performed at the beginning of relapse therapy once the patient is
registered and written consent has been received.
3.3.6 Monitoring
In addition to the mandatory bone marrow aspirates after the first (F1) and the second treatment
element (F2) further aspirates are scheduled at the beginning of the subsequent R blocks (first R2, first
R1, second R2) and on day 15 and 28 of protocol II-IDA as well as at the start of the first R1 block
following protocol II-IDA, respectively. The anti-leukemic efficacy of both strategies will be
compared using MRD. This will provide an answer in the short term as to which strategy is more
superior to eliminate minimal residual disease.
3.4 Stratification according to MRD after the second treatment element

Using clone specific DNA sequences leukemic cells can be detected below the cytological threshold at
a sensitivity of 10-4 to 10-5. Thus the kinetics of the treatment response can be monitored two to three
orders of magnitude below the threshold of cytological detection. The prognostic value of MRD has
already been proved during primary ALL therapy (Biondi et al.,2000; van Dongen et al.,1998). A
retrospective analysis of study ALL-REZ BFM 96 showed that the MRD result after the second
treatment element (F2) was a significant predictor of relapse-free survival for patients in group S2
with bone marrow involvement. To date 72 patients have been included in a prospective MRD study
which began in early 2001. The probability of event-free survival for patients with a residual tumor
load greater than 10-3 is 24% + 18% compared to 86% + 8% for patients with a residual tumor load
below this threshold (fig. 27, p.28) (Eckert et al., 2001). The prognosis of patients who are MRD-
negative at this time point, therefore, is remarkably good and further intensification of therapy is not
required to maintain a remission. Allogeneic SCT from an unrelated donor is not planned in this group
of patients. SCT from a related donor may be performed but is not mandatory. In contrast, the
prognosis of patients who are MRD-positive at this time point is so unfavorable that allogeneic SCT
from an HLA-identical related or unrelated donor is a mandatory intensification therapy to maintain
remission.
The MRD result leads to a modification of the indication for SCT from HLA-identical unrelated
donors. This modification affects all S2 subgroups. There are MRD-positive patients ( >10-3) among
those patients who up until now have had no indication for SCT (S2A) as well as MRD-negative
patients ( < 10-3) among those who have an unequivocal indication for SCT based on conventional
criteria (S2C). In addition the indication for SCT will be clarified for the intermediate group (S2B)
(table 6).
For the MRD study patients have to meet the following criteria:
• Bone marrow from the time of relapse and at the specified time points during therapy in
sufficient quantity (1x107 and 5x106 cells, respectively) and quality (for the isolation of
DNA).
• Clonal T cell receptor and immunoglobulin gene rearrangements are detectable in the DNA
sample collected at the diagnosis of relapse. At least two clonal markers will be used to
measure MRD.
• The clonal markers used for quantification have a typical sensitivity of 10-4 and a minimal
sensitivity of 10-3. In questionable cases a decision will be made by the study center.
Patients in strategic group S2, for whom a MRD result is not available, continue to be assigned to
treatment arms with and without SCT from an HLA-identical unrelated donor based on established
clinical risk factors.
The outcome measures for this question are the event-free and overall survival of the entire group S2
and the S2 subgroups in comparison with historical controls.
Tab. 6 Indication for transplantation based on subgroups 2A-C vs. result of MRD (status 08/01)
MRD neg. MRD pos. total

SCT - +
S2 A - 11 11 22 (31%)
S2 B ? 28 14 42 (58%)
S2 C + 4 4 8 (11%)
total 43 (60%) 29 (40%) 72 (100%)
Fig. 27: Event-free and overall survival dependent on MRD status after the second treatment
element, group S2, ALL-REZ BFM 95/96 (status 8/01)
1,0 1,0
,8 ,8
pOS
,6
pEFS
,6
,4 ,4
,2 ,2
0,0 0,0
0 1 2 3 4 5 6 0 1 2 3 4 5 6
years years
______
MRD neg.: n= 43; cens.= 39; pEFS= .89 ± .06 n= 43; cens.= 41; pOS= .98 ± .02
____
MRD pos.: n= 29; cens.= 18; pEFS= .46 ± .13 n= 29; cens.= 19; pOS= .27 ± .20
p = 0.001 p < 0.001
3.5 Increased treatment intensity during initial therapy as a result of

shorter intervals between the initial treatment blocks
Dose intensity of chemotherapy is thought to have prognostic relevance in the treatment of malignant
disease (Hryniuk, 1988). In the ALL-REZ BFM studies dose intensity was measured as the period of
time during which the first four treatment blocks were administered according to protocol. Dose
intensity decreased either as a consequence of longer intervals between the treatment blocks or of a
dose reduction within blocks. The time interval between the initial treatment blocks R1, R2 and R3
proved to be a significant prognostic factor in study ALL-REZ BFM 90 (fig. 9, p.12) ( Hartmann et
al., 1995). Study ALL-REZ BFM 95/96 confirmed the prognostic significance of the initial treatment
intensity. Comparison with the precursor study, however, is somewhat compromised by the different
design of induction therapy (fig 19, p.17). An analysis of time intervals between treatment blocks and
of complete blood counts prior to each block indicates that in clinical practice the interval specified in
the treatment overview was often adhered to in contrast to the principles of administering therapy that
were specified in the protocol. The current protocol, therefore, specifies shorter intervals between the
initial treatment blocks in the overview schema (14 days). Thus, an extension of intervals will only
occur in clinically indicated cases in accordance with the guidelines of the protocol for administering
therapy.
3.6 Improvement of the remission induction rate in strategic group S4

Strategic group S4 is made up of patients with an extraordinarily poor prognosis. This group is
characterized by a low remission induction rate, a high rate of death during induction and of
subsequent relapse after achieving a complete remission. This group was termed poor prognosis group
(PPG) in study ALL-REZ BFM 90 and excluded from the main study. Treatment consisted of R
blocks or various pilot protocols. These approaches continued to be associated with a high rate of
death during induction. (Dorffel et al., 1993; Henze et al., 1995, Neuendank et al., 1997). Study ALL-
REZ BFM 95/96 evaluated blocks I and S that had proved less intensive and better controllable in a
pilot study and that contained cytotoxic agents not used during primary therapy. This was based on the
results of in vitro drug resistance assays (Klumper et al., 1995). The new blocks, however, did not
prove successful. The rate of deaths during induction was greater than 10% and the remission
induction rate was only slightly higher than 50%. Of the patients who achieved a complete remission
more than 60% underwent bone marrow transplantation with an event-free survival of about 40% after
SCT (fig.15, p.16). Since studies ALL-REZ BFM 85 and 87 achieved a significantly higher remission
induction rate in this retrospectively defined group of patients with the induction blocks F1 and F2,
this type of induction therapy will be used again (table 1, p.16). As a consequence, induction therapy
with F blocks is uniform in all strategic groups.
3.7 Standardization and monitoring of treatment of L-asparaginase

All patients without an allergic reaction to native E. coli L-asparaginase during primary therapy
continue to be treated with this preparation on the relapse protocol. Data from study ALL-BFM 95
indicate that a dose of 10,000 units/m2 results in a serum activity of L-asparaginase of greater than 100
U/L for at least four days in the majority of patients (Muller et al., 2001). Protocol II-IDA, therefore,
uses a treatment interval of 5 days. In case of allergy and/or silent inactivation during primary or
relapse therapy PEG-L-asparaginase is used as an alternative at a dose of 1,000 units/m2 (Mueller et
al., 2000, Vieira Pinheiro et al., 2001). Pharmacokinetic data for PEG-L-asparaginase are available for
doses of 500 and 1,000 units/m2. According to these data a dose of 1,000 units/m2 appears appropriate
and efficacious. If hypersensitivity or early elimination of PEG-L-asparaginase is observed, Erwinia
L-asparaginase is used as a last alternative with three doses of 10,000 units/m2 i.m. during blocks F
and R and ten doses of 10,000 units/m2 i.m. during protocol II-IDA every 48 hours, respectively
(provided there has been no allergic reaction to this preparation).
The serum activity of L-asparaginase will be monitored on day 5 following native E. coli L-
asparaginase, on day 2, 7 and 14 following PEG-L-asparaginase and 48 hours after each Erwinia L-
asparaginase dose. Additionally, asparagine levels are measured in the CSF to document sufficient
CNS efficacy of therapy.
A pilot protocol evaluated the tolerance of native E.coli L-asparaginase following an allergic reaction
to PEG-L-asparaginase after December 2001. Severe allergic reactions were repeatedly observed so
that this sequence of L-asparaginase preparations was abandoned.
3.8 Additional aims and modifications
3.8.1 Simplification of continuation therapy – the use of 6-mercaptopurine and oral

methotrexate
The randomized comparison of treatment with 6-MP vs. 6-TG (in both cases guided by the peripheral
white blood cell count) did not reveal a difference of event-free survival but showed a higher toxicity
for 6-TG (Erb et al 1998; Harms&Janka-Schaub, 2000). In addition, patients with relapsed ALL
repeatedly showed prolonged periods of myelosuppression during continuation therapy that resulted in
lengthy interruptions of therapy. Eventually, the use of the better tolerated 6-mercaptopurine was
required. Since there is no evidence in the literature that supports a higher efficacy of 6-TG, the
current study will use 6-MP at the same dose during continuation therapy.
The intravenous administration of methotrexate every 14 days during continuation therapy frequently
resulted in problems with compliance. Occasionally the use of weekly oral methotrexate, therefore,
was required. Although the bioavailability of oral methotrexate is lower than that of parenteral
methotrexate, the efficacy of continuation therapy can be ensured by dose adjustments that are based
on the peripheral white blood cell count (Balis et al., 1998; Hamilton & Kremer,1997). The study
committee, therefore, decided to adapt the continuation therapy to that used during primary therapy
and to use weekly oral methotrexate.
3.8.2 Autologous SCT for an isolated CNS relapse with unfavorable prognosis
Additional risk factors allow the prognostic stratification of the group of children with an early or very
early isolated CNS relapse. In a multi-variate analysis sex, age at first diagnosis of ALL, blast
immunophenotype and time of relapse had independent prognostic significance. Based on subgroup
analysis a stratification of the entire cohort into a prognostically favorable and a prognostically
unfavorable group can be derived (table 7, p.30). Children in the prognostically favorable group
(CNS-S, 60%) are treated with chemotherapy and radiation therapy as designed for group S2. Children
in the prognostically unfavorable risk group (CNS-H), however, require an intensification of therapy
(fig 28 and fig 29). Since the risk of allogeneic SCT from an unrelated donor does not appear justified
in view of the questionable graft-versus-leukemia effect in the CNS (Borgmann et al., 1995a) and
since the Italian study group AIEOP published good results for autologous SCT in children with an
isolated CNS relapse (Messina et al., 1998), a modified autologous SCT with immune modulation,
reinduction and continuation therapy is used in this group. SCT should be planned following block R2
in week 16. The study center will send a corresponding treatment recommendation to the registering
institution if the above mentioned risk factors are present.
Tab. 7: Stratification of children with an early or very early isolated CNS relapse into a high (H) and standard (S) risk
group
Gender male female

Age at diagnosis of ≥6 <6 ≥6 <6
initial ALL [years]
immunophenotype time point of relapse
T very early H H
early
non-T very early H H S
early H S
Fig. 28: EFS of children with an isolated CNS relapse Fig. 29: OS of children with an isolated CNS relapse (early
(early or very early, S2) after stratification into a high (H) or very early, S2) after stratification into a high (H) and
and standard (S) risk group; ALL-REZ BFM 83-96; status standard (S) risk group; ALL-REZ BFM 83-96; status 09/01
09/01
1,0 1,0
,8 ,8
pOS
,6 ,6
pEFS
,4 ,4
,2 ,2
0,0 0,0
0 2 4 6 8 10 0 2 4 6 8 10
Years Years
CNS-S: n = 61; cens. = 43; pEFS = .64 ± .07 n = 61; cens. = 45; pOS = .65 ± .07
____
CNS-H: n = 50; cens. = 11; pEFS = 17 ± .06 n = 50; cens. = 19; pOS = 31 ± .06
__
p < 0.001 p = 0.003
3.8.3 Experimental treatment approaches for high risk groups

A modification of therapy during the course of study is planned for high risk patients, particularly
patients in group S4 and patients with BCR-ABL-positive leukemia as soon as it can be proved that
study ALL-REZ BFM 2002 does not result in an improvement compared to previous studies.
3.8.3.1 STI571 for BCR-ABL-positive patients

The agent STI571(GleevecTM, Novartis) inhibits the tyrosine kinase BCR-ABL and interferes with the
proliferation of BCR-ABL-positive cell lines in vitro. The drug is being evaluated in numerous clinical
studies mostly in adults with CML. A treatment study in children with CML before and after SCT is
being conducted in Germany (coordinator Prof. Suttorp, Dresden). Additional treatment studies of
patients with BCR-ABL-positive ALL are underway. As monotherapy STI571 results in transient and
partial remissions. Preclinical studies reveal a multitude of drug resistance mechanisms in
lymphoblastic and myeloid cell lines including the amplification of the oncogene (Schindler et
al.,2000, Weisberg & Griffin., 2000). The development of drug resistance during the treatment of
BCR-ABL-positive ALL can potentially be decreased by a combination of STI571 with other
cytotoxic agents. In vitro MTT cytotoxicity assays show a synergistic effect with most commonly used
agents including vincristine, doxorubicin, cyclophosphamide and etoposide. Only for methotrexate an
antagonistic effect could be demonstrated in most of the cell lines tested (Kano et. al, 2001). However,
the MTT assay proved not to be suitable for the evaluation of the cytotoxic efficacy of methotrexate
and this finding, therefore, requires confirmation with other methods.
Approximately four patients with a first relapse of a BCR-ABL positive ALL are registered in ALL-
REZ BFM studies each year. Since the molecular definition is already known at the time of relapse
there is an opportunity to evaluate the efficacy of STI571 in an initial therapeutic window. The
evaluation of STI571 is the objective of a separate study in accordance with the “Arzneimittelgesetz”
[drug act]. A two-week cytoreductive pre-phase with STI571will be used instead of the
dexamethasone pre-phase. Efficacy will be evaluated after 2 weeks based on the complete blood count
and a bone marrow aspirate. Treatment with STI571 continues in parallel to the treatment elements
specified in the protocol as long as they include the use of dexamethasone. During protocol II-IDA
(arm A) continuous treatment for three weeks is planned whereas treatment in arm B is given weekly
in parallel to the R blocks.
The dose follows the recommendations established by the International meeting for the use of STI571
in children with Philadelphia chromosome-positive ALL (June 25th 2001, Hannover Germany). The
exact administration and documentation of therapy will be coordinated with the study center. The use
of STI571 will be evaluated in a separate cooperative study of several European study groups in order
to reach conclusive results given the small case numbers. The efficacy of the treatment will be
compared to historical controls. In addition, BCR-ABL mRNA will be measured as a quantitative
parameter during the course of treatment.
3.8.3.2 Re-intensification for S3/4 patients with a positive MRD result prior to SCT
If the poor prognosis of patients in group S3/S4, who have a positive MRD result prior to SCT, is
confirmed during the course of the current study, the evaluation of a re-intensification block is planned
that aims at the elimination of MRD prior to SCT. To this end, a regimen including fludarabine, high-
dose cytarabine and daunoxome (FLAD) will be considered, which was designed based on the
experience with protocol IDA-FLAG (fludarabine, high-dose cytarabine, idarubicin and G-CSF) in the
treatment of relapsed AML (Bellott et.al, 2001; Fleischhack et.al, 1998; McCarthy et,al. 1999). A
corresponding concept is currently being evaluated by the MRC/UKALL study group. This group
reported a particularly high relapse rate in children with a positive MRD result prior to SCT possibly
as a result of a comparatively intensive T cell depletion during the conditioning phase prior to SCT
(Knechtli et al., 1998).
A corresponding treatment plan will be added as an amendment to the current protocol if the need
arises. Treatment will be planned in collaboration with the British study group.
3.9 Scientific companion studies

Study ALL-REZ BFM 2002 includes the following scientific studies in conjunction with the treatment
study.
3.9.1 Prognostic relevance of MRD at additional time points

In addition to the mandatory time point for the diagnosis of MRD after block F2 in group S2, three
(group S3/4) and four (group S2) additional bone marrow aspirates, respectively, are planned at the
start of the subsequent blocks (arm B) or treatment elements (arm A) in order to confirm the remission
status. The measurement of MRD is included at these time points. This applies to the start of each R
block including the second R1 block and coincides with a scheduled lumbar puncture (arm B).
Correspondingly, day 15 and 29 are used in protocol II-IDA as well as day 1 of the first R block (R1)
following protocol II-IDA (arm A). The additional MRD time points are used to monitor the anti-
leukemic efficacy of the randomized treatment elements and to determine the prognostic relevance of
MRD at these time points. This applies to all strategic groups. In children with an isolated
extramedullary relapse the clonal probes will be selected in close collaboration with the MRD
laboratories in Heidelberg (Dr. Flohr ALL-BFM), Hannover (Dr. Schrauder,ALL-BFM-HR) and
Hamburg (Dr. zur Stadt,. COALL) taking into account the clone specific DNA sequences derived
from samples at primary diagnosis. Instructions regarding the shipment of samples and lab addresses
are listed in chapters 9.6, 9.7, 9.8 (p.73-73). Requisitions are listed in the appendix (p.130).
3.9.2 Prognostic relevance of MRD prior to SCT

In retrospective analyses minimal residual disease prior to SCT was shown to be significant predictor
of relapse after SCT (Knechtli et al.,1998,Oakhill et al., 1996). The authors of the MRC-UKALL
group, however, used intensive ex vivo and in vitro T cell depletion with the monoclonal antibody
Campath-1 (anti CD52). Preliminary results of a retrospective analysis of patients with relapsed ALL
treated by the BFM group confirm the prognostic relevance of MRD prior to SCT. However, there are
patients with high MRD after SCT, who survive without relapse (P. Bader, personal communication).
Therefore, there is a need to determine prospectively the prognostic relevance of MRD prior to stem
cell transplantation before any treatment strategies can be evaluated that take a positive MRD result
into account. The time point for this analysis will be the bone marrow aspirate prior to the fourth R
block (second block R1) in arm B and prior to the first R block following protocol II-IDA (first block
R1) in arm A, respectively (approximately week 13 after diagnosis). This time point is preferred to the
aspirate immediately prior to SCT since the latter could not be used in the decision about the
performance of the procedure. A re-intensification block to reduce MRD prior to SCT or a
modification of the transplant procedure with reduced graft-versus-host prophylaxis or with adoptive
immunotherapy will be considered. The quantitative measurement of MRD starting from the time of
SCT will be performed by the molecular lab of the University of Tübingen (Dr. P. Bader) in parallel to
ongoing chimerism studies (Bader et al 1998, 1999, 2000) and in close collaboration with the
molecular lab of the Charitė in Berlin (Dr. Seeger, Ms. Eckert). Instructions regarding the shipment of
samples and lab addresses are listed in chapter 9.6, 9.7, 9.8. Requisitions are provided in the appendix
(p.130).
3.9.3 Monitoring of L-asparaginase activity

Serum activity of L-asparaginase will be monitored 5 days following the administration of native E.
coli L-asparaginase, 2, 7 and 14 days after administration of PEG-L-asparaginase and 48 hours after
administration of Erwinia L-asparaginase, respectively. The measurement of L-asparaginase activity is
mandatory since silent inactivation and early elimination occur in a substantial proportion of patients
and presumably result in a virtual loss of efficacy. Monitoring of L-asparaginase activity is essential
even after intramuscular administration of Erwinia L-asparaginase since there are currently no data
regarding the duration of activity with this route of administration. An adjustment of the dosing
interval may become necessary to ensure a comparable pharmacologic effect.
Samples for the assay of L-asparaginase activity are sent to the pharmacology lab of the Pediatric
University Hospital of the University of Münster (Prof J. Boos). A parallel evaluation of commercial
diagnostic kits for the measurement of L-asparaginase activity, manufactured by the company Medac,
is planned in selected centers.
3.10 Summary of rationale – risk-benefit analysis

The ALL-REZ BFM 2002 study protocol is aimed at the optimization of therapy. It is based on a
standard therapy that has been developed in consecutive precursor studies and that has achieved
excellent results by international comparison. At the same time comprehensive, disease-specific
diagnostic evaluation, a high standard of quality assurance and patient safety are maintained. The
concept of this study, therefore, meets the criteria of evidence-based therapy.
In principle, the relapse of ALL represents an unfavorable prognostic situation. Patients face an
approximately 35% probability of long-term cure. The majority of events are subsequent relapses,
which may occur up to 6 years after the diagnosis of the initial relapse. Treatment-induced deaths are
possible given the overall intensity and toxicity of therapy, particularly of allogeneic SCT, which is
required in a subset of patients. Late organ toxicity and rare cases of second malignancies are possible
following the renewed and intensified chemotherapy. Particularly after SCT a proportion of patients
may develop significant late effects that are frequently associated with chronic graft-versus-host
disease.
With this background the intensification of therapy appears justified for groups with a unfavorable
prognosis. A time of 4 years is planned for the accrual of patients. Follow-up observations for at least
another 5 years are required to capture frequent late events. Late effects beyond this time frame will be
assessed by additional specifically designed studies.
The results of this study have a direct impact on the future treatment of children with relapsed ALL.
Successful studies of the ALL-REZ BFM group are used as a standard therapy in many countries that
are not participating in this study. The consulting activity of the study center, therefore, by far exceeds
the geographic region of the main study.
• Protocol II-IDA vs. R blocks
Arm A (protocol II-IDA) is an approach to further optimization of therapy in comparison to standard
treatment in arm B (R blocks) in order to consolidate a remission. The aim is to optimize the anti-
leukemic efficacy and to reduce organ toxicity (see chapter 3.2, p.23). In addition, a significant
reduction of cost is anticipated due to the decreased need for in-patient treatment during protocol II-
IDA. The protocol allows a better degree of treatment control compared to the treatment blocks used
to date. The risk of increased toxicity associated with the new treatment arm containing protocol II-
IDA, therefore, is rated low. Extensive experience using a comparable protocol is available from
primary ALL therapy and by now also from the treatment of relapse.
• Stratification according to the MRD result after the second treatment element
Monitoring of MRD in patients of group S2 allows the distinction of patients with a high vs. a low risk
of recurrence. On this basis the indication for stem cell transplantation can be determined
unequivocally. The indication is no longer dependent on a subjective assessment by the treating
physician and the families or on the local interests of the treating centers. This has to be regarded as a
definite advantage for the patients. The risk that a good prognosis patient is treated too intensively
with bone marrow transplantation or, conversely, that a patient with a high probability of relapse does
not gain access to the necessary intensification of therapy by allogeneic SCT is significantly reduced
by a stratification that is based on the MRD result after the second treatment element. Table 6 (p.27)
shows that the indication for transplantation based on MRD is present in a larger number of patients
than in the previous studies. This fact, however, corresponds with the still unsatisfactory results in the
entire group S2 with an event-free survival of 35-40% and the inability to predict a subsequent relapse
for individual patients in this group.
The use of MRD for the stratification of this patient group, therefore, is necessary on ethical grounds
given the current status of our knowledge. In this instance neither the use of a standard arm nor the
randomized introduction of this criterium make sense since historically there has been no standard
approach. Potential statistical interactions with the main study question, therefore, have to be tolerated.
A favorable effect on the EFS in this group can be determined using historical controls.
• Shortening of treatment-free intervals
The design of the current study realizes the aim of intensifying induction therapy by shortening the
intervals between treatment blocks. This aim was already formulated in study ALL-REZ BFM 96 but
in clinical practice was not always realized according to protocol. In this regard this protocol
modification, therefore, represents a standardization of treatment. A delay of therapy for non-medical
reasons will be avoided. The increased treatment intensity during the initial phase of therapy can in
principle be associated with increased toxicity. The guidelines for administering chemotherapy that are
specified in the protocol are designed to avoid excessive risks. In view of the success achieved and the
data published so far, we anticipate that the patients will benefit from this intensification in form of an
increased remission induction rate and event-free survival. The risk of higher toxicity, therefore,
appears justified.
The efficacy of the increased treatment intensity can be compared with historical control using the first
end point of the study, the remission induction rate.
• Standardization of induction therapy for group S4
Induction therapy with blocks F1 and F2 in group S4 was already used in studies ALL-REZ BFM 85
and 87. The toxicity of this therapy, therefore, is known and can be estimated. In a comparison with
historical controls this induction therapy showed an advantage over the induction blocks I and S of
study ALL-REZ BFM 96. Particularly, the hope for decrease of deaths during induction did not
materialize. Induction therapy using F blocks, therefore, represents a benefit for the patients with a
decreased risk. An additional advantage is the standardized design of the induction therapy in all
strategic groups.
• Standardization of L-asparaginase therapy
The precise definition of treatment with L-asparaginase is also intended to standardize the clinical
practice when compared to the precursor studies. The risk of ineffective treatment due to silent
inactivation will be minimized by the mandatory monitoring of L-asparaginase activity. Endpoints for
this evaluation of L-asparaginase therapy are the duration of L-asparaginase activity in the serum and
the occurrence of hypersensitivity reactions.
• Modification of continuation therapy
The use of daily oral 6-mercaptopurine and weekly oral methotrexate during continuation therapy
results in an improvement of the quality of life for patients during this long treatment phase. This
therapy is well documented during primary therapy of ALL and usually is better tolerated. In addition,
problems of compliance with bi-weekly intravenous injections are avoided. A decreased efficacy is not
anticipated since the treatment will be adjusted based on white cell counts and liver function tests.
• Autologous SCT for children with prognostically unfavorable isolated CNS relapse.
The introduction of autologous SCT for children with a prognostically unfavorable isolated CNS
relapse is based on new results that allow the delineation of a group of patients with a very
unfavorable prognosis. Since the event-free survival in this patient group is less than 20% after
chemotherapy alone, intensification of consolidation therapy is absolutely mandatory. The anti-
leukemic efficacy of autologous SCT for this group is solely based on data in the literature. The
experience of the ALL-REZ BFM group does support the efficacy of allogeneic SCT for isolated
extramedullary relapse. The stratification proposed in this protocol allows a standardized approach and
defines a specific group of patients for whom there is certainly no indication to further intensity
therapy given the associated increase of toxicity.
• Modification of therapy for high risk patients during the course of the study
Possible modifications of therapy for patients with BCR-ABL-positive leukemia or for patients in
group S4 are mentioned in this study in order to ensure a close feedback with the study center.
Pertinent protocol modifications will be presented in a timely fashion to the responsible committees.
Such treatment modifications constitute separate protocols with independent reviews by the
institutional research ethics board and are not part of the current study protocol.
• Diagnostic monitoring during the course of the study
The confirmation of remission by bone marrow aspiration prior to the start of the treatment blocks
during induction and consolidation therapy was not standardized in the previous studies. Mandatory
bone marrow aspirates were specified in the protocol only until a cytologic remission was achieved.
The current protocol uniformly specifies bone marrow aspirates up until the start of the first block R1
following protocol II-IDA (arm A) and up until the start of the second block R1 (arm B), respectively.
These aspirates allow the confirmation of remission for all patients by cytology. Patients with an
incipient relapse prior to a scheduled SCT will be detected systematically and excluded. MRD results
at these time points allow a direct evaluation of the anti-leukemic efficacy of the used treatment
elements. MRD results can be used as a first end point for the randomized main question of the study.
At the same time the prognostic relevance of additional time points can be evaluated and taken in to
account by subsequent studies. The direct benefit for the patient is limited to the monitoring of
remission by cytology. The MRD data derived from additional bone marrow aspirates will not be
communicated but evaluated prospectively. The bone marrow aspirates are performed during the
sedation or general anesthetic for the lumbar punctures required by the protocol at the start of each
block. Dependent on local practice the bone marrow aspirate may require additional or increased
sedation/anesthesia. A moderate degree of pain, which in most cases may not require treatment, has to
be anticipated after bone marrow aspiration.
4 STUDY DESIGN
4.1 Features of the study

ALL REZ BFM 2002 is a study that aims at the optimization of therapy. The main objective is the
prospective randomized comparison of a continuous (arm A, experimental group) vs. discontinuous
form of consolidation chemotherapy (arm B, control group) with regard to efficacy in maintaining a
remission. The randomization will be performed in blocks and separately within strategic groups to
avoid imbalances between subgroups.
In addition the following issues will be addressed using a comparison with the historical control
groups of studies ALL-REZ BFM 83 to 90: improvement of the event-free survival in group S2 with
bone marrow involvement by stratification of further consolidation therapy with SCT vs.
chemotherapy according to the MRD result after the second induction treatment element;
improvement of the remission induction rate in all groups by a uniform use of shorter treatment-free
intervals during induction therapy (in accordance with the guidelines for administering chemotherapy)
and by standardizing the induction therapy for group S4.
Further modifications compared to the precursor study ALL-REZ BFM 96 are intended to standardize
therapy and increase the feasibility of the protocol therapy. They include the standardized use of L-
asparaginase and a modification of continuation therapy.
4.2 Study Organization

Almost 100 centers in Germany Austria and Switzerland participate in this study. The number of
patients registered per year by each center depends on the size of the center and ranges from less than
one to five. Participating centers have to have sufficient experience with pediatric oncology patients.
They must have appropriate facilities at their disposal to meet the diagnostic demands. The designated
physician who is responsible for the conduct of the study at each center has to be a pediatric oncologist
with board certification and expertise in the area. A list of all participating centers is included in the
appendix.
Based on the experience with previous studies we anticipate that virtually all children in Germany and
Austria with a diagnosis of relapsed ALL will be enrolled in this study. All patients treated at the
participating centers in Switzerland will be enrolled. The compliance with randomization was greater
than 80% in the precursor study and a similar rate is also anticipated for this study.
Prior to the onset of funding and the main study a pilot study was initiated in January 2002 to show the
feasibility of the protocol and to detect and solve logistical problems. We anticipate an accrual period
of four years to reach the required number of cases. An interim report with complete data on toxicity
and remission rates as well as preliminary results on event-free survival will be prepared
approximately six months after the end of the accrual period. The final analysis of event-free and
overall survival as well as initial data on late effects will be performed approximately five years after
completion of patient accrual.
4.3 Inclusion and exclusion criteria

Principally, all patients up to18 years of age with a morphologically confirmed diagnosis of relapsed
non-B ALL or non-B non-Hodgkin lymphoma are eligible for enrollment in the study.
The patients are informed about the study by the participating centers. Patients are registered with the
study center if the patient and/or his/her guardian(s) provide consent and if the start of treatment falls
within the study period. The type of primary ALL therapy has no impact on the eligibility of patients
for this study. The importance of primary therapy as a potential prognostic factor, however, will be
evaluated.
Study patients are defined as patients registered with the study center and enrolled in the study.
Protocol patients are defined as study patients that do not meet any exclusion criteria.
Observation patients are defined as study patients who are not protocol patients. These patients meet at
least one of the following exclusion criteria at diagnosis or during the duration of treatment. They are
evaluated as a separately.
Patients will be excluded from the study if:
• they have completed the 18th year of life at the time the relapse is diagnosed.
• curative therapy is declined either by patient himself/herself of the respective legal guardian
• the patient is pregnant
• the patient is breast feeding
• essential parts of the relapse therapy are declined either by the patient or his/her legal guardian or
cannot be administered because of medical reasons.
• no consent is given for transmission of data
• the patient has a severe concomitant disease that does not allow treatment according to the
protocol (e.g. malformation syndromes, cardiac malformations, metabolic disorders).
Patient with systemic diseases such as Down syndrome, cystic fibrosis or diabetes mellitus are eligible
for enrolment in this study. Due to the anticipated increase of toxicity dose reductions are suggested
after discussion with the study center.
Information about a subsequent relapse or relapse after SCT will also be collected as part of this
study. The study center also provides treatment recommendations for this group of patients.
4.4 Duration of study participation

The standard duration of participation in this study includes the intensive phase of treatment, the
continuation phase and the follow up period until 5 years after the diagnosis of relapse. To capture
rare late effects data will continue to be collected even after the standard participation in the study has
ended. Late effects are not systematically captured by the study center. Reports, however, will be
recorded and taken into account for the design of future studies.
Patients will be taken off study if there is no response to treatment, if there is a subsequent relapse, in
case of treatment-induced death and in cases of significant protocol violations for non-medical
reasons. A medically indicated deviation from protocol therapy is not a reason to come off study.
Rather, such a deviation will be documented and used in the assessment of the feasibility of the study.
The study center offers consultation on further therapy for patients without a response to treatment.
Patients who are off study continue to be observed including a report of death in order to allow the
assessment of overall survival.
4.5 Recommendations for cases with a subsequent relapse

Patients with a subsequent relapse may be registered again. The study center offers an assessment of
the individual prognosis and a recommendation regarding further management. For a proportion of
these patients a curative treatment approach can be pursued even after a second recurrence.
4.6 Registration and randomization

All patients with a relapsed ALL are registered in writing with the study center. For cases with
equivocal diagnostic results the study center offers consultation and an expedited central review.
Patients, who meet the inclusion criteria and for whom consent to participation in the study including
consent to randomization is available, are registered with the study center using the registration form
(see appendix). This form contains a complete documentation of all clinical data required to determine
the strategic group as well documentation if consent of the legal guardian to randomization was
obtained. The study center will only perform the randomization after the consent of the legal guardian
has been received. The result of the randomization will be sent to the registering center together with
a summary of the reported risk parameters, the assignment to a strategic group and a statement
regarding the indication for bone marrow transplantation.
Registration of a patient has to occur within fourteen days from the diagnosis of relapse. The result of
the randomization will be communicated within one business day.
4.7 Definition of risk groups

The risk groups S1 to S4 are defined as in study ALL-REZ BFM 95/96 (table 8). Time point (table 9)
and site of relapse (table 10) as well as the blast immunophenotype are the parameters underlying this
stratification.
Tab. 8: Definition of strategic groups S1 to S4
immunophenotype: non-T immunophenotype: (pre-) T
site isolated combined bone isolated bone isolated extra- combined bone isolated bone
extramedullary marrow marrow medullary marrow marrow
time
very early S2 S4 S4 S2 S4 S4
early S2 S2 S3 S2 S4 S4
late S1 S2 S2 S1 S4 S4
Tab. 9: Definition of the time point of relapse

time point after primary diagnosis after completion of primary therapy*
late ≥ 6 months
early ≥ 18 months and < 6 months
very early < 18 months and < 6 months
* in the rare case in wich the completion of primary therapy (typically the end of the preceding continuation therapy)
dates back ≥ 6 months and the primary diagnosis dates back < 18 months (e.g. after discontinuation of therapy or after
therapy B-NHL), the time point of relapse is defined as late.
Tab. 10: Definition of the site of relapse

bone marrow < 5% blasts 5% bis < 25% blasts ≥ 25% blasts
Extramedullary no no relapse requires follow-up isolated bone marrow relapse
Relapse yes isolated extramedullary relapse combined bone marrow relapse
4.7.1 Treatment group S1

Treatment group S1 contains all patients with a late isolated extramedullary relapse. This group has
the best prognosis with an event-free survival of greater than 75%. The aim of the study for this group
of patients is to confirm this favourable result. This group is included in the randomization to protocol
II-IDA vs. R blocks.

Treatment group S2 includes patients with a very early or early isolated extramedullary relapse,
patients with a late bone marrow relapse of a non-T ALL and patients with a combined early or late
relapse of a non-T ALL. The 5-year event-free survival in this group is approx. 45%. The aim of the
study in this group is to improve the prognosis by increasing the initial dose intensity and by refining
the indication for allogeneic SCT by monitoring of MRD. In addition the quality of remission will be
monitored by MRD as part of the randomized question. Based on specific risk groups, children with an
isolated CNS relapse are stratified into a therapeutic arm using chemotherapy and radiation therapy
and an arm using autologous SCT. Re-induction pulses during continuation therapy, which were
introduced in study 95/96, will be retained.

Treatment group S3 includes all patients with an early isolated bone marrow relapse of a non-T ALL
(EFS 25%). A second remission is achieved in approximately 80% of these children but has a median
duration of only 8 months after chemotherapy alone. The priority in this group, therefore, is to achieve
a remission and a condition that allows transplantation. The high treatment intensity during induction
is intended to improve the remission induction rate and the quality of remission prior to SCT.
Randomization will determine the best strategy to achieve a high remission induction rate, quality of
remission prior to SCT and event-free survival. SCT is planned at an early time point, usually after the
third R block in Arm B and at the end of protocol II-IDA in arm A, respectively.

Patients with a very early combined or isolated bone marrow relapse as well as all patients with a bone
marrow relapse of a T- ALL are assigned to treatment group S4. Remission is only achieved in 50 to
60% of cases and has a median duration of only 3 months after chemotherapy alone. Induction therapy
as well as randomization of consolidation therapy is performed as in all other groups. If a response to
therapy is not detectable, the children shall be spared a significant deterioration of their quality of life
due to inefficacious intensive therapy. If a remission is achieved, SCT shall be performed without
delay as in group S3. If the results in this treatment group do not improve during the course of the
study, experimental treatment approaches may be used for patients in this group after discussion with
study center.
4.8 Treatment Plan

A schema of the treatment plan for the four strategic groups is shown on page 40. The specified time
points are recommendations that should be adhered to if possible.
The interval between blocks F1, F2 and the first R blocks (R2 and R1) and protocol II-IDA,
respectively, should only be extended for clinical reasons and in accordance with the pertinent
guidelines for administering therapy. The sequence of R blocks have been inverted in all treatment
groups.
After a patient with relapsed ALL is registered and consent of the patient or legal guardian to
randomization has been received randomization to the treatment arm with R blocks (arm B) or
protocol II-IDA (arm A) is performed and the result communicated to the treating center. At the same
time a form letter commenting on the individual indication for transplantation at the time of
registration will be sent.
ALL - REZ BFM 2002 40 Protocol version: 25.06.03
Treatment Plan ALL - REZ BFM 2002

week 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29
arm
A Prot II - IDA
S1 F1 F2 R
R2 R1 R2
R1 R2 R1 Ð D 12
B
A Prot II - IDA R1 R2 R1 Ð D 24 / V
S2 F1 F2 R R1 R2 S
B R2 R1 R2 SCT
A Prot II - IDA
S3/4 F1 F2 R SCT
B R2 R1 R2
BMA/
MRD (S1) (S2)
D12/D24, 12/24 months continuation therapy; R, Randomization; S, Stratification; V, VP16-reinduction pulse; Ð, local radiation therapy;
, time point of bone marrow aspirate for stratification of post-remission therapy in S2; SCT, stem cell transplantation;
BMA, bone marrow aspirate; MRD, minimal residual disease; F1, F2, R2, R1, Protokoll II-IDA: blocks of chemotherapy.
4.8.2 Treatment plan for group S1

The cytoreductive pre-phase with dexamethasone is followed by induction blocks F1 and F2. In case
of a CNS relapse intensified intrathecal chemotherapy is administered according to the guidelines in
chapter 4.10 (p.43). Subsequent therapy is determined by the result of the randomization and consists
either of protocol II-IDA and three further blocks R1/R2/R1 or, alternatively, of six R blocks
beginning with block R2. Specific local therapy according to the guidelines described in chapter 4.10
(p.43) and continuation therapy for 12 months without reinduction pulses follow. Continuation therapy
consists of weekly oral methotrexate and daily oral 6-mercaptopurine.

The cytoreductive pre-phase with dexamethasone is followed by induction blocks F1 and F2.
Subsequent therapy is determined by the result of the randomization and consists either of protocol II-
IDA and five further blocks starting with R1 (arm A) or, alternatively, of eight R blocks beginning
with R2 (arm B). The precise administration of the first four treatment blocks or of the first part of
protocol II-IDA, respectively, is emphasized. In case of extramedullary involvement specific local
therapy according to the guidelines described in chapter 4.10 (p.43) follows. All children with an
isolated or combined bone marrow relapse receive preventative CNS irradiation at a age-dependent
dose (see chapter 4.9, p.42). Subsequently, continuation therapy with VP-16 reinduction pulses is
administered for 24 months to maintain remission. Continuation therapy consists of weekly oral
methotrexate and daily 6-mercaptopurine.
For children in group S2 with bone marrow involvement the availability of an HLA-identical sibling
as a stem cell donor has to be determined expeditiously. In this group the timely performance of a
bone marrow aspirate and prompt shipment of a sufficient sample to the study center is important to
allow the stratification based on the MRD result after the second treatment element (F2). If a clone-
specific probe is available in the diagnostic sample at relapse the result of this test is expected to be
available approximately 1 to 3 weeks after the start of the first R block and of protocol II-IDA,
respectively. If a MRD level above the threshold of 10-3 is detected, stem cell transplant from a (>
9/10) HLA-identical related or unrelated donor is indicated. The search for an unrelated donor should
be well prepared and started immediately after receipt of a positive MRD result. In this regard
communication is recommended with the respective transplantation center, the study center of the
transplantation protocol ALL SCT BFM 2003 as well as with consultants listed in chapter 4.11.4
(p.46). After an intensive search transplantation can be performed after five R blocks or two R blocks
following protocol II-IDA, respectively. If stratification based on MRD is not possible due to logistical
or technical reasons, the ALL-REZ BFM study center will advise with regards to the indication for
transplantation based on conventional criteria (S2A to S2D).
Children with an isolated CNS relapse in group S2 are further subclassified according to the criteria
described in chapter 3.8.2. (p.29). Standard risk patients are treated with chemo/radiotherapy and
subsequent continuation therapy including specific local therapy. For high-risk patients an autologous
SCT protocol is recommended (Schmid et al., 1996). Early communication with the transplant center
and the study center is necessary. Taking clone-specific probes derived from the sample at diagnosis
of primary ALL into account and assuming a sufficiently large diagnostic sample at relapse, the
monitoring of MRD is possible and in particular the detection of leukemic cells in the autologous
graft.

The cytoreductive pre-phase with dexamethasone is followed by induction blocks F1 and F2.
Subsequent therapy is determined by the result of the randomization and consists either of protocol II-
IDA or three R blocks beginning with R2, respectively. The exact administration of the first four
treatment blocks or the first part of protocol II-IDA, respectively, is emphasized.
In this group the indication for SCT is mandatory. The search for a stem cell donor has to be
preformed expeditiously. Transplantation should be performed after a complete remission is achieved
generally following protocol II-IDA or the third R block, respectively. If a matching related or
unrelated donor cannot be identified, experimental SCT should be performed.
The prospective monitoring of MRD is used to assess the quality of remission prior to SCT. At this
point no decision is made based on the MRD result prior to SCT. If the unfavorable prognostic value
of a highly positive MRD result (>10-3 ) is confirmed, an amendment of the protocol for these patients
during the course of the study is possible.

The same guidelines described for group S3 also apply to group S4. An important aim is to improve
the remission induction rate by introducing F blocks. A high residual leukemic cell load has to be
assumed particularly for patients in high-risk groups and allows the assessment of anti leukemic
efficacy of the randomized treatment elements. If an improvement of the remission induction rate is
not detectable during the course of the study, the evaluation of experimental induction therapy is
planned for group S4.
4.9 Radiation Therapy

The radiation of the CNS has great importance during the treatment of relapsed ALL for the
prevention of subsequent recurrences. This not only applies to patients with CNS relapse but also to all
patients with an isolated or combined bone marrow relapse.
The results of study ALL REZ BFM 85 show that children with a bone marrow relapse have a
significantly higher chance of cure after irradiation of the CNS even if there is no detectable CNS
involvement (Bührer et al., 1994).
In the ALL-REZ BFM studies all children with a CNS relapse received radiation therapy with rare
exceptions. Surprisingly, whether only the cranium including the upper cervical segments or the entire
neuroaxis is radiated has no impact on disease-free survival, although there was a trend to fewer
subsequent CNS relapses with the inclusion of the spine.
The dose of radiation therapy to the CNS depends on the age and previous radiation exposure of the
patient. A short interval to previous radiation therapy has to be regarded has an unfavorable factor. To
determine the acceptable maximal cumulative dose we suggest to contact the study center or the
radiation therapist of the study, Dr. Albrecht.
4.9.1 Bone marrow relapse

Children with a bone marrow relapse receive irradiation of the neurocranium and the upper three
cervical segments with 12Gy. If the previous radiation dose exceeds 24Gy (18Gy in children under 2
years of age) intensification of intrathecal chemotherapy instead of radiation therapy should be
considered after discussion with the study center. If irradiation as a part of primary therapy occurred
less than 24 months ago this recommendation already applies to a previous radiation dose of 18Gy
(15Gy in children under the age of two years).
4.9.2 CNS relapse

Patients with a CNS relapse receive irradiation of the cranium and the upper three cervical segments
with 18Gy. There is no clear evidence that craniospinal irradiation is superior to cranial irradiation.
Particularly in isolated CNS relapse, however, there is a trend in favor of cranio-spinal irradiation.
Craniospinal irradiation, therefore, is permitted.
If the previous exposure to irradiation exceeds 18Gy (15Gy in children under the age of two years) the
radiation dose is reduced to 15Gy. If the interval to the first course of radiation therapy is shorter than
24 months and the previous radiation dose exceeded 15Gy (12Gy in children under the age of two
years) the radiation dose should be reduced to 15Gy.
4.9.3 Testicular relapse

In case of a unilateral clinical involvement the contralateral testis should be biopsied during the
orchiectomy procedure. If the biopsy shows no involvement, local irradiation with 15Gy is given.
After this dose sufficient residual endocrine function is expected to allow the spontaneous onset of
puberty. If the biopsy is positive or not performed, the clinically not involved testis should be
irradiated as before with 18Gy. If a clinically involved testis is not removed irradiation with 24Gy
should be performed. Following this dose atrophy of the irradiated testis and absent endocrine function
has to be expected.
Testicular involvement documented by ultrasound alone without clinical enlargement has to be
confirmed by biopsy and will be treated like a clinically non-involved testis based exclusively on the
result of the biopsy.
4.9.4 Radiation technique and dose

Radiation therapy is principally performed using high-voltage technique (telecobalt or linear
accelerator). The exact reproducibility of the daily positioning has to be ensured (for example using
masks for immobilization).
During irradiation of the CNS individual attentuators have to be made to protect the viseral cranium
and the anterior cervical soft tissues. The retrorbital spaces and the skull base have to be well included
in the radiation field. If the entire neuraxis is irradiated dosage gaps and overlaps of adjacent fields
have to be avoided using divergence compensation.
Due to the low lying frontal skull base in children under two years of age the protection of the eye
lenses is not always possible. During follow-up regular ophthalmologic assessments, therefore, are
required to detect and treat radiation cataracts in a timely manner.
Emphasis is placed on a homogeneous distribution of the radiation dose. Principally, all fields are
irradiated in each session. Single fraction should have a minimum dose of 1.5Gy and a maximum dose
of 2.0Gy (1.8Gy in children under the age of 2 years) and should be administered 5 times per week.
To minimize the risk of leuko-encephalopathy CNS irradiation is started only after the intensive phase
of treatment is completed, i.e. after the last block.
The radiation therapy guidelines were prepared by Dr. Albrecht. For specific question please contact
her under the following address:
OA Dr. M. Albrecht Tel: +49 (0) 30/3976-3611
Klinikum im Friedrichshain Fax: + 49 (0) 30/3976-3609
Klink fur Strahlentherapie/Radioonkologie E-mail: u.ruehl@khf.de
Standort Moabit-Turmstraße
21, D-10559 Berlin
Germany
4.10 Other forms of local therapy
4.10.1 Intrathecal chemotherapy

All patients receive intrathecal chemotherapy at the time of the diagnostic lumbar puncture as well as
at the start of each chemotherapy block or at the start and during the course of protocol II- IDA,
respectively. Children with CNS involvement receive additional intrathecal injections on day 6 of
block F1, if blasts were still detectable on day 1 of block F1, and as a rule on day 5 of each block R2.
Patients with CNS involvement in treatment arm A receive an additional intrathecal injection on day 8
of protocol II-IDA. The interval between intrathecal injections should be at least five days.
Triple intrathecal chemotherapy is dosed according to age (chapter 5.2, p.49).
4.10.2 Orchiectomy
Orchiectomy is the local therapy of choice in case for a clinically involved testis. The procedure is
performed at the beginning therapy if the clinical finding is unequivocal or during the course of
therapy if histopathological confirmation is required. In this case the decrease in size of the testis can
be used as an indicator for the response to therapy. During orchiectomy a testicular prosthesis should
be implanted. The cosmetic result is typically better than that of testicular atrophy following local
irradiation with 24Gy. Subclinical involvement of the clinically not involved contralateral testis has to
be investigated by biopsy. Depending on the result local irradiation is given according to the
guidelines described in chapter 4.9.3.
4.11 Stem cell transplantation

Allogeneic stem cell transplantation (SCT) for patients in study ALL-REZ BFM 2002 with an
indication for this procedure is performed according to protocol ALL SZT-BFM 2003. This protocol
defines all transplant-related procedures and was designed in collaboration with the ALL-BFM study
group and the Pediatric Study Group for Bone Marrow and Peripheral Blood Stem Cell
Transplantation (Päd-AG-KBT). In contrast to the heterogenous and center-specific indications and
practice of allogeneic stem cell transplantation of the past, this protocol ensures standardized treatment
and thus a meaningful analysis of the results.
4.11.1 Definition of stem cell donor types

According to the degree of HLA-compatibility stem cell donors are classified into three groups.
1. HLA-identical sibling: Matched Sibling Donor = MSD
2. Related or unrelated stem cell donor who matches in 10/10 (HLA-matched family/unrelated
donor) or in 9/10 (1 antigen mismatched family/unrelated donor) HLA markers with the recipient: Matched Donor
3. Related or unrelated stem cell donor who matches in fewer than 9/10 HLA markers with the
recipient: Mismatched Donor = MMD
If more than one donor of a particular type is identified the following criteria apply.
• a donor with a 10/10 match is preferred to a 9/10 match
• an allele mismatch is preferred to an antigen mismatch
• HLA differences are preferred in the following sequence: class II > class C > class B > class A
mismatch.
The following additional criteria are used for the selection of donors.
• CMV status (should match the recipient if possible)
• sex (male donor preferred for male recipient)
• age of the donor (younger age preferred)
• stem cell source (bone marrow preferred from MSD and MD; peripheral stem cells preferred
from MMD).
• availability
4.11.2 Indications
A schematic overview of the indications for different forms of transplantation in the various risk
groups as determined by the study committee and the Pediatric Working Group for Bone Marrow and
Stem Cell Transplantation is shown in table 11 (p.46).
Mandatory stem cell transplantation is recommended for all patients of group S3 and S4. Group 1
donors (MSD) are considered as a first choice followed by group 2 donors (MD). If a suitable donor
cannot be identified within two to three months there is an option to perform a transplant using a group
3 donor (MMD). Whether a haploidentical parent or a HLA-mismatched unrelated donor is preferred
in this group depends on the individual HLA constellation and should be clarified in discussion with
the study centers of ALL SZT-BFM 2003 and ALL-REZ BFM.
The transplant indication for patients with bone marrow involvement in group S2 depends on the
MRD result after the second treatment element (F2). An expeditious search for an unrelated donor is
essential for patients with a MRD result of > 10-3 since the donor search will only start after the
relevant MRD results following the second treatment element has been received. This result can be
expected at the earliest one to three weeks after the beginning of the first R block (arm B) or of
protocol II-IDA (arm A). Transplant from an unrelated donor in group S2, therefore, can generally be
performed no sooner than after 5 R blocks or after two R blocks following the completion of protocol
II- IDA, respectively. For patients in group S2 with a MRD result > 10-3 only donors of group 1
(MSD) and group 2 (MD) are considered as unrelated donors. If no matching MSD or MD can be
identified the patient receives chemotherapy and radiotherapy as specified in the protocol followed by
continuation therapy. If stratification based on MRD testing is not available, the indication for
transplantation is determined according to conventional criteria.
Patients in group S2 with an isolated CNS involvement and high-risk criteria (see chapter 3.8.2, p.29)
proceed to autologous SCT.
4.11.3 HLA Typing

Patient with an indication for allogeneic SCT undergo expeditious HLA typing. Loci A, B, C, DRB1
and DRBQ 1 are determined for recipient and donor with high-resolution methods. Medium resolution
typing is only regarded as sufficient for the HLA typing of family members. In addition, blood group
and CMV status of patient and potential donors will be determined.
First parents and siblings are HLA typed. Patients with an indication for a MD or MMD-SCT proceed
immediately to an unrelated donor search if the HLA-typing of the family does not reveal a suitable
donor. Extended typing of the family can be useful for specific HLA constellations. Discussion of this
option with the HLA laboratory is recommended.
Tab. 11: Indication for transplantation dependent on risk group
S2
MRD
CNS
S1 <10-3 n.d. ≥10-3 S3/S4
subgroup* A B/C A B/C A/B/C SR HR
MSD-SCT - - + + + + - - +
MD-SCT - - - - + + - - +
MMD-SCT - - - - - - - - +
autologous SCT - - - - - - - + -
Legend: MSD, matched sibling donor (group 1); MD, matched (≥ 9/10 AG) family/unrelated donor (group
2); MMD, mismatched (< 9/10 AG) family/unrelated donor (group 3); MRD, minimal residual disease; CNS-
HR, isolated CNS relapse, high risk group; CNS-SR, isolated CNS relapse, standard risk group.
* for the definition of groups S2A-D, see table 3 (p.21); for the definition of groups CNS-SR/HR, see table 7
(p.30)
It is essential to initiate the search for an unrelated donor early in order to be able to perform
transplantation at the best point in time. The transplant center should be contacted in time to discuss
donor selection, preparation, appointments and possible alternative strategies.
The Institute for Transplantation Diagnostics and Cell Therapeutics at the University Hospital
Düsseldorf offers high resolution HLA-C typing as part of a study free of charge (contact PD. Dr. D.
Dilloo, tel 0211/8116224, or Dr. J. Enczmann, tel 0211/8118684).
4.11.4 Transplantation protocol

Stem cell transplantation is performed according to the current protocol ALL SZT-BFM 2003 that is
associated with the ALL-BFM and ALL-REZ BFM studies. This protocol covers all forms of
allogeneic transplantation in children with ALL in first and second remission. With regards to HLA
typing the guidelines of the German Society for Immune Genetics and the German Society for Blood
Cell Transplantation apply in addition to the criteria described above. Transplantation is only
performed in centers that agreed to participate in the transplant protocol mentioned above. A deviation
from the recommendations of the transplantation protocol should only occur in clinically indicated
cases and if possible after discussion with the study center. The indication for SCT is determined
according to the criteria specified in the protocol of the ALL-REZ BFM study. Contact addresses for
the ALL SZT-BFM 2003 study center and for questions about specific types of transplantation in
children with ALL in CR2 are listed in the following.
• ALL SZT-BFM 2003 Study Center
Dr. Christina Peters
St. Anna Kinderspital
Zentrum fur Kinder and jugendheilkunde
Forschungsinstitut for krebskranke Kinder
Kinderspitalgasse 6
A-1090 Wien
Austria
Tel: 43-1-40170-291
Fax: 43-1-40170-759
E-mail: peters@ccri.univie.ac.at
• Transplantation coordinator for the ALL-REZ BFM study

Klingebiel, Thomas, Prof.Dr. med.
Universitats-Kinderlinik, Haematologie/Onkologie
Theodor-Stern-Kai 7
60590 Frankfurt
Germany
Tel: 43(0) 69/6301 5094
Fax: 49 (0) 69/6301 6700
E-mail: tklingebiel@zki.uni-franfurt.de
• Contact for MD/MUD-SCT

Ebell, Wolfram, Dr.
Charity -Universitatsmedizin Berlin, CVK
Klink fur Allgemeine Pediatrics, Knochenmarktransplantation, OHC
D-13353 Berlin
Germany
Tel: 49-30-450-566014
Fax: 49-30-450-566919
E-mail: wolfram.ebell@charite.de
• Contact for MMD-SCT/haploidentical SCT

Friedrich, Wilhelm, PD, Dr.
Universitats-Kinderlinik and Poliklinik
Abteilung Pediatrics II
Prittwitzstrasse 43
D-89075 Ulm
Germany
Tel: 49-731-502-7726
Fax: 49-731-502-6685
E-mail: wilhelm.friedrich@medizin.uni-ulm.de
• Autologous SCT
Henze, Gunter, Prof.Dr. H.c
Kühl, Jorn, Dr. med.
Charite-Universitatsmedizin Berlin, CVK
Clinic for Pediatrics mit Schwerpunkt Hematology/Oncology, OHC
Augustenburger Platz 1
Tel: 49-30-450-566032
Fax: 49-30-450-566906
E-mail: guenter.henze@charite.de
4.11.5 Documentation
Following the registration of a patient the primary treating center receives the notification of the
randomization result, a summary of all clinical data available to the study center and a statement
regarding the indication for transplantation. Feedback regarding the already known types of donors
and the intention to perform a SCT will be provided using a form attached to the first statement. Once
the MRD result after the second treatment element (F2) is available for patients in group S2 with bone
marrow involvement the treating center receives a second updated statement. When the patient is
admitted to a transplant center for SCT the ALL-REZ BFM study center is notified using the data
form prepared by the Pediatric SCT Registry. The study center forwards the data to the Pediatric SCT
Registry and corresponding SCT coordinators and sends a summary of the available patient data to the
transplant center.
On day 100 after SCT the course of therapy will be documented by the transplant center using the
documentation form of the SCT Registry (Form Med A), which is sent to the ALL-REZ BFM study
center. The study center ensures the transfer of data to the Pediatric SCT Registry and the SCT
coordinators.
4.12 Continuation therapy

Treatment group S1and S2 receive continuation therapy. Treatment for 12 months is planned in
group S1 and for 24 months in group S2 following the completion of the intensive phase of therapy
and sufficient recovery of the bone marrow. Continuation therapy consists of 6-mercaptpurine
(50mg/m2 BSA p.o.qhs) and weekly methotrexate (20mg/m2 BSA p.o. weekly). The doses are
adjusted based on the white cell count.
4.12.1 Reinduction pulses with etopside

Four reinduction pulses with VP-16 are scheduled for treatment group S2. The first pulse is
administered at the beginning of the sixth week of continuation therapy. The interval from the start of
one pulse to the beginning of the subsequent pulse is eight weeks. Each pulse consists of oral
administration of etoposide at a dose of 50mg/m2 BSA/day for 10 days. Continuation therapy is not
interrupted during the reinduction pulses.
5 TREATMENT ELEMENTS
5.1 Cytoreductive prephase

The aim of the cytoreductive prephase is to achieve a well controlled reduction of the initial leukemic
cell mass. The acute tumour lysis syndrome is to be avoided by close monitoring of biochemical
parameters (LDH, uric acid, phosphate, potassium, calcium), treatment with allopurinol and
alkalization of the urine. Patients typically receive dexamethasone at a dose of 6 mg/ m2 for five days.
In children with a large leukemic cell mass a reduced dose should be used initially. If necessary the
phase can be extended to 10 days. If a cytoreductive effect is not observed or if the disease progresses,
this phase may also be shortened. The time of the prephase can be used to place a permanent central
venous line (e.g. Broviac catheter or port-a-cath system) and to complete the initial diagnostic tests.
5.2 Intrathecal chemotherapy

The first injection of intrathecal chemotherapy is performed at the time of the diagnostic lumbar
puncture. All patients receive triple intrathecal chemotherapy during the intensive phase of treatment
as specified in each block. Patients with CNS involvement receive an additional intrathecal injection
on day 6 of protocol F1 if the CSF is not clear of blasts on day 1 of protocol F1. Patients with CNS
involvement receive an additional intrathecal injection on day 5 of each block R2. Patients with CNS
involvement in treatment arm A receive an additional intrathecal injection on day 8 of protocol II-
IDA. The interval between intrathecal injections should be at least five days.
Tab. 12: Doses of triple intrathecal chemotherapy
Age (years) methotrexate cytarabine prednisone 0.9% NaCl

(mg) (mg) (mg) (ml)
<1 6 16 4 1.5
1 8 20 6 2.0
2 10 26 8 2.5
=> 3 12 30 10 3.0
It is recommended to inject methotrexate first followed by a mixture of cytarabine and prednisone

using each time a 5ml syringe. After the correct placement of the lumbar puncture needle first fill the
syringe by carefully aspirating as much CSF into the syringe as possible. Then inject the content of the
syringe while mixing its content continuously (inject 3ml, aspirate 2.5ml and again inject 3ml etc).
After that without further aspiration a volume of normal saline solution (see table 12) is injected and
the needle removed. All patients should lie down in a Trendelenburg position for two hours after the
lumbar puncture. The goal of this procedure is to achieve optimal mixing of all agents within the CSF
space and a sufficently high concentration in the upper portion of CNS.
In the following the individual block elements are shown as tables including the drugs, doses and
routes administration.
5.3 Block F1
drug dose route day
dexamethasone DEXA p.o. 20 mg/m2/d 1 2 3 4 5
vincristine VCR i.v. 1.5 mg/m2/d 1 6
methotrexate MTX 36h infusion 1 g/m2 1
E.Coli L-asparaginase Coli-ASP* 6h infusion 10.000 U/m2 4
methotrexate MTX intrathecal based on age 1
cytarabine ARA-C intrathecal based on age 1
prednisone PRED intrathecal based on age 1
* in case of allergic reaction or silent inactivation chose an alternative preparation according to the guidelines specified in the
protocol
5.4 Block F2
drug route dose day
vincristine VCR i.v. 1.5 mg/m2/d 1
cytarabine ARA-C 3h infusion 2 x 3 g/m2/d 1 2
* in case of allergic reaction or silent inactivation chose an alternative preparation according to the guidelines specified in the
protocol
5.5 R2-Block
drug route dose day
thioguanine 6-TG p.o. 100 mg/m2/d 1 2 3 4 5
vindesine VDS i.v. 3 mg/m2/d 1
methotrexate MTX 36h Infusion 1 g/m2 1
ifosfamide IFO 1h Infusion 400 mg/m2/d 1 2 3 4 5
daunorubicine DNR 24h Infusion 35 mg/m2 5
E.Coli L-asparaginase Coli-ASP* 6h Infusion 10.000 U/m2 6
* in case of allergic reaction or silent inactivation chose an alternative preparation according to the guidelines
specified in the protocol
in case of CNS envolvement repeat intrathecal chemotherapy on day 5
5.6 R1-Block
drug route dose day

2
dexamethasone DEXA p.o. 20 mg/m /d 1 2 3 4 5
2
mercaptopurine 6-MP p.o. 100 mg/m /d 1 2 3 4 5
vincristine VCR i.v. 1.5 mg/m2/d 1 6
methotrexate MTX 36h infusion 1 g/m2 1
cytarabine ARA-C 3h infusion 2x2 5
* in case of allergic reaction or silent inactivation chose an alternative preparation according to the guidelines
specified in the protocol
5.7 Protocol II-IDA

drug route dose day
dexamethasone DEXA p.po. 6 mg/m2/d 1 to 14 taper
vincristine VCR i.v. 1.5 mg/m2/d 1 8 15 22
idarubicine IDA i.v. 6 mg/m2/d 1 8 15 22
E.Coli L-asparagi-nase Coli-ASP* 6h infusion 10.000 U/m2 1 6 11 16
2 29
cyclophosphamide CPM i.v. 1 g/m /l h
cytarabine ARA-C i.v. 75 mg/m2/d 31 32 33 34 38 39 40 41
6-tioguanine 6-TG p.o. 60 mg/m2/d 29 to 43
methotrexate MTX i.t. based on age 1 15 31 38
cytarabine ARA-C i.t. based on age 1 15 31 38
prednisone PRED i.t. based on age 1 15 31 38
* in case of allergic reaction or silent inactivation chose an alternative preparation according to the guidelines specified in the protocol. In case of CNS involvement an additional dose
of intrathecal chemotherapy is given on day 8.
6 DRUGS
6.1 Instructions for the administration of chemotherapeutic agents
6.1.1 L-asparaginase
L-asparaginase is administered starting on day 4 of protocol of F1 and F2, day 6 of protocol R1 and
R2 and on day 1 of protocol II-IDA.
Native E.coli L-asparaginase is used for all patients unless there was an allergic reaction or silent
inactivation during primary therapy. The drug is administered on day 4 of block F1/F2, on day 6 of the
R blocks, and on day 1, 6 11 and 16 of protocol II-IDA at a dose of 10,000units/m2 as a 6-hour
infusion. The infusion of L-asparaginase should be started at a reduced rate and increased stepwise.
The measurement of L-asparaginase activity in the serum is mandatory five days after each
administration of E.coli L-asparaginase and will be performed by the pharmacology lab at the
University Children’s Hospital Münster (Prof. Dr. Boos). If these results demonstrate a silent
inactivation or if an overt allergic reaction is observed, PEG-L-asparaginase (oncospar, medac) will be
used instead at a dose of 1,000units/m2 BSA infused intravenously over two hours as long as this
preparation was tolerated during primary therapy. During protocol II-IDA PEG-L-asparaginase is
administered on day 1 and 11. Mandatory measurement of PEG-L-asparaginase activity is performed
2, 7 and 14 days after administration. If an allergy to this preparation is already known or occurs
during relapse therapy, Erwina L-asparginase (Erwinase, Ipsen, Ltd.), will be used as a third
preparation at a dose of 10,000 units/m2 BSA on days 4, 6 and 8 of the F blocks, on day 6, 8 and 10 of
the R blocks and on day 1, 3, 5, 7, 9, 11, 13, 15, 17 of 19 of protocol II-IDA, respectively. L-
asparginase activity will be measured 48 hours after each application.
After an allergic reaction the alternative L-asparaginase preparation is introduced during blocks F and
R blocks with the next block or protocol and during protocol II-IDA at the next scheduled
administration of the alternate preparation during the ongoing protocol.
During L-asparaginase therapy vital signs should be closely monitored. All necessary measures to treat
allergic reactions including an anaphylactic shock must be available.
6.1.2 Cyclophosphamide
Cyclophosphamide is administered during protocol II-IDA on day 29 at a dose of 1g/m2 a an
intravenous infusion over 1 hour. Mesna is administered intravenousy at a dose of 400 mg/m2 BSA
prior to as well as 4 and 8 hours after the cyclophosphomide infusion. Sufficient hydration with 3000
ml/m2 was to be ensured for 24 hours from the start of cyclophosphamide (see infusion orders).
6.1.3 Cytarabine
Cytarabine is administered during block F2 on day 1 and day 2 (two doses of 3g/m2 BSA) and during
block R1 on day 5 (two doses of 2g/m2 BSA). The interval between the two daily doses is 12 hours,
the duration of infusion is 3 hours. Attention should be paid to the administration of a sufficient
amount of fluids and to conjunctivitis prophylaxis. Prior to each infusion of cytarabine vitamin B6
should be given intravenously at a dose of 100mg/m2 BSA. Antiemetic prophylaxis using 5-HT3
antagonists is started one hour prior to cytarabine infusion (3 hours in case of oral administration) and
continued at 12 hourly intervals, e.g. ondansetron 5mg/m2 BSA p.o. or i.v. (see infusion orders sets in
the appendix, p.116,117)
During protocol II-IDA cytarabine is administered on days 31 to 34 and on days 38 to 41 at a dose of
75 mg/m2 BSA i.v.
In addition, cytarabine is part of the intrathecal therapy at an age-dependent dose (chapter 5.2, table
12, p.49).
6.1.4 Daunorubicin
Daunorubicin is infused on day 5 of block R2 at a dose of 35 mg/m2 BSA in normal saline over 24
hours (following the ifosfamide infusion). If a peripheral venous access is used a concentration of
0.05mg/ml should not be exceeded. The amount of normal saline infused in parallel to the ifosfamide
infusion has to be decreased accordingly. If a central venous access is used any concentration can be
selected.
6.1.5 Dexamethasone
Dexamethasone is administered at a dose of 20 mg/m2 BSA/day on day 1 through 5 of protocol F1, F2,
R1 and R2 and at a dose of 6mg/m2 BSA/day on day 1 through 14 and at a tapering dose (decrease the
dose by half every three days) on day 15 through 23 of protocol II-IDA. The daily dexamethasone
dose should be divided in two or three doses.
6.1.6 Etoposide
Etoposide is administered orally as a reinduction pulse during continuation therapy for group S2, at a
dose of 50mg/m2 BSA/day for 10 days. A total of four reinduction pulses are scheduled.
6.1.7 Idarubicin
Idarubicin is administered on day 1, 8, 15 and 22 of protocol II-IDA at a dose of 6 mg/m2 BSA as an
infusion over 6 hours. The drug is dissolved in 20-40 ml normal saline/mg idarubicin. If a peripheral
venous access is used a dilution to at least 0.01 mg/ml should be selected.
Children under the age 2 years should receive a reduced dose of idarubicin after discussion with the
study center. Renal or hepatic dysfunction may also require a dose reduction dependent on the degree
of impairment.
6.1.8 Ifosfamide
Ifosfamide is administered during block R2 on day 1 through 5 at a dose of 400 mg/m2 BSA as an
intravenous infusion over 1 hour. On day 1, ifosphamide is administered prior to the methotrexate
infusion, on day 2 after completion of the methotrexate infusion, and on day 5 prior to the
daunorubicin infusion. Mesna (200 mg/m2BSA) is administered intravenously prior to as well as 4 and
8 hours after each ifosfamide infusion. Simultaneously, the administration of a sufficient amount of
fluids has to be ensured.
6.1.9 Methotrexate
Methotrexate is administered on day 1 of block F1, R1 and R2 at a dose of 1000 mg/m2 BSA over 36
hours. One tenth of the solution is infused during the first half hour, the remaining nine tenth over 35.5
hours. In parallel forced alkaline diuresis with 3000 ml/m2BSA/24 hours is used on day 1 and 2 (see
infusion orders, appendix, p.115). Serum methotrexate levels are measured at the start, at the end and
48h after the start of the MTX infusion. The 48 hour level has to be measured immediately since it is
the basis of the folinic acid rescue. The result has to be communicated promptly to the responsible
physician.
In addition, methotrexate is part of the intrathecal chemotherapy at an age-dependent dose (see chapter
5.2, table 12, p. 49).
6.1.10 Folinic acid rescue

Rescue with folinic acid begins 48 hours after the start of the methotrexate infusion even before the
methotrexate level is available. A minimum of two doses of calcium folinate at dose of 15 mg/m2 BSA
are required at 48 hours and 54 hours. If the methotrexate level at 48 hours is greater than 0.5 µmol/L,
increased toxicity has to be anticipated. If the methotrexate level at 48h is greater than 1.0 µmol/L, an
increased dose and potentially an increased number of doses of folinic acid are required in accordance
with the rescue schema (see appendix, p.120). If the methotrexate level at 48 hours is greater than 2
µmol/L, it is in addition recommended to prolong the duration of forced alkaline diuresis. The
measurement of methotrexate levels and the corresponding administration of folinic acid are continued
at 6 hourly intervals until the methotrexate level falls below 0.25 µmol/L.
6.1.11 6-Mercaptopurine
6-Mercaptourine is administered orally at a dose of 100 mg/m2 BSA from day 1 to day 5 of block R1.
It is also administered daily during continuation therapy. The recommended dose is 50 mg/m2 BSA
with dose adjustments according to the white cell count (see guidelines for administering therapy,
p.60). Oral 6-mercaptopurine should be administered in the evening.
6.1.12 Prednisone
Prednisone is part of the intrathecal chemotherapy at an age-dependent dose (chapter 5.2., table 12, p.
49).
6.1.13 6-Thioguanine
6-Thioguanine is administered orally at a dose of 100 mg/m2 on day 1 to 5 of block R2. In addition, it
is administered orally at a dose of 60 mg/m2 from day 29 to 42 of protocol II-IDA. Thioguanine should
be given as a single dose in the evening.
6.1.14 Vincristine
Vincristine is administered strictly intravenously at a dose of 1.5 mg/m2 BSA on day 1 and 6 of block
F1 and R1, on day 1 of block F2 as well as on day 1, 8, 15 and 22 of protocol II-IDA. The maximal
single dose is 2 mg.
6.1.15 Vindesine
Vindesine is administered strictly intravenously at a dose of 3 mg/m2 BSA on day 1 of block R2.
6.2 Mechanisms of action and side effects

The mechanisms of action and side effects of cytotoxic agents that deserve specific consideration are
listed in the following. The information is based on data from ROTE LISTE 2001 (publisher Rote
ListeTM, Service GmbH) and was modified by the authors. Please consult in all cases the product
monographs in Rote Liste as well as pertinent specific information. The majority of these agents
should only be used by experienced hematologists/oncologists for the treatment of in-patients.
6.2.1 L-asparaginase
L-asparaginase is a bacterial enzyme that catalyzes the conversion of asparagine to aspartate and
ammonium as well as the conversion of glutamine to glutamate and ammonium. The depletion of L-
asparagine in the serum deprives leukemic lymphoblasts of this for them essential amino acid.
Although the cells of the human body are capable of synthesizing asparagine, organs with a high rate
of protein synthesis (liver, pancreas) will experience a relative deficiency of asparagine.
Contraindications include an episode or history of pancreatitis as well as pregnancy.
Documented side effects affect the skin (urticaria, hypersensitivity reaction), nervous system (cerebral
dysfunction with EEG changes, decreased level of consciousness), gastrointestinal system (anorexia,
nausea, vomiting, weight loss, acute hemorrhagic pancreatitis), liver (abnormal liver function,
increased bilirubine, alkaline phosphatase, decreased albumin and cholesterol, decreased
concentrations of clotting factors with abnormal coagulation and fibrinolysis), metabolism (impaired
glucose tolerance, decreased insulin level, hyperglycemia, ketoacidosis), circulation (hypotension,
shock), blood (abnormal blood counts, leukopenia, thrombocytopenia, hemolytic anemia), genito-
urinary system (renal toxicity, microhemoturia, albuminuria, casts, azotemia), and the immune system
(hypersensitivity reactions, urticaria, fever, hypotension, shock).
In case of a hereditary prothrombotic risk and an asparaginase-induced decrease of anti-thrombotic
factors the risk of thrombosis is increased. Treatment with low molecular weight heparin may be
considered in these cases.
6.2.2 Cyclophosphamide
Cyclophosphamide belongs to the group of oxazaphosphorins. It is an alkylating agent and interferes
with the replication and transcription of DNA. Its cytotoxic effect requires activation by microsomal
liver enzymes and intracellular cleavage of acrolein.
Contraindication include acute infections, severe myelosuppression as well as pregnancy and lactation.
Acrolein is toxic to mucosal surfaces and can cause hemorrhagic cystitis after renal elimination.
Mesna prevents this adverse effect by binding acrolein.
Additional documented side effects involve the skin (alopecia, dermatitis), nervous system (neural
toxicity), gastrointestinal system (gastrointestinal symptoms such as nausea, vomiting, diarrhea and
stomatitis), liver (liver damage), metabolism and endocrine system (hyperuricemia, impaired
spermatogenesis and ovulation), vascular system (irritation of vascular intima), blood (impaired
hematopoiesis) and genito-urinary system (renal injury and injury to the urinary tract).
Immunosuppressive effects as well as inflammation of skin and mucosal tissues (e.g. dermatitis,
stomatitis) are described. Cyclophosphamide interacts with other agents and measures that impair the
function of the bone marrow (increased cytotoxicity) and with anti-diabetic medications (resulting in
lower blood sugar).
6.2.3 Cytarabine
Cytarabine inhibits the synthesis of pyrimidines and is a member of the family of anti-metabolite
agents. Contraindications include acute infections, severe myelosupression as well as pregnancy and
lactation.
Documented side effects involve the skin (alopecia, skin reactions, dermatitis) and mucosal tissues
(ulcerations of the oral mucosa and the GI tract, stomatitis, conjunctivitis), musculo-skeletal system
(myalgia, arthralgia), nervous system (dysfunction of the central nervous system, neuritis, rarely
leukoencephalopathy, rarely paraplegia), gastrointestinal system (gastrointestinal symptoms such as
nausea, vomiting, diarrhea), liver (liver damage), metabolism (hyperuricemia), endocrine system
(impaired spermatogenesis and ovulation), heart (cardiac arrhythmia), respiratory system
(bronchospasm, pulmonary edema), blood (impaired hematopoiesis), genito-urinary system (abnormal
renal function) and the immune system (hypersensitivity reaction, immunosuppression). Interaction
with other agents and measures that suppress the function of the bone marrow results in increased
toxicity.
6.2.4 Daunorubicin
Daunorubicin is an anthracycline and belongs to the group of cytotoxic antibiotic drugs. The cytotoxic
effect is predominantly due to direct DNA damage.
Contraindications include acute infections, severe myelosuppression, a dose exceeding the maximal
cumulative anthracycline dose (risk of life-threatening cardiac damage), myocardial damage as well as
pregnancy and lactation. A limitation of the use of this agent should be considered in case of
pancytopenia, isolated leukopenia or thrombocytopenia, clinical heart failure, abnormal renal and liver
function, uncontrolled infection and a poor general health status of the patient.
Documented side effects affect the skin (reversible alopecia, dermatitis, local irritation),
gastrointestinal tract (ulcerative stomatis, nausea, vomiting, diarrhea), metabolism (hyperuricemia),
endocrine system (impaired spermatogenesis and ovulation, azoospermia, amenorrhea, irreversible
infertility), heart and circulation (cardiomyopathy - dependent on the dose, results in global cardiac
insufficiency, which may end in fatal cardiac failure-, bradycardia, cardiac arrhythmias), vascular
system (single cases of irritation of the intima after i.v. injection), blood (myelosuppression with
leukopenia, thrombocytopenia, anemia), genito-urinary system (urate nephropathy) and the immune
system (immunosuppression, allergic reactions). Interactions have to be considered with medications
such as other cytotoxic agents (increased cytotoxicity), cardiotoxic drugs (increased cardiotoxicity of
daunorubicin), irradiation (increased cardiotoxicity), hepatotoxic drugs (e.g. methotrexate, increased
hepatoxicity) and drugs that decrease the excretion of uric acid (e.g. sulfonamide and certain
diuretics).
Anthracyclines have to be infused strictly intravenously. Extravasation results in tissue ulceration and
irreversible local damage. Instructions for the management of an anthracycline extravasation are given
in chapter 8.1.3, p. 64.
6.2.5 Dexamethasone
Dexamethasone belongs to the halogenated glucocorticoids. Its mechanisms of action are multifold. It
blocks the release of arachidonic acid, the starting compound of prostaglandin and leukotriene
synthesis by inhibiting phospholipase 2. This results in anti-inflammatory, immunosuppressive and
ulcerogenic effects. Lymphoblastic leukemic cells express glucocorticoid receptors that have greater
affinity to dexamethasone than other glucocortocoids. Binding of dexamethasone to these receptors
results in programmed cell death of leukemic lymphoblasts.
Contraindications are gastrointestinal ulcers, severe osteoporosis, a psychiatric disorder, herpes
simplex, herpes zoster (viremic phase), varicella, a time period of approx. 8 weeks before to 2 weeks
after vaccinations, amoebal infection, systemic fungal disease, poliomyelitis with the exception of the
bulbar/encephalitic form, lymphadenitis after BCG vaccination, narrow and wide-angle glaucoma.
Parenteral administration of depot preparations and crystalline suspensions is not indicated in children
under the age of 6 years and children between 6 and 12 years, respectively. Restriction of its use has to
be considered in patients with a history of tuberculosis (reactivation!) and in case of severe infections.
Side effects are described involving the skin (striae, petechiae, ecchymoses, acne, delayed wound
healing), muskulo-skeletal system (muscle weakness, osteoporosis, avascular necrosis of femoral and
humeral head), eyes (glaucoma, cararact), psychiatric symptoms (depression, irritability, euphoria),
gastrointestinal tract (epigasric pain, peptic ulcer, pancreatitis), electrolytes, metabolism and endocrine
system (cushingoid face, truncal obesity, impaired glucose tolerance, diabetes mellitus, sodium
retention and edema, increased renal loss of potassium, adrenal insufficiency, decreased growth in
children, abnormal secretion of sex hormones – e.g. amenorrhoea, hirsutism, impotence), circulation
(hypertension), vascular system (increased risk of thrombosis, vasculitis – withdrawal syndrome after
long term use) and the immunsystem (allergic reaction including – rarely- shock, immunosuppression,
increased infectious risk).
Interactions have been observed with other medications such as cardiac glycosides (glycoside effect is
enhanced by hypokalemia), diuretics, loop diuretics (additional potassium secretion depending on the
mineralocorticoid effect), antidiabetics (increased blood sugar), oral anticoagulants (decreased
anticoagulant activity), induction of cytochrome p450 (e.g. rifampin, phenytoin, barbiturates,
primidone: decreased effect of corticoids), non-steroidal anti-inflammatory drugs (risk of
gastrointestinal bleeding and ulceration), ACE inhibitors (increased risk of abnormal blood counts),
chloroquin, hydroxychloroquin, mefloquin (increased risk of myopathies and cardiomyopathies),
somatotropin (decreased somatotropin activity), protirelin (decreased rise of TSH), laxatives
(increased potassium loss) and salicylates (increased risk of gastrointestinal bleeding).
6.2.6 Etoposide
Etoposide is a derivative of epipodophyllotoxin. It inhibits cell division in the pre-mitotic phase and is
predominantly cytotoxic during the late S- or early G-phase. Etoposide interferes with DNA repair by
inhibiting topoisomerase II. Contraindications and side effects - see cyclophosphomide.
6.2.7 Idarubicin
Idarubicin is anthracycline that belongs to the group cytoxic antibiotics. Contraindications and side
effects see daunorubicin.
6.2.8 Ifosfamide
Ifosfamide belongs to the group of oxaphosphorines. It is an alkylating agent that interferes with DNA
replicaton and transcription. The cytotoxic effect requires activation by microsomal liver enzymes and
intracellular cleavage of acrolein. For contraindications and side effects see cyclophosphamide.
6.2.9 Methotrexate
Methotrexate is a folate antagonist and belongs to the group of anti-metabolites. It interferes with
synthesis of purines and pyrimidines by inhibiting dihydrofolate reductase.
Contra indications include acute infection, severe myelosuppression, abnormal liver function,
gastrointestinal ulceration, renal insufficency (nephrotoxic even at low dose; at high doses causes
additional renal impairment by precipitation of methorexate), as well as pregnancy and lactation.
Documented side effects involve the skin (exanthems, toxic skin reactions - e.g. exanthems, pruritus,
photosensitivity, very rarely Lyell syndrome -, alopecia, dermatitis), the musculo-skeletal system
(osteoprosis), the gastrointestinal tract (gastrointestinal abnormalities, e.g. nausea, vomiting, diarrhea,
intestinal hemorrhage, ulceration of the oral mucosa and gastrointestinal tract, stomatitis), liver (liver
damage), metabolism and the endocrine system (hyperuricemia) impaired spermatogenesis and
ovulation), the vascular system (vasculitis), the respiratory system (pulmonary infiltrates, fibrosis) the
blood (impaired hematopoiesis), the genito-urinary system (renal dysfunction), the immune system
(allergic reactions immunosuppression). Inflammation of skin and mucosal surfaces (e.g. dermatitis,
stomatitis) and teratogenic effects are described.
Interactions with other medications and measures that are myelosuppressive and enhance the toxicity
of methotrexate are known. Non-steroidal anti-inflammatory drugs, phentoin, barbiturates,
tetracyclines, chloramphenicol, sulfonamides, p-amino benzoic acid, p-amino hippuric acid and
metamizole can increase the toxicity of methotrexate.
An impairment of the ability to eliminate high-dose methotrexate can result in life-threatening
complications. Guidelines for the management of decreased elimination of methotrexate are described
6.2.10 Mercaptopurine
6-Mercaptopurine is a purine analog that belongs to the anti-metabolite drugs. It results in chromatin
damage through the incorporation of false nucleotides into DNA.
The use of mercaptopurine is contraindicated during pregnancy and lactation.
Documented side effects involve the gastrointestinal tract (gastrointestinal symptoms, nausea,
vomiting, anorexia, ulceration of the oral mucosa and of the gastrointestinal tract), the liver (abnormal
liver function, liver damage), the genitourinary tract (secondary hyperuricemia) metabolism and the
endocrine system (impaired spermatogenesis and ovulation), blood (abnormal hematopoiesis,
leukopenia, thrombocytopenia). Drug-induced fever, pancreatitis and secondary leukemia have also
been described. Interaction of 6-mercaptupurine with allopurinol and anticoagulants has to be kept in
mind.
6.2.11 Prednisone
Prednisone belongs to the halogenated glucocorticoids. For contraindications and side effects see
dexamethasone.
6.2.12 6-Thioguanine
6-Thioguanine belongs to the anti-metabolites. The use of 6-thioguanine is contraindicated in Lesh-
Nyhan Syndrome (decreased efficacy) as well as during pregnancy and lactation.
Documented side effects affect the gastrointestinal tract (gastrointestinal abnormalities, nausea,
vomiting, anorexia, ulceration of the oral mucosa and of the gastrointestinal tract, stomatitis, necrosis
of the intestinal mucosa, intestinal perforation), liver (abnormal liver function, jaundice, veno-
occlusive disease, centrilobular liver necrosis), metabolism and endocrine system (impaired
spermatogenesis and ovulation) and blood (impaired hematopoieis, leukopenia, thrombocytopenia).
Interaction with other medications and measures that are myelosuppressive and increase toxicity are
known. Interactions with busulfan include nodular hyperplasia of the liver, portal hypertension and
esophageal varices.
6.2.13 Vincristine
Binding of vincristine to tubulin results in a blockade of mitosis. Vincristine belongs to the group of
vinca alkaloids.Contraindications include acute infections, severe mylosuppression as well as
pregnancy and lactation.
The predominant adverse effect is neurotoxicity. Loss of deep tendon reflexes, parathesias, cranial
nerve palsies, marked weakness particularly of the extremities, marked myalgia as well as a syndrome
of inadequate ADH secretion (SIADH) have been observed. Abnormal function of the autonomous
nervous system is possible resulting in constipation, paralytic ileus, urinary retention, hypotonia and
impotence.
Other potential side effects include nausea, vomiting, alopecia and myelosuppression.
Vincristine has to be administered strictly intravenously. Extravasation results in tissue ulceration and
irreversibe local damage. Guidelines for the treatment of a vinca alkaloid extravasation are described
6.2.14 Vindesine
Vindesine is a derivative of vinblastine and belongs to the group of vincalacaloids. For mechanism of
action, contraindications and side effects see vincristine.
7 GUIDELINES FOR THE ADMINISTRATION OF

PROTOCOL THERAPY
7.1 General principles

The analysis of the preceding studies suggest that treatment intensity is an essential parameter for the
success of relapse therapy. Consequently, a prolongation of treatment-free intervals particularly during
the first three treatment elements of the induction phase must only be accepted in case of life-
threatening complications. This guideline for the administration of therapy carries a greater risk than
one that is exclusively based on safety margins of peripheral blood counts. It poses particularly high
demands on the correct clinical assessment of the patient and the clinical judgment of the treating
physician. If previous experience with individual patients suggests that a timely delivery of therapy is
unlikely or associated with an undue risk because of insufficient tolerance, the protocol stipulates the
possibility of a dose reduction (see specific guidelines). In these cases we suggest to contact the study
coordinator.
7.2 F blocks
Both F blocks should be administered on time and regardless of the peripheral blood counts. Similar to
the practice of stem cell transplantation, platelet counts are maintained above 15 to 20,000 x 109/L
with HLA-matched platelet transfusions until a remission is achieved. Thus critical clinical situations
are safely manageable. Even fever and the in this scenario almost always necessary antibiotic therapy
alone are not a sufficient reason to delay therapy. The early achievement of a remission has priority
and frequently is an essential prerequisite for the long term control of infections. If the patient's
clinical condition is critical, for example in the case of blood pressure problems, sepsis, coagulopathy
and severe mucositis with massive protein loss, the ultimate decision rests with the treating physician.
7.3 First block R2

The first block R2 in this study is scheduled prior to the first block R1 and should be started when the
daily neutrophil count after the completion of the F blocks reaches or exceeds 0.5 x 109 /L unless
continuation of therapy would appear to result in a life-threatening situation. The result of the bone
marrow aspirate on day 14 after the start of the block F2 serves as an additional factor in this decision.
If persistent leukemic metaplasia is detected, treatment should be continued without delay since a
regeneration cannot be expected. Platelets have to be transfused as necessary. In special cases a 2/3
reduction of a treatment element can be performed to allow the timely delivery of therapy with a
justifiable risk. This has no impact on the dose of dexamethasone and the dose and time point of L-
asparaginase administration.
7.4 First block R1

The first block R1 starts as soon as the neutrophil count reaches or exceeds 0.5 x 109/L, unless the
continuation of therapy would appear to result in a life-threatening situation. Again, a dose reduction
can be performed in special cases. As in block R2, this has no impact on the dose of dexamethasone
and on the dose and time point of administration of L-asparaginase.
7.5 Subsequent treatment blocks R1 and R2

The subsequent blocks R1 and R2 are administered after a 21-day interval from the start of the
preceding block. Shorter intervals are possible but not required. As in previous studies the following
minimal requirements for the start of a treatment block apply:
leukocytes > 2.0 x 109/L
neutrophils > 0.5 x 109/L
platelet > 80 x 109 /L
If the start of a treatment block threatens to be delayed by more than 7 days, dose reductions according
to the specific guidelines outlined below have to be considered. Please contact the study center. The
need to delay therapy has to be reassessed at least every other day. Under no circumstances must a
delay of treatment be planned at weekly intervals merely for logistical reasons.
7.6 Protocol II-IDA

Protocol II-IDA starts (analogous to the first block R2) when the daily neutrophil count reaches or
exceeds 0.5 x 109/L, unless continuation of therapy would appear to result in a life-threatening
situation. The result of the bone marrow aspirate on day 14 after block F2 serves as an additional
factor in this decision. If persistent leukemic metaplasia is detected, treatment is continued without
delay since regeneration cannot be expected. Platelets have to be transfused as necessary.
The weekly administration of vincristine/IDA should be performed on time with a neutrophil count of
at least 0.5 x 109 /L. Platelets have to be transfused as necessary.
Minimal requirements for the start of the cyclophosphomide infusion (day 29) are:
leukocytes > 1.5 x 109/L
platelets > 80.0 x 109/ L.
Both courses of cytarabine (day 31 to 34 and day 38 to 41) are administered regardless of blood
counts. Only if the platelet count falls below 70 x 109/L or in case of overt infections should treatment
be interrupted (including 6-TG).
7.7 Reduction of the treatment intensity based on toxicity

Modified WHO criteria for the classification of specific side effects are used to assess toxicity (table
13, p.62).
If the solid line demarcating the zone of dangerous toxicity is crossed during the preceding block or if
the dashed line that demarcates the zone of alarming toxicity is crossed immediately prior to starting a
new treatment element the following recommendations apply.
• in a subsequent Block R1 cytarabine is reduced to 60% of the target dose and 6-mercaptopurine is
administered at the original dose but only on day 1 to 3.
• in a subsequent Block R2 ifosfamide and thioguanine are administered at the original dose but
only on days 1 to 3.
The suggested approach attempts to accommodate the wide range of individual treatment toxicity. It is
probable that not every situation that occurs in individual patients can be recorded and assessed in a
standardized fashion. Table 13 (p.62), therefore, should only be regarded as an aid. In case of doubt
we suggest to contact the study center by phone.
Tab. 13: Classification of toxicity according to modified WHO criteria
Toxicity grade 0 grade 1 grade 2 grade 3 grade 4
total bilirubin <12,0 >= 12 > 25 > 50 > 100

(µmol/L)
Creatinine <100 >= 100 > 250 > 450 > 800
[µmol/L]
Fever none < 38 °C <= 40 °C > 40 °C, > 40 °C, shock

hypotension
Stomatitis none soreness, erythema, ulcers, ulcers, liquid diet oral nutrition not
erythema hardly any solid possible
food
Diarrhea none Transient tolerable not tolerable, Bloody diarrhea,
≤2 days > 2 days treatment dehydration
required
Constipation none mild moderate subileus Ileus
Infection no signs mild moderate, severe, proved with hypotension

antibiotics
7.8 Continuation therapy

Continuation therapy (1 year in Group 1; 2 years in group S2 ) begins approximately two weeks after
the completion of the last R block as long the following criteria are met.
leukocytes > .0 x 109/L
platelets > 100 x 109/L
6-mercaptopurine 50 mg/m2 BSA/ day p.o.qhs.
Methotrexate 20 mg/ m2 BSAp.o. once weekly
The doses are adjusted according to the following guidelines:
if leukocytes > 3.0 x 109/L up to 150% of the dose
2 to 3 x 109/L 100% of the dose
1 to 2 x 109/L 50% of the dose
< 1.0 x 109/L. 0% of the dose.
if lymphocytes < 0.3 x 109/L 50% of the dose.
During continuation therapy transaminases are checked every three months. If the values exceed five-
fold normal values, continuation therapy is held for one week and only restarted after a marked
decrease of the transaminase values (usually within one week).
7.8.1 Reinduction Pulses

Group S2 receives four additional reinduction pulses with etoposide at a dose of 50 mg/m2 BSA/day
p.o. for 10 days. The first reinduction pulse is administered at the start of the sixth week of
continuation therapy. The interval between the start of one pulse and the start of the subsequent pulse
is 8 weeks. During a reinduction pulse continuation therapy with 6-mercaptopurine and methotrexate
is not interrupted.
The following criteria have to met at the start of a reinduction pulse:
leukocytes ≥ 2.0 x 109 /L
neutrophils ≥ 0.5 x 109 /L
platelet ≥ 100 x 109 /L.
8 SUPPORTIVE CARE
The main problem of intensive multi-agent chemotherapy is the combination of marked
immunosuppression, direct organ and mucosal toxicity and the resulting immunodeficieny toward
potentially pathogenic microorganisms. A number of protective and supportive measures are urgently
required to prevent potentially serious harm associated with therapy.
8.1 Emergencies
8.1.1 Acute tumour lysis syndrome

The acute tumour lysis syndrome is rare in children with relapsed ALL since this type of leukemia in
general is comparatively resistant to therapy. During the lysis of leukemic cells the purine degradation
products xanthine, hypoxanthine and uric acid as well potassium and phosphate are released. A rapid
lysis of large cell numbers may result in precipitation within the renal tubules and collecting ducts and
in life-threatening hyperkalemia.
To prevent the acute tumour lysis syndrome, forced diuresis with 3-6 L/m2/d D5 0.45NS (the fluid
balance is maintained as needed with furosemide), allopurinol (at a dose of 10 mg/m2/day) and the
alkalization of the urine (with sodium bicarbinate 40 - 80 mmol/L infused fluid solution, target urine
ph 7.0) are used.
In case of hyperuricemia, beginning renal insufficency or marked hyperleukocytosis treatment with
rasburicase (Fasturtec TM) may be indicated.
In case of marked hyperkalemia, hyperphosphatemia, hyperuricema, or renal insufficiency,
hemodialysis may become necessary.
8.1.2 Impaired elimination of methotrexate

The serum methotrexate level 48 hours after the start of the methotrexate infusion is generally below
0.5 umol/L. Otherwise, folinic acid is extended at six hourly intervals beyond the scheduled doses at
48 and 54 hours until the methotrexate level falls below 0.25umol/L. The dose of folinic acid depends
on the methotrexate level and is determinded according to diagram shown in the appendix (p.120). If
the methotrexate level at 48 hours is greater than 2.0 µmol/L, alkaline diuresis with 3 to 4.5 L/ m2 is
used in addition. If the methotrexate level at 48 hour is greater than 5 µmol/L or in cases of a marked
intolerance with a severe vomiting, diarrhea and neurological symptoms, the use of carboxypeptidase
should be considered. Carboxypeptidase results in a enzymatic cleavage of methotrexate. The
medication can be obtained through Mr. Cameron, UK, Tel: +44 -19-80612418, Fax +44 1980
610848.
If a decreased elimination of methotrexate is apparent at 36 hours (MTX level > 10µmol/L) a
methotrexate serum level at 42 hours is recommended. In this case the administration of leucovorin
should be moved up at a dose equivalent to that recommended by the rescue schema at 42 hours. If the
value is greater that 5µmol/L, the dose of folinic acid is calculated using the following formula:
leukovorine (mg) = MTX 42h (µmol/L) x body weight (kg).
8.1.3 Extravasation of anthracyclines or vinca alkaloids

In case of an extravasation of an anthracycline, first try to aspirate the extravasate, tissue fluid and
blood using the existing venous access and, if possible dilute the extravasate by instilling normal
saline before removing the vascular access. Topical application of the dimethylsulfoxide (DMSO
99%), four drops per 10cm2 skin TID for several days may ameliorate the course (Bertelli et al., 1995).
The local area of skin should be kept cool for several days.
In case of extravasation of a vinca alkaloid, first try to aspirate the extravasate, tissue fluid and blood
using the existing venous access. Then inject hyaluronidase (150 units/ mL normal saline) into the area
of the extravasation using the existing venous access before removing it. Subsequently, the affected
tissue can be infiltrated subcutaneously with several small injections of hyaluronidase (Bertelli, 1995).
The local area should be kept warm (in contrast to the cooling recommended for anthracycline
extravasations).
If a necrosis develops despite these local measures early surgical revision should be considered.
8.2 Prophylactic measures

From the beginning until approx. 4 weeks after the end of the intensive phase of therapy the following
measures are recommended.
• Pneumocystis carinii prophylaxis:
cotrimoxazole, 2-3 mg/kg trimethoprime (10-15mg/kg sulfamethoxazole) BID on 2 days per
week ( e.g Saturday and Sunday)
alternative: pentamidine 200mg by inhalation every 14 days.
• Candida prophylaxis:
Tab. 14: Candida prophylaxis
age (years) amphotericin B suspension (ml/d)

<=1.5 4 x 1.0
1.5-2 4 x 1.5
>=3 4 x 2.0
The amphotericin suspension is carefully spread over the entire oral mucosa and then swallowed. If
prophylaxis with amphotericin solution is not feasible or if thrush becomes apparent despite
prophylaxis, fluconazole (approx. 2 mg/kg/d) can be used as an alternative. Hepatic toxicity and
possible drug resistance have to be considered.
The inhalation of amphothericin B BID is urgently recommended. 2 ml Amphotericin B stock
solution (1 vial = 50mg, dissolved in 10 ml distilled water) is used for one inhalation. The inhalations
proved useful in the prevention of infections with Aspergillus fumigatus in the bronchial system.
8.3 Anti-emetic treatment

Ondansetron (two doses of 5mg/m2/day) is used for highly emetogenic treatment elements such as
high-dose Ara-C, ifosfamide and cyclophosphamide. Additional treatment with a dimenhydrinate may
be required if this agent is insufficient particularly in adolescents. All treatment elements with the
exception of cyclophosphamide already include the administration of dexamethasone so that no further
anti-emetic effect can be expected from this agent. Based on past experience, anti-emetic treatment is
not necessary during the first part of protocol II-IDA and is not always required during the Ara-C
cycles in the second part. If this treatment element is not well tolerated oral dimenhydrinate and if
necessary oral ondansetron (5 mg/m2) may be used once one hour prior to the injection of Ara-C.
8.4 Interventional supportive therapy
8.4.1 Mucosal Lesions

Care for oral mucosal lesions: oral rinses at least QID, e.g. with chamomile solution; at least once
daily local use of adstringents on open sores, e.g. watery solutions of methylene blue.
The topical treatment of mucosal lesions with rinses of active folate derivatives such as the rescue
agent 5-formyl-tetrahydrofolic acid (leucovorin TM, Rescurolin TM), during leukemia therapy has to be
regarded as an unacceptable therapeutic risk due to the associated mucosal absorption and a possible
enhancement of blast proliferation.
Severe large ulcerations generally are not limited to the mouth. They require close monitoring and a
consistent and early replacement of protein and electrolyte losses. In addition, sufficient analgesia
should be ensured including opiates as needed.
The mucosal area under the tongue generally is representative of the status of the entire
gastrointestinal tract. It remains almost always accessible to inspection and assessment even in cases
with marked swelling and pain.
8.4.2 Febrile Neutropenia

In case of a neutrophil count below 0.5 x 10 9/L and fever greater than 38.5 °C systematic antibiotic
and possibly anti-fungal treatment has to be administered. Particularly patients with a high therapeutic
risk (e.g. patients with a very early relapse during initial treatment or fever at the beginning of the
critical cytopenia) require a rapid escalation of antibiotic protection to be able to control severe septic
infections until regeneration occurs. The following table shows an example of such an escalation with
proved i.v. antibiotic combinations.
Tab. 15: Escalation of antibiotic therapy
start with ceftriaxone and gentamicin [single dose]
If still febrile 48h later add teicoplanin
If still febrile 48h later change to meropenem instead of ceftriaxone
If still febrile 48h later add amphotericin B and 5-flucytosine
This approach is simply an example that has to be supplemented by clinical findings and
microbiological results and requires modification according to the experience of the local treating
physician. Delays in the change of antibiotic medications may provide an irretrievable advantage to
problem organisms such as pseudomonas, coagulase negative staphylococci or aspergillus. If there is a
clinical suggestion of an infection with pseudomonas medication with certain efficacy such as
amikacin should be added. If an atypical pneumonia is suspected the combination of antibiotics should
include a macrolide antibiotic such as erythromycin.
Vigilance and clinical expertise are more important than pedantic adherence to a schema !
8.4.3 GCSF
GSCF (Filgrastim) was used in a randomized fashion during the precursor study ALL-REZ BFM 96. It
resulted in a shortening of treatment intervals. A prognostic impact, however, could not be
demonstrated.
Therefore, GCSF is used in protocol ALL-REZ BFM 2002 only with a supportive care indication. It is
used in patients who had a poor tolerance of therapy during preceding treatment blocks and who are
considered at risk of significant complications due to prolonged during periods of aplasia. The
decision to use of G-CSF lies with the treating clinician. G-CSF is used at a dose of 5 mg/kg body
weight/day s.c. or as a 4-hour infusion. It is administered 24 hours after the end of the preceding
chemotherapy block. G-CSF is discontinued if the neutrophil count exceeds 3.0 x109/L on two
subsequent occasions following the nadir of cell counts.
8.4.4 Transfusion of blood products

For red cell and platelet transfusions only leukocyte-depleted, irradiated (30 Gy) and filtered
concentrates should be used. HLA-compatible platelet concentrates should be used particularly after a
poor response to transfusion. Granulocyte concentrates are nowadays only used in rare and exceptional
circumstances, e.g. uncontrollable fungal infections during periods of prolonged aplasia.
9 DIAGNOSTIC TESTS
The relapse of ALL requires a comprehensive diagnostic evaluation in order to classify the disease
according to established parameters and to adapt treatment to the risk profile of the patient. An
additional aim of relapse study ALL-REZ BFM 2002 is to define parameters that may provide insight
into the origin, course and prognosis of the disease and be helpful in the development of novel,
specific, efficacious and risk-adapted therapeutic strategies.
9.1 Definitions
9.1.1 Site of Relapse

Isolated bone marrow relapse is diagnosed if the bone marrow contains > 25% lymphoblasts in the
absence of extramedullary involvement.
Combined bone marrow relapse is diagnosed if the bone marrow contains > 5% lymphoblasts and at
least one extramedullary manifestation of ALL is present.
CNS relapse is diagnosed if morphologically unequivocal leukemic lymphoblasts are detected in the
CSF and there is a pleocytosis of > 5/µl nucleated cells. If the CFS is contaminated with blood the
following procedure is recommended after discussion with the study center. If blasts are present in the
CSF and the peripheral blood shows no blasts, a CNS relapse is assumed. If the proportion of blasts in
the CSF is equivalent to the proportion of blasts in the peripheral blood and there is no additional
morphologic evidence that the blasts persist longer in the CSF, contamination is assumed. In unclear
situations a case-by-case decision may be necessary. If blasts are present the patient receives the
intensified intrathecal chemotherapy similar to patients with CNS involvement but not the increased
dose of cranial irradiation. If clinical signs of CNS involvement are present such as visual
disturbances, polyphagia, cranial nerve palsies in the absence of CSF pleocytosis, the presence of a
CNS relapse has to be confirmed or ruled out with all available diagnostic methods (head CT, MRI). If
evidence of meningeal infiltration is found by imaging, a biopsy may have to be performed.
Testicular relapse is diagnosed in case of a uni- or bilateral painless testicular enlargement with
infiltration of leukemic lymphoblasts confirmed by biopsy. In case of a clinically normal contralateral
testis a subclinical involvement has to be ruled out by biopsy.
A relapse at other sites is detected by appropriate imaging techniques and requires confirmation by
biopsy.
9.1.2 Response to therapy and course

The assessment of the response to therapy in the bone marrow and CSF is solely based on cytologic
criteria.
A remission bone marrow (M1) is diagnosed if a representative bone marrow aspirate contains less
than 5% lymphoblasts with satisfactory cellularity and signs of regenerating normal hematopoiesis.
An aplastic bone marrow (M0) is diagnosed if a representative bone marrow aspirate contains only
few nucleated cells (mostly lymphocytes) without signs of regenerating normal hematopoeisis
independent of the cytologic detection of residual leukemic cells.
A non-representative bone marrow is diagnosed if the cellularity is markedly reduced despite signs
of regeneration in the peripheral blood and if the differential count of nucleated cells in the marrow
largely corresponds to that in the peripheral blood. Such a bone marrow aspirate should be repeated
particularly when therapeutic decisions are taken based on the result.
A complete remission (CR) is diagnosed if a remission bone marrow is present and there is no further
evidence of persistent leukemic lymphoblasts based on cytologic, histopathologic radiologic or clinical
findings (the detection of leukemic cells below the threshold of cytologic detection using molecular or
flow cytometric methods is compatible with the definition of complete remission).
9.1.3 Subsequent Relapse

The site of a subsequent relapse is defined as described for the first ALL relapse.
9.2 Initial diagnostic tests at relapse of ALL

The diagnosis of an ALL relapse has to be established unequivocally using the criteria listed below
before relapse therapy is begun. In difficult cases the study center should be contacted.
9.2.1 Bone Marrow

The bone marrow aspirate has to be performed at two different aspiration sites. After bone marrow
smears are prepared from the first marrow aliquot using a cover glass (without addition of heparin or
EDTA; touch preps are of inferior quality and should be avoided) at least two aspirates of 5 mL are
collected from each site into a heparinized syringe (total volume approximately 20 mL). In case of a
dry tap at both sites a bone marrow biopsy is performed. The first heparinized bone marrow aspirate
collected from each site (e.g left and right iliac crest) is sent without delay to the ALL-REZ study
center (Prof. Dr. Dr. h.c. G. Henze, Charite Berlin) for immediate processing and molecular/cytoge-
netic studies (within 24 hours). Immunophenotyping is performed on the second bone marrow syringe
(Prof. Dr. W. D. Ludwig, Berlin-Buch). In general, the entire diagnostic evaluation and classification
of relapse is performed on the bone marrow sample collected at the time of relapse. This includes
cytomorphology, molecular tests (MRD, fusion genes), immunophenotyping and cytogenetics.
Tab. 16: ALL-Relapse: diagnostics, shipment and asservation of material
Time point Sample Laboratory
First BM-syringe from both Berlin
sites! Prof. Dr. Dr. h.c. G. Henze
Diagnosis 2-3 x 5 ml heparin. BM
- molekular genetics
5 - 10 ml heparin. PB
- cytology
isol. extramed. manifestation
smears, unstained (5 PB, 5
BM, 2 CSF)
Robert-Rössle-Klinikum Buch
2 ml hepar. BM Prof. Dr. W.-D. Ludwig
2 unstained smears - immunphenotyping
Monitoring First BM-syringe from both

sites! ALL-REZ Studienzentrale
• after F1 2-3 x 5 ml heparin. BM
• after F2 Berlin
® Prof. Dr. Dr. h.c. G. Henze
smears, unstained (2 PB, 2
Arm B Arm A BM, 2 CSF) - molekular genetics
R-Blocks Prot II-IDA - cytology
• after 1. R2 • day 15
• after 1. R1 • day 29
• after 2. R2 • after
completion
• prior to and after continu-
ation therapy
• immediately prior to SCT
Univ. Kinderklinik Tübingen

First BM-syringe from both Dr. P. Bader
sites! - molecular genetics
• after SCT* 2-3 x 5 ml heparin. BM
• smears, unstained (2 PB, Berlin
2 BM, 2 CSF) Prof. Dr. Dr. h.c. G. Henze
in case of a chromosomal - molecular genetics
translocation: - cytology
• 1 x 5 ml hepar. BM
• 1 x 5 ml hepar. PB
* Chimerism studies after SCT are performed according to protocol ALL BFM SZT 2003 in parallel in Tübingen
(PD Dr. P. Bader) and in Vienna (Prof. Dr. Dr. T. Lion).
9.2.2 CNS
Every time a relapse is diagnosed a diagnostic lumbar puncture is performed. This lumbar puncture
can be used to administer the first dose of intrathecal chemotherapy. If a CNS relapse is suspected a
CSF volume of at least 10 mL has to be collected since this sample is possibly the only material for the
design of a clonal probe to monitor MRD. The CSF has to be promptly assessed by cytology or
prepared for such an assessment.
If a CNS relapse is suspected and the CSF is unremarkable a cranial MRI should be performed to
detect a localized involvement. Such an involvement may have to be confirmed by biopsy.
9.2.3 Testis
In the interest of a precise diagnostic evaluation, the immunophenotyping of lymphoblasts and the
detection of molecular markers should also be performed in cases of isolated testicular relapse.
The biopsy sample should be sent in sterile saline to the local pathologist and to the study center for
review.
9.2.4 Other forms of relapse

Any other suspicious manifestations such as an infiltration, swelling, effusion or space-occupying
lesion should be imaged. Biopsy samples should be evaluated morphologically as well as by
immunophenotyping and molecular methods.
9.3 Diagnostic tests during the course of treatment

A summary of indispensible diagnostic tests prior to, during and after the intensive phase of therapy is
shown in table 17 (p.71).
9.3.1 Response to therapy

All manifestations of an ALL relapse have to be monitored until their complete resolution using the
most appropriate diagnostic methods. These include bone marrow aspirates and lumbar punctures at
the beginning of the treatment blocks or during protocol II-IDA, respectively, and imaging techniques
for other sites. Complete blood and differential counts are performed daily until the disappearance of
blasts, then 2 to 3 times per week.
Bone marrow aspirates are performed even after the achievement of a cytologic remission to
determine the level of MRD according to the guidelines described in chapter 9.5. This also applies to
patients with an isolated extramedullary relapse.
Samples collected at the transplant center to assess the remission status after SCT are sent to the
molecular lab in Tübingen (PD Dr. Bader) for the subsequent monitoring of MRD.
9.3.2 Infectious Diseases

Specific microbiological and serological tests are indicated in case of suspected sepsis, fever (> 38.5º
C) and neutropenia (ANC < 0.5 x 10 9 /L).
Mandatory tests:
• CRP (quantitative assay)
• blood cultures (aerobic, anaerobic, fungal)
Optional tests:
• throat swab, swab of skin lesions, anal swabs
• midstream urine (colony count and culture, including fungal culture)
• viral diagnostics
Tab. 17: Diagnostic tests at relapse of ALL
at diagnosis during the intensive phase after the

of therapy intensive phase
of therapy
Bone marrow (immunophenotype, +
cytogenetics)
Bone marrow (morphology, MRD, + prior to each treatment +
molecular tests) element up to R1 (incl.),
week 13, prior to SCT
CSF (cytospin, immunology) + at the start of each block
except F2
HLA typing (patient and familiy) +
CBC and differential + at the start and end of +
each block, q2-3d in case
of myelosuppression
Biochemistry (lytes, glucose, protein, + at the start and end of +
albumin, crea, urea, AST, ALT, LDH, AP, each block
CPK)
amylase (serum) + if clinically indicated +
uric acid + daily during the
cytoreductive prephase
Coagulation (aPTT, INR, fibrinogen, + at the start of each block +
thrombin time, ATIII)
protein C, protein S, APC-resistance, +
prothrombin G20210A mutation, Lp(a)
Immunoglobulins + prior to each block R2 +
virology (HBV, HCV, EBV, + +
CMV, VZV, HSV, HIV)
Ferritine + +
Methotrexate level (potentially folate level)
according to protocol
Urine analysis (glucostix) + daily during blocks +
EKG, echocardiogram + prior to each block R2 +
EEG + +
X ray Chest prior to each third chest
treatment element
Abdominal ultrasound + +
Brain MRI + if clinically
indicated
9.3.3 HLA Typing

If the family has not been HLA-typed at the time a relapse is diagnosed, this should be done now for
patients in group S2, S3 and S4. If an HLA-identical family donor is identified, the study center should
be contacted to plan further therapy. If a compatible family donor is not available the search for an
unrelated donor should be initiated for patients in group S3 and S4. For patients in group S2 the
unrelated donor search should only be initiated if it is indicated based on the MRD result after F2
(week 5). At the same time an application to the local health insurance provider for coverage of the
cost of an international donor search is submitted using the Stefan-Morsch Stiftung - Hilfe fur
Leukamiekranke see chapter 4.11.3 (p.45) for further details.
9.3.4 Diagnostic tests during continuation therapy

During this phase of treatment peripheral blood counts are initially performed once a week ten every
14 days provided counts are stable and drug doses remain unchanged. Basic biochemical parameters
are monitored approx. every 3 months. Regular physical examinations are required.
A bone marrow aspirate is recommended at the beginning of continuation therapy then every 6 months
and at the end of continuation therapy. In addition to the morphological evaluation a molecular
assessment of MRD is performed.
Additional bone marrow aspirates and lumbar punctures are only performed if clinical symptoms or
changes of the peripheral blood counts suggest the suspicion of relapse.
9.3.5 Diagnostic tests at the end of therapy

Continuing complete remission is documented six to eight weeks after completion of therapy by
lumbar puncture and bone marrow aspirate including molecular tests. In addition a chest x-ray,
echocardiogram as well as biochemical and serological follow-up investigations are obtained. An
ophthalmologic examination (refractory media of the eyes) is recommended. Recommendations as to
the extent of follow-up tests are described in the overview of diagnostic tests after the completion of
therapy, see appendix, p.128.
9.3.6 Follow-up investigations, detections of late effects

The follow-up assessment should include at a minimum a physical assessment and complete blood
count. The interval between follow-up visits after the completion of therapy should be 4 weeks during
the first year, 6-8 weeks during the second and third year, 3 months during the fourth year and 6
months during the fifth year. Thereafter a yearly assessment is sufficient. An evaluation of the bone
marrow as part of the MRD study is offered for the time point of one year after completion of therapy.
Late effects of chemotherapy, irradiation and SCT are prospectively documented using the schema
shown in the appendix, p.128. The data collection form for late effects has been designed in a way that
allows efficient documentation. Information is collected in broad categories that are subject to the
individual assessment of the treating physician. Late effects are not part of the primary end points of
the study. They may, however, provide information about the quality of life in case of event-free
survival and may highlight potential differences between the treatment strategies (SCT vs.
chemotherapy). The late effects after radiation therapy are assessed in a separate study (Late Effects of
Radiation Therapy, Dr. Schuck, Universitäts-Klink Münster).
9.4 Minimal Residual Disease (MRD)

Bone marrow aspirates for the assessment of MRD are performed according to the guidelines
described in chapter 9.6 and at the time points listed in chapter 9.5. The MRD result after F2 (prior to
the first block R2 or protocol II-IDA, in week 5, respectively) is used to stratify post-remission therapy
in patients of group S2 with bone marrow involvement. Patients with <10-3 leukemic cells receive
intensive multi-agent chemotherapy as well as radiation therapy and continuation therapy. Patients
with ≥10-3 leukemic cells undergo allogeneic SCT according to the guidelines described in chapters
4.11, p.44. Additional bone marrow aspirates provide evidence to answer the study question i.e. which
strategy (R blocks vs. protocol II-IDA) is more efficacious to reduce MRD and to maintain a negative
MRD result. The MRD result prior to the second block R1 and the first block R1 following protocol
II-IDA, respectively (week 13), will be evaluated prospectively regarding its prognostic relevance for
patients with SCT. If such a prognostic relevance can be demonstrated a therapeutic decision (e.g. the
use of reintensification therapy) may be based on this result in the future.
9.5 Time points for the collection of samples

Mandatory bone marrow aspirates are performed at the time of relapse, prior to block F2, and prior to
the first four R blocks and prior to the start of protocol II-IDA, on day 15 and day 29 of protocol II-
IDA and prior to the first block R1 following protocol II-IDA, respectively. Additional bone marrow
aspirates are performed prior to SCT and prior to start of continuation therapy, to document a
continuous cytologic remission. Following SCT bone marrow aspirates are scheduled on day 30, 60,
100, 180 as well as during month 9, 12 and 18 after SCT.
9.6 Shipment of samples

Samples collected at the diagnosis of relapse and during the course of treatment are collected and
shipped as summarized in table 16 (p.69). To streamline the process and to minimize the sample
requirements (e.g. avoid duplicate measurements) all cytologic, molecular and cytogenetic tests are
performed in the ALL-REZ reference lab in Berlin (Prof. Dr. Dr. h.c. G. Henze, Dr. Seeger). The
molecular lab in Berlin is also staffed on weekends. Bone marrow samples, therefore, can be sent any
time so that bone marrow aspirations and the subsequent treatment need not be postponed for
logistical reasons. Samples should be received within 24h and sent with a courier service. For sample
requisitions see appendix, p.130 and following.
9.7 Reference Institutions

The morphologic diagnosis is generally made at the treating center. The study center performs a
central review to ensure a uniform diagnostic evaluation. In case of unclear results, an expedited
review can be performed, the result of which is typically communicated within one business day. If the
result of the central review is different from that of the treating centre, the responsible study physician
at the treating center will be contacted immediately by phone. Immunophenotyping results are also
reviewed by the study center. In case of discrepant results the treating center will be contacted by
phone.
The MRD results of the reference lab in Berlin that are relevant for the stratification of patients will be
communicated by the study center to the treating center. This notification includes a statement if two
clonal markers with the required sensitivity could be established and the result of the MRD test after
the second treatment course (F2). At the same time a statement will be made regarding the indication
for SCT based on MRD. MRD results of all other time points will not be communicated to the treating
centers. This also includes the MRD results after SCT performed by the laboratory in Tübingen. If the
legal guardians wish to obtain the results pertaining to their child despite a detailed disclosure by the
local study physician the results will be communicated following a written request signed by the legal
guardians.
9.8 Addresses of laboratories

Samples are shipped to the addresses listed below. Patients in Austria and Switzerland whose samples
are sent to central laboratories in the respective countries are exempt.
9.8.1 Molecular biology and diagnosis of MRD

The detection of molecular markers, BCR-ABL, TEL-AML1, MLL fusion transcripts (MLL-AF4,
MLL-AF9, MLL-ENL), cytogenetic tests if necessary and MRD tests based on TCR delta, gamma,
IgH and Ig kappa gene rearrangements as clonal markers are performed in the reference laboratory for
relapsed ALL in Berlin.
ALL-REZ Studienzentrale, Prof. Dr. Dr. h.c. G. Henze
Molekularbiologisches Labor
Charite Universitätsklinikum, Campus Virchow Klinikum
Klinik for Pädiatrie mit Schwerpunkt Hämatologie/Oncologie
13353 Berlin
Germany
Tel: 030-450-566088
Fax: 030-450-566946
9.8.2 MRD Diagnostic following SCT

The diagnosis of MRD following SCT is performed in the reference lab for MRD and chimerism in
Tübingen.
PD Dr. Peter Bader
MRD-/Chimärismuslabor
Universitätsklinik for Kinderheilkunde and Jugendmedizin
Hoppe-Seyler-Strasse 1
72076 Tübingen
Germany
Tel: 07071 29-83809
Fax: 07071 29 5365
9.8.3 Immunology
Samples for immunophenotyping include at least 2 ml of heparinized bone marrow and 5 ml of
heparinized peripheral blood and should be sent to:
Prof Dr. W.-D. Ludwig
Immunologisches Zellmarkerlabor
Charite, Campus Berlin-Buch
Robert Rössle Klinik – MDC
Lindenberger Weg 80
13122 Berlin-Buch
Germany
Tel: 030 - 9417-1362
Fax: 030 - 9417 - 1308
9.9 Scientific Companion Studies

The scientific companion studies include investigations aimed at the molecular, genetic, immunologic
and other features directly linked to acute lymphoblastic leukemia. Diagnostic samples collected as
part of the ALL-REZ BFM 2002 protocol will be used for this purpose or frozen if excess material is
available. Examples of current research projects are listed in the following.
9.9.1 MRD diagnosis by flow cytometry

In addition to MRD diagnosis by molecular methods flow cytometry can be used to detect minimal
residual cells (principal investigator C. Eckert; Dr. Dr. K. Seeger). Assays using both methods in
parallel in the same patient cohort are used to validate and supplement each method. The assays are
performed in the immunology lab (Fr. L. Badiali) of the Klink für Pädiatrie m.S.
Onkologie/Hämatologie, Charite, in collaboration with Dr. Dworzak (St. Anna-Spital, Vienna,
Austria).
9.9.2 Spectral karotyping (SKY)

In a pilot project during the last year of study ALL REZ BFM 96 spectral karotyping at the time of the
diagnosis of an ALL relapse was established and validated as a supplementary method to convetional
cytogenetics (project leader: Dr. Dr. K. Seeger). It was demonstrated that with this method the
karyotype of leukemic cells could be obtained in over 90% of bone marrow samples at the time of
ALL relapse.
9.9.3 mRNA expression arrays/microchip analysis

To identify and characterize prognostically relevant genes a genom-wide mRNA expression analysis
of ALL cells derived from clinically and molecularly/cytogenetically defined patient cohorts is
planned within the National Genome Research Network. (BMBF, subproject: Childhood ALL) during
the next 3 years using high-density microchips (project leader, Dr. Dr. K. Seeger).
9.9.4 In vitro resistance to apoptosis-inducing agents

This project tests the pro-apoptotic effects of cytotoxic agents on lymphoblasts in vitro with the aim to
predict the in vivo response in the future. In vitro apoptosis assay using patient samples have
demonstrated that the anthracycline idarubicin not only has superior efficacy compared to the
currently used daunorubicin, but that it is also able to overcome existing drug resistance to
conventional anthracyclines. These investigations further aim to identify molecular prognostic markers
within the apoptotic signal cascades and to test novel cytotoxic agents that are able to overcome
resistance to apoptosis with a view to potential use in the treatment of relapsed ALL in children
(Dr.med. Dr. rer. nat. Aram Prokop, director Dr. med. Peter Daniel, Medizinische Klinik mit
Schwerpunkt Hämatologie, Onkologie und Tumorimmunologie, Charite, Campus Berlin-Buch,
Humboldt Universität)
10 PATIENT SAFETY
The study center regularly assesses the stoppage criteria to ensure that any significant increase of
treatment-related mortality or relapse either in comparison to historical controls within the randomized
prospective comparison is recognized and acted upon according to the guidelines described in chapter
11.5, p.79. Additionally, adverse events are documented by the treating centers and severe adverse
events are reported immediately to the study center.
10.1 Adverse Events

Adverse events are diseases, signs or symptoms that occur or worsen after enrollment of a patient in
the study. These events have a temporal association with the protocol therapy. Depending on severity
and causality in relationship to defined treatment elements they are rated as follows:
severity Minor moderate severe life-threatening
causality None possible probable Certain
10.1.1 Documentation and evaluation of adverse events

Every adverse event has to be documented. The documentation includes the type, onset, duration,
degree/severity and causality of the event. All adverse events have to be monitored until resolution or
stabilization. The events have to be summarized in a physician’s report. These reports are sent to the
study center.
10.2 Severe adverse events

The following adverse events are for defined as severe.
• each death independent of the cause of death that occurs during or up to six weeks after
completion of the protocol therapy.
• life-threatening disease.
• events that result in permanent disability.
10.2.1 Documentation and reporting of severe adverse events

The study physician at the local institution has to report each severe and/or unexpected adverse event
within 24 hours by phone or fax to the following address:
ALL-REZ Study Center, Prof Dr. med.Dr. h.c. G. Henze
Klinik für Pädiatrie m.S. Onkologie/Hämatologie
Charite- Universitätsmedizin Berlin, CVK
Augenstenburger Platz 1
13353 Berlin-Germany
Tel: 49 - 0-30450-566354, Fax: 49 - 0-30-450-566901
E-mail: allrez@charite.de
For the notification the data form for adverse events is used, see appendix p.123, 124.
The study director/sponsor notifies the responsible research ethics board of the reported events. Local
study physicians are responsible for the notification of the local research ethics boards.
Unexpected, presently unknown events for which a causal relationship with the study medication
cannot be ruled out as well as any unexpected accumulation of severe events are disclosed to the study
participants without delay.
11 EVALUATION CRITERIA AND STATISTICAL ANALYSIS
11.1 Definitions
Complete remission (CR)
-regenerating bone marrow with less than 5% blasts (M1) and
-peripheral blood without blasts and with evidence of regeneration and
-absence of extramedullary leukemic involvement.
Partial remission (PR)
Blast percentage in the bone marrow > 5% and < 25% (M2).
Early response
Patients have an early response if CR is achieved after the first treatment element (bone marrow
aspirate on day 15 following F1) or if the bone marrow is aplastic with blasts < 5% and the criteria of
CR are fulfilled within the subsequent four weeks.
Late response
Patients have a late response if a CR is achieved between day 15 and day 29 of protocol II-IDA in arm
A or after the fourth treatment element (first block R1) and prior to the fifth treatment element (second
block R2) in arm B.
Non-response (NR)
Non-response is diagnosed in patients who have not achieved a complete remission by day 29 of
protocol II-IDA in arm A or by the start of the fifth block (second block R2) in arm B.
Induction death (ID)
An induction death is a treatment- and/or disease-related death that occurs during induction prior to
the confirmation of a CR.
Treatment-related death (TRD)
A treatment-related death is a death with a temporal and/or causal relationship to treatment that occurs
during continuous CR.
11.2 Criteria for the evaluation of the study results

The efficacy of therapy will be evaluated using the remission rate (CR, PR), response rate (early, late
response, non-response) and probability of overall (OS) and event-free survival (EFS) of patients
treated according to the protocol. Probabilities will be calculated according to the Kaplan-Meier
method. OS is calculated from the first day of treatment to the date of death or last follow-up. EFS is
calculated from date a CR is achieved to the date of a subsequent event (relapse, second malignancy,
treatment-related death) or the date of last follow-up. Patients who do not achieve a complete
remission (induction death, non-response) are assigned a duration of EFS of zero days (1 day for the
Cox regression analysis, respectively).
A separate analysis of treatment regarding the prevention of subsequent relapse will also use the
Kaplan-Meier method. In this case only patients who achieved a CR (remission group) will be
analyzed. Events that are not relevant for a particular question are censored at the time of their
occurrence. Thus the probability of relapse-free survival (RFS) is determined. The efficacy of therapy
regarding the prevention of relapse at a particular site will be estimated by rating only the
corresponding type of relapse as an event.
To evaluate the overall efficacy of the protocol, the analysis will be performed independent of
treatment modalities. Patients who underwent transplantation after they achieved a CR, therefore, are
included in the calculation of the overall results of the study regarding OS, EFS and RFS. For the
specific evaluation of the efficacy of chemotherapy, patients with SCT are censored at the time of
SCT. To evaluate SCT separate Kaplan-Meier analyses and survival calculations starting with the time
point of SCT are planned.
The comparison of the therapeutic efficacy of protocol II-IDA (arm A) vs. the R blocks (arm B) is
possible based on the MRD results that were obtained prior to and during corresponding treatment
periods in both arms at corresponding time points. Since the vast majority of patients have already
achieved a complete remission following block F2, only highly sensitive semi-quantitative molecular
tests will allow the detection of a further reduction of leukemic cells in the bone marrow following
morphologic remission.
The feasibility of the protocol will be assessed using the ratio of actually administered therapy vs.
therapy specified by the protocol according to the treatment schedule. Treatment-related morbidity
will be recorded using modified WHO criteria and the toxicity data collection form enclosed in the
appendix. Treatment-related deaths will be evaluated by individual analysis of autopsy reports and
medical summaries.
11.3 Statistical methods

In protocol ALL REZ BFM 96 and 2002 various risk factors are used to define four strategic treatment
groups S1 to S4 that differ with regards to prognosis (see table 8, p.38). Because of the uniform
documentation of diagnostic parameters this stratification could also be applied to the precursor
studies. As a result, preceding studies (since 1983) can be used as historical controls. The results of
both randomization arms A and B in protocol ALL REZ BFM 2002 will be evaluated and compared
both for the overall patient population as well as for the subgroups S1 to S4.
Tables, histograms, contingency tables and Kaplan-Meier survival curves are used to define patient
cohorts, to describe treatment and toxicity data and to provide information about the composition and
prognosis of patient groups. The log rank test will be used as a statistic for Kaplan-Meier data. In
addition, a Cox regression model will be used since it allows compensation for differences in
parameter distributions between both randomization arms and between consecutive studies.
Treatment results in both randomization arms will be determined using the life table method and
‘intention to treat’ analysis. This analysis is based on the cohorts as defined by randomization. If more
than 5% of randomized patients are not treated according to the randomization the results will also be
analyzed and compared in ‘treatment received’ analysis. In both cases comparisons will use the log
rank test. This is a conventional comparison study that requires a two-sided test. Despite the lower
cumulative drug doses of the protocol II-IDA (arm A) an improved result compared to the arm
containing R blocks (arm B) is theoretically possible based on the documented efficacy of this
treatment element in the literature (see chapter 3.3, p.24). A comparison of the ’molecular response’ to
treatment elements in both randomization arms will use the Chi2- test and non-parametric tests.
During the generation of hypotheses descriptive p values will be calculated using the log rank test,
Cox regression and methods for contingency tables and non-parametric distributions.
11.4 Estimation of accrual

The study is projected for five years. The study consists of a four-year accrual phase followed by a
one-year follow up and evaluation period. 75-80% of events are expected to occur within this time
period.
During the preceding ten-year period, an average of 116 cases of first relapse were registered per year.
Of these, an average of 5% did not meet the inclusion criteria for the ALL-REZ BFM study protocol.
These patients, together with multiply relapsed registered patients are followed as observation patients
and are analyzed separately. We, therefore, anticipate that 110 patients per year will meet the criteria
for enrollment in the randomized study. If - based on the experience of the previous studies - an 80%
participation rate in the randomization is used, 88 protocol patients will be available per year for the
evaluation of the target group.
Using the conventional concept treatment in blocks during relapse therapy, study ALL-REZ BFM 96
achieved a current overall result of 40% EFS at 5 years. To test the study hypothesis that the
introduction of protocol II-IDA results in a clinically relevant improvement of event-free survival by
15% (arm A, pEFS 0.55) compared to conventional treatment in blocks in arm B (pEFS 0.40) a sample
size of 169 per group is required (two-sided log rank test, significance level 0.05, 1-beta=0.8). The
total of 338 patients that is required for the randomized test will be achieved after an accrual of 4
years.
The current protocol uses the intensification of therapy (stem cells transplantation) in strategic group
S2 dependent on the MRD result after block F2. The results of a retrospective analysis suggest that
this intervention can be expected to improve the EFS compared to the previous studies (Eckert et al.,
2001). The existing case numbers allow the detection of a 10-15% difference with a significance level
of alpha = 0.05 and a power of 0.8.
11.5 Stoppage criteria

During the accrual an interim analysis is planned after two years that may result in the early
termination of the study or randomization. A descriptive analysis of deaths will be performed each
time 30 new patients are registered or at least every six months.
Treatment study ALL REZ BFM 2002 will be terminated
• if the total number of induction and treatment-related deaths exceed the case-dependent stoppage
threshold listed in the following table. If the alarm threshold is reached the research ethics board
and the data safety monitoring committee will be notified.
Tab. 18: Stoppage and alarm thresholds
number of patients 30 60 90 120 150 180 =>180
alarm threshold 7 13 18 24 30 36 19%
stoppage threshold 10 17 23 29 34 39 20%
• if the pEFS is smaller than in the precursor study ALL-REZ BFM 96 with p<0.01; if p<0.05, the
data safety monitoring committee is assembled
• if during the course of the study a treatment concept becomes known that is clearly superior to
relapse study ALL-REZ BFM 2002
Randomization will be stopped in favor of the prognostically favorable arm if the pEFS differs
between both randomization arms A and B in all strategic groups at a p<0.05 or within one strategic
group at a p<0.01. The data safety monitoring board is notified at a p<0.10.
11.6 Documentation and Randomization

Data on patients, diagnostic tests and treatment will be documented using the data registration forms
listed in the appendix and will be forwarded to the study center. Documentation of these data should
be completed within one year after end of the accrual phase.
The primary registration with the study center includes the registration form and the shipment of five
unstained bone marrow and peripheral blood smears, CSF cytospins, as well as heparinized bone
marrow for the central cytological review and for molecular tests. The results of immunophenotyping
by the reference lab, Zell-Marker Labor, Prof. Ludwig, Berlin, and of the molecular tests by the lab of
Dr.Dr. Seeger, Berlin are directly communicated to the study center. If immunophenotyping or
molecular testing is only performed locally, a copy of these results should be forwarded to the ALL-
REZ BFM study center.
Once the study center has received written consent to randomization, the result of the randomization
result will be communicated to the registering center. The randomization is performed centrally. A
block randomization stratified according to groups S1 to S4 will be performed.
The course of treatment will be documented using the treatment documentation forms in the appendix
(p.102-120). These forms should be sent to the study centre as soon as possible after the completion of
the respective treatment element or immediately after the occurrence of a relevant event. Toxicity and
complications are documented and evaluated separately for the randomized treatment elements
protocol II-IDA (arm A) and the first three R blocks (arm B). (see appendix, p.125). The medical
summary after completion of treatment is an indispensable part of the documentation and should be
forwarded to the study center without delay. A summary form documenting the treatment administered
and the tolerance of treatment blocks and asparaginase completes the documentation of the course of
treatment (appendix, p.126). The originals of the documentation forms should be sent to the study
center and will be archived there. Patient-related data, test results and other medical information will
be stored at the study center for a time period of at least ten years and will then be destroyed.
Data entries and corrections in the documentation forms have to comply with GCP standards. Entries
that are changed are corrected in a way that the primary entry remains recognizable. Changes are
signed and dated.
11.7 Definition and report of adverse events

Adverse events (a further relapse, death, second malignancy or second malignant disease) will be
documented on the event form (appendix, p.124) and forwarded to the study center without delay.
Cases of induction death and treatment-related deaths are reported as severe adverse events to the
study center without delay if possible within 24 hours.
If an unexpected association of adverse events with specific treatment elements becomes apparent the
participating centers will be notified without delay by the study center.
A survey of all participating centers with regards to the actual remission status of the registered
patients is planned at the end of the course of the study and prior to the analysis. In addition, such a
survey will also be performed during the course of the study for all or for selected centers, if there is
evidence of incomplete or delayed documentation.
Questions that require follow-up beyond the study period will be addressed by separate
documentation in collaboration with other projects/institutions or will be performed as part of and
according to the guidelines of accompanying projects (Pediatric Malignancy Registry, Second
Malignancy study, late effects study, study of side effects and late effects of radiotherapy).
11.8 Quality Assurance

The completeness of the documentation will be evaluated at regular intervals by the study center. If
data are incomplete, the study centre will contact the treating center. If necessary a member of the
study center will visit a treating center to complete the documentation locally. As part of the network
of competency supported by the Ministry of Education and Research, larger centers have research and
data registry personnel that are responsible for the correct and complete documentation of the study
data. These research assistants will receive regular training sessions during which study-specific issues
are discussed. This provides assistance to the local study physicians regarding the time-consuming
documentation and ensures the complete and prompt documentation of data.
12 ETHICS
12.1 Declaration of Helsinki

The study is conducted in agreement with the latest revision of the Declaration of Helsinki (2000,
Edinburgh, Scotland).
12.2 Research Ethics Board

The study protocol, patient information and consent forms were submitted for review by the research
ethics board responsible for the principal investigator at the Charite, Humboldt Universtät in Berlin.
The ethics board approved the study on December 14, 2001, with conditions that were met in the
second version of the protocol. A copy of the decision is enclosed in the appendix, p.136.
The ethics board will be informed without delay by the principal investigator about all changes to the
study protocol that may affect the safety of patients. Further, the board will be notified of all severe
and unexpected adverse events reported to the principal investigator as well as of the scheduled or
premature closure of the study.
The study physicians are responsible for the consultation of the respective ethics boards before any
patient is enrolled in this study. It is necessary to await the decision of the local ethics review boards
and to inform the boards about changes to the protocol, adverse events and the termination of the study
as described above.
12.3 Disclosure and consent to participation in the study

Each patient and his/her legal guardians, respectively, will be informed by the treating physician about
the nature, aims, expected benefits and potential risks of the study prior to enrollment and
randomization. Each patient is asked to provide written consent to participation in the study and the
transmission of data. Each patient has to be given sufficient time and opportunity to decide about
his/her participation and to have questions answered. The consent form is signed by the patient and the
treating physician. If the patient is unable to sign a witness has to confirm by signature that a oral
disclosure took place. For children and adolescents, the signature of the legal guardian is required. If
an adolescent patient is competent, he/she has to provide written consent. If consent to participation in
the study or to the transmission of data is declined, the patient is only considered an observation
patient.
A copy of the patient information and consent form is enclosed in the appendix (p.96). Form and text
should be adapted to the use of the individual center. The final forms should be presented to the local
ethics review boards. Two copies of patient information and consent form are signed. One copy
remains with the study physician, the second is handed to the patient.
12.4 Use, storage and transmission of data

The patients are informed that disease-specific data are stored in anonymized form and may be used
for scientific analysis (e.g. publications). All patients have the right to be informed about the stored
data. The consent for data analysis and transmission has to be obtained separately from the consent to
participation in the study (appendix, p.100).
12.5 Pertinent laws and administrative guidelines

The recommendations pertaining to good clinical practice (see International Conference on
Harmonization - Good Clinical Practice, ICH-GCP), effective since 17 January 1997, are adhered to.
The ‘Grundsätze für die ordungsgemässe Durchführung der klinischen Prüfung von Arzneimitteln’
[principles for the proper conduct of the clinical evaluation of medical drugs](Bundesanzeiger Nr.243
from 30 December 1987), the rules of the German ’Arzneimittelgesetz’ [drug act] (AMG 1976, latest
revision 1998) and ’Arzneimittelprüfrichtlinien’ [guidelines for the evaluation of medical drugs](1999)
apply. By definition, this study is a treatment optimization study. All drugs used are either approved
for the respective indication in children or can be designated as standard medication because they have
been used in numerous studies for the respective indication in children. Beyond the liability insurance
of the treating center a proband insurance was considered necessary by the ethics review board and,
therefore, has been arranged for all patients treated in Germany.
The study is funded by the ‘Deutsche Kinderkrebsstiftung’[German Childhood Cancer Foundation].
The study protocol must be followed exactly. Any deviation from the specified diagnostic/therapeutic
measures and time points, for which the local study physician is responsible, has to be documented
and justified (e.g. emergency measures).
12.6 Process for Protocol Amendments

Protocol changes and additions can only be initiated and authorized by the principal investigator.
Relevant amendments require in addition the approval of the ethics review board. Changes are
communicated in written form as a study amendment to all participating centers.
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46. Muller, H.J., Loning, L., Horn, A., Schwabe, D., Gunkel, M., Schrappe, M., von Schutz, V.,
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47. Nachman, J., Sather, H.N., Gaynon, P.S., Lukens, J.N., Wolff, L. & Trigg, M.E. (1997).
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48. Neuendank, A., Hartmann, R., Bührer, C., Winterhalter, B., Klumper, E., Veerman, A.J. &
Henze, G. (1997). Acute toxicity and effectiveness of idarubicin in childhood acute
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49. Oakhill, A., Pamphilon, D.H., Potter, M.N., Steward, C.G., Goodman, S., Green, A., Goulden,
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50. Pui, C.H., Bowman, W.P., Ochs, J., Dodge, R.K. & Rivera, G.K. (1988). Cyclic combination
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51. Reid, J.M., Pendergrass, T.W., Krailo, M.D., Hammond, G.D. & Ames, M.M. (1990). Plasma
pharmacokinetics and cerebrospinal fluid concentrations of idarubicin and idarubicinol in
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54. Ritchey, A.K., Pollock, B.H., Lauer, S.J., Andejeski, Y. & Buchanan, G.R. (1999). Improved
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55. Rivera, G.K., Hudson, M.M., Liu, Q., Benaim, E., Ribeiro, R.C., Crist, W.M. & Pui, C.H.
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67. Vieira Pinheiro, J.P., Muller, H.J., Schwabe, D., Gunkel, M., Casimiro da Palma, J., Henze, G.,
von Schutz, V., Winkelhorst, M., Wurthwein, G. & Boos, J. (2001). Drug monitoring of low-
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71. Winick, N.J., Smith, S.D., Shuster, J., Lauer, S., Wharam, M.D., Land, V., Buchanan, G. &
Rivera, G. (1993). Treatment of CNS relapse in children with acute lymphoblastic leukemia: A
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Ritchey, A.K., Rosen, D., Haggard, M.E., Golembe, B.L. & et al. (1992). Treatment of occult or
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ALL-REZ BFM 2002 90 Protocol version 25.06.2003
14 Appendices
Appendix1
Disclosure and Consent
Guidelines for disclosure and consent to treatment ................................................................................92
Summary of disclosure session ...............................................................................................................94
Patient information and consent to treatment ..........................................................................................96
Consent to forwarding and processing of personal data .......................................................................100

Guidelines for the Disclosure and the Consent to Treatment

A detailed disclosure and consent obtained from the patient and/or legal guardian(s) prior to the
start of treatment are indispensible for participation in study ALL-REZ BFM 2002. We
specifcally refer to the current version of "Guidelines regarding the information of hospital
patients about planned medical interventions", which were jointly adopted by the board of the
Deutsche Krankenhausgesellschaft and the board of the Bundsärztekammer (Bundes-
ärztekammer, 1990). The disclosure should be made orally by the treating physician in the
presence of a witness and documented in written form. The following appendices of the protocol
were designed for this purpose.
• protocol of the disclosure session
• patient information and consent to treatment
• consent to transmission and processing of personal data
Principally, the consent of the legal guardian(s) is required for underage children. Legal
guardians are both parents, as far they have joint custody, or the parent with sole custody or a
legally appointed guardian. We particularly emphasize paragraph 41 section 3 of the
Arzneimittelgesetz (AMG), which stipulates that the underage patient - in addition to the legal
guardians - has to be appropriately informed and has to provide consent if he/she is able to
understand the nature, meaning and consequences of the treatment specified in the protocol and
to form a decision accordingly. The legal priniciple underlying paragraph 41, section 3, AMG
also applies to this protocol of a treatment optimization study. Whether the conditions of
paragraph 41, section 3 AMG are met in an underage patient can only be determined based on the
circumstances of the individual case. They may well be met in children older than 12 years of age
who are familiar with their disease. Therefore, it is the responsibility of the treating physician to
evaluate together with the legal guardian whether a disclosure to and consent by the underage
patient are required. In this case the disclosure should occur in a gentle and age-appropriate
manner in the presence and with the support of the legal guardians.
The disclosure to the legal guardian/patient should occur in steps. First, a disclosure of the
diagnosis and of the need for an immediate start of treatment is required. The legal
guardian/patient are - from the time of the primary diagnosis – already aware of the physical,
psychological and social burden and of the consequences that may arise from the disease and its
treatment. Therefore, they are going to be confronted with considerable problems after the
disclosure of a diagnosis of relapse, the generally less favourable prognosis and the renewed
treatment and and its side effects. The extent and content of the disclosure, therefore, have to be
adapted to the individual situation. Only after the oral disclosure should the disclosure and
consent form be given to the legal guardian/patient.
The disclosure should mention the protocol design and that it is the intent of this treatment
optimization study to ensure the quality of treatment. The purpose of the study as well as the
current scientific knowledge should be explained. In particular, information should be provided
about the type, extent, duration and effect of the treatment elements specified in the protocol,
about diagnostic tests and about side effects, possible complications and late effects. The nature
and risks of radiation therapy have to be disclosed separately by the treating radiation therapist.
Similarly, in case of stem cell transplantation or a surgical procedure the responsibility for the
disclosure lies with the transplant physician, surgeon or anesthetist.
The legal guardians have to be informed that they have the choice to decline the protocol therapy
and to decide in favour of treatment alternatives, an alternative treatment arm or to decline any
treatment. One of the previous ALL-REZ BFM protocols may be considered as a treatment
alternative, which achieved a high rate of continuous remissions without an increase of severe
complications when compared to the international literature. Additionally, it has to be disclosed
that treatment alternatives are available during any phase of the disease and that no disadvantage
will arise from such a decision for the affected patient.
The randomization (assignment of treatment by chance) of treatment element protocol II-IDA vs.
the sequence of blocks R2, R1, R2 aims to determine if the modified protocol II can achieve a
higher remission induction rate and a longer event-free survival. The high efficacy and
tolerability of protocol II have already been demonstrated in primary BFM-treatment studies for
acute lymphoblastic leukemia. It is not known, however, if the use of this protocol during relapse
therapy is superior to the administration of R blocks. The legal guardians have to be informed
about this as well as the merit of the scientific question for future therapies before treatment is
started and before the central randomization is perfomed. They have to be informed that they may
decline the randomization and choose together with the treating physician a treatment arm
without further impact on the overall treatment and without disadvantages for patient. Further,
they have to be informed about the diagnostic tests and scientific studies, which are planned
during the treatment, their purpose and any associated risks as well as the option to decline these
investigations at any point in time.
It is recommended to have the legal guardian and – depending on the circumstances - the patient
sign a consent form for treatment of relapse according to protocol ALL-REZ BFM 2002, which
documents the contents of the disclosure. In cases where the signature of the legal gaurdian
and/or patient is not obtained the disclosing physician and a witness must sign a summary of
items that were covered during the disclosure and carefully document the decisoin of the legal
guardian/patient.
Written consent of the legal guardian/patient to the transmission and processing of personal as
well as diagnostic and therapeutic data to the study center, the Childhood Cancer Registry in
Mainz and central diagnostic laboratories is indispensible. If a patient completes the 18th year of
life during the course of the treatment a separate consent for the processing of data has to be
obtained. For the purpose of documentation, analysis and transmission of data to third parties the
study center anonymizes all personal data using a code for electronic patient identification (PID).
A copy of the patient information and consent to treatment and a copy of the consent to the
transmission and processing of personal data have to handed to the patient or his/her legal
guardian.
Summary of the disclosure

regarding protocol ALL-REZ BFM 2002 for the treatment of children
with a relapse of acute lymphoblastic leukemia
Prinicipal Investigator: Prof. Dr. med. Dr. h.c. G. Henze, Charité, Klinik f. Pädiatrie m.S. Onkologie/Hämatologie, Augustenburger Platz 1, 13353
Berlin
The persons listed below discussed in detail the disease and treatment of patients with a relapse
of acute lymphoblastic leukemia on _____________.
Patient: ______________________ ______________________ ____________

Name First name Date of Birth
Legal Gaurdian: ______________________ ______________________

Name First name
Legal Gaurdian: ______________________ ______________________

Name First name
Physician: ______________________ ______________________ ____________

Name First name Function
Witness: ______________________ ______________________ ____________
During the disclosure the following topics were addressed (please check).
Ο Diagnosis
Ο Prognosis without appropriate therapy.
Ο Expected prognosis with treatment protocol ALL-REZ BFM 2002.
Ο Expected prognosis with tretament alternatives (e.g. ALL-REZ BFM 87/90/96)
Ο Effects of chemotherapy (elimination of the leukemic cells, restoration of normal bone marrow function;
need for a combination of different successive treatment phases)
Ο Side effects of chemotherapy (nausea, vomiting; temporary hair loss; effects on the bone marrow and the
peripheral blood counts; immunosuppression; occurrence of severe infections, which in rare cases cannot
be controlled; potential damage to organs; potential effect on fertility; risk of development a malignancy
later on; rarely, not controllable life-threatening toxicity.
Ο Mechanism of action of radiation therapy (elimination of leukemic cells e.g. in the central nervous
system and its membranes)
Ο Side effects of radiation therapy (lethargy syndrome after CNS radiation, potential late effects)
Ο Aims of the protocol (optimization and standardization of therapy to improve the prognois of children
with relapsed ALL using a risk-adapted treatment concept with chemotherapy, radiation therapy and
possibly stem cell transplantation; randomized comparison of a continuous chemotherapy with therapy
in blocks during consolidation therapy; MRD testing as a basis for the decision regarding stem cell
transplantation in group S2; increased treatment intensity through shorter intervals between blocks in
accordance with protocol guidelines; standardization of induction therapy and mandatory stem cell
transplantation in the high risk groups S3 and S4; standardized use of L-asparaginase with individual
monitoring of pharmacological efficacy during tretament blocks; answer to scientific questions which
may be important for the treatment of future patients)
Ο Randomization (use of either protocol II-IDA or treatment blocks R2-R1-R2 as part of the consolidation
therapy; potential advantages and disadvantages; nature and purpose of randomization; merit of the
scientific question.
Ο Potential primary or secondary indication for transplantation (information about the associated
transplantation protocol with separate disclosure and consent)
Ο Scientific companion studies (research into the molecular, genetic, immunologic and other directly
related features of acute lymphoblastic leukemia; use of leukemic cells collected during protocol ALL-
REZ BFM 2002; storage of left over cells and use only after approval by the ethics board after
consideration of the potential individual benefit for the patient and only after anonymization)
Ο Current scientific knowledge
Ο Transmission of patient-related data
Ο Insurance coverage of the patient by liabililty insurance and proband insurance
Ο Freedom of choice for the patient
Topics that are not marked were not covered.
The patient and/or his/her legal guardians have decided
O in favour of participation and treatment according to protocol ALL-REZ BFM 2002
Ο against participation and treatment according to protocol ALL-REZ BFM 2002
Ο in favour of randomization
O against randomization
O in favour of participation in scientific companion studies after approval by the
ethics board and consideration of the benefit for the child
O In favour of participation in scientific companion studies only after additional
information and consent
O against participation in scientific companion studies
I hereby declare that I have informed the legal guardian(s)/patient identifed above in detail about
the nature, meaning, impact and risks of treatment protocol ALL-REZ BFM 2002 and that I have
handed to them/him/her a copy of the patient information form and consent to treatment form.
Physician: ______________________ ___________ ______________________

Name Date Signature
Witness: ______________________ ___________ ______________________

Name Date Signature
Stamp of the
Hospital
Treating center (letterhead or stamp):
Patient information and consent to treatment

according to treatment protocol ALL-REZ BFM 2002
for the treatment of children with a relapse of
acute lymphoblastic leukemia
Principal Investigator: Prof. Dr. med. Dr. h.c. G. Henze, Charité, Klinik f. Pädiatrie m.S. Onkologie/Hämatologie, Augustenburger Platz 1, 13353
Berlin
The persons listed below discussed in detail the disease and treatment of patients with a relapse
of acute lymphoblastic leukemia on ______________.
Patient: ______________________ ______________________ ____________

Name First name Date of Birth
Legal Guardian: ______________________ ______________________
Name First name
Legal Guardian: ______________________ ______________________
Name First name
Physician : ______________________ ______________________ ___________
You hearby confirm that today you have been informed in detail by the physician named above
about your/your child’s disease and about your/your child’s planned treatment. The disease is
acute lympoblastic leukemia which has recurred (relapse). You have been informed that this
disease cannot be controlled without appropriate treatment. You have been informed about the
probability of success that is expected after treatment with the proposed protocol as well as with
other previously tested treatments.
In particular, the following aspects of treatment have been explained to you:
As part of the treatment protocol ALL-REZ BFM 2002 treatment is given according to a plan that
is used in approximately 100 hospitals in Germany, Austria and Switzerland. More than 100
patients up to 18 years of age will be treated each year according to this plan so that a total of
approximately 450 patients will participate in this study. The experience gained in the preceding
studies was used in the planning of the overall treatment. The main goal of this protocol is to
improve the chance of cure by adjusting the treatment to the variable risk of suffering another
relapse. In addition, novel insights into the disease and its treatment will be gathered (treatment
optimization study). The treatment plan, the anticipated duration of treatment according to
protocol ALL-REZ BFM 2002 and the difference to other treatment concepts and previous
treatment protocols were explained to you.
The current concept uses a combination of medications (chemotherapy) and radiation therapy
and/or stem cell transplantation. The chemotherapy consists of successive treatment blocks and
phases during which various medications (cytotoxic drugs) are combined to eliminate the
leukemic cells. The combination of several medications, the additional use of radiation therapy
and - if needed - of stem cell transplantation is aimed at preventing any leukemic cell from
escaping treatment.
In this treatment plan the effectiveness of a prolonged chemotherapy block (protocol II-IDA) will
be evaluated, which has been used in a similar form for many years in the treatment of new cases
of ALL. Since it is not known if it is better to use a prolonged treatment block or three short
blocks during the treatment of relapse it will be determined randomly if protocol II-IDA or the
blocks R2-R1-R2 will be used. This process of random selection is called randomization. Using
randomization one can later determine if the prolonged block or the three short blocks achieve a
better prognosis. You have been informed about the possibilty to participate in the
randomization. If you decline the randomization there will be no disadvantages for you/your
child.
The side effects and risks of chemotherapy have been explained to you in detail. The following
issues have been mentioned: the occurrence of nausea, vomiting, temporary hair loss, effects on
the mucosal membranes, blood cell formation in the bone marrow and blood counts, the high risk
due to potentially life-threatening infections, possible late effects such damage to organs,
potential impairment of fertility, the need for contraception and the risk of developing other
malignancies later on. It was mentioned that side effects may not always be controllable and may
even be fatal.
The purpose of radiation therapy - the elimination of leukemic cells in the central nervous system
and its membranes or in the testes - as well as potential side effects and late effects have been
explained to you. A detailed explanation through the radiation therapist will occur prior to this
treatment. You have been informed about the possibilty to participate in studies aimed at the
recognition of late effects as part of a radiation therapy study.
You have been informed that the treatment plan includes a stem cell transplantion if the chance
for a cure is unfavorable. This can often already be determined at the time the relapse is
diagnosed. It is, however, also possible that it becomes apparent only during the treatment that
chemotherapy is not effective enough and that leukemic cells remain the bone marrow (minimal
residual disease, MRD). In this case stem cell transplantion should be planned. Special highly
sensitive laboratory tests are used to detect the remaining leukemic cells. Bone marrow will be
collected for these tests at various time points under local or a brief general anesthesia.
The possibility of a stem cell transplantion and its role as a part of the treatment plan have been
discussed with you in detail taking into account your/your child’s special situation. If this
treatment becomes necessary you will receive detailed information about the specific risks and
the procedure from the treating physcian ahead of time and on a separate occasion.
The tests for the detection of remaining leukemic cells in the bone marrow (MRD) at the time the
relapse is diagnosed and during the treatment are used to determine the response to treatment.
The test results will be used to determine the appropriate treatment and the appropriate treatment
strategy within the overall protocol. The treatment should be intensive enough to eliminate all
leukemic cells. At the same time the side effects of the treatment should be kept to a minimum.
The MRD test uses specific markers of the leukemic cells that are determined with molecular and
immunologic laboratory methods. Compared to conventional methods leukemic cells can be
detected with a up to 10,000-fold higher sensitivity. In children with a first diagnosis of acute
lymphoblastic leukemia these test results have been used for the planning of treatment since
1999.
During the relapse protocol ALL REZ BFM 2002 the MRD tests will be performed at the start of
treatment and at different time points during the course of treatment. The result after the second
chemotherapy block is used to decide if further chemotherapy or stem cell transplantation is
necessary. MRD results from all other time points will not be used to change treatment. They
will be analyzed scientifically, however, to investigate and confirm the success of the treatment.
You have been informed that bone marrow aspirates and drawing of blood for the MRD test is
scheduled at the time of the diagnosis of the relapse and up to six times during the course of
chemotherapy for you/your child. The first aspirates until the achievement of a remission are
necessary to establish the diagnosis and to assess the course of the disease with conventional
methods (microscopy). Samples for the MRD test are collected at the same time. After stem cell
transplantation it is recommended to perform additional bone marrow aspirates and MRD
measurements in your/your child’s case.
The potential risks and complications of bone marrow aspirates and the drawing of blood have
been explained to you. You have been informed that to date there have been no reports of severe
or regularly occurring complications after bone marrow aspirates and the drawing of blood for
MRD tests. In rare cases, bleeding and local infections at the aspiration site may occur. The bone
marrow aspirate is performed under local or general anesthesia. Information about general
anesthesia which typically lasts ten minutes will be provided by the anesthetist.
You have been informed that your child's leukemic cells may used for research studies into the
molecular, genetic, immunologic and other immediately disease-related features of acute
lymphoblastic leukemia and may be potentially used for the development of novel treatment
approaches. No additional bone marrow aspirate or phlebotomy is necessary for this purpose.
Only cells that were collected during the diagnostic tests for protocol ALL-REZ BFM 2002 will
be used. Leftover cells will be frozen if they are available. The cells will be used anonymously
after approval by the local research ethics board or after additional information has been provided
to you and your consent has been obtained. They will only be used if a direct benefit for your
child is possible from these investigations.
During the participation in protocol ALL-REZ BFM 2002 the liability insurance of the
participating clinic/center, in which the treatment and the investigations take place, assumes
liability for adverse health effects that are due to negligence. Adverse health effects that are
directly related to the study question are additionally insured by a proband insurance (Gothaer
Versicherung, Probandenversicherungsnummer 37.907.546060, Gothaer Allee 1 50969 Köln). If
you or your child observe an adverse health effect during or after treatment, which may be related
to the participation in the treatment protocol mentioned above, you are obligated to contact the
treating physician promptly.
Declaration and consent:
I consent to my/my child’s treatment according to protocol ALL-REZ BFM 2002.
I have been informed that my consent to this treatment is voluntary, that I may decline
consent to this treatment or to specific treatment elements, that I may revoke my consent at
any time and that I have the right to chose a different treatment or decline any therapy.
I agree that one of two treatment elements specified in the protocol (a longer block or three
short blocks) will be selected randomly at the study center (central randomization) and that
this information will be forwarded to the treating physician. I have been informed that the
participation in the randomization is voluntary and that I have the right to decline the
treatment according to a performed randomization and to select one of the two treatment
elements on my own.
I agree to partipate in the MRD and scientific companion studies that are part of the
treatment protocol. The participation in these studies is voluntary. Additional scientific
studies with remaining samples will only be performed after approval by the research
ethics board after consideration of the benefit for my child or only after I receive additional
information and provide consent. I know that I can decline all or individual tests at any
time without giving reasons.
You have the right to delete single words, sentences or paragraphs of this consent form and to
change them if they do not apply to you/your child or if you do not agree.
You consider yourself sufficiently informed and have had sufficient opportunity to ask questions
of the physician mentioned above. You have understood the information provided herein and
received a copy of the consent form.
patient: ______________________ ___________ ______________________

name date signature
legal guardian: ______________________ ___________ ______________________
name date signature
legal guardian: ______________________ ___________ ______________________
name date signature
physician: ______________________ ___________ ______________________

name date signature
Treating center:
(letterhead/stamp)
Consent to the transmission and processing of personal data

Treatment protocol ALL-REZ BFM 2002 for the treatment of children
with a relapse of acute lymphblastic leukemia
Principal Investigator: Prof. Dr. med. Dr. h.c. G. Henze, Charité, Klinik f. Pädiatrie m.S. Onkologie/Hämatologie, Augustenburger Platz 1, 13353
Berlin
I agree that my/ my child's
______________________ ______________________ ____________

Name First Name Date of Birth
personal data (name, date of birth, address, diagnosis and results of diagnostic tests, treatment
and disease course) are transmitted to the study center of treatment protocol ALL-REZ BFM
2002 and processed as part of and according to the purpose of this protocol. Regarding the
transmission of the data as descibed above I hereby release the treating physician from his/her
obligation to patient confidentiality.
The processing of data (storage, transfer, modification, deletion) by the study center serves the
purpose of medical documentation to improve the diagnosis, confirm laboratory and clinical test
results and monitor treatment in the individual treating centers. This documentation is an
important aid of contemporary treatment and indispensable for the optimal implementation and
coordination of treatment as well as the assesment of treatment success of this protocol. For the
purpose of central documentation, analysis or transmission of results to third parties the study
center anonymizes all personal data using a code for the electronic patient identification (PID).
These data will be transmitted if necessary to the following recipients:
• ALL-REZ BFM-Study Center (Director: Prof. Dr. G. Henze), Klinik für Pediatric Hematology/Oncology,
Charité, Humboldt-Universität, Augustenburger Platz 1, 13353 Berlin
• ALL-BFM-Study Center (Director: Prof. Dr. M. Schrappe), Pediatric Hematology/Oncology,
Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover
• CoALL-Study Center (Leiterin: Prof. Dr. G. Janka-Schaub), Pediatric Hematology/Oncology, Universi-
tätsklinikum Hamburg, Martinistr. 52, 20246 Hamburg
• Kinderkrebsregister (Dr. P. Kaatsch), Insitute for Medical Science and Documentation, Project Group
Pediatric Oncology, Johannes-Gutenberg Universität, Langenbeckstr. 1, 55101 Mainz
• Immunology Laboratry (Director: Prof. Dr. W.-D. Ludwig), Medizinische Onkologie / Molekularbiologie,
Max-Delbrück-Centrum, Lindenberger Weg 80, 13122 Berlin-Buch
• Molecular Genetic Laboratory (Leiter: Dr. Dr. K. Seeger), Klinik für Pädiatrie m. S.
Onkologie/Hämatologie, Charité, Humboldt-Universität, Augustenburger Platz 1, 13353 Berlin
• Cytostatic Laboratory (Leiter: Prof. Dr. B. Dörken), Med. Klinik m. S. Hämatologie, Onkologie und
Tumorimmunologie, Charité, Humboldt-Universität, Robert-Rössle-Str. 10, 13092 Berlin-Buch
• Pharmacologial Laboratory Pediatric Oncology (Director Prof. Dr. J. Boos), Klinik und Poliklinik für
Kinderheilkunde, Westfälische Wilhelms-Universität, Albert-Schweitzer-Str. 33, 48149 Münster
• Radiological Late-Effect Study (Director: Prof. Dr. N. Willich), Klinik und Poliklinik für
Strahlentherapie, Westfälische Wilhelms-Universität, Albert-Schweitzer-Str. 33, 48149 Münster
In case of stem cell transplantation the data will be transmitted to
• Pediatric Stem Cell Transplant Registry (Director: Prof. Dr. T. Klingebiel), Pädiatrische Hämato-
logie/Onkologie, Johann-Wolfgang-Goethe Universität, Theodor-Stern-Kai 7, 60590 Frankfurt
• The coordinating and transplanting center, at which the transplantation will be performed (center and
address will be forwarded to the patient/legal guardian by the treating physician)
• MRD-Lab (Director: PD Dr. P. Bader), Allg. Pädiatrie Hämatologie/Onkologie, Universitätsklinikum
Tübingen, Hoppe-Seyler.Str. 1, 72076 Tübingen
Any person that has access to the data is obliged to protect the privacy of these data and to
conform with pertinent legislation according to EU guidelines for data protection, federal law for
data protection and applicable state laws.
I agree to the transmission and processing of personal data as well as data describing the
disease, treatment and diagnostic tests to the extent described above and for the exclusive
purposes described above.
In addition, I agree to the collection, isolation, transfer and analysis as well as the anonymized
storage of samples of blood, tissue and genetic material potentially derived from this material that
was collected as part of the treatment protocol by the treating physician and the laboratories
mentioned above. All samples will be anonymized and stored indefinitely after the analysis or
will be destroyed upon your request.
Patient-related data, test results and other medical data will be stored for a time period of at least
10 years and then destroyed. Data used as part of the medical record will be stored for 30 years.
You may at any time decline the processing of the your/your child's data, request information
about your/your child's data and ask for the correction of data. The results of the treatment
protocol and investigations will be published in scientific journals without information that will
allow your/your child’s identificaton.
Consent to the processing of data is voluntary and can be revoked at anytime without
disadvantages for the patient. In this case all stored personal data and the corresponding code will
be deleted as far as this is not prevented by legal or professional rules for data storage.
patient: ______________________ __________ ______________________

name date signature
legal guardian: ______________________ __________ ______________________

name date signature
legal guardian: ______________________ __________ ______________________

name date signature
APPENDIX 2
Documentation of treatment blocks
Block F1 .................................................................................................................................................103
Block F2 .................................................................................................................................................104
Block R2.................................................................................................................................................105
Block R1.................................................................................................................................................106
Protocol II-IDA........................................................................................................................................107
Order sets
Block F1 .................................................................................................................................................109
Block F2 .................................................................................................................................................110
Block R2.................................................................................................................................................111
Block R1.................................................................................................................................................112
Protocol II-IDA (part 1) ...........................................................................................................................113
Protocol II-IDA (part 2) ...........................................................................................................................114
Infusion orders for methotrexat (1 g/m2/36h) .........................................................................................115
Infusion orders for cytarabine during block F2.......................................................................................116
Infusion orders for cytarabine during block R1 ......................................................................................117
Infusion orders for ifosfamide during block R2 ......................................................................................118
Infusion orders for cyclophosphamide during protocol II-IDA................................................................119
Folinic acid rescue for methotrexat (1 g/m2/36h) ...................................................................................120

Block F1
Please fill in this form and the end of the block and send it to the ALL-REZ BFM study center in Berlin
(Prof. Dr. med. Dr. h.c. G. Henze, Charité, Klinik f. Paediatrie m.S. Haematologie/Onkologie,
Augustenburger Platz 1, 13353 Berlin).
name: _________________________ body surface area [m2] ____,_________
first name: _________________________ start of the block: _______________
date of birth: _______________ end of the block: _______________
drug dose route individual dose
2
dexamethasone 20 mg/m /d p.o. mg DEXA
2
vincristine * 1.5 mg/m /d i.v. mg VCR
2
methotrexate 1 g/m 36 h infusion g MTX
2
E.coli L- Asp. **10,000 U/m 6 h infusion U Coli-ASP
methotrexate based on age i.t. mg MTX
cytarabine based on age i.t. mg ARA-C
prednisone based on age i.t. mg PRED
day 1 2 3 4 5 6
Please consult the specific instructions regarding administration of medications as well as the protocol
guidelines.
* The maximal dose of vincristine is 2 mg.

** In case of an allergic reaction or silent inactivation chose an alternative preparation according to
the protocol guidelines.
date: _______________ signature:______________ stamp:

Block F2
2
dexamethasone 20 mg/m /d p.o. mg DEXA
2
vincristine* 1.5 mg/m i.v. mg VCR
2
cytarabine 2x3 g/m /d 3 h infusion g ARA-C
2
E. coli L- asp.** 10,000 U/m 6 h infusion U Coli-ASP
prednisone based on age i.t. mg PRED
day 1 2 3 4 5
Please consult the specific instructions regarding administration of medications as well as the protocol
guidelines.

** In case of an allergic reaction or silent inactivation chose an alternative preparation according to
date: _______________ Signature:________________ stamp:

Block R2
2
dexamethasone 20 mg/m /d p.o. mg
2
thioguanine 100 mg/m /d p.o. mg 6-TG
2
vindesine 3 mg/m i.v. mg VDS
2
methotrexate 1 g/m 36 h infusion g MTX
2
ifosfamide 400 mg/m /d 1 h infusion mg IFO
2
daunorubicin 35 mg/m 24 h infusion mg DNR
2
E.coli L- Asp. ** 10,000 U/m 6 h infusion U Coli-ASP
prednisolone based on age i.t. mg PRED
day 1 2 3 4 5 6
Please consult the instructions regarding the administration of medications as well as the protocol
guidelines.
In case of CNS involvement intrathecal chemotherapy is repeated on day 5.
** In case of an allergic reaction or a silent inactivation chose an alternative preparation according to

date: _______________ signature:______________ stamp:

Block R1
dexamethasone 20 mg/m2/d p.o. mg DEXA
6-mercaptopurine 100 mg/m2/d p.o. mg 6-MP
Vincristine* 1.5 mg/m2/d i.v. mg VCR
methotrexate 1 g/m2 36 h infusion g MTX
cytarabine 2 x 2 g/m2/d 3 h infusion g ARA-C
E.coli L- Asp. ** 10,000 U/m2 6 h infusion U Coli-ASP
prednisolone based on age i.t. mg PRED
day 1 2 3 4 5 6
Please consult the instructions regarding the administration of medications and the protocol guidelines.

** In case of allergic reations or a silent inactivation chose an alternative preparation according to the
protocol guidelines.
date: _______________ signature:______________ Stamp:

Protocol II-IDA
Please fill in this form at the end of the block and send it to the ALL-REZ BFM study center in Berlin (Prof. Dr. med. Dr. h.c. G. Henze, Charité, Klinik f. Pädiatrie
m.S. Onkologie/Hämatologie, Augustenburger Platz 1, 13353 Berlin).
name: ________________________ first name: __________________________ date of birth: _______________
body surface area [m2] ____,_________ start of the block: _____________________ end of the block: _______________
2
dexamethasone 6 mg/m /d p.o. ________ mg DEXA
2
vincristine* 1.5 mg/m /d i.v. ________ mg VCR
2
idarubicin 6 mg/m /d 6 h infusion ________ mg IDA
2
E.coli L–Asp. ** 10,000 U/m 6 h infusion ________ U Coli-ASP
2
cyclophosphamide 1 g/m /d 1 h infusion ________ g CPM
2
cytarabine 75 mg/m /d i.v. ________ mg ARA-C
2
thioguanine 60 mg/m /d p.o. ________ mg 6-TG
MTX/ARA-C/PRED based on age i.t. ___/___/___ mg MTX/ARA-C/PRED
day 1 8 15 22 29 36 43
Please consult the instructions regarding the administration of medications as well as the protocol guidelines.
In case of CNS involvement additional intrathecal chemotherapy is given on day 8.
** In case of an allergic reaction or silent inactivation chose an alternative preparation according to the protocol guidelines.
Order Sets
The order sets and worksheets printed below are meant to aid the practical administration of therapy. They, of
course, cannot take into account the particular additions of each hospital and are merely meant as general
framework that requires individual modification. The heparinization of all infused solutions (400 U/L), which is
customary at our center, for example, is therefore deliberately not included.
Block F1
patient: date of birth: _________
height: ________ cm weight:________kg body surface area________m2
Dexamethasone 20 mg/m2 p.o. day 1-5 DEXA ________ mg
Vincristine 1.5 mg/m2 i.v. day 1 and 6 VCR ________ mg

approx.1 hour prior to the start of MTX
Intermediate-dose MTX 1 g/m2 (see infusion orders methotrexate)
Triple intrathecal chemotherapy day 1: approx. 1 hour after the start of MTX
Age MTX ARA-C PRED MTX ________ mg

< 1 year 6 16 4 mg simultan.
1 year 8 20 6 mg intra- ARA-C________ mg
2 years 10 26 8 mg thecal
>=3 years 12 30 10 mg PRED ________ mg
L-Asparaginase (dep.on preparation) E.Coli / PEG / Erwinia – ASP ________ U
- E.Coli-ASP. (medac) 10,000 U/m2 i.v. day 4

2
in NaCl 0.9% ca. 250 ml/m as a 6-hour infusion NaCl 0.9% ________ ml
or - PEG-ASP (medac) 1,000 U/m2 i.v. day 4

2
in NaCl 0.9% ca. 250 ml/m as a 2-hour infusion
or - Erwinase (Speywood) 10,000 U/m2 i.m. day 4, 6, 8

undiluted
Mandatory measurement of serum L-asparaginase activity 5 days after E.coli L-asparaginase, 2, 7,

and 14 days after PEG-L-asparaginase, two days after each dose of Erwina L-asparaginase (prior to
the next dose).
date ______________ physician_________________________

Block F2
Vincristine 1.5 mg/m2 i.v. day 1 VCR ________ mg

approx.1 hour prior to the start of ARA-C on day 1
HD-ARA C 4 x 3 g/m2 (see infusion orders cytarabine during block F2)
Triple intrathecal chemotherapy day 5

>=3 years 12 30 10 mg PRED ________ mg
L-Asparaginase (dep. on preparation) E.coli / PEG / Erwinia – ASP ________ U
- E.coli-ASP. (medac) 10,000 U/m2 i.v. day 4

2
or - PEG-ASP (medac) 1,000 U/m2 i.v. day 4

in NaCl 0.9% ca. 250 ml/m2 as a 2-hour infusion
or - Erwinase (Fa. Speywood) 10,000 U/m2 i.m. day 4, 6, 8

undiluted

and 14 days after PEG L-asparaginase, two days after each dose of Erwina L-asparaginase (prior to
the next dose).
date ______________ physician:____________________

Block R2

10 mg/m2 p.o. day 6 ________ mg
6-Thioguanine 100 mg/m2 p.o. day 1-5 6-TG ________ mg
Vindesine 3 mg/m2 i.v. day 1 VDS ________ mg

Intermediate-dose MTX 1 g/m2 (see infusion orders methotrexate)
Triple intrathecal chemotherapy day 1 (in case of CNS involvement also on day 5)
approx.1 hour after the start of MTX
>=3 years 12 30 10 mg PRED ________ mg
IFO 400 mg/m2 (see infusion orders ifosfamide during block R2)
Daunorubicin 35 mg/m2 day 5 DNR ________ mg

in NaCl 0.9% 20 ml/mg* as a 24-hour infusion NaCl 0.9% ________ ml
* for a peripheral venous access this concentration should not be exceeded; the parallel normal
saline infusion is decreased accordingly; in case of a central venous access any concentration
may be selected.
L-Asparaginase (dep. on preparation) Coli / PEG / Erwinia – ASP ________ U
- Coli-ASP. (Fa.medac) 10,000 U/m2 i.v. day 6

2
2
or - PEG-ASP (Fa.medac) 1,000 U/m i.v. day 6
undiluted

the next dose).
date ______________ physician ________________

Block R1

10 mg/m2 p.o. day 6
6-Mercaptopurine 100 mg/m2 p.o. day 1-5 6-MP ________ mg
Vincristine 1.5 mg/m2 i.v. day 1und 6 VCR ________ mg

Intermediate-dose MTX 1 g/m2 (see infusion orders for methotrexate)
Triple intrathecal chemotherapy day 1: approx.1 hour after the start of MTX

>=3 years 12 30 10 mg PRED ________ mg
HD-ARA C 2 x 2 g/m2 (see infusion orders cytarabine durine block R1)
L-Asparaginase (dep. on preparation) E.coli / PEG / Erwinia – ASP ________ U
- Coli-ASP. (Fa.medac) 10,000 U/m2 i.v. day 6

2
2
or - PEG-ASP (Fa.medac) 1,000 U/m i.v. day 6
undiluted

the next dose).
date ______________ physician ________________

Protocol II-IDA (part 1)


taper dose day 15-23
Vincristine 1.5 mg/m2 i.v. day 1,8,15,22 VCR ________ mg

maximum dose 2 mg
Idarubicin 6 mg/m2 over 6 hours. i.v. day 1,8,15,22 IDA ________ mg

in NaCl 0,9% ca. 100 ml / mg* NaCl 0,9% ________ ml
* for a peripheral venous access the specified concentration should not be exceeded; the parallel
infusion of normal saline has to be reduced accordingly; in case of a central venous access any
concentration may be selected.
Triple intrathecal chemotherapy day 1, 15 (in case of CNS involvement also on day 8)

>=3 years 12 30 10 mg PRED ________ mg
L-Asparaginase (dep. on preparation) E.coli / PEG / Erwinia – ASP________ U
- Coli-ASP. (Fa.medac) 10,000 U/m2 i.v. day 1, 6, 11, 16

2
or - PEG-ASP (Fa.medac) 1,000 U/m2 i.v. day 1 and 11
2
in NaCl 0.9% ca. 250 ml/m as a 2-hour infusion
or - Erwinase (Fa. Speywood) 10,000 U/m2 i.m. day 1, 3, 5, 7, 9, 11, 13, 15, 17, 19

the next dose).
date ______________ physician ________________

Protocol II-IDA (part 2)
Cyclophosphamide 1 g/m2 day 29 (see infusion orders cyclophosphamide)
Thioguanine 60 mg/m2 p.o. day 29-43 6-TG ________ mg
Cytarabine 75 mg/m2 i.v. day 31-34, 38-41 ARA-C________ mg
Triple intrathecal chemotherapy day 31, 38

>=3 years 12 30 10 mg PRED ________ mg
Antiemetic prophylaxis prior to ARA-C: day 31-34, 38-41
May not be necessary for some patients; if it is required:

- dimenhydrinate suppository (at an age-dependent dose) 3 hours prior to ARA-C;
if this is not sufficient:
- Ondansetron 5 mg/m² p.o. 3 hours prior to ARA-C.
date: ______________ physician:____________________________

Infusion orders for methotrexate (1 g/m2/36h)
Methotrexate 1 g/m2 total dose MTX ________ g

1/10 of the dose as a ½-hour infusion 1/10 dose MTX ________ g
in 5% glucose ca. 50 ml 5% glucose _______ ml
9/10 of the dose as a 35½-hour infusion 9/10 dose MTX ________ g
in 5% glucose ca. 250 - 500 ml/g MTX 5% glucose _______ ml
Leucovorin rescue
Leucovorin 15 mg/m2 i.v. at 48 hours Leucovorin ________ mg
Leucovorin 15 mg/m2 i.v. at 54 hours Leucovorin ________ mg
Parallel infusion start with MTX (hour 0), infuse twice the volume over 48 hours
0.9% NaCl 1500 ml/m2 0.9% NaCl ________ ml
2
+ 5% glucose 1500 ml/m 5% glucose ________ ml
+ KCl 30 mmol/l (glucose + NaCl) KCl ________ mmol
+ Na-Bicarbonate 40 mmol/l (glucose + NaCl) NaHCO3 ________ mmol
measure urine pH, if pH < 6.0:

Na-Bicarbonate 1 mmol/kg as a short infusion NaHCO3 ________ mmol
in dest. water 1 ml/kg dest. water ________ ml
strict fluid balance and weights;

if fluid balance is positive > 500 ml/m2: max. positive fluid balance ________ ml
furosemide 1 mg/kg, max 20 mg i.v. furosemide ________ mg
Labs: Na, K, Ca, Cl, Mg, total protein, AST, ALT, alk. Phosph., bili, crea
Prior to as well as 24 and 48 hours after the start of the MTX infusion
MTX level prior to as well as 36 hours and 48 hours after the start of the MTX infusion
The MTX level at hour 48 has to be measured immediately and the result has to be
communicated to the physician!
(may change the leucovorin rescue, see appendix)
date ______________ physician __________________________________

Infusion orders for cytarabine during block F2
ARA-C infusion
Vit B6 100 mg/m2 i.v. prior to each ARA-C infusion 4 x Vit B6 ________ mg
Conjunctivitis prophylaxis q6h (eye drops)
ARA-C 3 g/m2 four doses q 12h 4 x ARA-C ________ g

infuse in 5% glucose (ca.1g/50ml) over 3 hours 5% glucose ________ ml
Parallel infusion
0.9%NaCl 1000 ml/m2 0.9%NaCl ________ ml
+ 5% glucose 1000 ml/m2 5% glucose ________ ml
infuse twice each time over 24 hours
Antiemetic prophylaxis:
e.g. ondansetron 5 mg/m2 q12h i.v./p.o. Ondansetron________ mg

first dose at least 1 hour (i.v.) to 3 hours (p.o.) prior to the start of ARA-C
at the start as well as 24 hours and 48 hours after the start of each ARA-C infusion
date: _______________ physician:___________________________

Infusion orders for cytarabine during block R1
ARA-C infusion
Vit B6 100 mg/m2 i.v. prior to each ARA-C infusion 2 x Vit B6 ________ mg
Conjunctivitis prophylaxis q6h (eye drops)
ARA-C 2 g/m2 two doses q 12h 2 x ARA-C ________ g

infuse in 5% glucose (ca.1g/50ml) over 3 hours 5% glucose ________ ml
Parallel infusion
0.9%NaCl 1000 ml/m2 0.9%NaCl ________ ml
+ 5% glucose 1000 ml/m2 5% glucose ________ ml
infuse over 24 hours
e.g. ondansetron 5 mg/m2 q12h i.v./p.o. Ondansetron________ mg

first dose at least 1 hour (i.v.) to 3 hours (p.o.) prior to the start of ARA-C
at the start as well as 24 hours and 48 hours after the start of each ARA-C infusion
date: ______________ physician:___________________________

Infusions orders for ifosfamide during block R2
IFO infusion day 1 to 5
Mesna 200 mg/m2 i.v. day 1 to 5 prior 3 x Mesna ________ mg

to as well as 4 and 8 hours after IFO
Ifosfamide 400 mg/m2 IFO ________ mg

in 0.9% NaCl (ca. 50ml/m2) over 1 hour i.v. 0.9% NaCl ________ ml
day 1: prior to the start of the MTX infusion

day 2: after the completion of the MTX infusion
day 5: prior to daunorubicin
Parallel infusion
0.9% NaCl 750 ml/m2 0.9% NaCl ________ ml
+ 5% glucose 750 ml/m2 5% Glucose ________ ml
Infuse on day 3-5 each time over 24 hours; on day 1-2 the parallel infusion to MTX is
sufficient.
e.g. ondansetron 5 mg/m2 q12h i.v./ p.o. Ondansetron ________ mg

the first dose 1 hour (i.v.) to 3 hours (p.o.) prior to the start of IFO
Labs: Na, K, Ca, Cl, total protein, AST, ALT, alk. Phosph., bili, crea
at the start of each IFO infusion
date ______________ physician:_____________________________

Infusion orders for cyclophosphamide during protocol II-IDA
Furosemide 0.5 mg/kg (max. 20 mg) hour 0, 6 i.v. Furosemid ________ mg
Mesna 400 mg/m2 i.v. Mesna ________ mg
Cyclophosphamide (1 g/m2) CYCLO ________ g

Infuse over 1 hour
Parallel infusion / 24 hours start at hour 0

0.9% NaCl + 5% gluc. 1 : 1, 3000 ml/m2 0.9% NaCl ________ ml
5% glucose ________ ml
with KCl 30 mEq/l KCl ________ mEq/L
Exact fluid balance and weight;

if the fluid balance is positive more max. positive balance_______ ml
than > 300 ml/m2, give furosemide i.v.
(dose see above)
Antiemetic prophylaxis (hour -1 and 12):

Ondansetron 5 mg/m2 p.o./i.v. Ondansetron ______ mg
Dipstick each void for glucose, hemoglobin
Labs: AST, ALT, total protein, bili at hour 0; electrolytes, crea at hour 0 and 24
date ______________ physician:_____________________________

Folinic acid rescue for methotrexate (1g/m2/36h)
MTX level[µmol/L]
5
75 mg/m²
4
60 mg/m²
3
45 mg/m²
2
30 mg/m²
1
15 mg/m²
0.25 no rescue
42 54 66 78 90
36 48 60 72 84 96
hours after the start
of the MTX infusion
expected : MTX36h ≤ 10.0 µmol/L, MTX48h ≤ 0.5 µmol/L
Rescue hour LVC i.v.
48h 15 mg/m²
54h 15 mg/m²
end of rescue
deviations: MTX36h > 10.0 µmol/L and/or MTX48h > 0.5 µmol/L
→ determine a MTX level every 6 hours (may include a level at 42 hours) !
Rescue every 6 hours. LVC i.v. until MTX level ≤ 0.25 µmol/L
dose: according to the diagram using the MTX level
measured 6 hours earlier (if MTX at 42h > 5.0 µmol/L
use the MTX level at 42h, however).
start: as soon as the MTX level at 48h (or 42h) is available
MTX48h > 2.0 µmol/L: - forced alkaline diuresis at 3 l/m²
MTX48h > 5.0 µmol/l: - carboxypeptidase (see chapter emergencies)
- forced alkaline diuresis 4.5 l/m²
- LCV dose (mg) = weight(kg) x MTX level at 42h (µmol/L)
- additional LCV doses are calculated based on the
methotrexate level measured 6 hour earlier until this level
falls below 5 µmol/L.
APPENDIX 3
Data collection forms
Registration form for patients with relapsed ALL ...................................................................................122
Report of a subsequent event................................................................................................................123
Report of a severe adverse event..........................................................................................................124
Toxcity form - arm A (protocol II-IDA) and arm B (R blocks) .................................................................125
Documentation of the course of therapy ...............................................................................................126
Checklist (required documentation) .......................................................................................................127
Documentation of late effects
Schedule of diagnostic tests during follow-up........................................................................................128
Monitoring of late effects........................................................................................................................129

Registration form - ALL- REZ BFM 2002

Please register each patient with an ALL relapse promptly with the study center. You may even
consider contacting the study center already when a relapse is suspected. This allows a discussion of
specific questions even before the diagnosis is confirmed and the treatment is started and may
potentially avoid additional aspirates for the patient.
name: ________________ first name: _________________ date of birth:____________
sex: male first relapse: yes no relapse number :____

female
Data regarding the primary therapy of ALL
date of diagnosis: __________ treatment protocol __________ treatment arm ____________
radiation therapy: yes no dose [Gy] ____________ cranial craniospinal
immunophenotype: T non-T treatment completed: yes no end of treatment ________
molecular studies: BCR/ABL yes no; TEL/AML1 yes no; MLL-abnormality yes no
Previous relapse (if applicable)
date of diagnosis:__________ treatment protocol ___________ treatment arm __________
radiation therapy: yes no dose [Gy] ____________ cranial craniospinal
end of treatment: yes no ____________ BMT: yes no
Current relapse
date of diagnosis: site BM CNS testes other

time point late early very early
9
white cell count[x10 /L] _______ peripheral blasts [%] _______ CSF cell count [1/µl] _______
treatment group S1 S2 pilot start of treatment:____________

(prephase)
S3 S4
Do the legal guardian(s)/patient consent to randomization (R blocks vs. protocol II-IDA) ?

yes no
clinic stamp date:______________ physician: ________________

Report of a subsequent event

In case of a subsequent event please send this form promptly to the ALL-REZ BFM study center in
Berlin (Prof. Dr. med. Dr. h.c. G. Henze, Charité, Klinik f. Pädiatrie m.S. Onkologie/Hämatologie,
name: _________________________ first name: _________________________
date of birth: _______________ strategic group:________ arm: ________
subsequent relapse date: _______________
site BM CNS testis Other
Is further treatment planned ?
yes no which protocol ? ______________________
_________________________________________________________________________________
second malignancy date: _______________
ALL NHL AML MDS
brain Tumor ostegenic sarcoma other tumor
_________________________________________________________________________________
death* date of death: _______________
cause of death: _______________
related to relapse
related to treatment complication
related to BMT
related to a second malignancy
_________________________________________________________________________________
termination of treatment date: _______________
Time point within the protocol: _____________________
reason: ________________________________________
date:_______________ signature:_________________ Clinic Stamp:
*complete documentation of a severe adverse effect if applicable

Report of a severe adverse event

A severe adverse event that occurs during treatment has to be documented and reported without
delay,i.e. within 24 hours to the ALL-REZ BFM study center in Berlin (Director. Dr. med. Dr. h.c. G.
Henze, Charité, Klinik f. Pädiatrie m.S. Onkologie/Hämatologie, Augustenburger Platz 1, 13353 Berlin)
Fax: (030) 450-566 901
name: _________________________ first name: _________________________
date of birth: _______________ strategic group:________ arm: ________
Severe adverse events are defined as follows:

♦ each death independent of cause that occurs during or up to 6 weeks after the completion of
protocol therapy
♦ life-threatening disease
♦ events resulting in permanent disability
_________________________________________________________________________________
date of event: _______________
description of the event (type, onset, duration, extent, severity):
_________________________________________________________________________________
causality:
Is the pre-existing condition of the patient or an unrelated disease responsible for this event ?
yes probable possible improbable no
Do you think the event is related to protocol therapy?
yes probable possible improbable no
date: _______________ signature: _____________________ clinic stamp:

Toxicity form
Please document the maximal toxicity that occurred during the entire period from the beginning of the
protocol until 14 days after the end of the protocol and prior to the start of the next treatment block,
respectively.
name: ______________________________________ date of birth: ____________________
start of the block : __________________ end of the block: _______________
Toxicity following treatment

arm A prot.II-IDA (part 1) prot.II-IDA (part 2) arm B first R2 first R1 second R2
Grade 0 1 2 3 4
General wellbeing very good good intermediate poor very poor
Hb[g/l] normal for age ≥ 100 ≥ 80 ≥ 65 < 65
9
WBC [x10 /L] ≥4 <4 <3 <2 <1
9
Neutrophils [x10 /L] ≥2 <2 < 1.5 <1 < 0.5
9
Platelets [x10 /L] ≥ 100 < 100 < 75 < 50 < 10
Infection none minor moderate severe life-threatening
no organism organism isolated; with hypotension
isolated; on i.v. on i.v. antibiotics
antibiotics
Fever [°C] none < 38 ≤ 40 > 40 > 40
< 24 hours ≥ 24 hours
Nausea none oral intake sufficient decreased intake no oral intake TPN required
Vomiting 0 1 2-5 6 - 10 >10

[1/24 h] TPN required
Stomatitis none painless ulcers, painful erythema painful erythema or TPN
erythema or ulcers; able to ulcersations; unable required due to
eat to eat stomatitis
Diarrhea none <4 <7 < 10 ≥ 10
[1/24h] also at night, incontinence, bloody diarrhea,
mild cramping severe cramping TPN required
Skin changes none erythema dry desquamation, wet desquamation, exfoliative
vasculitis, pruritus ulceration dermatitis,
necroses
Creatinine normal for age ≤ 1.5 x N ≤3xN ≤6xN >6xN
Proteinuria [g/l] none ≤3 ≤ 10 > 10 nephrotic syndrome
Hematuria none microscopic macroscopic macroskopic requiring
without clots with clots transfusion
Creatinine clearance ≥ 90 < 80 < 50 < 30 < 20

Bilirubin normal for age < 1.5 x N <3xN < 10 x N ≥ 10 x N
AST/ALT normal for age ≤ 2.5 x N ≤5xN ≤ 20 x N > 20 x N
CNS toxicity none transient lethargy somnolence somnolence coma,
< 50 % of the time; ≥ 50 % of the time; seizures
modeately markedly disoriented
disoriented
PNS toxicity none paresthesias severe intolerable paralysis
paresthesias paresthesias,
and/or mild marked weakness
weakness
Comments / other complications / drug intolerance:
date: _______________ signature: _________________ clinic stamp:

Documentation of the course of therapy

Please fill in this form at the end of the intensive phase of therapy and send to the study center in
Berlin (Prof. Dr. med. Dr. h.c. G. Henze, Charité – Campus Virchow Klinikum, Abt.
Hämatologie/Onkologie, Augustenburger Platz 1, 13353 Berlin).
name: _________________________ first name: _________________________
date of birth: _______________ strategic group: ________ arm: ________
start of the block allergy to L-

block type of L-asparaginase ?
( date ) asparaginase ? *
pre-phase
block F1
block F2
arm A
prot. II-IDA
arm B
block R2
block R1
block R2
block R1
block R2
block R1
block R2
block R1
* allergy to asparaginase 0 = well tolerated

1 = mild reaction, no treatment required
2 = moderate reaction, tretaed with steroids/ H2-antagonists
3 = severe reaction, bronchospasm, hypotension
Radiation therapy
site dose (Gy) from – to

CNS cranial
craniospinal
testis right
left
other
date: _______________ signature: _________________ clinic stamp:

Checklist of documentation for patients with relapsed ALL
name: ____________________ date of birth: __________ strategic group: _____ arm: _____
time point sent date
At diagnosis:
registration form with consent to randomization _________

⇒ required for randomization !
copy of the disclosure _________

⇒ required for scientific studies and data processing !
During the intensive phase of treatment:
Strategic group 1 to 4 / arm A und B
copy of blocks administered

arm A ⎢ protocol II-IDA _________
arm B ⎢ first block R2 _________

arm B ⎢ second block R2 _________
toxicity forms
arm A ⎢ protocol II-IDA (part 1) _________
arm A ⎢ protocol II-IDA (part 2) _________

arm B ⎢ second block R2 _________
documentation of the course of therapy _________

(documentation of reactions to L-asparaginase and
regarding radiation therapy)
copy of the discharge summary _________
for BMT:
copy of the BMT discharge summary _________
During follow-up
report of subsequent events ___________
report of severe adverse events ___________
follow-up (yearly)
Documentation of late effects

Overview of diagnostic tests after the completion of therapy
Diagnostic tests for the detection of late effects as suggested at the end of continuation therapy and
after BMT, respectively.
Time after completion of Month Year

therapy or BMT 0 3 6 9 12 18 24 3 4 5 8
Date
Transaminases + + + + + + + + + + +
Bilirubin + + + + + + + + + + +
Creatinine + + + + + + + + + + +
Blood pressure + + + + + + + + + + +
Height + + + + + + + + + + +
Weight + + + + + + + + + + +
Echocardiogram + + + + + + + + +
EKG + + + + + + + + +
Chest X ray + + + + + + + + +
Karnofsky/Lansky index + + + + + + + +
Learning + + + + + + + +
Skin + + + + + + + + +
Neurologic exam + + + + + + + +
Pulmonary function test + + + + + +
Coagulation + + + + +
Ophthalmologic exam + + + + + + +
Dental exam + + + + + + +
T3/ T4, TSH + + + + +

LH/FSH/Estr./Testosterone + + + + +
Brain MRI + +
Data collection form for the monitoring of late effects
name: _______________________________________ date of birth.: ________________
date of assessment: _______________________ / ________month/year
General health status O good O intermediate O poor

Karnofsky/Lansky index %
Weight (kg) kg
Height (cm) cm
chron. GvHD (only for O none O limited O Extended
Growth/Development O normal O mildly O severely impaired
Sexual maturation O normal O mildly O severely impaired
Endocrine function O normal O mildly O severely impaired
Learning O normal O mildly O severely impaired
Neurologic exam O normal O mildly O severely impaired
Skin O normal O mildly O severely impaired
Liver function O normal O mildly O severely impaired
Renal function O normal O mildly O severely impaired
Blood pressure O normal O mildly O severely impaired
Cardiac function O normal O mildly O severely impaired
Pulmonary function O normal O mildly O severely impaired
Eyes O normal O mildly O severely impaired
Thyroid function O normal O mildly O severely impaired
Dental status O normal O mildly O severely impaired
Immune system O normal O mildly O severely impaired
In case of a mild or severe impairment pls. provide diagnostic results and details in
the following (e.g. SF of the echocardiogram, biochemistry etc.):
Comments:
_________________________________________________________________________________
_________________________________________________________________________________
_________________________________________________________________________________
Current medication:_________________________________________________________________
_________________________________________________________________________________
_________________________________________________________________________________
Date/ signature / stamp

Appendix 4
Requisitions
Cytology, molecular studies, MRD.........................................................................................................131
Immunophenotyping ..............................................................................................................................132
Chimerism and MRD studies following SCT..........................................................................................134

Sender (clinic stamp) Prof. Dr. med. Dr. h.c. G. Henze

ALL-REZ BFM Studienzentrale
Charité - Campus Virchow-Klinikum
Pädiatrie Onkologie / Hämatologie
13353 BERLIN
_________________________________________________________________________________
Treatment study ALL-REZ BFM 2002

REQUISITION
_________________________________________________________________________________
patient: ______________________________________ date of birth: _______________________
date collected: ______________

_________________________________________________________________________________
sample:
bone marrow peripheral blood CSF ______________

_________________________________________________________________________________
requested test(s):
1. BM morphology at diagnosis (6 unstained slides)

2. BM morphology – central review (3 unstained slides)
3. CSF cytology (2 unstained cytospin slides)
4. molecular analysis of clonal markers / Minimal Residual Disease

5. drug resistance testing at diagnosis
diagnosis of relapse
prior to block F2 start of continuation therapy

prior to the first R2 block or protocol II-IDA end of continuation therapy
prior to the first R1 block or day 15 protocol II-IDA
prior to the second block R2 or day 29 protocol II-IDA prior to SCT
prior to the second block R1 or prior to the first block R1
2-3 x 5 ml BM and 5 - 10 ml peripheral blood

heparinized (Heparin Novo oder Vetren)
the sample should be shipped in a syringe or a sterile container

send by courier
_______________ _________________
date signature
Immunology
REQUISITION □ IMMUNOPHENOTYPING
□ DNA INDEX (only for ALL BFM-Study)
name: tel: fax:

first name:
date of birth: ward:
hospital address:
male □ female □
□ typing of leukemia/lymphoma cells □ AMLCG study/□ MRD pilot project

□ lymphocyte subsets □ ALL/NHL-BFM studies (pediatric)
□ PNH diagnostic □ AMML-BFM study (ped.) /□ MRD pilot project
□ initial diagnosis □ relapse
clinical diagnosis: MRD-AMLCG MRD-AML-BFM

morphologic diagnosis: timepoint of sample time point of sample
previous immunologic findings: □ intial diagnosis □ initial diagnosis
CBC: WBC(/µl) blasts □ after induction I □ day 8
platelets(/µl) Hb(g/dl) □ after induction II □ day 15
lymph. % gran. □ prior to consolid. □ day 22
organomegaly: □ after consolid. □ day 33
lymphoma: □ during mainten. □ day 52
previous chemotherapy □ yes □ no □ prior to BMT □ prior to first HR
date of last chemotherapy:
Sample: ___ml peripheral blood ___ml peripheral blood in EDTA (PNH/ lymphocyte
subsets)
___ml bone marrow ___ml pleural effusion, CSF
□ lymph node
Please always include unstained slides !
...................................................... ..............................................................................
place, date of sample collection legible signature and stamp of the requesting
physician
COLLECTION AND SHIPMENT OF SAMPLES

FOR IMMUNOLOGIC MARKERS
1. Samples
Draw bone marrow (at least 2 ml), peripheral blood ( amount depends of WBC or % blasts),
CSF(>300/3 cells/µl), pleural effusion, ascites into a heparinized syringe (50 U heparin/ml
sample).
Send lymph node or tissue biopsies unfixed in culture media (e.g. RPMI or MEM media) or in
a buffered saline solution (e.g. Hanks BSS or PBS), to which 10-15% fetal calf serum have
been added if possible.
PLEASE INCLUDE ONE UNSTAINED SLIDE PER SAMPLE!
For the PNH test (FACS) und the analysis of lymphocyte subsets please send 5-10 ml
peripheral blood in EDTA.
2. Packaging
If possible use plastic containers that cannot break. Do not use natural cork caps for tubes.
Remove needles form syringes and cap syringes well.
3. Shipment
Please send all samples by courier and label as “important diagnostic sample”.
If possible do not ship samples in which cells rapidly lose viability (e.g. lymph node, ascites,
pleural effusion, CSF) during the weekend.
4. Requisition
Please fill in the form completely (name, first name, date of birth of the patient;
clinically/morphologically suspected diagnosis; initial test or relapse; previous immunological
result if known; clinical results; date of sample collection; legible signature of the
physician and address of the sending hospital).
5. Our shipping address

ALL-REZ BFMKlinik
2002 134 und Jugendmedizin
für Kinderheilkunde Tübingen
Protocol version 25.06.2003
Eberhard-Karls-Universität
Universitätsklinikum Tübingen
sender Chimerism and

MRD - Analysis
[Bitte nicht ausfüllen - Laborintern]
Probeneingang:
Probennummer:
Probenmenge:
Universitätsklinikum Tübingen
Klinik für Kinderheilkunde und Jugendmedizin
MRD-/ Chimärismuslabor PD Dr. P. Bader
Labor C02 Raum 305
Hoppe-Seyler-Straße 1
72076 Tübingen
Tel.: + 49 (0)7071 29-83809
Fax.: + 49 (0)7071 29-5365 Email: peter.bader@med.uni-tuebingen.de
sample: 5ml EDTA blood 5ml EDTA bone marrow

diagnosis: __________________ date of sample collection: ______________
CHIMERISM MRD-ANALYSIS ALL
First sample: Diagnosis of relapse:

Recipient (pre) Leukemic blasts
Donor Transplant:
Post BMT:
Test sample (+ 30d) post SZT
Subpopulationen: (+ 60d) post SZT
CD 15 (+ 100d) post SZT
CD 14 (+ 6 mon) post SZT
CD 56
(other time point:________________)
A report will be sent within 3 business days after receipt

of the sample (abnormal results will be faxed): These analysis is performed as part of a reserach study.
• A report will not be sent.

• The assessment of chimersim is not free of
charge! • MRD testing is free of charge.
In case of questions do not hesitate to contact us by phone or email.

APPENDIX 5
Review by the research ethics board ................................................................................ 136
List of particpating centers................................................................................................. 138

Participating Centers
Prof.Dr.G.Mau Frau OÄ Dr. D. Möbius
OA Dr. Eberl Frau OÄ Dr. E. Holfeld
Stadt.Klinikum-Kinderklinik Carl-Thiem-Klinikum Cottbus
Holwedestr.16 Kinderklinik
38118 BRAUNSCHWEIG Thiemstr. 111
Tel: (0531) 595-1222 (Pforte)-1338 (Stat) O3048 COTTBUS
Fax: (0531) 595-1400 Tel.: (0355) 46-2332 (Stat.)
Fax (0355) 46-2182
OA Dr. H.-J. Spaar
OA Dr. Th. Lieber Prof. Dr. W. Andler
Kliniken d. Freien Hansestadt Bremen Dr. Th. Wiesel
Prof. Hess-Kinderklinik Vestische Kinderklinik
St.-Jürgen-Str. Universität Witten / Herdecke
28205 BREMEN Dr. Friedrich-Steiner-Str. 5
Tel.: (0421) 497-1 (Pforte) -5413 (Stat.) 45711 DATTELN
Fax (0421) 497-3421 Tel.: (02363) 975-506 (Stat.)
Fax (02363) 642-11
Prof. Dr. M. Kirschstein
Allg. Krankenhaus - Kinderabteilung Frau CÄ Dr. C. Niekrens
Siemensplatz 4 Städt. Krankenanstalten
29223 CELLE Kinderklinik
Tel.: (05141) 72-2040 (Stat.) Wildeshauser Str. 92
Fax (05141) 72-2049 (Stat.) 27753 DELMENHORST
Tel.: (04221) 99-4401 (Poli)
OA Dr. K. Hofmann Fax (04221) 99-4405
Frau OÄ Dr. I. Krause
Klinikum Chemnitz gGmbH OA Dr. H. Breu
Klinik für Kinder – u. Jugendmedizin Frau OÄ Dr. H. Olschewski
Flemmingstr. 4 Städt. Kliniken Dortmund - Kinderklinik
O9116 CHEMNITZ Beurhausstr. 40
Tel.: (0371) 3332-4124 (Stat.) 44123 DORTMUND
Fax (0371) 3332-4125 Tel.: (0231) 50-21721 (Stat.)
Fax (0231) 50-20105
OA Dr. R. Frank
Landkrankenhaus / Kinderklinik PD Dr. M. Suttorp
Ketschendorfer Str. 33 Frau Dr. I. Lauterbach
96450 COBURG Universitätsklinikum Carl Gustav Carus
Tel.: (09561) 22-5553(Stat.) Klinik u. Polikl. für Kinderheilkunde
Fax (09561) 22-5552 Fetscherstr. 74
O1307 DRESDEN
Prof. Dr. E. B. Lang Tel.: (0351) 458-2340 (Stat.)
Frau OÄ Dr. R. Siegler Fax (0351) 458-4337
St. Vincenz-Hospital / Kinderabteilung
Südring 41 Frau Dr. V. Scharfe
48653 COESFELD Städt. Krankenhaus Dresden-Neustadt
Tel.: (02541) 89-2022 Kinderklinik
Industriestr. 40
O1129 DRESDEN
Tel.: (0351) 856-2550 (Stat.)
Fax (0351) 856-2500
PD Dr. G. Weinmann Prof. Dr. U. Göbel

OA Dr. A. Lemmer Universitäts-Kinderklinik
Klinikum Erfurt GmbH Hämatologie/Onkologie

Klinik für Kinderheilkunde Moorenstr. 5
Am Schwemmbach 32 A 40225 DÜSSELDORF
99012 ERFURT Tel.: (0211) 811-7662(Stat.)
Tel.: (0361) 781-4603 (Stat.) Fax (0211) 811-6206
Fax (0361) 781-4502
Dr. P. Zickler
Prof. Dr. J. D. Beck Städt. Kliniken
Universitäts-Kinderklinik Zu den Rehwiesen
Hämatologie/Onkologie 47055 DUISBURG
Loschgestr. 15 Tel.: (0203) 733-3201
91054 ERLANGEN Fax (0203) 733-3202
Tel.: (09131) 853-3118 (Pforte)
Fax (09131) 853-3113 Prof. Dr. T. Klingebiel
PD Dr. D. Schwabe
Prof. Dr. W. Havers Universitäts-Kinderklinik
Universitäts-Kinderklinik Hämatologie/Onkologie
Hämatologie/Onkologie Theodor-Stern-Kai 7
Hufelandstr. 55 60590 FRANKFURT
45122 ESSEN Tel.: (069) 6301-5243 (Stat.)
Tel.: (0201) 723-2255 (Stat.) Fax (069) 6301-6056 (Stat.)
Fax (0201) 723-2359
Frau Prof. Dr. C. Niemeyer
Prim. Dr. E. Ludescher Universitäts-Kinderklinik
Landeskrankenhaus - Pädiatrie "Station von Pfaundler"
A - 6807 FELDKIRCH / AUSTRIA Mathildenstr. 1
Tel.: (0043-5522) 24511 79106 FREIBURG i. Br.
Tel.: (0761) 270-4552 (Stat.)
Prof. Dr. med. J. F. Beck Fax (0761) 270-4518
OA Dr. S. Weigel
Universitäts-Kinderklinik Dr. med. A. Feldges
Hämatologie / Onkologie OA Dr. R. Uhlmann
Soldmannstr. 15 Schweizer Kinderspital
17487 GREIFSWALD Claudiusstr. 6
Tel.: (03834) 86-6321(Stat.) CH-9006 SANKT GALLEN/ SCHWEIZ
Fax (03834) 86-6323 Tel.: (0041-71) 2437-111
Fax (0041-71) 2437-699
Dr. G. Makosch
Frau Dr. I. Schmidt Prof. Dr. A. Reiter
Kreiskrankenhaus Gummersbach Frau Dr. Dr. R. Blütters-Sawatzki
Kinderklinik / Hämatoonkologie Universitäts-Kinderklinik
Wilhelm-Breckow-Allee 20 Hämatologie/Onkologie
51643 GUMMERSBACH Feulgenstr. 12
Tel.: (02261) 17-1602 (Stat.) 35385 GIESSEN
Fax (02261) 17-1592 Tel.: (0641) 99-43532 (Stat.)
Fax (0641) 99-43429
Prof. Dr. S. Burdach
Frau OÄ Dr. R. Schobeß
Universitäts-Kinderklinik
Abt. Päd. Hämatologie/Onkologie
Ernst-Grube-Str. 40
06097 HALLE/WITTENBERG
Tel.: (0345) 557-2492 (Stat.)
Fax (0345) 557-2495
Prof. Dr. R. Schneppenheim Prof. Dr. L. Schweigerer
Frau Prof. Dr. G. Janka PD Dr. A. Pekrun
Universitäts-Kinderklinik Universitäts-Kinderklinik
Hämatologie/Onkologie Hämatologie/Onkologie
Martinistr. 52 Robert-Koch-Str. 40
20246 HAMBURG 37070 GÖTTINGEN
Tel.: (040) 42803-2725 (Stat.) Tel.: (0551) 39-6227(Stat.)
Fax (040) 42803-3725 (Stat.) Fax (0551) 39-6252
Prof. Dr. K. Welte Prof. Dr. C. Urban

Prof. Dr. M. Schrappe Universitäts-Kinderklinik
Medizinische Hochschule Hannover Hämatologie/Onkologie
Kinderklinik – Hämatologie / Onkologie Auenbruggerplatz 30
Carl-Neuberg-Str. 1 A - 8036 GRAZ / AUSTRIA
30625 HANNOVER Tel.: (0043-316) 385-2630 (Stat.)
Tel.: (0511) 532-3288 (Stat.) Fax. (0043-316) 385-3450
Fax (0511) 532-9029
Prof. Dr. A. Kulozik
Dr. med. Knust OA Dr. W. Behnisch
Ev. Krankenhaus Bethanien Universitäts-Kinderklinik
Abt.Kinder- u. Jugendmedizin Hämatologie / Onkologie
Hugo-Fuchs-Allee 3 Im Neuenheimer Feld 150
58644 ISERLOHN 69120 HEIDELBERG
Tel.: (02371) 2123-00 Tel.: (06221) 56-2383 (Stat.)
Fax (02371) 2123-02 Fax (06221) 56-5505
Prof. Dr. F. Zintl Prof. Dr. W. Kachel

Prof. Dr. J. Hermann Dr. H. Full
Klinikum der FSU Jena Klinikum Heilbronn
Klinik für Kinder- u. Jugendmedizin Klinik f. Kinderheilkunde u. Jugendmedizin
Kochstr. 2 Am Gesundbrunnen
O7740 JENA 74064 HEILBRONN
Tel.: (03641) 9-38253 (Stat.) Tel.: (07131) 49-3751 (Stat.)
Fax (03641) 9-38470 Fax (07131) 49-3709
Prof. Dr. G. Rupprath Dr. Ch. Tautz

OA Dr. F. J. Gutwein Dr. A. Längler
Städt. Krankenhaus - Kinderklinik Gemeinschaftskrankenhaus
Friedrich-Engels-Str. 25 Abt. Pädiatrie
67653 KAISERSLAUTERN Gerhard-Kienle-Weg 4
Tel.: (0631) 203-1381 58313 HERDECKE
Fax (0631) 203-1386 Tel.: (02330) 62-3917 (Stat.)
Fax (02330) 62-3220
OA Dr. R. German
Dr. W. Dupuis Prof. Dr. N. Graf
Städt. Klinikum - Kinderklinik Frau Dr. P. Riesinger
Karl-Wilhelm-Str. 1 Universitäts-Kinderklinik
76131 KARLSRUHE Päd. Hämatologie/Onkologie
Tel.: (0721) 974-3265 Im Walde
Fax (0721) 974-3269 66421 HOMBURG/Saar
Tel.: (06841) 162-8399 (Stat.)
Fax (06841) 162-8424 (Stat.)
Prof. Dr. H. Wehinger PD Dr. W. Nürnberger

Frau OÄ Dr M. Rodehüser Klinik f. Knochenmarktransplantation
Städt. Kinderklinik und Hämatologie/Onkologie GmbH
Mönchebergstr. 41 Päd. Hämatologie/Onkologie
34125 KASSEL 55743 IDAR-OBERSTEIN

Tel.: (0561) 9803-395 (Stat.) Tel.: (06781) 66-1500 (Sekr.)
Fax (0561) 9806-971 Fax (06781) 66-1504
OA Dr. A. Claviez Prof. Dr. F. M. Fink

Universitäts-Kinderklinik AÖ Landeskrankenhaus
Klinik für Allgemeine Pädiatrie Universitäts-Kinderklinik
Schwanenweg 20 Anichstr. 35
24105 KIEL A - 6020 INNSBRUCK / AUSTRIA
Tel.: (0431) 597-1640 (Stat.) Tel.: (0043-512) 504-0 (Pforte)
Fax (0431) 597-1641 Fax (0043-512) 504-3484
CA Dr. C. v. Klinggräff OA Dr. W. Sternschulte

Städt. Krankenhaus Städt. Kinderkrankenhaus
Klinik für Kinder- u. Jugendmedizin Amsterdamer Str. 59
Chemnitzstr. 33-35 50735 KÖLN
24116 KIEL Tel.: (0221) 8907-5243 (Stat.)
Tel.: (0431) 1697-0 (Pforte) Fax (0221) 8907-5330
Fax (0431) 1697-406
Frau OÄ Dr. S. Völpel
Prim. Prof. Dr. W. Kaulfersch OA Dr. P. Thomas
AÖ Krankenhaus - Kinderabteilung Klinikum Krefeld - Kinderklinik
St. Veiter Str. 47 Lutherplatz 40
A - 9026 KLAGENFURT / AUSTRIA 47805 KREFELD
Tel.: (0043-463) 538 Tel.: (02151) 32-2375 (Stat.)
Fax (0043-463) 538-23043/23017 Fax (02151) 32-2391
Prof. Dr. M. Rister Frau Dr. M. Nenadov-Beck

OA Dr. R. Ferrari Frau Dr. C. Dessing
Städt. Krankenhaus Kemperhof / Kinderklinik Centré Hospitalier Universitaire Vaudois
Koblenzer Str. 115 - 155 Department de pédiatrie
56065 KOBLENZ Unité d’onco-hématologie
Tel.: (0261) 499-2651(Stat.) CH 1011 LAUSANNE / SCHWEIZ
Fax (0261) 499-2030 Tel.: (0041-21) 314-1111 (Zentrale)
Fax (0041-21) 314-3332
Prof. Dr. F. Berthold
Frau Dr. D. Schwamborn Prof. Dr. D. Körholz
Universitäts-Kinderklinik Frau OÄ Dr. med. K. Rieske
Hämatologie/Onkologie Universitäts-Kinderklinik
Joseph-Stelzmann-Str. 9 Hämatologie/Onkologie
50924 KÖLN Oststr. 21-25
Tel.: (0221) 478-6820 (Stat.) O4317 LEIPZIG
Fax (0221) 478-6821 (Stat.) Tel.: (0341) 97-26113 (Stat.)
Fax (0341) 26 15 728
Prim. Dr. O. Stöllinger
AÖ Krankenhaus Barmh. Schwestern / Kinderabt. Prof. Dr. I. Mutz
Langgasse 16 AÖ Landeskrankenhaus / Kinderabt.
A - 4010 LINZ / AUSTRIA Vordernberger Str. 42
Tel.: (0043-732) 7677-7244 (Stat.) A - 8700 LEOBEN / AUSTRIA
Tel.: (0043-3842) 401-1 (Zentrale)
Fax (0043-3842) 401-2738
Frau Dr. L. Nobile Buetti Prim. Dr. K. Schmitt

Consulente d’oncologica ped. Dr. G. Ebertsberger
Reparto pediatria Landes-Kinderkrankenhaus
Ospedale La Carità Krankenhausstr. 26
CH - 6600 LOCARNO / SCHWEIZ A - 4020 LINZ / AUSTRIA
Tel.: (0041-91) 756-7580 Tel.: (0043-732) 6923-2202 (Stat.)

Fax (0041-91) 811-4570 Fax (0043-732) 6923-2207
Prof. Dr. H. C. Dominick Prof. Dr. P. Gutjahr

Frau OÄ Dr. B. Selle Universitäts-Kinderklinik
Kinderklinik St. Annastift Hämatologie/Onkologie
Karolina-Burger-Str. 51 Langenbeckstr. 1
67065 LUDWIGSHAFEN/Rhein 55101 MAINZ
Tel.: (0621) 5702-269 (Stat.) Tel.: (06131) 17-2642 (Stat.)
Fax (0621) 5702-221 Fax (06131) 17-6686
Prof. Dr. P. Bucsky PD Dr. W. Scheurlen

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All - Relapsed - All-Rez BFM 2002

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ALL-REZ BFM 2002

Protocol for the Treatment of Children with

by the Society of Pediatric Oncology and Hematology (GOPH)

Principal Investigator: G. Henze

Address of the study center:

Klinik für Pädiatrie m.S. Onkologie/Hämatologie

Tel: +49-(0)-30-450-566 354

Privileged information for investigational use only

Principal investigator Prof. Dr. med. Dr. h.c. Günter Henze 1

Co-principal investigator Dr. med. Rüdiger Fengler 1

Study coordinator Dr. med. Arend von Stackelberg

Documentation Andrea Kretschmann 1

Radiation therapy Dr. med. M. Albrecht 2

Bone marrow transplant coordinator Prof Dr. T. Klingebiel 3

Universitäts – Kinderklinik, Hämatologie/Onkologie

Members of the study committee

Dr. med. M. Albrecht u.ruehl@khf.de

Prof. Dr. med. J.D. Beck joern.beck@kinder.imed.unierlangen.de

Prof. Dr. med. U. Bode bode@ukb.uni-bonn.de

Dr. med. W. Dörffel wdoerffel@berlin.helios-kliniken.de

Dr. med. W. Ebell wolfram.ebel@charite.de

Dr. med. R. Fengler ruediger.fengler@charite.de

Prof. Dr. med. H. Gadner gadner@ccri.univie.ac.at

Prof. Dr. med. U. Göbel KK04AMBZ@uni-duesseldorf.de

Prof. Dr. med. G. Henze guenter.henze@charite.de

Frau Prof. Dr. med. G. Janka janka@uke.uni-hamburg.de

Prof. Dr. med. T. Klingebiel tklingebiel@zki.uni-frankfurt.de

PD Dr. med. E. Koscielniak cws.study@olgahospital.s.shuttle.de

Dr. med. G. Mann mann@ccri.univie.ac.at

Prof. Dr. med. S. Müller-Weihrich smq@lrz.tu-muenchen.de

PD Dr. med. Ch. Peters peters@ccri.univie.ac.at

Prof. Dr. med. J. Ritter ritterj@uni-muenster.de

Prof. Dr. med. M. Schrappe schrappe.martin@mh-hannover.de

_____________________________________________ Berlin, 10.02.2003

_____________________________________________ Berlin, 10.02.2003

_____________________________________________ Berlin, 10.02.2003

4.4 Duration of study participation ................................................................................... 37

6.2.3 Cytarabine ................................................................................................................................ 56

9.8.2 MRD Diagnostic following SCT.............................................................................................. 74

APPENDIX 1: DISCLOSURE AND CONSENT......................................................................91

APPENDIX 2: DOCUMENTATION OF TREATMENT BLOCKS..........................................102

ORDER SETS ......................................................................................................................108

APPENDIX 3: DATA COLLECTION FORMS.......................................................................121

APPENDIX 4: REQUISITIONS ............................................................................................130

ETHICS REVIEW .................................................................................................................136

Fig. 1: Number of registrations of a first relapse by year and treatment strategy

2.1 Design and results of previous studies

2.1.1 Results of studies ALL-REZ BFM 83-90

Fig. 2: Studydesign ALL-REZ BFM 83 to 90

ALL- group week 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27

C, cytoreductive pre-phase; D 24 / 12 , continuationtherapy 24 / 12 month; R, randomization; , radiation

2.1.2 Results of randomizations

2.1.3 Prognostic Factors

p < 0.001 p < 0.001

non-T: n = 669; cens.= 394; pEFS= .45 ± .02

p < 0.001 p < 0.001

2.2 Study ALL-REZ BFM 95/96

2.2.1 Definition of risk groups (S groups)

pEFS = .75 ± .06 n = 29; cens. = 24; pEFS = .79 ± .09

2.2.2 Study design

Fig. 14: Design of study ALL-REZ BFM 95/96

S3 R C F1 G? F2 G? R1 G? R2 stemm cell transplantation

S4 I G S G S G S G stemm cell transplantation