Prospective Evaluation of Measurable Residual Disease in Intensively Treated Patients With Acute Myeloid Leukemia (AML) as Surrogate Endpoint for Survival
Conditions: Leukemia, Myeloid, Acute
Sponsor: University Hospital Heidelberg

 
 
 
PERDAM  
Trial Protocol 
 
Prospective Evaluation of Measurable Residual Disease in Intensively 
Treated Patients with Acute Myeloid Leukemia (AML) as Surrogate 
Endpoint for Survival 
 
 
Trial Code: 
PERDAM 
Therapeutic Area: 
Hematology/Oncology 
Protocol Number: 
NCT-2018-0554 
Version and date: 
V1.1,  9.4.2018   
Registered in 
clinicaltrials.gov 
Database: 
Yes  
 
No 
 
Principal 
Investigator 
Prof. Dr. Richard F. Schlenk 
 
NCT-Trial Center 
National Center for Tumor Diseases  
Im Neuenheimer Feld 130.3 
D-69120 Heidelberg 
Tel.:  +49(0)6221 56-6228 
Fax: +49(0)6221 56-5863 
Email: richard.schlenk @nct-heidelberg.de 
 
 
 
 9.4.2018  
Prof. Dr. Richard F. Schlenk 
Principal Investigator 
 
 
This document contains confidential information belonging to the NCT-Trial Center of the National Center 
for Tumor Diseases in Heidelberg. Except as may be otherwise agreed to in writing, by accepting or 
reviewing these materials, you agree to hold such information in confidence and not to disclose it to 
others (except where required by applicable law), nor to use it for unauthorized purposes. In the event of 
actual or suspected breach of this obligation, the NCT-Trial Center should be promptly notified. 
 
 

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Responsibilities  
Principal Investigator 
Statistics/Biometry 
Prof. Dr. Richard F. Schlenk 
 
NCT-Trial Center 
National Center for Tumor Diseases  
Im Neuenheimer Feld 130.3 
D-69120 Heidelberg 
Tel.:  +49(0)6221 56-6228 
Fax: +49(0)6221 56-5863 
Email: richard.schlenk @nct-heidelberg.de 
Dipl. Stat. A. Benner, Dr. Christina Kunz 
 
Deutsches Krebsforschungszentrum 
Abteilung für Biostatistik 
Im Neuenheimer Feld 581, Gebäude TP4 
D-69120 Heidelberg 
Tel.:  +49(0)6221 42-2231 
Fax:  +49(0)6221 42-2397 
Email: a.benner @dkfz-heidelberg.de 
 
 
Trial Coordination (HD) 
Trial Coordination (DD)  
Dr. Lucian Le Cornet   
 
NCT-Trial Center 
National Center for Tumor Diseases  
Im Neuenheimer Feld 130.3 
D-69120 Heidelberg 
Tel.:  +49(0)6221 56-6294 
Fax: 
+49(0)6221 56-5863 
Email: studienzentrale @nct-heidelberg.de 
PD Dr. Christoph Röllig, MSc  
 
SAL-Studienzentrale 
Medizinische Klinik und Poliklinik I 
Universitätsklinikum Dresden 
Fetscherstraße 74 
01307 Dresden 
Tel.:  +49(0)351 458 4969 
Fax: 
+49(0)351  
Email: sal @uniklinikum-dresden.de  
 
 
Leading clinical site (HD) 
Leading clinical site (DD) 
Prof. Dr. Carsten Müller-Tidow  
 
 
Klinik für Innere  Medizin V 
University Hospital Heidelberg 
Im Neuenheimer Feld 410 
D-69120 Heidelberg 
Tel.:  +49(0)6221 56-8000 
Fax: 
+49(0)6221 56-5813 
Email: direktor.med5 @med.uni-heidelberg.de 
Prof. Dr. med. Gerhard Ehninger, Prof. Dr. 
med. Martin Bornhäuser 
 
Medizinischen Klinik und Poliklinik I 
Universitätsklinikum Carl Gustav Carus  
Fetscherstr.74  
01307 Dresden 
 
Tel.: +49(0)351 458-4190 
Fax: +49(0)351 458-5362 
 
 
Laboratory for flow cytometry (HD) 
Laboratory for flow cytometry (DD) 
PD Dr. M. Hundemer, Dr. K. Kriegsmann 
 
Klinik für Innere  Medizin V 
Universitätsklinikum Heidelberg,  
Labor für Durchflusszytometrie, 
Im Neuenheimer Feld 410 
69120 Heidelberg  
Tel.: +49(0)6221 56 8001 
Fax: +49(0)6221 56 4659 
Email: michael.hundemer @med.uni-
heidelberg.de 
Dr. rer. medic Uta Oelschlägel, Dr. med. 
Malte von Bonin, Dr. med. Maximilian 
Röhnert 
 
Labor Durchflusszytometrie  
MK1-L06 Haus 31, 1. Etage, R 216 
Universitätsklinikum  Carl Gustav Carus 
Fetscherstr. 74 
01307 Dresden 
Germany 
Tel.: +49(0)351 458-5621 
Email: malte.bonin @uniklinikum-
dresden.de 

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Summary 
Acute myeloid leukemia is a genetically and phenotypically heterogeneous disorder with an 
incidence of 3 to 4 per 100 000 men and women per year and a median age at diagnosis of 
about 70 years. Prognosis, especially in older patients, has remained very poor. In patients 
considered suitable for intensive chemotherapy, the combination of an anthracycline and 
cytarabine remains the standard of care. For patients achieving a complete remission (CR), 
postremission therapy (PRT) ranging from chemotherapy to allogeneic hematopoietic stem cell 
transplantation is required; intensive PRT is still under debate in older patients.  
Beyond pre-treatment genetics-based risk stratification, measurable residual disease (MRD) 
during treatment and follow up emerges as an important prognostic factor in first CR. 
Furthermore, MRD may provide a tool for a read-out of therapeutic efficacy.  
In this diagnostic meta-study we intend to measure MRD using multiparameter flow cytometry 
across up-front randomized clinical trials which in total will accrue more than 1000 patients. 
MRD will be assessed early (after induction) and late (after consolidation) during treatment. The 
aim of the study is to analyse if levels of MRD measured early during treatment are closely 
related to overall survival and thus may serve as an early surrogate. There is a growing public 
demand that new, promising drugs are approved for therapy as rapidly as possible. Therefore, it 
is of great interest to obtain these approvals based on early biomarker endpoints such as MRD 
rather than on long-term survival endpoints. 
Zusammenfassung 
Die Akute Myeloische Leukämie ist eine genetisch und phänotypisch heterogene Erkrankung 
mit einer Inzidenz von 3-4 Fällen pro 100.000 Männer und Frauen pro Jahr. Das 
durchschnittliche Diagnosealter liegt bei etwa 70 Jahren. Die Prognose ist nach wie vor 
ungünstig, insbesondere bei älteren Patienten. Unverändert besteht die Standard-
Induktionstherapie für fitte Patienten aus einer Kombination von Anthracyclinen und Cytarabin. 
Patienten mit Erreichen einer kompletten Remission (CR) nach der initiale Chemotherapie 
benötigen eine Postremissionstherapie (PRT), die aus weiterer Chemotherapiezyklen oder 
einer allogenen hämatopoetischer Stammzelltransplantation je nach Risikoprofil besteht. Der 
Nutzen der intensiven PRT ist jedoch für ältere Patienten umstritten.  
Neben der etablierten Risikostratifikation anhand genetischer Merkmale nimmt die Bedeutung 
der „messbaren Resterkrankung“ (MRD) als prognostischer Parameter während und nach 
Abschluss der Behandlung insbesondere in erster CR zu. Zusätzlich kann die MRD als Indikator 
für therapeutische Effekte herangezogen werden. 
In dieser diagnostischen Meta-Studie ist beabsichtigt, MRD mittels Multiparameter-
Durchflusszytometrie im Rahmen mehrerer randomisierter Studien an insgesamt mehr als 1.000 
Patienten zu bestimmen. Die MRD wird nach Induktionstherapie und nach Abschluss der 
Konsolidierungstherapie im Therapieverlauf gemessen. Das Ziel der Meta-Studie ist zu 
evaluieren, ob die MRD Messungen während der Therapie mit dem Gesamtüberleben 
zusammenhängen und als frühe Surrogatparameter verwendet werden können. Zunehmend 
besteht in der Gesellschaft der Wunsch, dass aussichtsreiche neue Therapeutika rasch zur 
Anwendung zugelassen werden. Deshalb besteht ein großes Interesse neue Therapeutika auf 
der Basis von frühen Biomarker-Endpunkten anstatt späten Überlebensendpunkten zuzulassen.   
 
 
  
 

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Table of Contents 
RESPONSIBILITIES .................................................................................................................. 2 
SUMMARY ................................................................................................................................. 3 
ZUSAMMENFASSUNG ............................................................................................................. 3 
TABLE OF CONTENTS ............................................................................................................. 4 
PROTOCOL SYNOPSIS ............................................................................................................ 6 
ABBREVIATIONS ...................................................................................................................... 7 
1 
BACKGROUND INFORMATION AND RATIONALE........................................................... 8 
1.1 
GENERAL INTRODUCTION ................................................................................................. 8 
1.2 
MRD IN ACUTE MYELOID LEUKEMIA .................................................................................. 8 
2 
OBJECTIVES AND ENDPOINTS ...................................................................................... 10 
2.1 
OBJECTIVES.................................................................................................................. 10 
2.2 
ENDPOINTS ................................................................................................................... 10 
2.2.1 
Primary Surrogate Parameter Endpoint ................................................................. 10 
2.2.2 
Secondary Surrogate Parameter Endpoint ............................................................ 10 
2.2.3 
Primary Clinical Endpoint ...................................................................................... 10 
2.2.4 
Secondary Clinical Endpoints ................................................................................ 10 
3 
TRIAL DESIGN AND RATIONALE ................................................................................... 10 
3.1 
DETAILED DESIGN ......................................................................................................... 10 
3.1.1 
Study Alliance Leukemia (SAL) and Heidelberg Leukemia Network (HeLeNe) trials
 
10 
3.1.2 
Inclusion of additional studies during the run-time of PERDAM ............................. 11 
4 
PATIENT SELECTION ...................................................................................................... 12 
4.1 
PATIENT INCLUSION CRITERIA ........................................................................................ 12 
4.2 
PATIENT EXCLUSION CRITERIA ....................................................................................... 12 
4.3 
WITHDRAWAL OF PATIENTS............................................................................................ 12 
4.4 
PREMATURE CLOSURE OF THE STUDY AND EXCLUSION OF PARTICIPATING STUDIES ........... 12 
5 
SAMPLE PROCUREMENT & SHIPMENT ........................................................................ 12 
5.1 
SAMPLE SHIPMENT TO THE UNIVERSITY HOSPITAL HEIDELBERG ....................................... 12 
5.2 
SAMPLE SHIPMENT TO THE UNIVERSITY HOSPITAL DRESDEN ........................................... 13 
6 
MRD ASSESSMENT BY MPFC ........................................................................................ 13 
6.1 
SAMPLE PREPARATION AND MEASUREMENT .................................................................... 13 
6.2 
REGULAR MRD ASSESSMENT CONFERENCES AND CROSS VALIDATION ............................. 13 
7 
PERDAM DATABASE....................................................................................................... 13 
7.1 
REGISTRATION PROCESS AND DATA INPUT ...................................................................... 13 
8 
CLINICAL DATA ............................................................................................................... 14 
9 
STATISTICAL ANALYSES ............................................................................................... 14 
9.1 
DESIGN ASPECTS .......................................................................................................... 14 
9.1.1 
Experimental assessment: .................................................................................... 15 
9.1.2 
Standard assessment: .......................................................................................... 15 
9.1.3 
Proposed sample size/Power calculations ............................................................ 15 
9.1.4 
Statistical Analysis ................................................................................................ 16 
10 
QUALITY ASSURANCE AND MONITORING ................................................................ 17 
11 
EXECUTIVE COMMITTEE ............................................................................................. 17 
12 
ETHICAL AND LEGAL ASPECTS ................................................................................. 17 
12.1 
GOOD CLINICAL PRACTICE & DECLARATION OF HELSINKI ............................................. 17 
12.2 
PATIENT INFORMATION AND INFORMED CONSENT ........................................................ 17 
12.3 
CONFIDENTIALITY ....................................................................................................... 18 
12.4 
APPROVAL OF TRIAL PROTOCOL AND AMENDMENTS..................................................... 18 
12.5 
LEGAL STATUS ........................................................................................................... 18 
12.6 
FINANCIAL STATUS ..................................................................................................... 18 
12.7 
PATIENT INCENTIVES .................................................................................................. 18 
12.8 
REGISTRATION OF THE TRIAL ...................................................................................... 19 
13 
SIGNATURES ................................................................................................................ 20 
13.1 
SIGNATURES HEIDELBERG .......................................................................................... 20 
13.2 
SIGNATURES DRESDEN .............................................................................................. 21 

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14 
REFERENCES ............................................................................................................... 22 
15 
APPENDICES ................................................................................................................ 25 
15.1 
TEMPLATES FOR PATIENT INFO AND INFORMED CONSENT .............................................. 25 
15.1.1 
Patienteninformation .......................................................................................... 25 
15.1.2 
Einwilligungserklärung ....................................................................................... 26 
15.2 
DECLARATION OF COMMITMENT TO THE PERDAM DIAGNOSTIC META-STUDY................. 27 
 

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Protocol Synopsis 
Title 
Prospective evaluation of measurable residual disease in intensively treated 
patients with acute myeloid leukemia (AML) as surrogate endpoint for 
survival 
Therapeutic area 
Hematology / Oncology 
Indication 
Newly diagnosed or first relapsed acute myeloid leukemia  
Protocol Acronym 
PERDAM 
Principle Investigator  
Prof. Dr. Richard F. Schlenk  
Summary  
Acute myeloid leukemia is a genetically and phenotypically heterogeneous 
disorder with an incidence of 3 to 4 per 100 000 men and women per year 
and a median age at diagnosis of about 70 years. Prognosis, especially in 
older patients, has remained very poor. In patients considered suitable for 
intensive chemotherapy, the combination of an anthracycline and cytarabine 
remains the standard of care. For patients achieving a complete remission 
(CR), postremission therapy (PRT) ranging from chemotherapy to 
allogeneic hematopoietic stem cell transplantation is required; intensive 
PRT is still under debate in older patients. Beyond pre-treatment genetics-
based risk stratification, measurable residual disease (MRD) during 
treatment and follow up emerges as an important prognostic factor in first 
CR. Furthermore, MRD may provide a tool for a read-out of therapeutic 
efficacy. In this diagnostic meta-study we intend to measure MRD using 
multiparameter flow cytometry across up-front randomized clinical trials 
which in total will accrue more than 1000 patients. According to the 
leukemia-associated phenotype at diagnosis or the different-from-normal 
approach, MRD will be assessed early (after induction) and late (after 
consolidation) during treatment. The aim of the study is to show that levels 
of MRD measured early during treatment are closely related to overall 
survival and thus may serve as an early surrogate. There is a growing 
public demand that new, promising drugs are approved for therapy as 
rapidly as possible. Therefore, it is of great interest to obtain these 
approvals based on early biomarker endpoints such as MRD rather than on 
long-term survival endpoints. 
Objectives 
 
 
To 
demonstrate 
that 
measurable 
residual 
disease 
assessed 
by 
multiparameter flow cytometry during intensive treatment is a surrogate for 
overall survival and thus an early read-out for drug efficacy 
Study design 
Surrogate endpoint trial to establish that measurable residual disease 
assessed by multiparameter flow cytometry during intensive treatment is a 
surrogate for overall survival 
Data protection   
The rights of ownership are addressed by trial-specific contracts of 
conveyance. In addition, the generic concept of data protection proposed by 
the Telematic Platform of Medical Research Networks (Telematik Plattform 
Medizinischer Forschungsnetze, TMF) is in place for the network of clinical 
trials. Thus all samples will undergo pseudonymization before shipment to 
the two laboratories for flow cytometry.  
Inclusion criteria 
i) Acute myeloid leukemia according to the WHO classification 
ii) Informed consent in place for a randomized study of the Study Alliance 
Leukemia (SAL) including the Heidelberg Leukemia Network (HeLeNe) 
covering assessment of MRD by MPFC in the reference laboratories in 
Heidelberg and Dresden.  
Exclusion criteria 
No signed informed consent compliant with the requirements of PERDAM   
 
 

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Abbreviations 
AML 
Acute Myeloid Leukemia 
CBF 
Core-binding factor 
CR 
Complete remission 
CRF 
Case report form 
CTEP  
Cancer Therapy Evaluation Program 
ddPCR 
droplet digital Polymerase Chain Reaction 
EFS 
Event free Survival 
ELN 
European LeukemaNet 
EC 
executive committee 
FACS 
Fluorescence Activated Cell Sorter 
FDA 
Food and Drug Administration  
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HeLeNe 
Heidelberg Leukemia Network 
HCT 
hematopoietic cell transplantation 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethical Committee  
IPD 
individual patient data 
LAP 
leukemia-associated phenotype  
NIS  
Non-Interventional Study  
MPFC 
multiparameter flowcytometry 
MRD 
Measurable residual disease 
OS 
Overall survival 
PRT 
Postremission Therapy 
RFS  
Relapse free survival 
RQ-PCR 
Real Time Quantitative Polymerase Chain Reaction 
SAL 
Study Alliance Leukemia 
SAP 
statistical analysis plan 
STE  
surrogate threshold effect  
TMF 
Telematic Plattform Medizinischer Forschungsnetze 
WHO  
World Health Organization 
 
 
 
 

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1 Background information and rationale  
1.1 General Introduction 
Acute myeloid leukemia (AML) is a genetically and phenotypically very heterogeneous disorder 
with an incidence of 3 to 4 per 100 000 men and women per year with a median age at 
diagnosis ranging from 66 to 71 years [1][2]. It is characterized by the accumulation of 
somatically acquired genetic changes in hematopoietic progenitor cells that alter normal 
mechanisms of self-renewal, proliferation, and differentiation. Outcome is influenced by various 
factors, including patient features such as age, comorbidities, and performance status and 
disease characteristics of which the genetic profile of the disease is the most important. 
According to the recommendations from an international expert panel, on behalf of the 
European LeukemiaNet (ELN), AML can be grouped into 3 risk groups, favorable, intermediate 
and unfavorable [1]. In patients considered suitable for intensive induction therapy, the 
combination of an anthracycline and cytarabine remains the standard of care. Complete 
remission (CR) can be achieved in 65% to 75% of younger adult patients (≤60 years) and in 
approximately 40% to 60% of older patients (>60 years). In patients who achieve a CR after 
induction chemotherapy, some postremission therapy (PRT) is required to prevent relapse 
[1][2][3]. Although the value of PRT in the older patients continues to be debated, in younger 
patients, the choice for consolidation is based on genetic features and can range from high 
dose cytarabine to allogeneic hematopoietic cell transplantation (alloHCT), with a 5-year overall 
survival (OS) rate of 40% to 45%; OS in older patients still remains poor at <10% after 5 years 
[1][3]. In patients ineligible for intensive chemotherapy, the spectrum of treatment options is 
limited and includes best supportive care with hydroxyurea, low-dose cytarabine, and the 
hypomethylating agents decitabine or azacitidine. Using such low-dose therapy, CR can be 
achieved in 10% to 30% of patients and the OS at 3 years is approximately 5% [1][2].  
Beyond pre-treatment risk stratification, measurement of the disease burden named 
measurable residual disease (MRD) during treatment and follow up emerges as one of the most 
important prognostic factors once a CR of the disease is achieved [4][5][6][7][8][9]. 
In addition to prognostic and predictive importance of MRD, the assessment of MRD may 
provide a tool to receive an early read-out of therapeutic efficacy. Based on the still poor 
outcome of AML in general, there is an increasing public demand that new, promising drugs are 
approved for therapy as rapidly as possible. Therefore, it is of great interest to obtain these 
approvals based on early biomarker endpoints such as MRD rather than on long-term clinical 
endpoints such as OS [6]. Exemplarily, the international CALGB 10603 (RATIFY, 
NCT00651261) trial evaluating midostaurin as adjunct to intensive chemotherapy in younger 
adults with AML and activating FLT3 mutations recruited after screening of 3279 a total of 714 
patients between 2008 and 2011. The analysis of the primary endpoint OS was planned after 
507 events (deaths). However, the event rate reached a plateau with only 3 deaths in 2015 and 
in total 357 deaths. Thus, 507 events have been predicted to occur in the year 2025. After 
approval by the Data Safety Monitoring Board of the trial and the Cancer Therapy Evaluation 
Program (CTEP) the statistical analysis plan was amended and final adjusted statistical analysis 
was performed after 357 deaths [10]. Fortunately, a significant better OS in the experimental 
arm compared to the standard arm could be shown despite effective and diverse salvage 
therapy strategies in patients with refractory disease [11] or relapse AML [12]. Therefore the 
approval of midostaurin in AML with activating FLT3 mutations has been achieved in US and 
Europe. Data from the original publication suggested that the difference in the two arms 
occurred early and was mainly due to midostaurin added to the first treatment cycle [10]. 
Unfortunately, MRD was not measured within this trial. However, MRD measured early and late 
during treatment would have added enormous value in interpreting the differences observed in 
event-free, relapse-free and OS and in better defining when the treatment effect was most 
pronounced (during induction, consolidation or the one year maintenance therapy). 
1.2 MRD in acute myeloid leukemia 
MRD can be measured and quantified by Real Time Quantitative Polymerase Chain Reaction 
(RQ-PCR) in AML with gene mutations (e.g. NPM1 mutation) [7][13] and gene fusions (e.g. 
RUNX1-RUNX1T1, CBFβ-MYH11 [7]). However, only in 30-45% of all AML cases well-

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established methods are available nowadays in routine care based on this technique [4]. With 
newer methods such as whole genome or exon sequencing [7][14] and droplet digital 
Polymerase Chain Reaction (ddPCR) [7][15][16] MRD is measurable in the majority of patients 
and with an enormous precision. However, the different mutational patterns in individual 
patients and the difficulty in the interpretation of clearance or persistence of specific gene 
mutations after intensive chemotherapy on the background of clonal hematopoiesis of 
indeterminate potential [17][18][19] currently lead to limitations in the applicability of these new 
methods in the context of prospective multicenter clinical trials [19][20]. An alternative method is 
the assessment of MRD by multiparameter flowcytometry (MPFC). With this method individual 
pathologic leukemia-associated phenotypes (LAPs) can be defined at diagnosis in more than 
90% of all AML cases and retrieved after induction and consolidation therapy with a sensitivity 
of 10-4-10-5 [4][5][6][7][8][21]. In addition, MRD can be defined via a comparison to either normal 
or regenerating marrow by visual inspection as a cell population showing deviation from normal 
antigen-expression patterns seen in specific cell lineages at specific stages of maturation 
[22][23]. Within the studies evaluating MRD with MPFC the antibody-panel used were 
somewhat different including CD2, CD3, CD5, CD7, CD8, CD11b, CD11c, CD13, CD14, CD15, 
CD16, CD19, CD20, CD22, CD34, CD33, CD38, CD42b, CD45, CD56, CD61, CD64, CD65, 
CD71, CD90, CD117, CD123, CD133, HLA-DR measured in a four [21] and up to ten 
[22][23][24][25] colour flowcytometer. Of note, despite some variability of the used panels and 
the amount of the fluorescence channels the threshold to define a LAP was consistent across 
all the trials with a cut point of 0.1% of all nucleated cells providing highest prognostic 
information with regard to risk of relapse and overall survival. [5][21][22][23][24][25][26]. Thus 
from a practical point of view the LAPs and patterns different from normal defined for all patients 
individually resulted in MRD parameters independent of the LAPs and patterns different from 
normal with a value of zero in case of MRD levels below 0.1% or a continuous value between 
0.1 and 100% in case of MRD levels above the cut point. So far the vast majority of analyses 
have been based on the comparison of MRD negative versus MRD positive patients at a certain 
time-point [4][5][21][22][23][24][25][26][27]. MRD levels are more and more integrated in clinical 
decision making after induction therapy [25] and during consolidation therapy including 
allogeneic HSCT [24][28]. However, so far no prospective confirmatory evaluation has been 
performed within randomized clinical trials defining the sensitivity and specificity MRD 
measurement using MPFC [3][6][7][29]. In addition, the prognostic and predictive impact of 
discrete values [27] of MRD and their changes over time instead of the dichotomized (positive 
vs. negative) approach of MRD assessment has also not been prospectively evaluated. Based 
on the very strong prognostic impact of dichotomized MRD (positive vs. negative) measured by 
MPFC in patients receiving an allogeneic HSCT, [23][24] the value of treatment intensification 
(e.g. with an allogeneic HSCT) to counterbalance a higher risk of relapse in MRD positive 
patients is still open [6][7][29]. 
Drug development in patients with AML is currently somewhat more focussed on older patients 
not eligible for intensive chemotherapy because clinical endpoints event-free and overall 
survival can be observed within a short time period due to the overall very unfavourable 
prognosis of this patient population [30]. In contrast, drug development in intensively treated 
younger patients is mainly hampered by confounding therapeutic interventions such as 
allogeneic HSCT during first line therapy or after AML relapse. Current examples are i) the 
CALGB 10603 international randomized double blinded placebo-controlled phase-III study in 
newly diagnosed FLT3-mutated AML evaluating the FLT3 inhibitor midostaurin (NCT00651261) 
in which the event-driven final analysis on the primary endpoint OS was reported at the annual 
meeting 2015 of the American Society of Hematology after amendment of the statistical 
analysis plan [10] as well as ii) the double blinded placebo-controlled phase-III VALOR study 
evaluating vosaroxin in relapsed or refractory AML in combination with cytarabine in which 
results were overall not significant (p=0.06) for the endpoint OS due to the not significant 
(p=0.60) results in younger patients with nearly superimposable survival curves [31]. In contrast, 
results were significant (p=0.02) if patients receiving an allogeneic HSCT were censored at the 
time of transplant and in the subgroup of patients above the age of 60 years (p=0.003). These 
examples illustrate that surrogate early biomarker endpoints are of high interest to provide an 
early read-out of clinical efficacy. Such early read-outs will allow designing reasonable adaptive 
drug development plans with the aim to integrate new drugs as early as possible in routine 

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patient care. Quantifying MRD by MPFC has the potential to serve as an early biomarker 
surrogate for survival endpoints but has so far not been evaluated in a confirmatory prospective 
manner [32]. In addition, the direct comparison of quantified MRD evaluated by MPFC, by RQ-
PCR [33] (or ddPCR) for gene mutations and the gene fusions, and by next generation 
sequencing (NGS) within prospectively randomized trials offers the unique opportunity of a 
pivotal reference cross validation of the different methods for recent and future studies. 
2 Objectives and Endpoints  
2.1 Objectives 
 
To assess quantitatively measurable residual disease by multiparameter flow cytometry 
in patients with acute myeloid leukemia who are intensively treated after induction (newly 
diagnosed AML) or salvage chemotherapy (relapse/refractory AML) and at the end of 
consolidation therapy (newly diagnosed AML and relapse/refractory AML)  
 
To evaluate the association of measurable residual disease at two different time points 
with survival endpoints, primarily overall survival, secondarily event-free and relapse-free 
survival. 
2.2 Endpoints  
2.2.1 Primary Surrogate Parameter Endpoint  
 
Measurable residual disease assessed after induction therapy (newly diagnosed AML) 
or salvage chemotherapy (relapse/refractory AML) 
2.2.2 Secondary Surrogate Parameter Endpoint  
 
Measurable residual disease assessed at the end of consolidation therapy (newly 
diagnosed AML and relapse/refractory AML) 
2.2.3 Primary Clinical Endpoint  
 
Overall survival 
2.2.4 Secondary Clinical Endpoints 
 
Event-free survival 
 
Relapse-free survival 
3 Trial design and rationale  
3.1 Detailed Design  
Patients with AML participating in interventional prospective randomized trials of the Study 
Alliance Leukemia including interventional prospective randomized trials initiated from the 
University Hospital Heidelberg are aimed to be included into this diagnostic meta-study on 
MRD. In all evaluable patients initial diagnostic flow cytometric analysis and assessment of 
MRD after induction (newly diagnosed AML) or salvage chemotherapy (relapse/refractory AML) 
and at the end of consolidation therapy (newly diagnosed AML and relapse/refractory AML) are 
intended.  
Within the PERDAM study no additional clinical data is collected. All data is collected within the 
activities of the participating trials in the randomized clinical trials. MRD measurement with 
MPFC is done in the two laboratories named in chapter 5). 
3.1.1 Study Alliance Leukemia (SAL) and Heidelberg Leukemia Network 
(HeLeNe) trials 
Independently of the PERDAM trial, patients with either newly diagnosed or relapsed AML in the 
centers of the Study Alliance Leukemia (SAL) including the Heidelberg Leukemia Network 
(HeLeNe) are registered in the SAL-registry (NCT03188874) after informed consent is 
obtained. Samples including peripheral blood and bone morrow are sent to the reference labs 

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and analyzed for cyto- and molecular-genetics, immunophenotype and cryopreserved for 
biobanking. All patients with either newly diagnosed or relapsed AML are screened for eligibility 
for up-front randomized clinical trials. If patients are eligible and informed consent is obtained, 
patients may be included in these trials. 
Currently, 2 studies are open for recruitment, the BLAST trial (ClinicalTrials.gov Identifiers: 
NCT02502968) and the DaunoDouble trial (ClinicalTrials.gov Identifier: NCT02140242). New 
studies may be added without need for an amendment of the PERDAM trial protocol.   
 
3.1.2 Inclusion of additional studies during the run-time of PERDAM 
During the run-time of PERDAM new studies are integrated into PERDAM via a uniform 
procedure. Prerequisites for eligibility are 
1. 
Investigator-initiated study (Pharma-sponsored studies are not eligible)  
2. 
The IC of the respective study fulfils the minimum requirements (see chapter 12.2)  
3. 
Access to study data guaranteed by the principle investigator of the respective study. 
4. 
Either i) centralized assessment of flow-cytometry for evaluation of leukemia-associated 
phenotypes (LAPs) at diagnosis/relapse or ii) the different from normal approach 
5. 
Centralized assessment of flow-cytometry for evaluation of MRD based on predefined LAPs 
from diagnosis/relapse or the different from normal approach 
6. 
Studies of the SAL including those of the Heidelberg Leukemia Network  
7. 
Access to the central web-based PERDAM database  
 
The aim of the PERDAM study is only achievable on the basis of academic research. Therefore, 
the primary prerequisite for inclusion of additional studies is that the new study is an 
Investigator-initiated trial with an academic sponsorship. 
Furthermore, a new study will be included upon completion and signature of the data access 
form by the principle investigator of the new study (Appendix 15.2) to guarantee access to the 
study data comprising baseline characteristics including a minimal set of laboratory and genetic 
data, unblinded randomization (after unblinding of the study), response to induction therapy, 
type of induction and consolidation treatment including date of alloHCT if applicable, event-free, 
relapse-free and overall survival.  
The primary outcome measure in this study is MRD assessed by multiparameter flow cytometry 
(MPFC). MPFC is assessed at the time of diagnosis/relapse and subsequently after induction 
therapy (newly diagnosed AML) or salvage therapy (relapse/refractory AML) and completion of 
consolidation therapy (newly diagnosed AML and relapse/refractory AML) at the laboratory for 
flow cytometry in Heidelberg and Dresden, respectively. Assessments in other laboratories of 
MRD with MPFC may be into the PERDAM study after standardization. 
Documentation of MPFC is performed in the web-based PERDAM database. Lab data of MRD 
assessed by MPFC from diagnosis, after induction/salvage and completion of consolidation 
therapy are uploaded via a file import procedure or manually. Based on the documented data 
within the PERDAM database regular virtual meetings are performed to discuss results for 
continuous harmonization of laboratory procedures and MRD evaluations between the two 
involved laboratories. 
 
 

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4 Patient selection  
4.1 Patient Inclusion Criteria 
 
Acute myeloid leukemia according to the WHO classification 
 
Informed consent in place for a registry study and/or a randomized study of the Study 
Alliance Leukemia (SAL) including the Heidelberg Leukemia Network (HeLeNe) covering 
assessment of MRD by MPFC in the reference laboratories in Heidelberg and Dresden. 
 
4.2 Patient Exclusion Criteria 
 
No signed informed consent compliant with the requirements of PERDAM   
 
4.3 Withdrawal of Patients  
A patient must be withdrawn from the study for the following reasons: 
 
At any time at their own request.  
 
Withdrawal of patient’s consent to use their data  
 
If the patient withdraws consent for disclosure of information, no additional data can be 
collected. Data already being transferred to the PERDAM database before the withdrawal may 
still be uses unless, the signed Informed Consent of the respective clinical trials imposes a 
deletion.  
 
4.4 Premature Closure of the study and exclusion of participating 
studies  
The trial can be prematurely closed or suspended by the PI. Participating studies can be 
excluded. Furthermore, the IEC themselves may decide to stop or suspend the study.  
 
Reasons for premature closure or exclusion of participating studies: 
 
Non-compliance with the protocol 
 
Poor data quality  
 
No recruitment in 6 months 
 
Non-adequate IC  
  
The PIs of all participating and affected studies have to be informed immediately about a 
cessation/suspension of the study. No further data will be collected.   
 
 
5 
Sample procurement & shipment 
5.1 
Sample shipment to the University Hospital Heidelberg  
Send biosamples and their accompanying routing forms at room temperature, Monday to 
Friday, carrier for next day delivery before 9 a.m., to  
 
Universitätsklinikum Heidelberg 
Medizinische Klinik, I. OG, Zimmernummer 01.136 ,  
Weiterleitung an die Hämatologische Diagnostik/Leitung PD. Dr. Hundemer. 
INF 410,  
69120 Heidelberg 
Phone: 06221-56 36955 (Frau Ute Bauer) 

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e-mail: Katharina.Kriegsmann@med.uni-heidelberg.de 
 
            Michael.Hundemer @med.uni-heidelberg.de 
 
 
5.2 
Sample shipment to the University Hospital Dresden 
Send biosamples and their accompanying routing forms at room temperature, Monday to 
Friday, via overnight carrier for next day, delivery before 9 a.m., to:  
 
Hämatologisches Labor Haus 65, EG 
Medizinische Klinik und Poliklinik I 
Universitätsklinikum  Carl Gustav Carus 
Fetscherstr. 74 
01307 Dresden 
Germany 
Tel.: +49(0)351 458-5621 
Email: malte.bonin@uniklinikum-dresden.de 
 
 
 
6 
MRD assessment by MPFC 
6.1 
Sample preparation and measurement 
In order to obtain comparable results, instrument set up, sample preparation and surface 
staining will be performed in the same manner in both laboratories. The procedures are based 
on the HAROMIZE initiative [34] and listed in detail in the lab manual.  
6.2 
Regular MRD assessment conferences and cross validation 
In terms of cross validation and harmonization the same SOPs for MRD assessment by MPFC 
are used in the two laboratories. In addition, regular MRD assessment phone/web conferences 
are hold every three months to discuss all cases of the three month time period and achieve 
agreement. A cross validation between the two laboratories is performed at the beginning and 
thereafter every 6 months during the PERDAM study conduct with divided samples send out to 
the two laboratories and measured in both laboratories at the same time-points, at 
diagnosis/relapse and after induction/salvage therapy (see lab manual).  
 
7 Perdam Database 
Data management is performed by the NCT trial center. The Web-based registration platform 
for the PERDAM study is based on the generic data protection concept of the Telematics 
Platform for Medical Research Networks (Telematikplattform für Medizinische Forschungsnetze, 
TMF) using appropriate measures for data protection and disaster recovery. 
7.1 Registration process and data input 
During the registration process every patient already identified via a unique pseudonym 
consisting of short name of the randomized study and the study-specific patient-identifier 
receives a second unique second pseudonym, the PERDAM identifier. Data obtained in the two 
laboratories are handled in certified lab-specific IT-systems and transferred to the PERDAM 
databases via secured file-upload or are manually documented. The PERDAM database fulfills 
EudraLex Volume 4 Annex 11 and FDA Title 21 CFR Part 11 requirements. MRD assessed by 
MPFC is documented for patients who at least have one MPFC result at diagnosis/relapse 
describing the LAPs for an individual patient and one MRD assessment by MPFC after 
induction/salvage therapy. Patients responding to induction/salvage therapy but without 

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evaluable LAPs are documented with the different to normal approach in the PERDAM 
database. In addition, the MRD assessment after completion of consolidation therapy is 
included as third assessment time point. The registration process, file-upload and manual input 
are described in detail in the PERDAM database manual (separates document). 
 
8 Clinical data 
The demographic, laboratory, clinical and outcome data of the interventional randomized clinical 
trials are documented in trial-specific case report forms and after validation stored in trial-
specific databases (Trial-databases) fulfilling EudraLex Volume 4 Annex 11 and FDA Title 21 
CFR Part 11. Linkage between data of the Trial-databases and the PERDAM database are 
achieved via the uniform patient-specific pseudonym. Regular data exports from the Trial-
databases including a core dataset (excluding explicitly the randomization) including data 
assessed at diagnosis/relapse (age at diagnosis/relapse, sex, date of diagnosis/relapse, WBC, 
bone marrow blast percentage, AML-entity according to WHO-2016), induction/salvage 
treatment (start of induction/salvage treatment, dose-reduction (yes/no) of induction- and/or 
consolidation therapy, response to induction/salvage treatment, date of assessment, date of 
response), consolidation treatment data (start of consolidation treatment, date of allogeneic 
HCT) and outcome data (date of relapse, date of last follow-up or date of death, vital status) are 
implemented on a three monthly basis. These data are imported into the PERDAM database to 
provide clinical background for the regular MRD-assessment conferences.  
 
 
9 Statistical analyses 
9.1 Design aspects 
Clinical development of new drugs in hematology/oncology is an increasingly challenging 
endeavor. With the number of new compounds that can potentially be tested in the clinic, and 
the need to reach conclusions about the safety and efficacy of new treatments as quickly as 
possible, the search for early clinical endpoints and biomarkers that can be used as surrogate 
endpoints for long-term clinical endpoints has emerged as a new discipline in its own right [35].   
Prentice’s definition of a surrogate endpoint was that of a response variable for which the test of 
the null hypothesis of no relationship to the treatment groups under comparison was also a valid 
test of the corresponding null hypothesis based on the true endpoint [36]. Subsequently, 
Freedman et al. and Buyse and Molenberghs emphasized estimation and prediction rather than 
hypothesis testing in the process of endpoint validation [37][38]. The measures proposed using 
data from a single trial, such as the proportion of treatment effect explained, have however been 
shown to be insufficient to establish surrogacy [39]. The focus therefore shifted to methods 
based on a meta-analytic approach using data from several randomized trials [40][41]. When 
data from several trials are available, a surrogate endpoint can be assessed both at the 
individual level and at the trial level for its ability to predict the effect of treatment on the true 
endpoint. Using the trial level association between the effects of treatment on the surrogate and 
on the true endpoint, a calculation of the surrogate threshold effect (STE), which is the minimum 
effect required on the surrogate to predict a significant effect on the true endpoint in a future trial 
can be performed [42]. Hence, if a surrogate was accepted as valid (qualified), a future trial 
could be designed to show that the treatment effect on the surrogate exceeds the surrogate 
threshold effect, rather than to show a treatment effect on the true endpoint. Therefore, our aim 
is to benefit from our established trial infrastructure with randomized interventional clinical trials 
running in parallel and to evaluate MPFC as a general approach to measure MRD for surrogacy 
in respect to survival endpoints.  

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9.1.1 Experimental assessment:  
MRD 
assessed 
by 
flow- 
cytometry 
as 
described 
previously 
[5][6][7][8] 
[21][22][23][24][25][26][27] is assessed in patients after induction (newly diagnosed AML) or 
salvage chemotherapy (relapsed/refractory AML) and after completion of consolidation therapy 
(newly diagnosed AML and relapse/refractory AML) in the two laboratories at the University 
Hospital Heidelberg and the University Hospital Dresden. MRD assessed by MPFC will be 
evaluated first at the same time as the remission status based on morphology after 
induction/salvage therapy. This MRD assessment by MPFC after induction/salvage therapy is 
used to test the primary hypothesis. A second MRD assessment by MPFC will be performed 
after completion of consolidation therapy including high-dose chemotherapy and alloHCT. MRD 
positive values are documented as discrete numbers up to 100%. 
9.1.2 Standard assessment:  
Overall survival (OS) is defined as time from entry into the study until death from any cause. 
Event-free survival (EFS) is measured from entry into the study until one of the following events, 
whichever comes first, i) no response to induction therapy, ii) relapse, iii) death from any cause. 
For assessment of response to induction therapy and relapse, morphological evaluation of 
peripheral blood and bone marrow smears is the standard assessment. Relapse-free survival 
(RFS) is measured in patients who achieve a first CR. RFS is measured from achievement of 
first CR until one of the following events, whichever comes first i) relapse, ii) death from any 
cause. For assessment of relapse morphological evaluation of peripheral blood and bone 
marrow smears is the standard assessment. OS, EFS, and RFS are censored at the date of last 
follow up in case of no event. The survival endpoints OS, EFS, and RFS defined according to 
the ELN recommendations [1] are accepted standards. Within the proposed study the primary 
survival endpoint is OS, EFS and RFS are included as secondary survival endpoints. 
9.1.3 Proposed sample size/Power calculations 
For validation of MRD assessed by MPFC as surrogate endpoint for OS, it is critical that the 
effect of treatment on MRD assessed by MPFC is closely correlated with the effect of treatment 
on OS. In our previous work [43] evaluating EFS as a surrogate endpoint for OS in AML we 
were able to show in an individual-patient data approach of 1,811 patients from four randomized 
trials (AMLHD 98B [44] AMLSG 06-04, [45] AMLSG 07-04, [46] and AMLSG 12-09, [47]) with 7 
independent treatment comparisons due to multiple therapeutic questions that although EFS is 
only moderately correlated with OS (Spearman’s rho = 0.76, 95% CI: [0.73 , 0.79]) the treatment 
effects on EFS were strongly correlated with treatment effects on OS (correlation coefficient R = 
0.99, for log hazard ratios). A two-level modelling approach was used to estimate the 
association between EFS and OS, and between treatment effects on EFS and OS [48]. At the 
individual level, a bivariate (Hougaard-copula-based) survival model with Weibull marginal 
hazards was fitted to model the joint distribution of EFS and OS, and Spearman’s rank 
correlation coefficient (rho) was used to quantify the association between the endpoints. At the 
trial-level, an error-in-variables linear regression model was fitted to the estimated treatment 
effects (Weibull‑model‑based log hazard ratios) on EFS and OS, taking into account the 
estimation error. The correlation coefficient (R) was used to quantify the strength of association 
between the treatment effects. 

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regression model of the log transformed HRs on the log transformed ORs. The trial-level 
coefficient of determination RT
2 is then used to quantify the strength of association between the 
treatment effects on MRD assessed by MPFC and on the survival endpoints at the trial level.  
In addition the surrogate threshold effect (STE) [42] will be estimated as the minimum effect of 
MRD assessed by MPFC that predicts a statistically significant effect on EFS, RFS and OS. 
In addition, exploratory analyses will be performed on  
 
MRD assessed by MPFC after consolidation as a surrogate for OS, EFS and RFS 
 
Correlation of MRD assessed by MPFC after induction therapy and after consolidation 
therapy with respect to applied postremission treatment 
A detailed statistical analysis plan (SAP) will be finalized before database closure. 
 
10 Quality assurance and monitoring 
Quality within the randomized interventional studies is assured by central and by on-site 
monitoring according to German law. On-site monitoring is implemented via each randomized 
interventional clinical trial including source data verification. Quality of laboratory procedures 
and analyses is assured by a quality-management system in place and regular MRD 
conferences and cross validation described above (see 6.2). 
11 Executive committee 
Tasks and responsibilities: 
The executive committee (EC) is a collaborative operative board for the PERDAM study. Its 
overall roles are to review the results and outcomes collected in the PERDAM database, to 
define, foster and lead all multiparty publications of the PERDAM database. It has to assure that 
investigators of all study sites contributing to the PERDAM study will be appropriately involved 
in writing committees and authorship of publications. For number of authors and order, number 
of patients per site and the specific contributions must be taken into account. Details of 
operation and the interfaces to the other parties involved will be defined in a separate manual. 
Members of the EC are all collaborators listed on signature page-I and – II. 
12 Ethical and legal aspects  
12.1 Good Clinical Practice & Declaration of Helsinki 
The procedures set out in this trial protocol, pertaining to the conduct, evaluation, and 
documentation of this trial, are designed to ensure that all persons involved in the trial abide by 
Good Clinical Practice (GCP) and the ethical principles described in the current version of the 
Declaration of Helsinki. The trial will be carried out in keeping with local legal and regulatory 
requirements. 
 
12.2 Patient Information and Informed Consent 
Prior to using data from any individual, the respective patient must be informed about the 
potential use of the data and consent in written form to the usage of his data.  
 
For the PERDAM study no study specific patient information or study specific informed consent 
is needed, as long as the IC used in the respective clinical trial matches the following minimum 
requirements:  
 
Witten consent to transfer pseudonymized data for other research projects  
 
Consent to use the data is voluntary and does not influence the possibility of 
participation in the respective clinical trial  

PERDAM study protocol 
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 
Duration of data storage must be addressed  
 
Appropriate data protection has to be ensured  
 
The IC has to be approved by the responsible ethical review board.  
 
If the IC of the respective study does not match the needed minimum requirements, the IC must 
be changed per amendment or an additional IC must be handed to the patient. Recommended 
phrases for informed consent and patient information can be found in appendix 15.1. 
 
12.3 Confidentiality 
The data obtained in the course of the trial will be treated pursuant to the Federal Data 
Protection Law (Bundesdatenschutz- bzw. Landesdatenschutzgesetz, BDSG, LDSG), as well 
as the General Data Protection Regulation (GDPR, EU 2016/679).   
During the study, patients will be identified solely by means of an individual identification code 
(PERDAM identifier). Only pseudonymized data will be used, name and address will neither be 
stored nor transferred.  
Storage of study data on a computer will be done in accordance with local data protection law 
and will be handled in strictest confidence. For protection of these data, organizational 
procedures are implemented to prevent distribution of data to unauthorized persons. The 
appropriate regulations of local data legislation will be fulfilled in its entirety. 
The patient consents in writing to relieve the investigator from his/her professional discretion 
(“ärztliche Schweigepflicht”) in so far as to allow inspection of original data for monitoring 
purposes by health authorities and authorized persons (inspectors, monitors, auditors). 
Authorized persons (clinical monitors, auditors, inspectors) may inspect the patient-related data 
collected during the trial, ensuring the data protection law. 
No unauthorized person will have insight to the data.  
Only pseudonymized data may be transferred.  
 
12.4 Approval of Trial Protocol and Amendments 
Before the start of the trial, the trial protocol, informed consent document and any other 
appropriate documents will be submitted to the independent Ethics Committee (EC). A written 
favorable vote of the EC is a prerequisite for initiation of the trial.  
All substantial changes will be submitted to EC. 
 
12.5 Legal status  
The PERDAM trial is a non-interventional study (NIS). According to §4 Section 23 AMG this 
meta-study is classified as other study (“Sonstige Studie”).  
 
12.6 Financial status  
The study is exclusively funded by intuitional funds and supplemented by a research grant from 
the German Research Foundation (DFG grant number: Schl 2118/2-1).  
 
12.7 Patient incentives  
No patient incentives or compensations will be paid.  
 

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12.8 Registration of the Trial 
The coordinating / principal investigator will register the trial at the public accessible clinical trial 
register www.clinicaltrials.gov. 
 
 

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13 Signatures 
13.1 Signatures Heidelberg 
The present trial protocol was subject to critical review and has been approved in the present 
version by the persons undersigned. The undersigning persons  
 
agree that moral, ethical, and scientific principles as set out in the applicable version of 
Declaration of Helsinki are met  
 
are willing to support this study and will conduct the study according to the protocol  
 
will enrol patients only after all ethical requirements are fulfilled  
 
 
Principle  Investigator  
 
 
  
 
 
Date 
 Prof. Dr. Richard F. Schlenk 
National Center for Tumor Diseases 
 
 
Trial Coordination (HD) 
 
 
  
 
 
Date 
 Dr. Lucian Le Cornet  
National Center for Tumor Diseases 
 
 
Biometry 
 
 
  
 
 
Date 
 Axel Benner 
German Cancer Research Center 
Heidelberg 
 
 
 
 
 
  
 
 
Date 
 Dr. Christina Kunz 
German Cancer Research Center 
Heidelberg 
 
 
Leading Clinical Site (HD)  
 
 
  
 
 
Date 
 Prof. Dr. Carsten Müller-Tidow  
Klinik für Innere  Medizin V 
 
 
Flow cytometry (HD) 
 
 
  
 
 
Date 
 PD Dr. M. Hundemer,  
Labor für Durchflusszytometrie  
 
 
 
 
 
  
 
 
Date 
 Dr. K. Kriegsmann 
Labor für Durchflusszytometrie 
 
 
 
 

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13.2 Signatures Dresden  
The present trial protocol was subject to critical review and has been approved in the present 
version by the persons undersigned. The undersigning persons  
 
agree that moral, ethical, and scientific principles as set out in the applicable version of 
Declaration of Helsinki are met  
 
are willing to support this study and will conduct the study according to the protocol  
 
will enrol patients only after all ethical requirements are fulfilled  
 
 
Trial Coordination (DD) 
 
 
 
 
 
 
Date 
 
PD Dr. Christoph Röllig 
Medizinischen Klinik und Poliklinik I 
 
 
Leading Clinical Site (DD) 
 
 
 
 
 
 
Date 
 
Prof. Dr. med. Gerhard Ehninger 
Medizinischen Klinik und Poliklinik I 
 
 
 
 
 
 
 
 
 
Date 
 
Prof. Dr. med. Martin Bornhäuser 
Medizinischen Klinik und Poliklinik I 
 
 
Flow cytometry (DD) 
 
 
 
 
 
 
Date 
 
Dr. rer. Medic Uta Oelschlägel  
MK1-L06, Labor Durchflusszytometrie 
 
 
 
 
 
 
 
 
 
 
Date 
 
Dr. med. Malte von Bonin 
MK1-L06, Labor Durchflusszytometrie 
 
 
 
 
 
 

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15 Appendices  
15.1 Templates for patient info and informed consent  
 
The following passages are recommended to be implemented in the patient information and 
written informed consent of the respective, participating trials. The passages do not need to be 
implemented literally but should match by content. The study specific informed consent and 
patient information have to fulfil the key requirements laid down in chapter 12.2.  
As the studies will be performed in Germany and thus require ICs in German lay language the 
templates will be in German too.  
 
15.1.1 Patienteninformation  
Datennutzung außerhalb der Studie  
Außerhalb der klinischen Studie XYZ möchten wir Ihre pseudonymisierten Daten gern für 
weitere Forschungsprojekte wie im Folgenden beschrieben verwenden:  
 
 
Zum jetzigen Zeitpunkt können wir noch nicht genau sagen, in welche medizinischen 
Forschungsvorhaben Ihre Daten einfließen werden und welche Ziele diese Projekte 
verfolgen. Die Forschungsvorhaben müssen jedoch folgende Kriterien erfüllen:   
o Positives Votum der zuständigen Ethikkommission  
o Ausschließlich medizinisch-wissenschaftliche, krankheitsbezogene Forschung 
die direkt oder indirekt der Verbesserung von Diagnose, Therapie und/oder 
Lebensqualität dient  
o keine direkte kommerzielle Nutzung 
 
 
Ihre Einwilligung in die Weiterverwendung Ihrer Proben und Daten für weitere 
Forschungsprojekte ist freiwillig. Wenn Sie der Weiterverwendung nicht zustimmen 
oder Ihre Einwilligung später zurückziehen, entstehen Ihnen keine Nachteile. Ihre 
Entscheidung über die Weiterverwendung Ihrer Daten hat keinerlei Einfluss auf Ihre 
Teilnahme an der Studie XYZ. Ihre Einwilligung zur Studie und zur Weiterverwendung 
können Sie im Anschluss an diese Patienteninformation gesondert schriftlich erteilen 
und später auch gesondert widerrufen. 
 
 
Sollten Sie Ihre Einwilligung in die Weiterverwendung später widerrufen, werden Ihre 
Daten ab Ihrem Widerruf für keine weiteren Forschungsprojekte verwendet. Sind Ihre 
Daten zu diesem Zeitpunkt bereits in andere Forschungsprojekte eingeflossen, werden 
sie in diesen allerdings weiter verwendet, sofern dies für die Güte des 
Forschungsprojekts notwendig ist. Bis zum Rückzug Ihrer Einwilligung an Ihren Daten 
generierte Daten werden ebenfalls weiter verwendet, sofern diese für die Güte des 
jeweiligen Forschungsprojekts notwendig sind. 
 
 
Jedem weiterführenden Forschungsprojekt und damit jeder Weiterverwendung Ihrer 
Daten 
muss 
vorab 
eine 
zuständige 
Ethikkommission 
zustimmen. 
Die 
Ethikkommissionen schützen im Rahmen von Forschungsvorhaben die Interessen der 
teilnehmenden Patienten, und vertreten deren Rechte gegenüber den forschenden 
Ärzten und Wissenschaftlern. 
 
 
Die 
weitere 
Speicherung 
sowie 
die 
Verwendung 
Ihrer 
Daten 
erfolgt 
in 
pseudonymisierter Form. Pseudonymisiert bedeutet, dass keine Angaben von 
Namen oder Initialen verwendet werden, sondern nur ein Nummern- und/oder 
Buchstabencode. Eine Entschlüsselung der Pseudonymisierung ist nur durch eine an 

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Ihrer Prüfstelle hinterlegte Identifizierungs-Liste, welche die Sie identifizierenden 
persönlichen Daten (z.B. Name und Geburtsdatum) enthält, möglich.  
 
 
Möglicherweise ergeben sich in Zukunft neue wissenschaftliche Fragestellungen, die 
mithilfe Ihrer Daten beantwortet werden können. Daher kann heute noch nicht festgelegt 
werden, wie lange Ihre Daten aufbewahrt werden. Ggf. werden die Daten nicht 
gelöscht. 
 
 
Unter Umständen möchten wir Ihre Daten auch Forschern außerhalb der Studie XYZ 
(sogenannte berechtigte Dritte) für Untersuchungen zur Verfügung stellen. Jede 
Weitergabe an Dritte erfolgt in pseudonymisierter Form. Die Identifizierungs-Liste 
verbleibt in jedem Fall an Ihrem Prüfzentrum, so dass ein Rückschluss auf Ihre Person 
allein aus diesen Daten nicht möglich ist.  
 
 
 
Aus 
Ihren 
Daten 
gewonnene 
Erkenntnis 
und 
Ergebnisse 
werden 
nur 
in 
pseudonymisierter Form in wissenschaftliche Veröffentlichungen verwendet.  
 
 
15.1.2 Einwilligungserklärung  
  
 
Ich willige ein, dass meine Daten nach Beendigung oder Abbruch der Prüfung 
mindestens zehn Jahre aufbewahrt werden, wie es die Vorschriften über die klinische 
Prüfung von Arzneimitteln bestimmen. 
 
 
Ich willige ein, dass meine im Rahmen der klinischen Studie XYZ erhobenen 
personenbezogenen Daten pseudonymisiert (verschlüsselt) und ohne zeitliche 
Begrenzung für weitere Forschungsprojekte verwendet werden dürfen und im 
Rahmen dessen zweckgebunden an Dritte weitergegeben werden dürfen Die 
Forschungsvorhaben müssen jedoch folgende Kriterien erfüllen:   
o Positives Votum der Zuständigen Ethikkommission  
o Ausschließlich medizinisch-wissenschaftliche, krankheitsbezogene Forschung 
die direkt oder indirekt der Verbesserung von Diagnose, Therapie und/oder 
Lebensqualität dient  
o keine direkte kommerzielle Nutzung  
 
 
Die Einwilligung zur Weiterverwendung meiner Daten in weiteren Forschungsprojekten 
kann ich jederzeit widerrufen, ohne dass dies Einfluss auf meine Teilnahme an der 
Studie XYZ hat. Ich habe das Recht, jederzeit Auskunft über die Weitergabe bzw. 
Verwendung meiner Daten zu erhalten. 
 
 
Ich willige ein, dass ich nicht über Forschungsergebnisse und Zufallsbefunde informiert 
werde, auch wenn diese mit meiner Erkrankung in Zusammenhang stehen sollten. 
Zufallsbefunde können Erkenntnisse über weitere Erkrankungen oder Veranlagungen zu 
Erkrankungen sein. 
 
Ich willige in diese Weiterverwendung meiner Daten außerhalb der klinischen Studie XYZ 
ein: 
    ja  
 
    nein 
 
 
 
 

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15.2  Declaration of commitment to the PERDAM diagnostic meta-
study 
Interventional trial principle investigator’s declaration of commitment to the PERDAM diagnostic 
study 
 
Information on the interventional clinical trial: 
Title:______________________________________________________________ 
       ______________________________________________________________ 
EudraCT No:________________________________________________________ 
Clincaltrials.gov identifier:_______________________________________________ 
Sponsor:___________________________________________________________ 
 
As principle investigator of the above mentioned interventional clinical trial I hereby agree to 
include this trial into the PERDAM diagnostic study with diagnostic- and MRD-assessment by 
multiparameter flow cytometry at diagnosis and after induction as well as consolidation therapy, 
respectively, and I confirm unreserved access to clinical data (defined in chapter 8 of the 
PERDAM protocol) during and after completion of the above mentioned trial and/or the 
PERDAM study for single patients and cumulative evaluation as described in the PERDAM 
protocol. 
I confirm that individual data will only be transferred if the respective patient has 
consented the transfer and use of his data outside of the above mentioned trial.  
 
Date/Signature 
 
Title:______________________________________________________________ 
First name:_________________________________________________________ 
Family name:________________________________________________________ 
Affiliation:___________________________________________________________