Clinical trial NCT02278796
Conditions: Lymphoma, Large B-Cell, Diffuse Lymphoma, Follicular Lymphoma, Mantle-Cell
Keywords: Diffuse large B-cell lymphomas (DLBC) Follicular lymphomas (FL) Mantle cell lymphomas (MCL)
Sponsor: Insel Gruppe AG, University Hospital Bern
Start date: 2015-04-01; Completion date: 2020-11-01
Enrollment: 108 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
In the treatment of patient with lymphoma the most common high-dose chemotherapy regimen used prior to autologous transplantation (ASCT) is the BEAM regimen. It consists of four chemotherapy drugs together (BCNU, etoposide, cyclophosphamide, melphalan), whose initial letters are grouped together for BEAM regimen. One of the most common organ damage this intensive treatment is caused by the drug BCNU; it involves a lung injury, which manifests itself in the months after ASCT with increasing shortness of breath and cough, and can result in pulmonary fibrosis. The drug bendamustine is used successfully in different lymphoma types, and its efficacy in lymphoma therapy is well documented. Moreover bendamustine doesn't cause lung injury. Initially experience with bendamustine instead of BCNU - in the so-called BeEAM scheme - shows that this scheme is quite effective and well tolerated, without lung injury. In BeEAM scheme therefore bendamustine replace the BCNU, while the other three drugs are administered in the same dosage and order. The aim of the present study conducted at four centers (Bern and Zurich in Switzerland, Vienna and Linz in Austria) is to compare these two high-dose chemotherapy schemas and to show that the BeEAM scheme causes significantly less lung injury than the BEAM regimen.

Detailed description:
Background

High-dose chemotherapy (HDCT) followed by autologous stem cell transplantation (ASCT) is considered the treatment of choice for relapsed/refractory lymphomas. On the basis of the results of the PARMA study group trial, high-dose chemotherapy followed by ASCT has become the standard of care for patients with relapsed, chemo-sensitive aggressive lymphoma and it is the treatment of choice in patients relapsing with follicular lymphoma and Hodgkin's disease. The BEAM (BCNU, etoposide, cyclophosphamide, melphalan) chemotherapy regimen is the most frequently used conditioning regimen since more than thirty years. Toxic pneumonia with interstitial infiltration and impairment of the diffusion capacity of the lung is a recognized complication of HDCT regimens containing BCNU. Recently, it has been shown that the EAM regimen (thus omitting BCNU) is not sufficient to obtain equal response rates if compared with BEAM and poorer disease control resulted in impaired disease-free survival (DFS). Thus, it might be detrimental for patients just to eliminate BCNU without an appropriate substitution. Replacing BCNU by Bendamustine with its potential to eradicate residual or treatment-resistant lymphoma cells could be a promising clinical approach and should be investigated in a randomized phase II clinical trial comparing standard BEAM with BeEAM. Bendamustine combines the alkylating activity of the mustard group with the antimetabolite activity of the purine analogue and was studied in several entities of B-cell neoplasms and demonstrated significantly superior efficacy compared with standard therapies in the treatment of relapsed chronic lymphocytic leukemia (CLL) and indolent NHL and myeloma. The BRIGHT study confirmed the non-inferiority of a immunochemo-therapy with Rituximab-Bendamustine when compared with R-CHOP or Rituximab, Cyclophosphamide, Vincristine, Prednisone (R-CVP) in indolent lymphoma or mantle cell lymphoma. Recently, Visani et al have shown that Bendamustine, coupled with fixed doses of Etoposide, Cytarabine, and Melphalan (ie, BeEAM) in the conditioning regimen for ASCT for resistant/relapsed lymphoma (HD and NHL) patients is highly active and resulted in promising results concerning safety and efficacy. No treatment mortality was observed and no relevant pulmonary toxicity was seen. Non-hematological toxicity was moderate, and most prominent toxicities were gastroenteritis grade 3 to 4 in 34% and mucositis grade 3 to 4 in 35%, respectively. No grade 3 to 4 cardiac toxicity or toxic pneumonia was observed. Engraftment was rapid and trilinear, and stable hematopoiesis was observed. BeEAM was very effective, with 81% of patients in complete response after a median observation time of 18 months. A recent update of this study showed that at 41 months still 72% of the patients are still in complete remission and the 3-year performance status (PS) was 75%. Four patients showed a first remission ever with the Bendamustine containing regimen. In 35 patients treated at the Vienna centre according to the Visani BeEAM protocol, these encouraging data of Visani et al could be reproduced; similar toxicities and rapid and stable engraftment were observed. Finally, the combination of Bendamustine with sequential application of high-dose Cytarabine was reported to improve the response rates in relapsing lymphomas. In conclusion, it seems promising to integrate Bendamustine in myeloablative regimens in ASCT, but a randomized clinical trial is lacking so far.

Objective

Replacing the chemotherapeutic drug BCNU by Bendamustine within the four-drug chemotherapy regimen BEAM reduces the occurrence of early and late pulmonary toxicity in lymphoma patients undergoing high-dose chemotherapy with autologous stem cell transplantation. Primary Objective: To show a clinically meaningful reduction of lung toxicity - defined as a a decrease of the diffusion capacity of the lung for carbon monoxide (DLCO) by 20% or more from baseline before ASCT - from 25% of patients in the BEAM group to 4% of patients in the BeEAM group at 3 months after ASCT. Use Dinakara equation for adjusting DLCO for hemoglobin. Secondary Objectives: Acute and late toxicity/adverse events (CTCAE 4.0). Hematologic recovery and engraftment after 3 months. Early and late lung toxicity Cardiac assessment by ECHO/ECG and quality of life before,3 and 12 months after ASCT. Overall survival and progression free survival after 12 months and then yearly as routine follow-up assessments.

Methods

Two high-dose chemotherapy regimens (BeEAM versus BEAM) used for conditioning treatment before autologous stem cell transplantation will be compared in a 1:1 randomization. The experimental arm is the BeEAM regimen. The BEAM regimen is the control treatment. Lung toxicity will be assessed by spiroergometry at the 60% level of maximum exercise capacity, as well as by assessing the diffusion capacity of the lung for carbon monoxide (DLCO). This analysis will be performed before ASCT, as well as 3 months and 12 months after ASCT. Patients will be assessed for cardio-pulmonary toxicity before ASCT, as well as 3 and 12 months after ASCT. Thereafter, patient follow-up will be performed clinically once per year.

Arms: arm 1: Chemotherapy regimen consisting of bendamustine intravenously on days -7 and -6 at 200 mg/m2; cytarabine, 400 mg/m2 intravenously daily from day -5 to day-2; etoposide, 200 mg/m2 intravenously daily from day -5 to day -2; and melphalan, 140 mg/m2 intravenously on day -1 before reinfusion of autologous stem cells arm 2: Chemotherapy regimen with carmustine (BCNU) 300 mg/m2 on day -6, cytarabine, 400 mg/m2 intravenously daily from day -5 to day-2; etoposide, 200 mg/m2 intravenously daily from day -5 to day -2; and melphalan, 140 mg/m2 intravenously on day -1 before reinfusion of autologous stem cells
Interventions: intervention 1: BeEAM intervention 2: BEAM
Intervention descriptions: intervention 1: Chemotherapy regimen consisting of bendamustine intravenously on days -7 and -6 at 200 mg/m2; cytarabine, 400 mg/m2 intravenously daily from day -5 to day-2; etoposide, 200 mg/m2 intravenously daily from day -5 to day -2; and melphalan, 140 mg/m2 intravenously on day -1 before reinfusion of autologous stem cells intervention 2: Chemotherapy regimen with carmustine (BCNU) 300 mg/m2 on day -6, cytarabine, 400 mg/m2 intravenously daily from day -5 to day-2; etoposide, 200 mg/m2 intravenously daily from day -5 to day -2; and melphalan, 140 mg/m2 intravenously on day -1 before reinfusion of autologous stem cells

Protocol documents:
Prot_SAP_000.pdf: 
 
BeEAM vs. BEAM in lymphoma, Version 05; 31/08/2017  
 
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Change history 
Version 
Nr 
Version date 
Modified 
without version 
change 
Description, comments 
Control 
4.0 
25.08.2015 
 
Amended version 
 
5.0 
31.08.2017 
x 
Adapted to new Swissethics Template 
Change of principal investigators at participating sites 
For clarification - information for adjustment of DLCO for 
hemoglobin using Dinakara equation was added 
Clarify the number of participants 
Analysis of screening failure patients revealed that many 
patients had HTCTI scores higher than 3 due to reduced 
DLCO. This special parameter is not routinely analyzed 
prior to high-dose 
Clarification that any maintenance treatment after ASCT 
is allowed and does not lead to exclusion of patient(s) 
from analysis. 
Delete pregnancy test on day Day 80 to 120 
Clarification of events not to be reported as AEs 
Clarification that the German Version of HCT-CI score 
listed in protocol version 2.0 is not used in this trial. 
HCT-CI score from Sorror 2013 is used instead. 
Clarification that EORTC QLQ-C30 (Version 3.0) is used  
Clarify handling of obese patients regarding dosing of 
treatment 
Clarify that the the BSA (body surface area) is calculated 
using the.DuBois Method 
Delete  Appendix 5: Declaration of Helsinki, add as a 
reference 
 
 
 
 


 
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A randomized phase II trial comparing BeEAM with BEAM as 
conditioning regimen for autologous stem cell transplantation 
(ASCT) in lymphoma patients (BEB-trial). 
 
Clinical Study Protocol 
 
 
Study Type: 
Clinical trial investigating the chemotherapeutic compound 
Bendamustine (Ribomustin) in lymphoma patients. 
Study Categorisation: 
Risk category according to LHR: category B 
Study Registration: 
EudraCT2014-003629-16 
 
Study Identifier: 
BEB-trial 
Sponsor, or Principal Investigator: 
This is an investigator initiated trial (IIT); Sponsor is Prof. Dr. 
med. Thomas Pabst; Associate Professor; Department of 
Medical Oncology; University Hospital/Inselspital; 3010 Bern; 
Switzerland. Phone +41 31 632 84 30; Fax +41 31 632 34 10; 
Email: thomas.pabst@insel.ch;   
Coordinating investigator for the entire trial is: Prim. Univ. Prof. 
Dr. 
Felix 
Keil; 
Hanusch 
Krankenhaus 
der 
Wiener 
Gebietskrankenkasse; 3. Medizinische Abteilung; Heinrich Collin-
Straße 30; 1140 Wien; Tel.: +43 1 910 21 – 85411; Fax.: +43 1 
910 21 – 85419; E-Mail: felix.keil@wgkk.at 
 
Investigational Product: 
Bendamustine hydrochloride (Ribomustin) 
Protocol Version and Date: 
Version 05, 31.08.2017, incl. Amendment 2 
 
 
 
CONFIDENTIAL 
The information contained in this document is confidential and the property of the sponsor. The information may 
not - in full or in part - be transmitted, reproduced, published, or disclosed to others than the applicable 
Competent Ethics Committee(s) and Regulatory Authority(ies) without prior written authorisation from the 
sponsor except to the extent necessary to obtain informed consent from those who will participate in the study. 
 
 


 
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Signature Page(s)  
 
Study number 
EudraCT2014-003629-16 
Study Title 
A randomized phase II trial comparing BeEAM with BEAM as 
conditioning regimen for autologous stem cell transplantation 
(ASCT) in lymphoma patients (BEB-trial). 
 
 
The Sponsor and trial statistician have approved the protocol version 05 (dated 31/08/2017), and confirm 
hereby to conduct the study according to the protocol, current version of the World Medical Association 
Declaration of Helsinki, ICH-GCP guidelines or ISO 14155 norm if applicable and the local legally applicable 
requirements. 
 
Sponsor: 
Prof. Dr. Thomas Pabst; Department for Medical Oncology; University Hospital/Inselspital; 3010 Berne. 
 
 
 
 
 
Place/Date 
 
Signature 
 
 
 
 
 


 
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Local Principal Investigator at study site*: 
I have read and understood this trial protocol and agree to conduct the trial as set out in this study protocol, the 
current version of the World Medical Association Declaration of Helsinki, ICH-GCP guidelines or ISO 14155 
norm and the local legally applicable requirements. 
 
Site 
…………………………………………………………….. 
 
Principal investigator 
…………………………………………………………….. 
 
 
 
 
Place/Date 
 
Signature 
 
 
 
*Note: In multicentre studies, this page must be individually signed by all participating Local Principal 
Investigators. 
 
 
 


 
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Table of Contents  
STUDY SYNOPSIS ................................................................................................................................. 8 
STUDY SUMMARY IN LOCAL LANGUAGE  ....................................................................................... 13 
ABBREVIATIONS  ................................................................................................................................. 14 
STUDY SCHEDULE .............................................................................................................................. 16 
1. 
STUDY ADMINISTRATIVE STRUCTURE .................................................................................... 17 
1.1 
Sponsor, .......................................................................................................................................17 
1.2 
Principal Investigator(s) ................................................................................................................17 
1.3 
Statistician ("Biostatistician") ........................................................................................................17 
1.4 
Laboratory ....................................................................................................................................17 
1.5 
Monitoring institution ....................................................................................................................17 
1.6 
Data Safety Monitoring Committee ..............................................................................................17 
1.7 
Any other relevant Committee, Person, Organisation, Institution ................................................18 
2. 
ETHICAL AND REGULATO RY ASPECTS .................................................................................. 18 
2.1 
Study registration .........................................................................................................................18 
2.2 
Categorisation of study.................................................................................................................18 
2.3 
Competent Ethics Committee (CEC) ...........................................................................................18 
2.4 
Competent Authorities (CA) .........................................................................................................18 
2.5 
Ethical Conduct of the Study ........................................................................................................18 
2.6 
Declaration of interest ..................................................................................................................19 
2.7 
Patient Information and Informed Consent ..................................................................................19 
2.8 
Participant privacy and confidentiality ..........................................................................................19 
2.9 
Early termination of the study .......................................................................................................19 
2.10 Protocol amendments ..................................................................................................................19 
3. 
BACKGROUND AND RATIO NALE .............................................................................................. 20 
3.1 
Background and Rationale ...........................................................................................................20 
3.2 
Investigational Product and Indication .........................................................................................21 
3.3 
Evidence of clinical activity of Bendamustine from previous studies ...........................................21 
3.4 
Evidence for selecting Bendamustine as a component of a high-dose chemotherapy regimen: 21 
3.5 
Dose Rationale for Bendamustine in the BeEAM regimen ..........................................................22 
3.6 
Explanation for choice of comparator (or placebo) ......................................................................22 
3.7 
Risks / Benefits .............................................................................................................................22 
3.8 
Justification of choice of study population ....................................................................................22 
4. 
STUDY OBJECTIVES ................................................................................................................... 23 
4.1 
Overall Objective ..........................................................................................................................23 
4.2 
Primary Objective .........................................................................................................................23 
4.3 
Secondary Objectives ..................................................................................................................23 
4.4 
Safety Objectives .........................................................................................................................23 
5. 
STUDY OUTCOMES ..................................................................................................................... 23 
5.1 
Primary Outcome .........................................................................................................................23 
5.2 
Secondary Outcomes ...................................................................................................................23 
5.3 
Other Outcomes of Interest ..........................................................................................................23 
5.4 
Safety Outcomes ..........................................................................................................................23 
6. 
STUDY DESIGN ............................................................................................................................ 24 
6.1 
General study design and justification of design ..........................................................................24 
6.2 
Methods of minimising bias ..........................................................................................................24 


 
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6.2.1 Randomisation .....................................................................................................................25 
6.2.2 Blinding procedures .............................................................................................................25 
6.2.3 Other methods of minimising bias ........................................................................................25 
6.3 
Unblinding Procedures (Code break) ...........................................................................................25 
7. 
STUDY POPULATION .................................................................................................................. 26 
7.1 
Eligibility criteria ............................................................................................................................26 
7.2 
Recruitment and screening ..........................................................................................................26 
7.3 
Assignment to study groups .........................................................................................................26 
7.4 
Criteria for withdrawal / discontinuation of participants ................................................................27 
8. 
STUDY INTERVENTION ............................................................................................................... 28 
8.1 
Identity of Investigational Products (treatment) ............................................................................28 
8.1.1 Experimental Intervention (treatment)..................................................................................28 
8.1.2 Control Intervention (standard treatment) ............................................................................28 
8.1.3 Packaging, Labelling and Supply (re-supply) ......................................................................28 
8.1.4 Storage Conditions...............................................................................................................29 
8.2 
Administration of experimental and control interventions ............................................................29 
8.2.1 Experimental Intervention - high-dose chemotherapy BeEAM (with Bendamustine) ..........29 
8.2.2 Control Intervention - high-dose chemotherapy BEAM (with BCNU) ..................................29 
8.3 
Dose modifications .......................................................................................................................30 
8.4 
Compliance with study intervention ..............................................................................................30 
8.5 
Data Collection and Follow-up for withdrawn participants ...........................................................30 
8.6 
Trial specific preventive measures ...............................................................................................30 
8.7 
Concomitant Interventions (treatments) .......................................................................................30 
8.8 
Supportive treatment during neutropenia after ASCT ..................................................................30 
8.9 
Study Drug Accountability ............................................................................................................31 
8.10 Return or Destruction of Study Drug ............................................................................................31 
9. 
STUDY ASSESSMENTS ............................................................................................................... 32 
9.1 
Study flow chart / table of study procedures and assessments / Study Schedule ......................32 
9.2 
Assessments of outcomes ...........................................................................................................33 
9.2.1 Assessment of primary outcome ..........................................................................................33 
9.2.2 Assessment of secondary outcomes ...................................................................................33 
9.2.3 Assessment of safety outcomes ..........................................................................................33 
9.2.4 Assessments in participants who prematurely stop the study .............................................33 
9.3 
Procedures at each visit ...............................................................................................................33 
9.3.1 Screening visit (Day -28 to -8): ............................................................................................33 
9.3.2 Assessments during ASCT (Day -7 until day of hospital discharge ....................................34 
9.3.3 Assessments three months after ASCT (Day 80 to 120) .....................................................34 
9.3.4 Assessments after one year (Day 350 to 400) ....................................................................34 
9.4 
Response criteria .........................................................................................................................35 
10. SAFETY ......................................................................................................................................... 36 
10.1 Drug studies .................................................................................................................................36 
10.1.1 Definition and assessment of (serious) adverse events and other safety related events ...36 
10.1.2 Reporting of serious adverse events (SAE) and other safety related events ......................37 
10.1.3 Reporting to the manufacturer of bendamustine hydrochloride: ..........................................37 
10.1.4 Reporting of SAEs................................................................................................................38 
10.1.5 Reporting of Deaths .............................................................................................................38 


 
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10.1.6  Reporting of SUSARs .........................................................................................................38 
10.1.7  Reporting of Safety Signals .................................................................................................38 
10.1.8  Reporting and Handling of Pregnancies .............................................................................38 
10.1.9  Periodic reporting of safety (ASR) ......................................................................................38 
10.1.10 Follow up of (Serious) Adverse Events ..............................................................................39 
11. STATISTICAL METHODS  ............................................................................................................. 39 
11.1 Hypothesis ....................................................................................................................................39 
11.2 Determination of Sample Size ......................................................................................................39 
11.3 Statistical criteria of termination of trial ........................................................................................39 
11.4 Planned Analyses .........................................................................................................................40 
11.4.1 Datasets to be analysed, analysis populations ....................................................................40 
11.4.2 Primary Analysis ..................................................................................................................40 
11.4.3 Secondary Analyses ............................................................................................................40 
11.4.4 Interim analyses ...................................................................................................................40 
11.4.5 Safety analysis .....................................................................................................................40 
11.4.6 Deviation(s) from the original statistical plan .......................................................................41 
11.5 Handling of missing data and drop-outs.......................................................................................41 
12. QUALITY ASSURANCE AN D CONTROL .................................................................................... 41 
12.1 Data handling and record keeping / archiving ..............................................................................41 
12.1.1 Case Report Forms ..............................................................................................................41 
12.1.2 Specification of source documents ......................................................................................41 
12.1.3 Record keeping / archiving ..................................................................................................41 
12.2 Data management ........................................................................................................................41 
12.2.1 Data Management System ..................................................................................................41 
12.2.2 Data security, access and back-up ......................................................................................42 
12.2.3 Analysis and archiving .........................................................................................................42 
12.2.4 Electronic and central data validation ..................................................................................42 
12.3 Monitoring .....................................................................................................................................42 
12.4 Audits and Inspections .................................................................................................................42 
12.5 Confidentiality, Data Protection ....................................................................................................42 
12.6 Storage of biological material and related health data .................................................................42 
13. PUBLICATION AND DISS EMINATION POLICY.......................................................................... 43 
14. FUNDING AND SUPPORT ............................................................................................................ 43 
14.1 Funding ........................................................................................................................................43 
14.2 Other Support ...............................................................................................................................43 
15. INSURANCE .................................................................................................................................. 43 
16. APPENDICES ................................................................................................................................ 44 
16.1 Appendix 1: Toxizitätskriterien nach CTCAE 4.0 .........................................................................44 
16.2 Appendix 2: Performance status scale (ECOG) ..........................................................................46 
16.3  Appendix 3: Remissionsbeurteilung RECIST ..............................................................................47 
16.4 Appendix 4: HCT-CI score ...........................................................................................................48 
16.5 Appendix 5: Fragebogen zur Lebensqualität EORTC QLQ-C30 (Version 3.0) ...........................49 
17. REFERENCES ............................................................................................................................... 52 
 
 
 


 
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STUDY SYNOPSIS  
 
Sponsor / Sponsor-
Investigator 
This is an investigator initiated trial (IIT); Sponsor is Prof. Dr. med. Thomas 
Pabst; Associate Professor; Department of Medical Oncology; University 
Hospital/Inselspital; 3010 Berne; Switzerland. Phone +41 31 632 84 30; 
Fax +41 31 632 34 10; Email: thomas.pabst@insel.ch;   
Coordinating investigator for the trial is: Prim. Univ. Prof. Dr. Felix Keil; 
Hanusch Krankenhaus der Wiener Gebietskrankenkasse; 3. Medizinische 
Abteilung; Heinrich Collin-Straße 30; 1140 Wien; Tel.: +43 1 910 21 – 
85411; Fax.: +43 1 910 21 – 85419; E-Mail: felix.keil@wgkk.at 
Study Title: 
A randomized phase II trial comparing BeEAM with BEAM as conditioning 
regimen for autologous stem cell transplantation (ASCT) in lymphoma 
patients (BEB-trial). 
Short Title / Study ID: 
Bendamustine for autologous transplant. 
Protocol Version and 
Date: 
Version 05: 31/08/2017   
Trial registration: 
EudraCT2014-003629-16 
Study category and 
Rationale 
Risk category according to LHR: category B. Bendamustine is licensed in 
Switzerland for the treatment of lymphoma patients; in this study, it is used 
as a part of a conditioning regimen before autologous transplant in 
lymphoma patients. 
Clinical Phase: 
Randomized prospective non-blinded clinical phase II trial investigating the 
drug bendamustine hydrochloride. 
Background and 
Rationale: 
BCNU containing BEAM is one of the most commonly used conditioning 
regimens in lymphoma patients treated with autologous stem cell 
transplantation (ASCT). One of the most frequently observed non-
hematological complications of high-dose BCNU containing regimens is 
pulmonary toxicity, with a reported incidence varying from 2% to 64%. 
Pulmonary fibrosis is developing months or years after treatment with 
BCNU. Acute lung injury with a toxic inflammatory reaction after high-dose 
BCNU in ASCT might result in irreversible impairment of pulmonary 
function, and, generally, these effects are not reported in clinical trials, 
which typically focus on overall survival (OS) and progressionfree survival 
(PFS). Although treatment related mortality in ASCT is usually low, 
pulmonary toxicity might result in significant morbidity and in late deaths 
because of impairment of pulmonary function and or impairment of the right 
heart because of pulmonary hypertension. Thus, replacing BCNU by a 
promising cytotoxic compound - such as bendamustine - might result in 
better PFS without the impairment of lung function. Thus, a head-to-head 
comparison of BeEAM with BEAM with a focus on acute and late toxicity 
and on PFS - is an unmet clinical need to improve results in lymphoma 
patients receiving ASCT. As older patients with higher comorbidity scores 
might also profit from ASCT, a less toxic regimen might also improve 
clinical results in this age cohort. 


 
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Objective(s): 
 
Primary objective:  
To show a clinically meaningful reduction of lung toxicity - defined as a a 
decrease of the diffusion capacity of the lung for carbon monoxide (DLCO)  
by 20% or more from baseline before ASCT - from 25% of patients in the 
BEAM group to 4% of patients in the BeEAM group at 3 months after 
ASCT. Use Dinakara equation for adjusting DLCO for hemoglobin 
 
Secondary objectives:  
To assess acute and late toxicity/adverse events (CTCAE 4.0) during entire 
study period 
To assess the hematologic engraftment after 3 months 
To assess early and late lung toxicity by pulmonary function tests, 
spiroergometry, DLCO,  HRCT and venous BGA after 3 and 12 months.  
To perform cardiac assessment by ECHO/ECG 
To assess the quality of life prior to ASCT and 3 and 12 months thereafter.  
To assess overall survival and progression free survival after 12 months 
and then yearly. 
Outcome(s): 
To show a clinically meaningful reduction of lung toxicity - defined as a 
reduction of the DLCO by at least 20% - from 25% of patients in the BEAM 
group to 4% of patients in the BeEAM group at 3 months after ASCT. 
Study design: 
Randomized open-label prospective phase II trial 
Inclusion / Exclusion 
criteria: 
 
Key inclusion criteria: 
Mantle cell lymphoma (MCL) in first or second remission or second 
chemosensitive relapse 
Diffuse large B-cell lymphoma (DLBCL) in first remission or second 
remission or second chemosensitive relapse 
Follicular lymphoma (FL) in second remission or second chemosensitive 
relapse  
Aged between 18 years and 75 years 
Neutrophils ≥ 1000/μl; Platelets ≥ 100 x 109/L 
 
Key exclusion criteria: 
Acute infection  
Relevant co-existing disease excluding a treatment according to protocol 
HCTCI > 5 (Use Dinikara equation for adjusting DLco for hemoglobin) 
Concurrent malignant disease with the exception of basalioma/spinalioma 
of the skin or early-stage cervix carcinoma, or early-stage prostate cancer. 
Previous treatment for other malignancies (not listed above) must have 
been terminated at least 24 months before registration and no evidence of 
active disease must be documented since then. 
Lack of patient cooperation to allow study treatment as outlined in this 
protocol  
Pregnancy or lactating female patients 
Major coagulopathy or bleeding disorder  
Major surgery less than 30 days before start of treatment  
Contraindications and hypersensitivity to any of the active chemotherapy 
compounds  


 
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Measurements and 
procedures: 
Two high-dose chemotherapy regimens (BeEAM versus BEAM) used for 
conditioning treatment before autologous stem cell transplantation will be 
compared in a 1:1 randomization. The experimental arm is the BeEAM 
regimen. The BEAM regimen is the control treatment. Both regimens use 
the three drugs etoposide, cytarabine and melphalan at identical doses and 
at identical days. The only difference is the replacement of the standard 
drug BCNU (carmustin; given in the BEAM group at day -6) by the 
experimental drug bendamustine (given in the BeEAM group at days -7 
and -6).  
Lung toxicity will be assessed by venous blood gas assessment, thereby 
assessing the diffusion capacity of the lung for carbon monoxide (DLCO), 
and by spiroergometry . This analysis will be performed before ASCT, as 
well as 3 months and 12 months after ASCT. 
BeEAM chemotherapy regimen consisting of bendamustine intravenously 
on days −7 and −6 at 200 mg/m2; cytarabine, 400 mg/m2 intravenously 
daily from day −5 to day−2; etoposide, 200 mg/m2 intravenously daily from 
day −5 to day −2; and melphalan, 140 mg/m2 intravenously on day −1 
before reinfusion of autologous stem cells will be compared with the 
standard BEAM regimen with carmustine 300 mg/m2 on day -6, followed by 
the EAM regimen as described above, in a randomized phase II trial. 
Toxicity and efficacy will be compared. 
Study Product / 
Intervention:  
The experimental treatment group is treated according to the BeEAM 
regimen. 
The 
BeEAM 
chemotherapy 
regimen 
is 
consisting 
of 
bendamustine intravenously on days −7 and −6 at 200 mg/m2; cytarabine, 
400 mg/m2 intravenously daily from day −5 to day−2; etoposide, 200 
mg/m2 intravenously daily from day −5 to day −2; and melphalan, 140 
mg/m2 intravenously on day −1 before reinfusion of autologous stem cells. 
Control Intervention (if 
applicable): 
The standard (control) treatment group is treated according to the BEAM 
regimen. The BEAM chemotherapy regimen is consisting of BCNU 
(carmustine) 300 mg/m2 on day -6; cytarabine, 400 mg/m2 intravenously 
daily from day −5 to day−2; etoposide, 200 mg/m2 intravenously daily from 
day −5 to day −2; and melphalan, 140 mg/m2 intravenously on day −1 
before reinfusion of autologous stem cells. 
Number of Participants 
with Rationale: 
Applying a statistical power of 80% and a two-sided significance level of 
5%, 49 evaluable patients will be needed in each group to show a clinically 
meaningful reduction of events (lung toxicity defined as a reduction of the 
DLCO by at least 20% compared to baseline), i.e. from 25% of patients in 
the BEAM group to 4% of patients in the BeEAM group. Thus, a total of 
108 evaluable patients is needed. Expecting a rate of ineligible patients of 
10%, a total of 108 patients is needed, with 54 patients in each of the two 
arms. 
Study Duration: 
The total study duration is 36 months.  
Study Schedule: 
First-Participant-In (planned): January 2015 
Last-Participant-Out (planned): December 2018 


 
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Investigator(s): 
 
For Vienna / Austria:  
Prim. Univ. Prof. Dr. Felix Keil; Hanusch Krankenhaus der Wiener 
Gebietskrankenkasse; 3. Medizinische Abteilung; Heinrich Collin-Straße 
30; 1140 Wien; Tel.: +43 1 910 21 – 85411; Fax.: +43 1 910 21 – 85419; E-
Mail: felix.keil@wgkk.at 
 
For Linz / Austria:  
OÄ Dr. Veronika Buxhofer-Ausch, Ordensklinikum - Krankenhaus der 
Elisabethinen Linz, Interne 1 - Hämato-Onkologie, , Fadingerstrasse 1, A-
4020 Linz, Veronika.Buxhofer-Ausch@ordensklinikum.at; Telefon: +43 732 
7676 4409, Fax: +43 732 7676 4418  
 
For Berne / Switzerland:  
Prof. Dr. Thomas Pabst; Department for Medical Oncology; University 
Hospital/Inselspital;; 3010 Berne; Phone +41 31 632 84 30; Fax +41 31 
632 34 10; Email: thomas.pabst@insel.ch 
 
For Zurich / Switzerland: 
Dr. Antonia Müller; Klinik für Hämatologie; Universitätsspital Zürich; 
Rämistrasse 100; CH-8091 Zürich; Tel. +41 442555371; Fax. +41 
442554560; Email: AntoniaMaria.Mueller@usz.ch 
 
Study Centres: 
2 centres in Austria: Vienna; Linz  
2 centres in Switzerland: Berne; Zurich 


 
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Statistical 
Considerations: 
This study involves two treatment arms and applies a 1:1 randomization, 
additionally considering the stratification for lymphoma subtypes: diffuse 
large B-cell lymphoma versus mantle cell lymphoma versus follicular 
lymphoma. No interim analysis is planned, and all calculations will be 
performed per evaluable patient. The primary endpoint is to show a 
clinically meaningful reduction of events (lung toxicity defined as a 
reduction of the DLCO by at least 20%) at three months, i.e. from 25% of 
patients in the BEAM group to 4% of patients in the BeEAM group. 
Arm A is the experimental arm (BeEAM chemotherapy), and arm B is the 
standard arm (BEAM chemotherapy). The null hypothesis is that the lung 
toxicity determined at three months is equal in both arms (LT3A = LT3B). 
The aim of the study is to ultimately show 20% less lung toxicity of the 
experimental (BeEAM) arm, with LT3A < LT3B.  
Based on previous reports, we anticipate observing lung toxicity in the 
standard (BEAM) arm in 25% (LT3B). Our hypothesis is that the 
experimental (BeEAM) arm will show lung toxicity in only 4% or less of the 
patients (LT3A), thus a difference of at least 20 percentage points. Thus, 
the superiority margin in the proposed prospective randomized study is 
0.20, i.e. the reduction of lung toxicity is considered a success compared to 
the standard (BEAM) arm if its lung toxicity rate is more than 20 percentage 
points better. 
With LT3A and LT3B being the (true) success rates in the BeEAM arm and 
in the BEAM arm, respectively, the hypotheses are: 
     H0: LT BeEAM chemotherapy is > 0.04 when LT BEAM is 25%. 
     H1: LT BeEAM chemotherapy is ≤ 0.04 when LT BEAM is 25%. 
Applying a statistical power of 80% and a two-sided significance level of 
5%, 49 evaluable patients will be needed in each group to show a clinically 
meaningful reduction of events (lung toxicity defined as a reduction of the 
DLCO by at least 20%), i.e. from 25% of patients in the BEAM group to 4% 
of patients in the BeEAM group using Fishers Exact Test. Thus, a total of 
108 evaluable patients are needed. Expecting a rate of ineligible patients of 
10%, a total of 108 patients is needed, with 54 patients in each of the two 
arms. 
The significance level actually achieved by this design is 0.0497. All 
statistical analysis for sample size calculations were performed using the 
software package nQuery Advisor 7.0.  
For statistical analysis of this study, continuous endpoints will be 
summarized using descriptive statistics including mean, median, standard 
deviation, first and third quartiles, minimum and maximum values, and 
where appropriate by graphical techniques (e.g. histogram, box plot). For 
categorical endpoints, the number and percentage of patients in each 
category will be summarized. Where appropriate, a two-sided 95% 
confidence interval for the proportion will be reported. The primary endpoint 
in the two groups will be tested using Fishers Exact Test. 
GCP Statement: 
This study will be conducted in compliance with the protocol, the current 
version of the Declaration of Helsinki, the ICH-GCPas well as all national 
legal and regulatory requirements.  
 
 


 
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STUDY SUMMARY IN LOCAL LANGUAGE   
Lymphome sind bösartige Lymphdrüsen-Erkrankungen. Die häufigsten Lymphom-Typen umfassen dass Diffus 
Grosszellige B-Zell-Lymphom (DLBCL), das Mantelzelllymphom (MCL) und das follikuläre Lymphom (FCL). 
Patienten mit diesen Lymphom-Erkrankungen in erster oder zweiter Remission stellen die häufigste Indikation 
dar zur Hochdosis-Chemotherapie mit autologer Stammzell-Transplantation (ASCT), oft und zunehmend 
häufiger dabei mit endgültiger Heilung als Ziel.  
Das häufigste Hochdosis-Chemotherapie Schema vor autologer Transplantation ist das BEAM-Schema. Es 
setzt sich aus vier Chemotherapeutika zusammen (BCNU, Etoposid, Cytarabin,  Melphalan), deren 
Anfangsbuchstaben zum BEAM-Schema zusammengefasst werden. Eine der häufigsten Organ-Schädigungen 
dieser intensiven Therapie wird durch das Medikament BCNU verursacht; es handelt sich dabei um eine 
Lungenschädigung, die sich in den Monaten nach der ASCT mit zunehmender Atemnot und Husten äussert, 
und in einer Lungenfibrose enden kann. Das Ausmass dieser Lungenschädigung variiert beträchtlich, und sie 
kommt in 2 bis 64% aller Patienten vor. Die Lebensqualität kann dadurch nachhaltig und dauerhaft geschädigt 
sein, was bei kurativen Situationen umso belastender ist.  
Das Medikament Bendamustin wird mit gutem Erfolg heute bei verschiedenen Lymphom-Typen eingesetzt, und 
seine Wirksamkeit in der Lymphom-Therapie ist bestens belegt. Vor allem aber verursacht Bendamustin keine 
Lungenschädigung. Erste Erfahrungen mit Bendamustin anstelle von BCNU – im sogenannten BeEAM Schema 
– zeigen nun, dass dieses Schema durchaus wirksam und gut toleriert wird, aber die Lungenschädigung nach 
der BEAM-Therapie nicht zu verursachen scheint. Im BeEAM Schema ersetzt also Bendamustin das BCNU, 
während die drei anderen Medikamente in gleicher Dosierung und Reihenfolge verabreicht werden  
In der vorliegenden Studie an vier Zentren (Bern und Zürich in der Schweiz; Wien und Linz in Österreich) soll 
nun randomisiert in einem 1:1 Vergleich zwischen diesen beiden Schemas gezeigt werden, dass eine 
Hochdosis-Chemotherapie nach dem BeEAM-Schema signifikant weniger Lungenschädigung verursacht zum 
Zeitpunkt drei Monate nach ASCT (<4%) als nach dem BEAM-Schema (>25%). Die klinisch relevante 
Lungenschädigung soll dabei definiert werden als eine Abnahme der Diffusionskapazität der Lunge für 
Kohlenmonoxid (DLCO) um mindestens 20% zum Zeitpunkt drei Monate nach ASCT. Gleichzeitig wird die 
Wirksamkeit dieser beiden Schemas verglichen. Total sind 54 Lymphom-Patienten (DLBCL, MCL oder FCL in 
erster oder zweiter Remission) in jedem Behandlungsarm geplant, mit einer Studiendauer von 36 Monaten.  
 
 


 
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ABBREVIATIONS  
AE 
Adverse Event  
AGES 
Arzneimittelbehörde in Oesterreich 
ASCT 
ASR 
BCNU 
BEAM 
BeEAM 
BGA 
BSA 
CBV 
Autologous stem cell transplantation 
Annual Safety Report 
1,3-Bis(2-chloroethyl)-1-nitrosourea, Carmustine 
BCNU-Etoposide-Cytarabin-Melphalan 
Bendamustine-Etoposide-Cytarabine-MelphalanBlood gas analysis 
Blood gas analysis 
Body Suface Area 
Cyclophosphamide-BCNU-Etoposide 
CEC 
Competent Ethics Committee 
CRF 
Case Report Form  
ClinO 
Ordinance on Clinical Trials in Human Research (in German: KlinV, in French: 
OClin) 
eCRF 
Electronic Case Report Form  
CTCAE 
DLBCL 
DLCO 
Common terminology criteria for adverse events 
Diffuse large B-cell lymphoma 
Diffusing capacity of the lung for carbon monoxide 
DSMC 
Data safety monitoring committee 
ECG 
ECHO 
FCL 
FEV1 
FVC 
GCP 
HCTCI 
HDCT 
Electrocardiography 
Echocardiography 
Follicular lymphoma 
Forced expiratory volume in first second 
Forced vital capacity 
Good Clinical Practice  
hematopoietic cell transplantation comorbidity index 
High-dose chemotherapy 
IB 
Investigator’s Brochure 
H1 
Alternative hypothesis 
HFG 
Humanforschungsgesetz (Law on human research) 
HRCT 
High-resolution computed tomography 
IMP 
Investigational Medicinal Product 
IIT 
IPI 
IPS 
Investigator-initiated Trial 
international prognostic index 
Idiopathic pneumonia syndrome 
ISO 
International Organisation for Standardisation 
ITT 
Intention to treat 
KlinV 
Verordnung über klinische Versuche in der Humanforschung (in English: ClinO, in 
French OClin) 
MCL 
Mantle cell lymphoma 
NHL 
Non Hodgkin’s lymphoma 


 
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OClin 
Ordonnance sur les essais cliniques dans le cadre de la recherche sur l'être 
humain (in German : KlinV, in English : ClinO) 
RBC 
Red blood cell  
SPC 
Summary of product characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
TRM 
QoL 
Treatment related mortality 
Quality of life 
 
 
 


 
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STUDY SCHEDULE  
Study Periods 
 
Screening 
Treatment / Intervention 
Visit 
1 
2 
3 
43 
Time (days) 
-28 to -8 
-7 until dismissal 
80-120 
350-400 
Patient information & informed consent 
x 
 
 
 
Height / weight / BMI 
x 
 
 
 
Medical history 
x 
 
 
 
In- /exclusion criteria 
x 
 
 
 
Physical examination 
x 
x 
x 
x 
HCTCI score 
x 
 
 
 
ECOG score 
x 
x 
x 
x 
Vital Signs 
x 
x 
x 
x 
Hematology (complete blood counts with differential) 
x 
x 
x 
x 
Routine serum biochemistry (according to center 
policy) 
x 
x 
x 
x 
Pregnancy Test 
x 
 
 
 
Randomization 
x 
 
 
 
ECG 
x 
 
x 
x 
Echocardiography 
x 
 
x 
x 
Pulmonary function (FEV1 & FVC), DLCO1 
x 
 
x 
x 
Spiroergometry  
x 
 
x 
x 
Response (CT, MR or PET) thorax/abdomen 2,4 
x 
 
x 
x 
VBGA 
x 
 
x 
x 
HR-CT chest 
x 
 
x 
x 
QoL (EORTC Q30) 
x 
 
x 
x 
CTCAE 4.0 toxicity score 
 
x 
x 
x 
Engraftment, neutrophil and platelet recovery 
 
x 
 
 
Days until platelets >50 G/L 
 
 
x 
 
Number of CD34+ cells used 
 
x 
 
 
RBC & platelet transfusions 
 
x 
 
 
Days of T>38.0°; number of febrile episodes 
 
x 
x 
 
Administer study medication 
 
x 
 
 
Adverse Events 
 
x 
x 
x 
1Adjusted DLCO = measured DLCO  / (0.06965 x Hb) 
2 The selection of the radiologic assessment is at  the discretion of the center and the treating physician 
3 Patients withdrawn from protocol are documented for a total of 12 months. All patients terminating study 
treatment before 12 months will be analyzed until the last documented follow-up. 
4 After the 12 months control, assessments will be done once per year after that as routine follow-up 
assessments. If relapse is suspected, CT, MR or PET-CT assessments are recommended. The follow-up is 
performed at the discretion of the center; if relapse or progression of lymphoma is suspected, standard 
radiological examination has to be performed. 


 
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1. STUDY ADMINISTRATIVE STRUCTURE  
1.1 Sponsor,  
Prof. Dr. Thomas Pabst (Sponsor) 
Department for Medical Oncology 
University Hospital/Inselspital 
3010 Bern  
Tel: +41 31 632 84 30 
Fax: +41 31 632 34 10 
E-Mail: thomas.pabst@insel.ch 
1.2 Principal Investigator(s) 
 
Prim. Univ. Prof. Dr. Felix Keil  (Coordinating Investigator) 
Hanusch Krankenhaus der Wiener Gebietskrankenkasse 
3. Medizinische Abteilung  
Heinrich Collin-Straße 30  
1140 Wien  
Tel: +43 1 910 21 - 85411  
Fax: +43 1 910 21 - 85419  
E-Mail: felix.keil@wgkk.at 
 
Prof. Dr. Thomas Pabst (Principal Investigator for Switzerland) 
Department for Medical Oncology 
University Hospital/Inselspital 
3010 Bern  
Tel: +41 31 632 84 30 
Fax: +41 31 632 34 10 
E-Mail: thomas.pabst@insel.ch 
1.3 Statistician ("Biostatistician") 
 
Univ. Prof. DI Dr. Andrea Berghold 
Institut für Med. Informatik, Statistik und Dokumentation 
Medizinische Universität Graz  
Auenbruggerplatz 2  
8036 Graz 
Tel: +43/316/385-4261 
Fax: +43/316/385-3590 
E-Mail: andrea.berghold@medunigraz.at 
1.4 Laboratory  
Not applicable; No central specific laboratory analyses are planned in this trial. 
1.5 Monitoring institution
 
For Berne and Zurich, Switzerland: Monitoring will be performed by the Clinical trial Unit (CTU) of the University 
of Berne, Switzerland. 
For the two Austrian centres:  Mag.Dr. Judith Schuster, Groisbach 47, A-2534 Alland, Tel: +43 664 3934498, 
Fax: +43 2258 2047, E-Mail: j.schuster@medtest.at 
1.6 Data Safety Monitoring Committee 
 
not applicable; no DSMC is needed for this trial. 


 
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1.7 Any other relevant Committee, Person, Organisation, Institution
  
Not applicable 
2. ETHICAL AND REGULATO RY ASPECTS  
Before the study will be conducted, the protocol, the proposed patient information and the consent form as well 
as other study-specific documents will be submitted to the Competent Ethics Committee (CEC) in Berne 
(leading CEC for Switzerland) and to the competent authorities (Swissmedic and to the Austrian competent 
authorities) in agreement with local legal requirements, for formal approval. Any amendment to the protocol will 
as well be approved (if legally required) by these institutions. 
The decision of the CEC and Swissmedic/foreign competent authority concerning the conduct of the study will 
be made in writing to the Sponsor before commencement of this study. The clinical study can only begin once 
approval from the required authoritiy has been received. Any additional requirements imposed by the authorities 
shall be implemented. 
2.1 Study registration  
The study is registered in a registry listed in the WHO International Clinical Trials Registry Platform (ICTRP, 
http://www.who.int/ictrp/en/) (http://clinicaltrials.gov). In addition,it is registered in a national language in the 
Swiss Federal Complementary Database (http://www.kofam.ch) 
2.2 Categorisation of study 
 
This clinical trial falls into Category B since the investigational compound Bendamustine is approved in 
Switzerland for the treatment of lymphoma patients. In this trial, Bendamustine is used for the treatment of 
lymphoma patients, but it is used as a part of a high-dose chemotherapy regimen (BeEAM regimen), thus 
outside its approved indication. 
2.3 Competent Ethics Committee (CEC) 
 
The responsible investigator at each site ensures that approval from an appropriately constituted Competent 
Ethics Committee (CEC) is sought for the clinical study.  
All changes in the research activity and all unanticipated problems involving risks to humans will be reported 
including in case of planned or premature study end and the final report. No changes will be made to the 
protocol without prior Sponsor and CEC approval, except where necessary to eliminate apparent immediate 
hazards to study participants. 
Premature study end or interruption of the study is reported within 15 days. The regular end of the study is 
reported to the CEC within 90 days, the final study report shall be submitted within one year after study end. 
Amendments are reported according to chapter 2.10. 
2.4 Competent Authorities (CA) 
 
The Sponsor will obtain approval from the competent authority (e.g. Swissmedic) before the start of the clinical 
trial.  
All changes in the research activity and all unanticipated problems involving risks to humans will be reported 
including in case of planned or premature study end and the final report. No changes will be made to the 
protocol without prior Sponsor and CEC approval, except where necessary to eliminate apparent immediate 
hazards to study participants. 
Premature study end or interruption of the study is reported within 15 days. The regular end of the study is 
reported to the CEC within 90 days, the final study report shall be submitted within one year after study end. 
Amendments are reported according to chapter 2.10. 
2.5 Ethical Conduct of the Study 
 
The study will be carried out in accordance to the protocol and with principles enunciated in the current version 
of the Declaration of Helsinki, the guidelines of Good Clinical Practice (GCP) issued by ICH. The CEC and 
regulatory authorities will receive annual safety and interim reports and be informed about study stop/end in 
agreement with local requirements.  


 
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2.6 Declaration of interest 
 
No conflicts of interest are reported 
2.7 Patient Information and Informed Consent
 
Participants will be comprehensively informed about the study and consent is sought from each participant; no 
compensation for study participation is made in this trial. The investigators will explain to each participant the 
nature of the study, its purpose, the procedures involved, the expected duration, the potential risks and benefits 
and any discomfort it may entail. Each participant will be informed that the participation in the study is voluntary 
and that he/she may withdraw from the study at any time and that withdrawal of consent will not affect his/her 
subsequent medical assistance and treatment.  
The participant will be informed that his/her medical records may be examined by authorised individuals other 
than their treating physician. 
All participants for the study will be provided a participant information sheet and a consent form describing the 
study and providing sufficient information for participant to make an informed decision about their participation in 
the study. Enough time needs to be given to the participant to ask questions and decide whether to participate 
or not.  
The patient information sheet and the consent form will be submitted to the CEC to be reviewed and approved. 
The formal consent of a participant, using the approved consent form, must be obtained before the participant is 
submitted to any study procedure.   
The participant will read and consider the statement before signing and dating the informed consent form, and 
should be given a copy of the signed document. The original consent form will also be signed and dated by the 
investigator (or his designee) and it will be retained as part of the study records. 
2.8 Participant privacy and confidentiality 
 
The investigator affirms and upholds the principle of the participant's right to privacy and that they shall comply 
with applicable privacy laws. Especially, anonymity of the participants shall be guaranteed when presenting the 
data at scientific meetings or publishing them in scientific journals.  
Individual subject medical information obtained as a result of this study is considered confidential and disclosure 
to third parties is prohibited. Subject confidentiality will be further ensured by utilising subject identification code 
numbers to correspond to treatment data in the computer files. 
For data verification purposes, authorised representatives of the Sponsor (-Investigator), a competent authority 
(e.g. Swissmedic), or an ethics committee may require direct access to parts of the medical records relevant to 
the study, including participants’ medical history. 
2.9 Early termination of the study 
 
The Sponsor (and any competent authority) may terminate the study prematurely according to certain 
circumstances for example:. 
 
ethical concerns, 
 
insufficient participant recruitment, 
 
when the safety of the participants is doubtful or at risk, respectively, 
 
alterations in accepted clinical practice that make the continuation of a clinical trial unwise,  
 
early evidence of benefit or harm of the experimental intervention  
2.10 Protocol amendments  
The Principle-Investigator and Sponsor are allowed to amend the protocol or to provide suggestions for a 
protocol amendment. Substantial amendments are only implemented after approval of the CEC and CA 
respectively. 
Under emergency circumstances, deviations from the protocol to protect the rights, safety and well-being of 
human subjects may proceed without prior approval of the sponsor and the CEC/CA. Such deviations shall be 
documented and reported to the sponsor and the CEC/CA as soon as possible. 
All Non-substantial amendments are communicated to the CA as soon as possible if applicable and to the CEC 
within the Annual Safety Report (ASR)  .  


 
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3. BACKGROUND AND RATIO NALE  
3.1 Background and R ationale  
Autologous stem cell transplantation (ASCT): High-dose chemotherapy (HDCT) followed by ASCT is considered 
the treatment of choice for relapsed/refractory lymphomas. On the basis of the results of the PARMA study 
group trial, high-dose chemotherapy followed by ASCT has become the standard of care for patients with 
relapsed, chemo-sensitive aggressive lymphoma1 and it is the treatment of choice in patients relapsing with 
follicular lymphoma and Hodgkin’s disease2 3 4. Worldwide, about 11’000 patients are treated with ASCT per 
year because of relapsing lymphoma. The BEAM chemotherapy regimen is the most frequently used 
conditioning regimen since more than thirty years. Thus, challenging this established regimen is of high clinical 
relevance. 
Several chemotherapy preparative regimens are used in ASCT, and the chemotherapeutic agents are selected 
because of activity against particular lymphoma subtypes; however, there has not been a single adequately 
powered randomized clinical trial to support the superiority of one regimen against another. Therefore, regimens 
are frequently chosen by institutional preference, and most of them contain (among others) with BCNU as in the 
BEAM (BCNU, etoposide, cytarabine, melphalan) or in the CBV regimens (cyclophosphamide, BCNU, and 
etoposide [VP-16]), with these two representing the most frequently used ASCT preparative regimens for 
patients with lymphoma.  
 
The “delayed” Idiopathic Pneumonia Syndrome (IPS) and toxicity of BCNU after ASCT: Toxic pneumonia with 
interstitial infiltration and impairment of the diffusion capacity of the lung is a recognized complication of HDCT 
regimens containing BCNU.5 The idiopathic pneumonia syndrome (IPS) clinically presents with dyspnea or 
cough6, decreased reduction of the diffusion capacity of carbon monoxide of the lung (DLCO), and radiological 
signs of interstitial infiltration. This IPS after ASCT differs from that observed after allogeneic SCT as its onset 
occurs later (median onset at day 45 vs. day 19 after allogeneic SCT) and its usually better clinical outcome. 
Although mortality is significantly lower compared with IPS after allogeneic SCT (with a less than 10% mortality 
rate) and IPS is responsive to steroid therapy,7 it is associated with significant morbidity and late toxicity or long 
term impairment of pulmonary function which might adversely affect the quality of life in patients otherwise cured 
from their underlying disease. 
The underlying mechanism of BCNU-associated pulmonary toxicity is not entirely clear. Oxidative stress and 
glutathione dysfunction, as well as immune-mediated injury have been implicated as causative factors. The 
delayed presentation after ASCT may be consistent with initial tissue injury followed by pneumonia progression 
at the time of lymphocyte recovery. Toxicities of BCNU containing regimens, such as BEAM, result in the 
incidence of IPS of between 2% and up to 64%,8,28,29 depending on the BCNU dose, pre-treatment modalities, 
and co-morbidity of the patient. Furthermore, results from the Bone Marrow Transplant Survivor Study showed a 
relative risk of death not related to relapse of 2.27 (95% confidence interval 1.42-3.64) for patients receiving 
ASCT for hematologic malignancies with BCNU based regimens9,10  
Although treatment related mortality in ASCT is low, undetected late toxicity might impair long term results and 
quality of life in patients receiving ASCT. Lane et al showed in a population of patients with lymphoma treated 
with high-dose CBV and ASCT11 a 31% median reduction in DLCO three months after treatment. In addition to 
the BCNU dose, prior mediastinal radiation and a total dose of BCNU exceeding 1000 mg were identified as 
significant risk factors for developing IPS induced pneumonia.12 In addition, in 20% of patients receiving BCNU 
less than 750 mg, an IPS incidence of 20% was observed. The delayed median onset of symptoms (50 days 
post-ASCT) may not be detected in an outpatient setting as the focus on posttransplant investigation is usually 
focusing on hematological recovery and disease free survival. However, delayed pulmonary toxicity should be 
documented and BCNU sparing regimens might be of clinical relevance; in addition, new promising 
combinations of cytotoxic agents may increase response rate and decrease late toxicity after ASCT. In 
summary, a BCNU-induced reduction of DLCO of 20% might ultimately not cause treatment related mortality, but 
it might affect quality of life by impaired long-term pulmonary function. 
Recently, replacement of BCNU by Lemustine13 showed a trend towards reduced TRM. The causes of death at 
day 100 in the BEAM group (TRM at day 100 was 4.67%) were pneumonia (n=3), sepsis (1), relapse (1), 
myocardial infarction (1) and TRM after dismissal of hospital (1). In the LEAM group (TRM at day 100 was 
1.8%), there was only one single death from pneumonia.  
Although the dose of BCNU in the BEAM protocol is lower (300 mg/m2) than in the CBV protocol (600 mg/m2), it 
might have a significant impact on deterioration of pulmonary function as BEAM is frequently used as a rescue 
therapy before ASCT in relapse of lymphoma patients and, thus, the total dose of infused BCNU might exceed 
the critical threshold of 1000 mg/m2. 


 
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3.2 Investigational Product 
and Indication  
The potential role of Bendamustine in treating relapsed lymphoma patients in combination with Etoposide, Ara C 
and Melphalan (BEAM): Bendamustine combines the alkylating activity of the mustard group with the 
antimetabolite activity of the purine analogue. 14,15  Bendamustine was studied in several entities of B-cell 
neoplasms and demonstrated significantly superior efficacy compared with standard therapies in the treatment 
of relapsed chronic lymphocytic leukemia16 (CLL) and indolent NHL and myeloma.17,18  Rummel et al have 
demonstrated that bendamustine was highly effective in indolent lymphoma such as follicular lymphoma (FCL) 
and mantle cell lymphoma (MCL). Compared to CHOP chemotherapy, the toxic profile was somewhat 
preferable, and in mantle cell lymphoma better response rates were seen.19,20  The BRIGHT study confirmed the 
non-inferiority of a immunochemo-therapy with Rituximab-Bendamustine when compared with R-CHOP or R-
CVP in indolent lymphoma or mantle cell lymphoma.21  
3.3 Evidence of clinical activity of Bendamustine from prev
ious studies   
Recently, Visani et al have shown that Bendamustine, coupled with fixed doses of Etoposide, Cytarabine, and 
Melphalan (ie, BeEAM) in the conditioning regimen for ASCT for resistant/relapsed lymphoma (HD and NHL) 
patients is highly active and resulted in promising results concerning safety and efficacy. 22 No treatment 
mortality was observed and no relevant pulmonary toxicity was seen. Non-hematological toxicity was moderate, 
and most prominent toxicities were gastroenteritis grade 3 to 4 in 34% and mucositis grade 3 to 4 in 35%, 
respectively. No grade 3 to 4 cardiac toxicity or toxic pneumonia was observed. Engraftment was rapid and 
trilinear, and stable hematopoiesis was observed. BeEAM was very effective, with 81% of patients in complete 
response after a median observation time of 18 months. A recent update of this study showed that at 41 months 
still 72% of the patients are still in complete remission and the 3-year PS was 75%.31 Four patients showed a 
first remission ever with the Bendamustine containing regimen. In 35 patients treated at the Vienna centre 
according to the Visani BeEAM protocol, these encouraging data of Visani et al could be reproduced; similar 
toxicities and rapid and stable engraftment were observed.23 Finally, the combination of Bendamustine with 
sequential application of high-dose Cytarabine was reported to improve the response rates in relapsing 
lymphomas.24,25 In conclusion, it seems promising to integrate Bendamustine in myelobablative regimens in 
ASCT, but a randomized clinical trial is lacking so far. 
3.4 Evidence for selecting 
Bendamustine as a component of a high
-dose 
chemotherapy regimen:
  
Since ASCT remains an important component of therapy for lymphomas, any improvement in conventional 
chemotherapy is warranted. Although there is currently an increasing focus on so-called targeted therapies, 
standard chemotherapy should be improved in clinical trials and it is mandatory that BEAM or CBV regimen are 
challenged in new clinical trials. Recently, it has been shown that the EAM regimen (thus omitting BCNU) is not 
sufficient to obtain equal response rates if compared with BEAM and poorer disease control resulted in impaired 
DFS.26 Thus, it might be detrimental for patients just to eliminate BCNU without an appropriate substitution. 
Replacing BCNU by Bendamustine with its potential to eradicate residual or treatment-resistant lymphoma cells 
could be a promising clinical approach and should be investigated in a randomized phase II clinical trial 
comparing standard BEAM with BeEAM.  
Although transplant related mortality is generally low in ASCT, long term cardio-pulmonary toxicity might be 
underestimated.27 Almost all patients with lymphoma receive anthracyclins as first line treatment or later in 
reinduction chemotherapy and some of them are treated with bleomycin containing regimen followed by a 
combination of BCNU; thus, both pulmonary and cardiac toxicity with impairment in cardiopulmonary function 
might deteriorate over the years after ASCT. Any additional pulmonary toxicity by BCNU may result in impaired 
diffusion capacity of the lung28 with deterioration of oxygenation and possible increase in right heart blood 
pressure. This may result in myocardial insufficiency. Many late effects are not documented and about 50 
percent of patients eligible for ASCT achieve long term remission or even cure. Thus, prevention of late cardio-
pulmonary toxicity is of particular interest for these patients. 
Treatment of lymphoma patients usually is performed in highly specialized hematological centres, and after 
achieving stable remission, such patients are typically no longer seen by transplant physicians. Thus, late 
toxicities with pulmonary or cardiac impairment 29 are often not documented. A replacement of BCNU by 
bendamustine might be an attractive concept as so far no specific cardio-pulmonary toxicity of bendamustine is 
known. As cited above, bendamustine is a highly active component in the treatment of follicular or aggressive 
lymphomas and - in combination with high-dose cytarabine - very efficient in the treatment of relapsing mantle 
cell lymphoma.25 Therefore, the high-dose cytarabine containing EAM might be the ideal combination for 
cytotoxic drugs with Bendamustine. In our multicenter academic trial, we plan to compare the standard BEAM 
protocol with BeEAM thereby replacing BCNU and to document early and late effects of BCNU on cardio-
pulmonary function. 


 
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Justification and definition of primary endpoint: The pulmonary diffusion capacity is the prominent tool to 
assess lung specific toxicity and it is assessed by the single breath carbon monoxide method DLCO. It 
demonstrates the ability to absorb alveolar gases into the capillary blood flow, representing the function of the 
alveolar membrane, and it is affected by hemoglobin level, cardiac output, and distribution of diffusion capacity, 
ventilation and perfusion. As the hemoglobin level is relevant for interpretation of DLCO and since changes of 
DLCO as a function of hemoglobin will be documented, DLCO will be evaluated before ASCT (baseline), 3 months 
after ASCT when recovery of erythropoietin can be expected, as well as 12 months after ASCT. DLCO will be 
adjusted according to the Dinikara equation34: Adjusted DLCO = measured DLCO  / (0.06965 x Hb) 
A 20 % reduction of DLCO can be interpreted as a significant impairment of pretransplant values. It has been 
shown that post transplant DLCO showed lower values in patients receiving toxic lung chemotherapy, with 
maximum effects observed around 100 days after ASCT.30 We expect significantly fewer patients with lung 
specific toxicity measured by DLCO defined as a decrease by at least 20% from baseline value in the BeEAM 
group (4%) compared to the BEAM group (25%).  
Other standardized spirometric parameters as forced expiratory volume in first second (FEV1) and forced vital 
capacity (FVC) seem not to be affected 3 months after ASCT. On the other hand, impaired lung function has 
been predictive for IPS after SCT and is recommended as a pre-transplant control in many centers and a 
parameter for the hematopoietic cell transplantation comorbidity index (HCTCI). Therefore, we will perform FEV1 
and FVC before ASCT as well as 3 and 12 months after ASCT to demonstrate possible differences in the 
decline of pulmonary function in BeEAM versus BEAM treated patients.  
Additionally, VBGA,spiroergometry as well as cardiac assessments (ECHO and ECG) will be performed before 
(baseline) as well as 3 months and 12 months after ASCT to evaluate the functional cardio-pulmonary status of 
the patients before and after ASCT. 
3.5 Dose Rationale for Bendamustine in the BeEAM regimen
 
Visani et al have reported their experience with the BeEAM regimen thereby replacing BCNU with 
Bendamustine. They have used bendamustine at 200mg/m2 on days -7 and -6 before ASCT. In this study we 
use this (same) bendamustine dosage given the promising experience both for efficacy and tolerance with this 
dosage. 
3.6 Explanation for choice of comparator (or placebo) 
 
Based on our clinical experience using the BeEAM regimen as well as on the report of Visani et al, a 
randomized clinical trial comparing the standard conditioning regimen (BEAM) with the experimental BeEAM 
regimen appears a clinical need to demonstrate non-inferiority of the BeEAM regimen as well as better 
pulmonary tolerance.  
3.7 Risks / Benefits  
Routinely performed high-dose chemotherapy with ASCT is associated with significant side effects requiring 
detailed information of the patient. Usually, it is associated with a hospitalization of at least 3 weeks. A particular 
side effect of the commonly used BEAM chemotherapy regimen is its (early or late occurring) pulmonary toxicity. 
It is usually caused by the chemotherapy component BCNU. In this study, we investigate whether the use of 
Bendamustine instead of BCNU might decrease the rate of pulmonary toxicity observed after BEAM 
conditioning. 
Bendamustine might affect the duration until hematologic recovery, which has to be carefully monitored during 
the study. Bendamustine might increase or cause other organ dysfunction or toxicities, and therefore, such 
observations will have to be comprehensively collected and reported in this study. 
No competing trials are currently reported. 
3.8 Justification of choice of study population 
 
This study does not involve vulnerable participants (e.g. minors, adolescents, participants incapable of 
judgement or participants under tutelage, emergency treatment of unconscious patients or others). The age 
limits are between 18 and 75 years.  


 
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4. STUDY OBJECTIVES  
4.1 Overall Objective  
This study aims to demonstrate that replacing the chemotherapeutic drug BCNU by Bendamustine within the 
four-drug chemotherapy regimen BEAM reduces the occurrence of early and late pulmonary toxicity in 
lymphoma patients undergoing high-dose chemotherapy with autologous stem cell transplantation. 
4.2 Primary Objective  
This study intends to show a clinically meaningful reduction of lung toxicity - defined as a decrease of the 
diffusion capacity of the lung for carbon monoxide (DLCO) by 20% or more from baseline before ASCT - from 
25% of patients in the BEAM group to 4% of patients in the BeEAM group at 3 months after ASCT. Use 
Dinakara equation for adjusting DLCO for hemoglobin 34 . Adjusted DLCO = measured DLCO  / (0.06965 x Hb) 
4.3 Secondary Objectives  
This study intends  
 
to assess acute and late toxicity/adverse events (CTCAE 4.0) during the entire study period 
 
to assess the hematologic recovery and engraftment after 3 months 
 
to assess early and late lung toxicity by pulmonary function tests, spiroergometry, DLCO, HRCT and 
venous BGA performed before ASCT, 3 and 12 months after ASCT.  
 
to perform cardiac assessment by ECHO/ECG before, 3 and 12 months after ASCT 
 
to assess the quality of life prior to ASCT, 3 and 12 months thereafter.  
 
to assess overall survival and progression free survival after 12 months and then yearly as routine 
follow-up assessments. 
4.4 Safety Objectives  
The study aims to assess early- and long-term pulmonary and cardiac toxicity of the new regimen replacing the 
chemotherapeutic compound BCNU by Bendamustine within the polychemotherapy BEAM regimen as 
compared to the standard BEAM regimen in lymphoma patients undergoing high-dose chemotherapy with 
autologous stem cell transplantation. Any other acute or late adverse event will be recorded in the CRFs. 
5. STUDY OUTCOMES  
5.1 Primary Outcome  
A clinically meaningful reduction of lung toxicity is defined as a reduction of the DLCO by at least 20% from 
baseline before ASCT. 
5.2 Secondary Outcomes  
Acute and late toxicity/adverse events are assessed according to the CTCAE 4.0 during the entire study period. 
Hematologic engraftment after ASCT is defined as the first day of neutrophils rising above 0.5 G/l, and of 
platelets rising above 20 G/L in the absence of platelet transfusions in the previous 3 days. 
Overall survival is defined as the time from ASCT until death of any cause or date of last follow-up. 
Progression free survival is defined as the time from ASCT until first recurrence of lymphoma or date of last 
follow-up whatever occurs first. 
5.3 Other O utcomes of Interest  
Not applicable 
5.4 Safety Outcomes  
This study intends to assess cardiac and pulmonary toxicities associated with high-dose chemotherapy before 
autologous stem cell transplantation. Patients will be screened for the occurrence of such toxicities by 
pulmonary and cardiac assessments at specified time points during the study protocol. 


 
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6. STUDY DESIGN  
6.1 General study design and justification of design 
 
A schematic diagram of trial design, procedures and stages 
 
 
This is a randomized parallel open-label prospective phase II trial investigating chemosensitive lymphoma 
patients in first or second remission considered clinically fit to undergo high-dose chemotherapy with autologous 
stem cell transplantation. Lymphoma types include mantle cell lymphoma, diffuse large B-cell lymphoma or 
follicular lymphoma.  
Two high-dose chemotherapy regimens (BeEAM versus BEAM) used for conditioning treatment before 
autologous stem cell transplantation will be compared in a 1:1 randomization (see trial diagram above). The 
experimental arm is the BeEAM regimen. The BEAM regimen is the control treatment. Both regimens use the 
three drugs etoposide, cytarabine and melphalan at identical doses and at identical days. The only difference is 
the replacement of the standard drug BCNU (carmustine; given in the BEAM group at day -6) by the 
experimental drug bendamustine (given in the BeEAM group at days -7 and -6).  
Lung toxicity will be assessed by spiroergometry, as well as by assessing the diffusion capacity of the lung for 
carbon monoxide (DLCO) and venous BGA. This analysis will be performed before ASCT, as well as 3 months 
and 12 months after ASCT. 
BeEAM chemotherapy regimen consisting of Bendamustine intravenously on days −7 and −6 at 200 mg/m2; 
cytarabine, 400 mg/m2 intravenously daily from day −5 to day−2; etoposide, 200 mg/m2 intravenously daily from 
day −5 to day −2; and melphalan, 140 mg/m2 intravenously on day −1 before reinfusion of autologous stem cells 
will be compared with the standard BEAM regimen with carmustine 300 mg/m2 on day -6, followed by the EAM 
regimen as described above, in a randomized phase II trial. Toxicity and efficacy will be compared. 
There will be 49 evaluable patients needed in each group to show a clinically meaningful reduction of events 
(lung toxicity defined as a reduction of the DLCO by at least 20% from baseline vaule), i.e. from 25% of patients in 
the BEAM group to 4% of patients in the BeEAM group, at three months. Thus, a total of 108 evaluable patients 
are needed. Expecting a rate of ineligible patients of 10%, a total of 108 patients is needed, with 54 patients in 
each of the two arms. 
The anticipated study duration will be 36 months. 
Patients will be assessed for cardio-pulmonary toxicity before ASCT, as well as 3 and 12 months after ASCT. 
Thereafter, patient follow-up will be performed clinically once per year. 
6.2 Methods of minimising bias 
 
This is a 1:1 randomized parallel open-label prospective phase II trial investigating chemosensitive lymphoma 
patients in first or second remission considered clinically fit to undergo high-dose chemotherapy with autologous 
stem cell transplantation. Patients will be stratified for lymphoma subtypes. 
 
 
Bendamustine 
200 mg/m
2 d -7, -6 
or BCNU 
300 mg/m
2
 d -6 
Cytarabine  
400 mg/m
2
 d -5 to -2 
Etoposide       
200 mg/m
2
 d -5 to -2 
Melphalan       
140 mg/m
2
 d -1 
Lymphoma 
patients  
n = 98 


 
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6.2.1 
Randomisation  
Randomisation is centrally performed in this trial by the “Institut für Med. Informatik, Statistik und 
Dokumentation; Medizinische Universität Graz; Auenbruggerplatz 2; 8036 Graz; phone: +43/316/385-4261; fax: 
+43/316/385-3590; E-Mail: andrea.berghold@medunigraz.at)“. The web-based randomization software 
(„Randomizer for Clinical Trials“, www.randomizer.at) will be applied. Patients can be registered 24 h / 7 days. 
6.2.2 
Blinding procedures 
 
Not applicable; this is an open-label trial. 
6.2.3 
Other methods of minimising bias 
 
Not applicable 
6.3 Unblinding Procedures (Code break) 
 
Not applicable; this is an open-label trial. 
 
 


 
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7. STUDY POPULATION  
7.1 Eligibility criteria 
 
Participants fulfilling all of the following inclusion criteria are eligible for the study: 
 
Informed Consent as documented by signature (Appendix Informed Consent Form) 
 
Chemosensitive diffuse large B-cell lymphomas (DLBCL), follicular lymphomas (FL), and mantle cell 
lymphomas (MCL) in first or second remission 
 
Aged between 18 years and 75 years 
 
Neutrophils ≥ 1000/μl; Platelets ≥ 100 x 109/L 
The presence of any one of the following exclusion criteria will lead to exclusion of the participant: 
 
Acute uncontrolled  infection  
 
Other clinically significant concomitant disease states (e.g., renal failure, hepatic dysfunction, 
cardiovascular disease, etc.) excluding a treatment according to this protocol  
 
HCTCI > 5 (Use Dinikara equation for adjusting DLco for hemoglobin) 
 
Concurrent malignant disease with the exception of basalioma/spinalioma of the skin or early-stage 
cervix carcinoma, or early-stage prostate cancer. Previous treatment for other malignancies (not listed 
above) must have been terminated at least 24 months before registration and no evidence of active 
disease must be documented since then. 
 
Known or suspected non-compliance excluding participation to the treatment as outlined in this protocol  
 
Inability to follow the procedures of the study, e.g. due to language problems, psychological disorders, 
dementia, etc. of the participant, 
 
Major coagulopathy or bleeding disorder  
 
Major surgery less than 30 days before start of treatment  
 
Contraindications to the class of drugs under study, known hypersensitivity or allergy to class of drugs 
or the investigational product 
 
Women who are pregnant or breast feeding; Women with the intention to become pregnant during the 
course of the study,  
 
Lack of safe contraception, defined as: Female participants of childbearing potential, not using and not 
willing to continue using a medically reliable method of contraception for the entire study duration, such 
as oral, injectable, or implantable contraceptives, or intrauterine contraceptive devices, or who are not 
using any other method considered sufficiently reliable by the investigator in individual cases. Female 
participants who are surgically sterilised / hysterectomised or post-menopausal for longer than 2 years 
are not considered as being of child bearing potential. 
 
Participation in another study with investigational drug within the 30 days preceding and during the 
present study, 
 
Previous enrolment into the current study, 
 
Enrolment of the investigator, his/her family members, employees and other dependent persons. 
7.2 Recruitment and s creening  
Participants are recruited to this study by screening lymphoma patients routinely referred to one of the study 
centres for autologous stem cell transplantations. No specific advertisement for this study is performed. 
Screening procedure is outlined in section 9.3.1. No payment or compensation is given to study participants. 
7.3 Assignment to study groups 
 
Randomization is centrally performed in this trial by the Institut für Med. Informatik, Statistik und Dokumentation; 
Medizinische Universität Graz; Auenbruggerplatz 2; 8036 Graz; phone: +43/316/385-4261; fax: +43/316/385-
3590; E-Mail: andrea.berghold@medunigraz.at. The web-based randomization software („Randomizer for 
Clinical Trials“, www.randomizer.at) will be applied. Patients can be registered 24 h / 7 days. 
Stratification is performed for lymphoma subtypes. If an already registered patient is later found not to 
completely fulfill the inclusion/exclusion criterias, he/she will be documented on the enrollment-log at the centre. 
The exclusion of this patient will be reported to the coordinating investigator and to the sponsor. The patient will 


 
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not be included in the final analysis, and his/her patient number will not be replaced by another patient. 
7.4 Criteria for withdrawal / discontinuation of participants 
 
 
withdrawal of informed consent by the participant 
 
lack of compliance of the participant to follow the study procedures  
 
relevant protocol violation 
 
lost to follow up 
 
Unacceptable toxicity or death 
Any participant has the right to withdraw the consent to participation in this trial at any time. Details of the time 
and the circumstances of the withdrawal have to be recorded in the patient charts and in the CRFs. The treating 
physician can withdraw the patient from the study if considered necessary. Again, the time and the 
circumstances of the withdrawal have to be recorded in the patient charts and in the CRFs. Patients withdrawn 
from this protocol are documented for a total of 12 months. All patients terminating study treatment before 12 
months will be analyzed until the last documented follow-up. 
 
 
 


 
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8. STUDY INTERVENTION  
8.1 Identity of Investigational Prod
ucts (treatment )  
Two high-dose chemotherapy regimens (BeEAM versus BEAM) used for conditioning treatment before 
autologous stem cell transplantation will be compared in a 1:1 randomization. The experimental arm is the 
BeEAM regimen. The BEAM regimen is the control treatment. Both regimens use the three drugs etoposide, 
cytarabine and melphalan at identical doses and at identical days. The only difference is the replacement of the 
standard drug BCNU (carmustin; given in the BEAM group at day -6) by the experimental drug Bendamustine 
(given in the BeEAM group at days -7 and -6).  
Lung toxicity will be assessed by spiroergometry, as well as by assessing the diffusion capacity of the lung for 
carbon monoxide (DLCO) and venous BGA. This analysis will be performed before ASCT, as well as 3 months 
and 12 months after ASCT. 
 
BeEAM chemotherapy regimen consisting of Bendamustine intravenously on days −7 and −6 at 200 mg/m2; 
Cytarabine, 400 mg/m2 intravenously daily from day −5 to day−2; Etoposide, 200 mg/m2 intravenously daily from 
day −5 to day −2; and Melphalan, 140 mg/m2 intravenously on day −1 before reinfusion of autologous stem cells 
will be compared with the standard BEAM regimen with Carmustine 300 mg/m2 on day -6, followed by the EAM 
regimen as described above, in a randomized phase II trial. Toxicity and efficacy will be compared. 
 
8.1.1 
Experimental Interven tion (treatment ) 
Investigational arm: 
 
 
BeEAM 
Bendamustine  
 
 
200mg/m2 
 
days -7 and -6 
Etoposide 
 
 
 
200mg/m2  
 
days -5, -4, -3, -2 
Cytarabine 
 
 
 
400mg/m2  
 
days -5, -4, -3, -2 
Melphalan 
 
 
 
140mg/m2 
 
day -1 
 
8.1.2 
Control Intervention (standard
 treatment)  
Standard arm:  
 
 
BEAM 
BCNU  
 
 
 
300mg/m2 
 
day -6 
Etoposide 
 
 
 
200mg/m2 
 
days -5, -4, -3, -2 
Cytarabine 
 
 
 
400mg/m2  
 
days -5, -4, -3, -2 
Melphalan 
 
 
 
140mg/m2 
 
day -1 
 
8.1.3 
Packaging, Labelling and Supply (re
-supply)  
Bendamustine will be provided in single brown glass vials containing 25 mg or 100 mg of bendamustine 
hydrochloride (HCl) powder. 
Labeling of bendamustine is performed by the manufacturer in accordance to GMP and the local regulatory 
requirements.  
Each vial will be affixed with a label describing the protocol number, patient number, content of each vial, 
dosage form, and route of administration, lot number, expiration date, storage conditions, and the Sponsor’s 
name. 
Packaging and shipping will be according to the manufacturer’s standards and local regulations. 
Upon receipt of bendamustine by the study site/ pharmacy personnel should check for damage and verify 
proper quantity, identity, and integrity. Any complaints and deviations from the delivery notes have to be 
reported to the monitor upon discovery. 
Ordering and distribution of Bendamustine to the study sites will be performed country-specific.  
Switzerland: Mundipharma Medical Company will receive orderings for bendamustine study medication via a 
specific fax ordering form. Distribution of bendamustine will be performed by Alloga Switzerland to the pharmacy 
of Swiss study sites. 
For each Swiss study site, a stock of study medication will be provided in advance which has to be replenished 


 
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by fax-order sent to Mundipharma Medical Company (Switzerland). 
Appropriate fax ordering forms and fax numbers are provided in the Investigator Study File. 
Austria: Mundipharma GmbH (Austria) will be responsible for providing study medication directly to the 
pharmacy of the study sites.  
Note: Drug supply has to be ordered by fax for each patient prior to treatment start.  
Appropriate fax ordering forms and fax numbers are provided in the Investigator Study File. 
Commercial products will be used for the comparator BCNU as well as for the EAM regimen.  
8.1.4 
Storage Conditions  
Storage of Investigational Product: The investigational product will be stored at < 25°C and protected from light 
in a secure location accessible only by authorized personnel. All drug supplies are to be used only for this 
protocol and not for any other purpose. 
8.2 Administration of experimental and control interventions 
 
8.2.1 
Experimental Intervention 
- high -dose chemotherapy BeEAM (with Bendamustine)
 
Bendamustin: Before administration, bendamustine powder must be dissolved in sterile water for injection and 
then immediately diluted in 500 ml of 0.9% sodium chloride. Once reconstituted, bendamustine is chemically 
and physically stable in conventional polyethylene i.v. bags and infusion sets for 3.5 hours at room temperature 
(25°C/60% relative humidity) or for maximally 2 days under refrigerated conditions (2º-8ºC) and is photostable. 
From a microbiological point of view, the solution should be used immediately. If not used immediately, in-use 
storage times and conditions prior use are the responsibility of the user. Because compatibility studies have not 
been performed, bendamustine should not be combined with other agents or solutions (e.g. glucose). 
Bendamustine dose will be given at a dose of 200mg/m2 at days -7 and -6, and the dose will be calculated 
according to the BSA (body surface area) using the.DuBois Method. No dose capping (e.g. for under-weight or 
over-weight patients) will be performed. The BSA has to be determined only once at screening. Bendamustine 
is administered by i.v. infusion over 120 minutes. An in-line filter is not required for administration. 
As bendamustine is a mildly to moderately emetogenic drug, premedication with antiemetic drugs is advised 
(e.g. a 5-HT3 receptor antagonist). 
Bendamustine is not considered to be a vesicant when diluted and administered as recommended. However, if 
bendamustine extravasates during infusion, it might cause some irritation to affected tissues (follow instructions 
of SmPC in case of extravasation). 
Vials are for single use only. Vials used for one subject may not be used for any other subject. 
Partly unused or expired medication can be destroyed by the pharmacy at the study site according to local 
guidelines, but only after monitor's approval. The destruction shall be either documented by completing the drug 
return or the drug destruction log. 
 
Etoposide at a dose of 200mg/m2 will be administered as single i.v. Infusion over 30 minutes at days -5, -4, -3 
and -2 before stem cell re-transfusion. No dose capping (e.g. for under-weight or over-weight patients) will be 
performed. Antiemetics, hydration and supportive care are according to local hospital guidelines. 
 
Cytarabine at a dose of 400mg/m2 will be administered as single i.v. Infusion over 30 minutes at days -5, -4, -3 
and -2 before stem cell re-transfusion. No dose capping (e.g. for under-weight or over-weight patients) will be 
performed. Antiemetics, hydration and supportive care including konjunctival prophylaxis are according to local 
hospital guidelines. 
 
Melphalan at a dose of 140mg/m2 will be administered as single  i.v. Infusion over 60 minutes at day -1 before 
stem cell re-transfusion. No dose capping (e.g. for under-weight or over-weight patients) will be performed. 
Antiemetics, extensive hydration, control of renal function and supportive care are according to local hospital 
guidelines. 
8.2.2 
Control Intervention
 - high -dose chemotherapy BEAM (with BCNU)
 
BCNU at a dose of 300mg/m2 will be administered as a single i.v. Infusion over 120 minutes at day -6 before 
stem cell re-transfusion. No dose capping (e.g. for under-weight or over-weight patients) will be performed. 
Antiemetics, hydration and supportive care are according to local hospital guidelines. The prophylactic 
administration before BCNU infusion of an antihistamin (e.g. clemastin 2mg i.v.), of steroids (solumedrol 125mg 
i.v.) and of akineton (1mg-2.5mg i.v. depending on body weight) is recommended or according to local hospital 


 
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guidelines.  
 
Etoposide at a dose of 200mg/m2 will be administered as single i.v. Infusion over 30 minutes at days -5, -4, -3 
and -2 before stem cell re-transfusion. No dose capping (e.g. for under-weight or over-weight patients) will be 
performed. Antiemetics, hydration and supportive care are according to local hospital guidelines. 
 
Cytarabine at a dose of 400mg/m2 will be administered as single i.v. Infusion over 30 minutes at days -5, -4, -3 
and -2 before stem cell re-transfusion. No dose capping (e.g. for under-weight or over-weight patients) will be 
performed. Antiemetics, hydration and supportive care including konjunctival prophylaxis are according to local 
hospital guidelines. 
 
Melphalan at a dose of 140mg/m2 will be administered as single i.v. Infusion over 60 minutes at day -1 before 
stem cell re-transfusion. No dose capping (e.g. for under-weight or over-weight patients) will be performed. 
Antiemetics, extensive hydration, control of renal function and supportive care are according to local hospital 
guidelines. 
8.3 Dose modifications   
No discontinuation of (one or several) study compounds or dose modification of the allocated interventions is 
allowed by this protocol for a given trial participant. Dosing of study treatment in obese patients (body mass 
index BMI > 35) is recommended to be adapted as follows: ad half of the overweight to normal weight (height in 
cm minus 100; eg. height 170 cm then normal weight is 70 kg) and adjust treatment dose for that. 
8.4 Compliance with study intervention 
 
According to the intention-to-treat principle, non-compliant patients will not be excluded from the analysis. Non-
compliant patients will be documented for a total of 60 months. 
 All patients terminating study treatment before 12 months will be analyzed until the last documented follow-up. 
8.5 Data Collection and Follow
-up for withdrawn participants 
 
Any participant has the right to withdraw the consent to participation in this trail at any time. Details of the time 
and the circumstances of the withdrawal have to be registered in the patient charts and in the CRFs. The 
treating physician can withdraw the patient from the study treatment if considered necessary. Again, the time 
and the circumstances of the withdrawal have to be registered in the patient charts and in the CRFs. Patients 
withdrawn from this protocol are documented for a total of 12 months. All patients terminating study treatment 
before 12 months will be analyzed until the last documented follow-up. 
 
If patients withdraw their consent to this study, their study data will be anonymized after completion of the study 
analysis. 
8.6 Trial specific preventive measures
 
Not included in this trial will be female participants of childbearing potential, which are not using and not willing 
to continue using a medically reliable method of contraception for the entire study duration, such as oral, 
injectable, or implantable contraceptives, or intrauterine contraceptive devices, or who are not using any other 
method considered sufficiently reliable by the investigator in individual cases. Female participants who are 
surgically sterilised / hysterectomised or post-menopausal for longer than 2 years are not considered as being 
of child bearing potential. 
Men should not father a chilld during and up to 12 months after the trial intervention. 
8.7 Concomitant Intervent
ions (treatments)  
No specific recommendations are made excluding specific medication not allowed during study treatment. 
Maintenance treatment after ASCT is allowed within this protocol but has to be documented in medical records 
and case report form 
8.8 Supportive treatment during neutropenia after ASCT
 
 
All patients receive G-CSF (filgrastim) 5 µg/kg b.w. starting at day +6 after ASCT 
 
Platelet infusions are given < 10.000/µl; or in case of fever or coagulopathy if platelets are <20.000 µl  


 
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 
Red cell transfusions if Hb < 8 /dL. Packed RBCs and platelet transfusions should be given to maintain 
a hemoglobin level > 8 g/dL and a platelet count > 10x109/L.  
 
Fungal prophylaxis with 400mg of fluconazole p.o.  ought be given once per week. 
 
Cotrimoxazole prophylaxis three times a week for 3 weeks after ASCT, and Acyclovir prophylaxis twice 
daily 500mg p.o. for three months will be administered to the patients or according to the hospital policy. 
 
Daily clinical assessment and documentation of toxicities exceeding grade 2 during neutropenia. 
8.9 Study Drug Accountability  
The investigational product is Bendamustine. Accordingly, Bendamustine is provided free of charge for all 
patients in this study by the company Mundipharma and all Bendamustine sent to the sites must be accounted 
for. All other components of the polychemotherapy conditioning before ASCT are considered standard of care, 
and they are reimbursed by the insurance of the patients.  
The investigator is responsible for the control of application and handling of the drugs as requested per protocol. 
Adequate records of receipt, administration, storage, destruction or return of the study drugs have to be 
maintained. All logs have to be completed by the study site staff in a timely manner, and thus should be kept 
current. 
All records, logs and study drugs (used and un-used) at the site have to be available for the inspection at any 
time. 
Upon termination of the study, all logs have to be completed and returned to the monitor to be passed to the 
Sponsor. Copies thereof, have to be maintained by the study site. 
8.10 Return or Destruction of Study Drug 
 
Bendamustine Dispensing and Accounting: All Bendamustine sent to the site must be accounted for. In addition, 
the amount (in mg) of Bendamustine dispensed for each patient must be recorded on an Investigational Product 
Accountability Log and the amount (in mg) administered documented on the case report form (CRF). An 
accurate record of the date and amount of Bendamustine dispensed to each patient must be available for 
inspection at any time. Partially used vials may be destroyed per institutional guidelines and documented. All 
unopened and unused vials of Bendamustine will be destroyed upon completion of the study or if drug expires 
unless otherwise directed by the Sponsor. The study site will document all receipt, complete destruction, and 
return (if applicable) of Bendamustine. 
 


 
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9. STUDY ASSESSMENTS  
9.1 Study flow chart  / table of study procedures and assessments
 / Study Schedule  
Study Periods 
 
Screening 
Treatment / Intervention 
Visit 
1 
2 
3 
43 
Time (days) 
-28 to -8 
-7 until dismissal 
80-120 
350-400 
Patient information & informed consent 
x 
 
 
 
Height / weight / BMI 
x 
 
 
 
Medical history 
x 
 
 
 
In- /exclusion criteria 
x 
 
 
 
Physical examination 
x 
x 
x 
x 
HCTCI score 
x 
 
 
 
ECOG score 
x 
x 
x 
x 
Vital Signs 
x 
x 
x 
x 
Hematology (complete blood counts with differential) 
x 
x 
x 
x 
Routine serum biochemistry (according to center policy) 
x 
x 
x 
x 
Pregnancy Test 
x 
 
 
 
Randomization 
x 
 
 
 
ECG 
x 
 
x 
x 
Echocardiography 
x 
 
x 
x 
Pulmonary function (FEV1 & FVC), DLCO1 
x 
 
x 
x 
Spiroergometry  
x 
 
x 
x 
Response (CT, MR or PET) thorax/abdomen 2 4 
x 
 
x 
x 
VBGA 
x 
 
x 
x 
HR-CT chest 
x 
 
x 
x 
QoL (EORTC Q30) 
x 
 
x 
x 
CTCAE 4.0 toxicity score 
 
x 
x 
x 
Engraftment, neutrophil and platelet recovery 
 
x 
 
 
Days until platelets >50 G/L 
 
 
x 
 
Number of CD34+ cells used 
 
x 
 
 
RBC & platelet transfusions 
 
x 
 
 
Days of T>38.0°; number of febrile episodes 
 
x 
x 
 
Administer study medication 
 
x 
 
 
Adverse Events 
 
x 
x 
x 
1Adjusted DLCO = measured DLCO  / (0.06965 x Hb) 
2 The selection of the radiologic assessment is at  the discretion of the center and the treating physician 
3 Patients withdrawn from protocol are documented for a total of 12 months. All patients terminating study 
treatment before 12 months will be analyzed until the last documented follow-up. 
4 once per year after that as routine follow-up assessments. If relapse is suspected, CT, MR or PET-CT 
assessments are recommended. The follow-up is performed at the discretion of the center; if relapse or 
progression of lymphoma is suspected, standard radiological examination has to be performed. 


 
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9.2 Assessments of outcomes 
 
9.2.1 
Assessment of primary outcome 
 
The primary outcome – thus, to show a clinically meaningful reduction of lung toxicity - will be assessed by 
measuring the diffusion capacity of the lung for carbon monoxide (DLCO) at baseline before ASCT, as well as 3 
months and 12 months after ASCT. Since this is an open-label trial, assessment of the primary endpoint cannot 
occur in a blinded manner. 
9.2.2 
Assessment of  secondary outcomes
 
 
To assess acute and late toxicity/adverse events (CTAE 4.0) during the entire study period by clinical 
assessment 
 
To assess the hematologic engraftment after 3 months by determining hemoglobin, leukocyte and 
platelet counts at three months after ASCT 
 
To assess early and late lung toxicity by pulmonary function tests, spiroergometry, DLCO and HRCT and 
venous BGA performed at baseline before ASCT, as well as 3 months and 12 months after ASCT. 
 
To perform cardiac assessment by ECHO/ECG at baseline before ASCT, as well as 3 months and 12 
months after ASCT. 
 
To assess the quality of life assessed at baseline before ASCT, as well as 3 months and 12 months 
after ASCT using the EORTC-Q30 questionnaire. 
 
To assess overall survival and progression free survival after 12 months and then yearly as routine 
follow-up assessments. 
9.2.3 
Assessment of safety outcomes
 
9.2.3.1 
Adverse events  
For AE definition and procedures, see section 10.  
9.2.3.2 
Laboratory parameters 
See Study Schedule 9.1. 
9.2.4 
Assessments in participants who p
rematurely stop the study
 
According to the intention-to-treat principle, non-compliant patients will not be excluded from the analysis. Non-
compliant patients will be documented for a total of 12 months. 
All patients terminating study treatment before 12 months will be analyzed until the last documented follow-up.  
Any participant has the right to withdraw the consent to participation in this trail at any time. Details of the time 
and the circumstances of the withdrawal have to be registered in the patient charts and in the CRFs. The 
treating physician can withdraw the patient from the study treatment if considered necessary. Again, the time 
and the circumstances of the withdrawal have to be registered in the patient charts and in the CRFs. Patients 
withdrawn from this protocol are documented for a total of 12 months. All patients terminating study treatment 
before 12 months will be analyzed until the last documented follow-up. 
If patients withdraw their consent to this study, their study data will be anonymized after completion of the study 
analysis. 
9.3 Procedures at each visit
 
9.3.1 
Screening visit (Day -28 to -8): 
 
Written informed consent  
 
Height and weight 
 
Complete medical history (lymphoma histology and localisation, IPI, date of diagnosis, relapse(s), prior 
treatment(s) ( first and second line) and response before ASCT 
 
Pregnancy test  
 
Physical examination 
 
hematopoietic stem cell transplantation comorbidity score (HCT-CI) 33 (see Appendix 4) 
 
ECOG Score (see Appendix 2), body mass index (BMI),  


 
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 
ECG 
 
Echocardiography 
 
Pulmonary function tests (FEV1 and FVC) and evaluation of DLCO 
 
Spiroergometry  
 
Venous BGA 
 
Hematology (complete blood counts with differential) 
 
Routine serum biochemistry (according to the centres policy) 
 
Disease assessment and CT Staging (or MRI or CT-PET) of abdomen/thorax at discretion of the center 
 
HR-CT chest 
 
QoL (EORTC Q30, Version 3.0) (see Appendix 5) 
All screening procedures should be performed within 4 weeks prior to start of study treatment 
9.3.2 
Assessments during ASCT (Day 
-7 until day of hospital discharge
 
 
Date of ASCT and date of engraftment 
 
Number of CD34+ cells transplanted 
 
Unit number of infused red blood cell (RBC) and platelet transfusions 
 
Time to platelet recovery > 20x  109/L and  > 50x  109/L 
 
Time to recovery of ANC > 0,5x109/L 
 
Number of days of temperature > 38.0° and number of febrile episodes 
 
Duration in days of platelets Plt < 50x  109/L since day of ASCT  
 
Assessment of CTCAE 4.0 highest toxicity score observed during ASCT until dismission from hospital 
(see Appendix 1) 
9.3.3 
Assessments three months after ASCT (Day 80 to 120)
 
 
Physical examination 
 
ECOG Score 
 
ECG 
 
Echocardiography 
 
Pulmonary function tests (FEV1 and FVC) and  evaluation of DLCO 
 
Spiroergometry  
 
Venous BGA 
 
Hematology (complete blood counts with differential) 
 
Routine serum biochemistry (according to the centres policy) 
 
Disease assessment and CT staging (or MRI or CT-PET) of abdomen/thorax at discretion of the center 
 
HR-CT chest 
 
Acute and late toxicity/adverse events (CTCAE 4.0) 
 
Engraftment/best response (at 3 months after ASCT) 
 
QoL (EORTC Q30) 
 
Number of days of temperature > 38.0° C, and number of febrile episodes 
9.3.4 
Assessments after one year (Day 350 to 4
00) 
 
Physical examination  
 
ECOG Score 
 
ECG 
 
Echocardiography 
 
Pulmonary function tests (FEV1 and FVC) and  evaluation of DLCO 
 
Spiroergometry  
 
Venous BGA 


 
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 
Hematology (complete blood counts with differential) 
 
Routine serum biochemistry (according to the center policy) 
 
Disease assessment and CT staging (or MRI or CT-PET) of abdomen/thorax at discretion of the center 
 
HR-CT chest 
 
Acute and late toxicity/adverse events (CTCAE 4.0) 
 
QoL (EORTC Q30) 
 
Any relapse or death or other reason for study discontinuation will be reported as soon as known. The remission 
status will be assessed using the RECIST-Criteria Version 1.1. (see Appendix 3) at three months and 12 
months after ASCT, and once per year after that as routine follow-up assessments. If relapse is suspected, CT, 
MR or PET-CT assessments are recommended. The follow-up is performed at the discretion of the center; if 
relapse or progression of lymphoma is suspected, standard radiological examination has to be performed. 
9.4 Response criteria  
 
See Appendix 3 attached 
 
 
 


 
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10. SAFETY  
10.1 Drug studies  
This is a Category B trial. During of the study, all serious adverse events (SAEs) until d100 after ASCT are 
collected, fully investigated and documented in source documents and case report forms (CRF). Study duration 
encompassed the time from when the participant signs the informed consent until the last protocol-specific 
procedure has been completed, including a safety follow-up period.  
 
Adverse Events have to be reported in case report forms from the time the participant is randomised until 30 
days after ASCT. Serious Adverse Events have to be reported in case report forms from the time the participant 
signs the informed consent until 100 days after ASCT 
 
Adverse Events have to be reported, with the exception of: 
 
A pre-existing condition that does not increase in severity; the pre-existing condition should 
be reported on the baseline concomitant diseases CRF 
 
AEs of CTCAE grade ≤2 
 
Abnormal laboratory values that have been recorded as being not clinically significant by the 
investigator in the source documents 
 
Progression of the disease under study; complications as a result of disease progression 
remain reportable Adverse Events 
 
Alopecia 
 
Nausea/vomiting/loss of appetite 
 
Hematological toxicities 
 
Diarrhoea 
 
Weight loss not exceeding 10% of body weight before HDCT/ASCT 
 
Febrile neutropenia  
 
Other expected AEs during HDCT 
10.1.1 Definition and assessment of (serious) adverse events and other safety related events
 
An Adverse Event (AE) is any untoward medical occurrence in a patient or a clinical investigation participant 
administered a pharmaceutical product and which does not necessarily have a causal relationship with the 
study procedure. An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not related to the medicinal (investigational) product. ICH E6 1.2 
Laboratory test value abnormalities should not be recorded in the AE section of the CRF as AEs unless they are 
considered clinically significant as defined below. Any treatment-emergent abnormal laboratory result that is 
clinically significant should be recorded as a single diagnosis in the AE section of the CRF. Clinical significance 
is defined as meeting one or more of the following conditions: 
• 
Accompanied by clinical symptoms 
• 
Leading to a change in study medication (e.g. dose modification, interruption or permanent 
 
discontinuation) 
• 
Requiring a change in concomitant therapy (e.g. addition of, interruption of, discontinuation of, or any 
 
other change in a concomitant medication, therapy or treatment 
Serious Adverse Event (SAE) is classified as any untoward medical occurrence that: 
 
results in death, 
 
is life-threatening, 
 
requires in-patient hospitalization or prolongation of existing hospitalisation, 
 
results in persistent or significant disability/incapacity, or 
 
is a congenital anomaly/birth defect. 
In addition, important medical events that may not be immediately life-threatening or result in death, or require 
hospitalisation, but may jeopardise the patient or may require intervention to prevent one of the other outcomes 
listed above should also usually be considered serious. ICH E2A 
SAEs should be followed until resolution or stabilisation. Participants with ongoing SAEs at study termination 
(including safety visit) will be further followed up until recovery or until stabilisation of the disease after 
termination.  


 
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Assessment of Causality 
Both Investigator and Sponsor make a causality assessment of the event to the study drug, based on the 
criteria listed in the ICH E2A guidelines: 
Relationship 
Description 
Definitely 
Temporal relationship 
Improvement after dechallenge* 
Recurrence after rechallenge 
(or other proof of drug cause) 
Probably 
Temporal relationship 
Improvement after dechallenge 
No other cause evident 
Possibly 
Temporal relationship 
Other cause possible 
Unlikely 
Any assessable reaction that does not fulfil the above conditions 
Not related 
Causal relationship can be ruled out 
*Improvement after dechallenge only taken into consideration, if applicable to reaction 
 
Unexpected Adverse Drug Reaction 
An “unexpected” adverse drug reaction is an adverse reaction, the nature or severity of which is not consistent 
with the applicable product information (e.g. Investigator’s Brochure for drugs that are not yet approved and 
Product Information for approved drugs, respectively).  
 
Suspected Unexpected Serious Adverse Reactions (SUSARs) 
The Sponsor evaluates any SAE that has been reported regarding seriousness, causality and expectedness. If 
the event is related to the investigational product and is both serious and unexpected, it is classified as a 
SUSAR.  
 
Assessment of Severity 
To document the severity grades, the “Common Terminology Criteria for Adverse Events CTCAE Version 4.0” 
terminology will be used.  
10.1.2 Reporting of serious adverse events (SAE) and other 
safety related events  
All SAEs and other relevant safety related events until d100 after ASCT have to be reported by the local 
investigator immediately to the Prinicipal Investigator and Sponsor within 24h of knowledge. The appropriate 
fax-numbers and email addresses are provided on the SAE-reporting form. 
SAEs of all patients, who received study medication in this trial, have to be reported to the Sponsor until d100 
after ASCT  
Excluded from the reporting are as follows:  
 
All planned surgeries or hospitalizations known at the time of study initiation, 
 
All routinely required hospitalizations for chemo- and radiotherapy as well as for ASCT,  
 
Progression or death due to the underlying malignancy. Hematological toxicities 
 
Expected SAEs during HDCT 
 
10.1.3 Reporting to the manufacturer of bendamustine hydrochloride:
 
The Sponsor will supply Mundipharma (i.e.Mundipharma Research GmbH & Co.KG, Germany, Mundipharma 
Medical Company, Switzerland and Mundipharma Ges. m.b.H., Austria) with  


 
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 A copy of all SAEs until d100 after ASCT within 24 hours of being aware of the event regardless of whether 
or not the event is listed in the reference document (Product Information). 
 A copy of all pregnancy reports within 24 hours of being aware of the event. 
 A copy of all SUSARs within one business at the time of the submission to the regulatory authorities, the 
ECs and investigators  
 A copy of the ASR at the time of the submission to the regulatory authorities and the ECs.  
 
The appropriate and actual fax-numbers and email addresses are provided in the separate Safety Data 
Exchage Agreement (SDEA) agreement with Mundipharma. 
 
10.1.4 Reporting of SAEs  
All SAEs must be reported immediately and within a maximum of 24 hours to the Sponsor and Principal 
Investigator of the study by using the SAE reporting form. The Sponsor and Principal Investigator will re-
evaluate the SAE and return the form to the site.  
 
10.1.5 Reporting of Deaths  
SAEs resulting in death are reported to the local Ethics Committee (via local Investigator) and to AGES (via 
Principal Investigator for Austrian centers) within 7 days.  
The other in the trial involved Ethics Committees receive SAEs resulting in death in Switzerland via Sponsor 
within 7 days. 
 
10.1.6 Reporting of SUSARs  
A SUSAR needs to be reported to the local Ethics Committee (local event via local Investigator) and to 
Swissmedic for category B and C studies (via Sponsor for Swiss centers) and to AGES (via Principal 
Investigator for Austrian centers) within 7 days, if the event is fatal, or within 15 days (all other events). 
This is a multi-centre trial: The Sponsor must inform all investigators participating in the clinical study of the 
occurrence of a SUSAR. All in the trial involved Ethics Committees will be informed about SUSARs in 
Switzerland via Sponsor and in Austria via Principal Investigator according to the local reporting requirements, 
directives and timelines. 
 
10.1.7 Reporting of Safety Signals
 
All suspected new risks and relevant new aspects of known adverse reactions that require safety-related 
measures, i.e. so called safety signals, must be reported to the Sponsor and Principal Investigator within 24 
hours. The Sponsor (for Swiss centers) or the Principal Investigator (for Austrian centers) must report the safety 
signals within 7 days to the local Ethics Committee (local event via local investigator) and to Swissmedic (for 
Swiss centers) as well as to AGES in Austria (for Austrian centers). 
This is a multi-centre trial: The Sponsor must immediately inform all participating investigators about all safety 
signals. The other in the trial involved Ethics Committees will be informed about safety signals in Switzerland via 
the Sponsor and in Austria via the Principal Investigator. 
 
10.1.8 Reporting and Handling of Pregnancies
 
Pregnant participants must immediately be withdrawn from the clinical study. Any pregnancy during the 
treatment phase of the study and within 6 months after discontinuation of study medication will be reported to 
the Sponsor within 24 hours. The course and outcome of the pregnancy should be followed up carefully until 
birth of the child, and any abnormal outcome regarding the mother or the child should be documented and 
reported according to local reporting requirements, directives and timelines. 
 
10.1.9 Periodic reporting of safety
 (ASR) 
The ASR (annual safety report) is submitted once a year to the local Ethics Committee and to Swissmedic via 
the Sponsor and to AGES (via the Principal Investigator for Austrian centers). Since this is a multi-centre trial, 
the annual ASR contains information from all sites including information from sites outside of Switzerland. The 
Sponsor is responsible for the data collection and preparation of the ASR, and submits it to the participating 
Investigators. The participating Investigators submit it to the local Ethics committees.   


 
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10.1.10 Follow up of (Serious) Adverse
 Events  
The follow up of participants terminating the study (either regularly or prematurely) with reported ongoing SAE, 
or any ongoing AEs of laboratory values or of vital signs being beyond the alert will be documented until 
resolution or death of the patient. All adverse events (AE) (until 30 days after ASCT) including all serious 
adverse events (SAE) (until d100 after ASCT) are collected, fully investigated and documented in the source 
document and appropriate case report form (CRF) during the entire study period, i.e. from patient’s informed 
consent until the last protocol-specific procedure, including a safety follow-up period. 
11. STATISTICAL METHODS  
11.1 Hypothesis  
The hypothesis of this study is to show a clinically meaningful reduction of lung toxicity - defined as a reduction 
of the DLCO by at least 20% from baseline value- from 25% of patients in the standard group to 4% of patients in 
the experimental group at 3 months after autologous stem cell transplantation in lymphoma patients. The 
standard group of patients is treated with the BEAM high-dose chemotherapy regimen whereas the 
experimental group is treated with the BeEAM regimen.  
11.2 Determination of Sample Size 
 
This study involves two treatment arms and applies a 1:1 randomization, additionally considering the 
stratification for lymphoma subtypes: diffuse large B-cell lymphoma versus mantle cell lymphoma versus 
follicular lymphoma. No interim analysis is planned, and all calculations will be performed per evaluable patient. 
The primary endpoint is to show a clinically meaningful reduction of events (lung toxicity defined as a reduction 
of the DLCO by at least 20%) at three months, i.e. from 25% of patients in the BEAM group to 4% of patients in 
the BeEAM group. 
Arm A is the experimental arm (BeEAM chemotherapy), and arm B is the standard arm (BEAM chemotherapy). 
The null hypothesis is that the lung toxicity determined at three months is equal in both arms (LT3A = LT3B). The 
aim of the study is to ultimately show less lung toxicity of the experimental (BeEAM) arm, with LT3A < LT3B.  
Based on previous reports, we anticipate observing lung toxicity in the standard (BEAM) arm in 25% (LT3B). Our 
hypothesis is that the experimental (BeEAM) arm will show lung toxicity in only 4% or less of the patients (LT3A), 
thus a difference of at least 20 percentage points. Thus, the superiority margin in the proposed prospective 
randomized study is 0.20, i.e. the reduction of lung toxicity is considered a success compared to the standard 
(BEAM) arm if its lung toxicity rate is more than 20 percentage points better. 
With LT3A and LT3B being the (true) success rates in the BeEAM arm and in the BEAM arm, respectively, the 
hypotheses are: 
     H0: LT BeEAM chemotherapy is > 0.04 when LT BEAM is 25%. 
     H1: LT BeEAM chemotherapy is ≤ 0.04 when LT BEAM is 25%. 
Applying a statistical power of 80% and a two-sided significance level of 5%, 49 evaluable patients will be 
needed in each group to show a clinically meaningful reduction of events (lung toxicity defined as a reduction of 
the DLCO by at least 20%), i.e. from 25% of patients in the BEAM group to 4% of patients in the BeEAM group 
using Fishers Exact Test. Thus, a total of 108 evaluable patients is needed. A drop-out rate of 10% is expected, 
thus 54 patients are supposed to be included in each arm.   
The significance level actually achieved by this design is 0.0497. All statistical analysis for sample size 
calculations were performed using the software package nQuery Advisor 7.0.  
For statistical analysis of this study, continuous endpoints will be summarized using descriptive statistics 
including mean, median, standard deviation, first and third quartiles, minimum and maximum values, and where 
appropriate by graphical techniques (e.g. histogram, box plot). For categorical endpoints, the number and 
percentage of patients in each category will be summarized. Where appropriate, a two-sided 95% confidence 
interval for the proportion will be reported. The primary endpoint in the two groups will be tested using Fishers 
Exact Test. Progression free survival and overall survival will be assessed using Kaplan-Meier plots and log-
rank test. 
11.3 Statistical criteria of termination of trial 
 
Given the existing (own and by others) data on the promising tolerance and efficacy of the experimental 
treatment (BeEAM chemotherapy), no stopping rules or discontinuation criteria are planned in this trial for 
individual participants, for parts of the trial and for the entire trial. 


 
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11.4 Planned Analyses  
All analyses will be performed per patient treated. All other statistical testing will be two-tailed at the 5% level of 
significance. 
The final analysis of the study will be initiated 12 months after inclusion of the last study patient. No subgroup 
analysis is planned. No interim analysis is planned.  
Safety analysis will be performed at the end of the study. No data safety monitoring board is planned in this 
study. 
Analysis of demographics and baseline characteristics: Continuous measurements (e.g. age) will be 
summarised using n, mean, standard deviation (SD), median, minimum and maximum while discrete 
measurements (e.g. sex) will be summarised using frequency counts and percentages. No formal statistical 
testing will be performed on these data. 
Randomization is centrally performed in this trial by the Institut für Med. Informatik, Statistik und Dokumentation; 
Medizinische Universität Graz; Auenbruggerplatz 2; 8036 Graz; phone: +43/316/385-4261; fax: +43/316/385-
3590; E-Mail: andrea.berghold@medunigraz.at. The web-based randomization software („Randomizer for 
Clinical Trials“, www.randomizer.at) will be applied. Patients can be registered 24 h / 7 days. 
11.4.1 Datasets to be analysed, analysis
 populations  
All patients randomised to treatment who have taken at least one dose of study medication will be considered 
evaluable and will be included in the evaluation of safety. 
Three populations will be defined:  
(1) The intention to treat (ITT) population. The ITT set includes all randomized patients in the groups to which 
they were randomly assigned, regardless of their adherence with the entry criteria, regardless of the treatment 
they actually received, and regardless of subsequent withdrawal from treatment or deviation from the protocol. 
The evaluation of efficacy will be based on the intention to treat (ITT) population.  
(2) The per protocol (PP) population. The PP set includes all patients who fulfil the protocol in the terms of the 
eligibility, interventions, and outcome assessment. The PP set will be used for assessing sensitivity. 
(3) All patients randomized to treatment who have taken at least one dose of study medication will be 
considered evaluable and will be included in the safety population for the evaluation of safety data. 
The evaluation of efficacy will be based on two analysis sets, the full analysis (intent-to-treat) set and the per 
protocol set. The full analysis set is the primary population and will be those patients in the safety population 
who satisfy all inclusion criteria and who have efficacy data for the primary parameter recorded for baseline and 
at least one post baseline period assessment. The per protocol set will be those patients in the full analysis set 
who have no major protocol violations. 
11.4.2 Primary Analysis  
This is a superiority trial. Specifically, a clinically meaningful reduction of lung toxicity - defined as a reduction of 
the DLCO by at least 20% from baseline value- from 25% of patients in the standard group to 4% of patients is 
anticipated in the experimental BeEAM group as compared to the standard BEAM group at 3 months after 
autologous stem cell transplantation.The primary endpoint DCLO at baseline and three months will be compared 
using Fishers Exact Test. 
11.4.3 Secondary Analyses  
For the description of quantitative variables, median and mean values will be used as well as standard 
deviations, minimum and maximum values. For qualitative variables such as hematologic recovery and 
engraftment after three months, percentages and absolute frequency will be indicated.  
Early and late lung toxicity by pulmonary function tests, spiroergometry, DLCO, venous BGA and HRCT, cardiac 
assessment by ECHO/ECG and quality of life assessment performed before ASCT, 3 and 12 months after 
ASCT as well as response rates (CR; PR) at three and 12 months will be compared using Fishers Exact Test 
tests. Survival rates (OS; PFS) after 12 months.  
11.4.4 Interim analyses  
No interim analysis planned. 
11.4.5 Safety analysis  
Acute and late toxicities will be graded and described using the highest grade observed.   


 
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11.4.6 Deviation(s) from the original statistical plan 
 
No major deviation(s) from the original statistical plan are to be expected. 
11.5 Handling of missing data and drop
-outs  
A drop-out rate of 10% is expected, thus 54 patients are supposed to be included in each of the two treatment 
arms.   
12. QUALITY ASSURANCE AN D CONTROL  
The following procedures guarantee quality of trial conduct: 
 
Reviews of protocol and forms according to standard operating procedures 
 
Paper data forms will be entered into a database at the site of Prim. Univ. Prof. Dr. Felix Keil; Hanusch 
Krankenhaus der Wiener Gebietskrankenkasse; 3. Medizinische Abteilung; Heinrich Collin-Straße 30; 
1140 Wien  
 
Computerized and manual consistency checks will be performed. 
 
Data review by the primary local investigatoror a delegated person (all forms will be reviewed and 
checked on medical content) 
 
Safety monitoring 
 
Validation of database and statistical analysis 
 
Accountability of study drugs 
 
Requirements for potential sub-investigators for participation: signed and dated CV. 
12.1 Data handling and record keeping / archiving 
 
Source data are kept available for auditing and monitoring by the Sponsor or Sponsor delegates or  competent 
authorities. 
12.1.1 Case Report Forms  
Study data will be recorded on paper case report forms (p-CRF). For each enrolled study participant a CRF is 
maintained. CRFs will be kept current to reflect subject status at each phase during the course of study. 
Participants will not be identified in the CRF by name or initials and birth date. Appropriate coded identification, 
e.g. participant number will be used (e.g. combination of initials and year of birth). 
A defined study nurse will be identified to be authorized to perform CRF entries, and it will be assured that any 
authorized person can be identified.  
12.1.2 Specification of source documents 
 
Source data will be available at the site to document the existence of the study participants. Source data will 
include the original documents relating to the study, as well as the medical treatment and medical history of the 
participant. 
12.1.3 Record keeping / archiving 
 
All study data will be archived in the center for a minimum of 10 years after study termination or premature 
termination of the clinical trial. The investigator will retain copies of the patient trial records (CRFs, patient 
informed consent statement, laboratory printouts, drug transportation and destruction forms, and all other 
information collected during the trial) and documentation until at least 10 years after the termination of the trial. 
In the event that the investigator retires or changes employment, custody of the records may be transferred to 
another suitable person who will accept responsibility for those records. Notice of such transfer will be given in 
written to the EC. 
12.2 Data management  
12.2.1 Data Management System   
Study data will be recorded on paper case report forms (p-CRF). For each enrolled study participant a CRF is 
maintained. CRFs will be kept current to reflect subject status at each phase during the course of study. 
Participants will not be identified in the CRF by name or initials and birth date. Appropriate coded identification, 


 
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e.g. participant number will be used (e.g. combination of initials and year of birth). 
12.2.2 Data security,  access and back -up  
It is planned to use Excel-Database to enter data collected via p-CRF. Access to database information will be 
restricted to sponsor, to data management team and to responsible statistician Prof. Berghold. Changes to 
database entries as well as user information will be documented using audit trial function of Excel-Database. 
Backup-files will be made after each data entry session. Data entries will only be made by authorized personnel 
of data management team. Patient data are entered anonymously using unique patient identification number 
and not using full name or complete date of  birth. Key (patient identification log) to get information about patient 
identity is only available at treatment site of patient. The key will not be available to sponsor (with exception of 
patient data from site of sponsor) and  third parties. 
12.2.3 Analysis and archiving
 
All study data will be archived in the center for a minimum of 10 years after study termination or premature 
termination of the clinical trial. The investigator will retain copies of the patient trial records (CRFs, patient 
informed consent statement, laboratory printouts, drug transportation and destruction forms, and all other 
information collected during the trial) and other relevant documentation (protocol, contracts etc.) until at least 10 
years after the termination of the trial. In the event that the investigator retires or changes employment, custody 
of the records may be transferred to another suitable person who will accept responsibility for those records. 
Notice of such transfer will be given in written to the Sponsor and CEC. 
12.2.4 Electronic and central data validation 
 
Computerized and manual consistency checks will be performed. 
12.3 Monitoring  
The clinical trial unit (CTU) in Berne will perform monitoring of this trial in Switzerland and Mag. Dr. Judith 
Schuster will be responsible for monitoring in Austria. The monitors will be allowed to inspect the various 
records of the trial in accordance with local requirements. The monitor will maintain patient confidentiality. 
Source data verification of the following data will be performed for every patient: 
· 
Informed consent 
· 
Inclusion/exclusion criteria 
· 
Serious Adverse Events (SAE) 
· 
Primary endpoint 
· 
Accountability of study drugs 
12.4 Audits and Inspections 
 
Regulatory authorities and delegates of the local Ethic Committees have the right to perform inspections and to 
verify original data. The investigators are obliged to actively participate during an audit or inspection. They have 
to ensure that all required source data and collected patient data are made available during an audit or 
inspection and that adequate facilities are provided for the audit or inspection. Access to source data verification 
has to be provided within a reasonable peiod of time, In case of an announcement of an inspection, the 
investigator has to inform the Sponsor promptly.   
12.5 Confidentiality, Data Protection 
 
The investigator affirms and upholds the principle of the participant's right to privacy and that they shall comply 
with applicable privacy laws. 
 All patients will be informed as to the strict confidentiality of their patient data, which will not be handed over to 
non-authorized third parties. However, they will also be informed and have given written informed consent that 
their medical records (anonymised data) may be reviewed for trial, scientific or monitoring purposes by 
authorized individuals other than their treating physicians. 
12.6 Storage of biological material and related health data 
 
No samples are stored in this study, and no biobank will be involved in this study.  


 
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13. PUBLICATION AND DISS EMINATION POLICY  
Sponsor and Principal/Coordinating Investigator will commonly publish the data of the trial in a peer-reviewed 
journal within 12 months after study completion, All study data collected will be kept confidential by all 
investigators prior to publication.  Release of any abstract, manuscript or presentation will be shared and 
discussed between the Sponsor-, Principal/Coordinating Investigator and Co-investigators. The companies 
supplying the study medications have the right to review manuscripts and abstracts prior to submission for 
publication as defined in the separate agreements. 
The Sponsor agrees to inform the companies supplying the study medication about any impending publication 
and release of any abstract, relating to the outcome of the trial. Without prejudice to the Sponsor’s autonomy in 
respect to the publication of the results of the trial, the Sponsor agrees to provide to the companies the 
proposed manuscript in advance at least thirty and abstracts at least fourteen days before. The Supplier may 
propose changes to the text up to twenty-eight days from receipt of the manuscript and up to twelve days from 
receipt of the abstract. The Sponsor shall respond in good faith to any reasonable and justified requested 
revisions of the manuscript, always provided that Sponsor shall have the final say in deciding on the contents 
and wording of the text. The Sponsor shall give appropriate acknowledgement to the Supplier’s or its Associates 
employees, if applicable, in the publication. 
14. FUNDING AND SUPPORT  
14.1 Funding  
This study is supported in Switzerland by grants from the „Gemeinnützige Stiftung Empiris“ in Zürich and a grant 
from the company Mundipharma Medical Company. Bendamustine hydrochloride is provided free of charge by 
the company Munidpharma Medical Company in Switzerland and Mundipharma Ges. m.b.H. in Austria.  
14.2 Other Support  
No other support is available for this study. 
15. INSURANCE  
The Inselspital Berne is sponsor of this study. The insurance for patients in Switzerland will be provided by the 
Sponsor, and a separate insurance solution is defined for the Austrian centers. A copy of the certificate is filed in 
each investigator site file and the trial master file. 
 
 


 
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16. APPENDICES 
16.1 Appendix 1: Toxizitätskriterien nach CTCAE 4.0 
 
 
CTC adverse events version v4.0 : http://ctep.cancer.gov/reporting/ctcnew.html 
Adverse event/ 
Toxizitäts -Grad 
1 gering –  
Leicht  
2 
mäßig 
– 
deutlich  
3 stark – 
ausgeprägt  
4 lebensbedrohlich  
Neutropenie  
< LLN – 1500/mm³ < 1500 – 1000/mm³ 
< 
1000 
– 
500/mm³ 
< 500/mm³ 
Thrombopenie  
< 
LLN 
– 
75.000/mm³ 
< 
75.000 
– 
50.000/mm³ 
< 
50.000 
– 
25.000/mm³ 
< 25.000/mm³ 
Anämie  
Hb < LLN –  
10.0 g/dl 
Hb 10.0 – 8.0 g/dl 
Hb 8.0 – 6.5 g/dl  
Hb < 6.5 g/dl 
Nausea 
Appetitsverlust 
ohne 
Veränderung der 
normalen 
Essgewohnheiten 
Nahrungsaufnahme 
etwas vermindert- , 
Kein 
Gewichtsverlust 
Unzureichende 
orale 
Kalorien 
bzw. 
Flüssigkeitszufuhr
; i.v. Flüssigkeits- 
zufuhr, 
parenterale 
Ernährung > 24h 
Lebensbedrohliche 
Konsequenzen 
Erbrechen  
1 Episode in 24 h 
2 – 5 Episoden in 24 
h; 
i.v. 
Flüssigkeitszufuhr < 
24 h 
6 
oder 
mehr 
Episoden in 24 h; 
i.v. 
Flüssigkeits- 
zufuhr 
bzw. 
parenterale 
Ernährung > 24 h  
Lebensbedrohliche 
Konsequenzen 
Diarrh oe  
Anstieg auf < 4 
Stühle pro Tag 
über baseline 
Anstieg 
auf 
4-6 
Stühle pro Tag über 
baseline; 
i.v. 
Flüssigkeitszufuhr < 
24 h; beeinträchtigt 
Alltagsaktivitäten 
nicht 
Anstieg 
über 
7 
Stühle pro Tag 
über baseline; i.v. 
Flüssigkeitszufuhr 
> 24 h; stationäre 
Aufnahme; 
beeinträchtigt 
Alltagsaktivitäten 
Lebensbedrohliche 
Konsequenzen 
d. 
Diarrhoe 
Fatigue  
Leichte 
Fatigue; 
stärker 
als 
bei 
baseline 
Mäßige 
Fatigue; 
beeinflusst 
Ausübung 
einiger 
Aktivitäten 
Schwere Fatigue; 
Alltagsaktivitäten 
beeinträchtigt 
Inaktivierend  
Mukositis  
klin. 
Untersuchung  
Erythem 
der 
Schleimhaut 
Nicht konfluierende 
Ulzerationen 
od. 
Pseudomembranen 
Konfluierende 
Ulzerationen 
od. 
Pseudomembran
en; Blutung bei 
Minimaltrauma  
Gewebsnekrose; 
signifikante 
spontane 
Blutung; 
lebensbedrohliche 
Konsequenzen 
Neuropathie 
Sensorisch  
Abgeschwächte 
Sehnenreflexe 
oder 
Parästhesien; 
keine  
Funktions- 
Einschränkung 
Veränderung 
der 
Sensorik 
od. 
Parästhesien; 
Funktions-
Einschränkung, 
jedoch 
Alltagsaktivität nicht 
beeinträchtigt 
Veränderung der 
Sensorik 
od. 
Parästhesie; 
Alltagsaktivität 
beeinträchtigt 
Inaktivität 


 
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Infektion – 
Febrile 
Neutropenie  
 
--- 
--- 
Bestehende 
febrile 
Neutropenie  
Lebensbedrohliche 
Konsequenzen 
(z.B. 
septischer 
Schock, 
Hypotension, Acidose, 
Nekrose)  
Allergien  
Transienter Rush   
Fieber< 38° 
Rush, 
Urtikaria, 
Dyspnoe  
Fieber>38° 
Symptomatische 
Bronchospasmen 
die 
intravenöse 
Medikation 
erfordern, 
Hypotension 
 
Anaphylaxie 
Schmerzen  
Leicht, 
keine 
Funktionseinschr
änkung 
Mittel 
mit 
Funktionseinschränk
ung 
Schwer 
mit 
massiver 
Funktionseinschrä
nkung 
 
Dysphagia  
Symptomatisch, 
kann 
normale 
Ernährung zu sich 
nehmen 
Symptomatisch, mit 
veränderten 
Ess- 
und 
Schluckgewohnheite
n; 
i.v. 
Flüssigkeitszufuhr < 
24 h 
Symptomatisch 
mit 
stark 
veränderten Ess- 
und 
Schluckgewohnhe
iten; 
i.v. 
Flüssigkeits 
zufuhr, 
parenterale 
Ernährung >24 h 
Lebensbedrohliche 
Konsequenzen 
(z.B. 
Obstruktion, 
Perforation) 
Gewichtsverlust  
5 – < 10 % von 
Baseline 
 10 – < 20 % von 
Baseline; 
Zusatzernährung 
indiziert 
> 
20 
% 
von 
Baseline; 
PEG-
Sonde 
oder 
parenterale 
Ernährung 
indiziert 
___ 
Soor  
___ 
Lokalisiert; 
lokale 
Therapie nötig 
i.v. 
Intervention 
nötig;  
Radiologischer 
oder 
operativer 
Eingriff nötig  
Lebensbedrohliche 
Konsequenzen 
(z.B. 
septischer 
Schock, 
Hypotonus, 
Acidose, 
Nekrose)   
 
 
 


 
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16.2 Appendix 2: Performance status scale (ECOG)
 
 
0   
 normale Aktivität möglich ohne Einschränkung 
1 
Einschränkung bei körperlich anstrengender Tätigkeit aber leichte Tätigkeiten möglich und keine 
 
Bettlägerigkeit 
2 
nicht arbeitsfähig, selbständig, tagsüber weniger als 50% Ruhe bzw. Hinlegen erforderlich 
3 
Selbstversorgung sehr eingeschränkt möglich, tagsüber mehr als 50% Ruhe bzw. Hinlegen erforderlich, 
 
Pflege bzw. Hilfe erforderlich 
4 
bettlägerig und völlig pflegebedürftig 
5 
tot 


 
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16.3 Appendix 3: Remissionsbeurteilung RECIST
 
 
Nach RECIST: response evaluation criteria in solid tumors Version 1.1. 
(Eisenhauer EA, Therasse P, Bogaerts J, et al.: New response evaluation criteria in solid tumours:  
revised RECIST guideline (version 1.1). In: Eur. J. Cancer. 45, Nr.2, Januar 2009, S.228–47) 
Messbare Läsionen (Target lesions): in mindestens einer Dimension messbar und ≥ 10mm im  
längsten Durchmesser(LD)  im CT (2 CT-Schichtdicke) oder klinisch oberflächlich (Foto),  
≥ 20 mm LD im Thorax-Röntgen; Lymphknoten ≥ 15 mm im kurzen Durchmesser (KD) 
Nicht-messbare Läsionen (Non-target lesions): kleiner 10mm im CT,  
osteoblastische Knochenläsionen(Szintigraphie, PET oder Konv. RÖ), leptomeningeale Erkrankung,  
Ascites, Pleuraerguß, Perikarderguß, Lymphangiose, zystische Läsionen 
 
 
Ausgangsmessung muss innerhalb 4 Wochen vor Therapiebeginn erfolgen 
 
Gleiche Methode der Messung sollte im Verlauf verwendet werden 
 
Radiologische Methoden werden vor klinischen Methoden bevorzugt 
 
Ultraschall sollte nur in wenigen Fällen herangezogen werden (zB LK Größe) 
 
Zytologie oder Histologie unterscheidet in  manchen Fällen zwischen PR und CR 
 
Bei neuen Ergüssen entscheidet Zytologie zwischen PD und SD/PR/CR 
 
Tumorlast: Basisuntersuchung: Alle messbaren Läsionen bzw. wenn multipel: die größten und/oder am  
besten messbaren Läsionen (target lesions) - maximal 5 Läsionen (≤ 2 pro Organ) insgesamt.  
Summe der längsten Durchmesser aller target lesions. 
 
Target lesions: 
Komplette Remission (CR): 
 Verschwinden aller extranodalen Herde, alle Lymphknoten sind im    
KD < 10 mm;  
Partielle Remission (PR): 
mindestens 30% Verminderung der Summe der längsten Durchmesser  
der target lesions im Vergleich zum Ausgangsbefund. 
Progredienz (PD): 
mindestens 20% Vergrößerung der Summe der längsten Durchmesser  
der target lesions (in Beziehung zum besten Meßergebnis seit Beginn  
der Therapie) oder Auftreten von 1 oder mehr neuen Läsionen 
Stabile Erkrankung (SD): 
zwischen PR und PD 
 
Non-target lesions: 
CR:  
Verschwinden aller Läsionen,  
Incomplete response/SD: 
Persistieren einer oder mehrerer Läsionen  
PD:  
Ein oder mehrere neue Läsionen und/oder eindeutige Progredienz einer  
 
non-target lesion 
 
 
 
 


 
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16.4 Appendix 4: HCT-CI score  33 
 
Comorbidity  
Explanation  
HCT-CI score
Arrhythmia 
Atrial fibrillation or flutter, sick sinus syndrome, or ventricular 
arrhythmias 
1 
Cardiac 
Coronary artery disease, congestive heart failure, myocardial 
infarction or EF
50% 
1 
IBD 
Crohn's disease or ulcerative colitis 
1 
Diabetes 
Requiring treatment with insulin or oral hypoglycemics 
1 
CVD 
Transient ischemic attack or cerebrovascular accident 
1 
Psychiatric disturbance 
Depression or anxiety requiring psychiatric consult or treatment 
1 
Hepatic, mild 
Chronic hepatitis, bilirubin >ULN to 1.5 × ULN, or AST/ALT >ULN 
to 2.5 × ULN 
1 
Obesity 
Patients with a body mass index >35 kg/m2  
1 
Infection 
Requiring treatment after day 0 
1 
Rheumatologic 
SLE, RA, polymyositis, mixed CTD, or polymyalgia rheumatica 
2 
Peptic ulcer 
Requiring treatment 
2 
Moderate/severe renal 
Serum creatinine >2 mg 100 mL, on dialysis, or prior renal 
transplantation 
2 
Moderate pulmonary 
DLCO and/or FEV1 66–80% or dyspnea on slight activity 
2 
Prior solid tumor 
Treated at any time point in the patient's history, excluding non-
melanoma skin cancer 
3 
Heart valve disease 
Except mitral valve prolapse 
3 
Severe pulmonary 
DLCO and/or FEV1 
65% or dyspnea at rest or requiring oxygen 
3 
Moderate/severe 
hepatic 
Liver cirrhosis, bilirubin >1.5 × ULN, or AST/ALT >2.5 × ULN 
3 
 Abbreviations: AST/ALT=aspartate aminotransferase/alanine aminotransferase; CTD=connective tissue 
disease; CVA=cerebrovascular disease; DLCO=diffusion capacity of carbon monoxide; EF=ejection fraction; 
FEV1, force expiratory volume in 1 second; HCT-CI=hematopoietic cell transplantation-specific comorbidity 
index; IBD=inflammatory bowel disease; RA=rheumatoid arthritis; SLE=systemic lupus erythmatosis; 
ULN=upper limit of normal. 
 
 


 
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16.5 Appendix 5: Fragebogen zur Lebensqualität EORTC QLQ
-C30 (Version 3.0)  
 
 
UPN: ……….  
 vor ASCT    
 3 Monate nach ASCT   
 12 Monate nach ASCT 
Wir sind an einigen Angaben interessiert, die Sie und Ihre Gesundheit betreffen. Bitte beantworten Sie die 
folgenden Fragen selbst, indem Sie die Zahl ankreuzen, die am besten auf Sie zutrifft. Es gibt keine 
"richtigen" oder "falschen" Antworten. Ihre Angaben werden streng vertraulich behandelt. 
 
 
 
 
überhaupt 
 
 
 
nicht      wenig   mäßig  sehr 
 
1. 
Bereitet es Ihnen Schwierigkeiten sich körperlich  
 
anzustrengen (z.B. eine schwere Einkaufstasche oder  
 
einen Koffer zu tragen?) 
1 
2 
3 
4 
 
2. 
Bereitet es Ihnen Schwierigkeiten, einen längeren  
 
Spaziergang zu machen? 
1 
2 
3 
4 
 
3. 
Bereitet es Ihnen Schwierigkeiten, eine kurze  
 
Strecke außer Haus zu gehen? 
1 
2 
3 
4 
 
4. 
Müssen Sie tagsüber im Bett liegen oder in einem  
 
Sessel sitzen? 
1 
2 
3 
4 
 
5. 
Brauchen Sie Hilfe beim Essen, Anziehen, Waschen  
 
oder Benutzen der Toilette? 
1 
2 
3 
4 
 
Während der letzten Woche: 
überhaupt 
 
 
nicht     wenig   mäßig   sehr 
 
6. 
Waren Sie bei Ihrer Arbeit oder bei anderen 
 
tagtäglichen Beschäftigungen eingeschränkt? 
1 
2 
3 
4 
 
7. 
Waren Sie bei Ihren Hobbys oder anderen 
 
Freizeitbeschäftigungen eingeschränkt? 
1 
2 
3 
4 
 
8. 
Waren Sie kurzatmig? 
1 
2 
3 
4 
 
9. 
Hatten Sie Schmerzen? 
1 
2 
3 
4 
 
10. 
Mußten Sie sich ausruhen? 
1 
2 
3 
4 
 
11. 
Hatten Sie Schlafstörungen? 
1 
2 
3 
4 
 
12. 
Fühlten Sie sich schwach? 
1 
2 
3 
4 
 
13. 
Hatten Sie Appetitmangel? 
1 
2 
3 
4 
 
14. 
War Ihnen übel? 
1 
2 
3 
4 
 
 
 
 
 
Bitte wenden 
 
 
 


 
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Während der letzten Woche: 
überhaupt 
 
 
nicht 
wenig mäßig sehr 
 
15. 
Haben Sie erbrochen? 
1 
2 
3 
4 
 
16. 
Hatten Sie Verstopfung? 
1 
2 
3 
4 
 
17. 
Hatten Sie Durchfall? 
1 
2 
3 
4 
 
18. 
Waren Sie müde? 
1 
2 
3 
4 
 
19. 
Fühlten Sie sich durch Schmerzen in Ihrem 
 
alltäglichen Leben beeinträchtigt? 
1 
2 
3 
4 
 
20. 
Hatten Sie Schwierigkeiten sich auf etwas zu 
 
konzentrieren, z.B. auf das Zeitunglesen oder  
 
das Fernsehen? 
1 
2 
3 
4 
 
21. 
Fühlten Sie sich angespannt? 
1 
2 
3 
4 
 
22. 
Haben Sie sich Sorgen gemacht? 
1 
2 
3 
4 
 
23. 
Waren Sie reizbar?  
1 
2 
3 
4 
 
24. 
Fühlten Sie sich niedergeschlagen? 
1 
2 
3 
4 
 
25. 
Hatten Sie Schwierigkeiten, sich an Dinge zu erinnern? 
1 
2 
3 
4 
 
26. 
Hat Ihr körperlicher Zustand oder Ihre medizinische 
 
Behandlung Ihr Familienleben beeinträchtigt? 
1 
2 
3 
4 
 
27. 
Hat Ihr körperlicher Zustand oder Ihre medizinische 
 
Behandlung Ihr Zusammensein oder Ihre gemeinsamen 
 
Unternehmungen mit anderen Menschen beeinträchtigt? 
1 
2 
3 
4 
 
 
28. 
Hat Ihr körperlicher Zustand oder Ihre medizinische 
 
Behandlung für Sie finanzielle Schwierigkeiten 
 
mit sich gebracht? 
1 
2 
3 
4 
 
 
Bitte kreuzen Sie bei den folgenden Fragen die Zahl zwischen 1 und 7 an, die am 
besten auf Sie zutrifft 
 
29. Wie würden Sie insgesamt Ihren Gesundheitszustand während der letzten Woche  einschätzen? 
 
 
 1 
2 
3 
4 
5 
6 
7 
 
 sehr schlecht 
 
 
 
 
         ausgezeichnet 
 
30. Wie würden Sie insgesamt Ihre Lebensqualität während der letzten Woche einschätzen? 
 
 
1  
2 
3 
4 
5 
6 
7 
 
 sehr schlecht 
 
 
 
 
         ausgezeichnet 
 
 
 
 


 
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Um Sie bei der Einschätzung, wie gut oder wie schlecht Ihr Gesundheitszustand ist, zu unterstützen, haben wir eine Skala 
gezeichnet, ähnlich einem Thermometer. Der best denkbare Gesundheitszustand ist mit einer „100“ gekennzeichnet, der 
schlechteste mit „0“. 
Wir möchten Sie nun bitten, auf dieser Skala zu kennzeichnen, wie gut oder schlecht Ihrer Ansicht nach Ihr persönlicher 
Gesundheitszustand ist, indem Sie einen horizontalen Strich auf der Skala setzen.  
                         Ihr aktueller Zustand  
                   
 


 
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17. REFERENCES 
                                                     
1 Philip T, Guglielmi C, Hagenbeek A, et al. Autologous bone marrow transplantation as compared with salvage 
chemotherapy in relapses of chemotherapy sensitive non Hodgkin's lymphoma. N Engl J Med 1995;333:1540-
1545. 
2 Gisselbrecht C, Glass B, Mounier N, et a. lSalvage regimens with autologous transplantation for relapsed large 
B-cell lymphoma in the rituximab era. J Clin Oncol 2010 28:4184–4190. 
3 Gribben JG, Linch DC, Singer CR, et al. Successful treatment of refractory Hodgkin's disease by high-dose 
combination chemotherapy and autologous bone marrow transplantation. Blood 1989;73:340-344. 
4 Sureda A. et al. Autologous and allogeneic stem cell transplantation in Hodgkin’s lymphoma. Hematol Oncol 
Clin North Am. 2007;21:943–960. 
5 Durant JR, Norgard MJ, Murad TM, et al. Pulmonary toxicity associated with bischloroethylnitrosourea (BCNU) 
Ann Intern Med. 1979;90:191–194. 
6 Weaver CH, Appelbaum FR, Petersen FB. High-dose cyclophosphamide, carmustine, and etoposide followed 
by autologous bone marrow transplantation in patients with lymphoid malignancies who have received dose-
limiting radiation therapy. J Clin Oncol 1993;11:1329–1335. 
7 Kalaycioglu M, Kavuru M, Tuason L, Bolwell B. Empiric prednisone therapy for pulmonary toxic reaction after 
high-dose chemotherapy containing carmustine (BCNU) Chest. 1995;107:482–487. 
8 van Besien K, Tabocoff J, Rodriguez M, et al. High-dose chemotherapy with BEAC regimen and autologous 
bone marrow transplantation for intermediate grade and immunoblastic lymphoma: durable complete remissions, 
but a high rate of regimen related toxicity. Bone Marrow Transplant 1995;15:549-555. 
9  Bhatia S, Robinson LL,Francisco L, et al. Late mortality in survivors of autologous hematopoietic-cell 
transplantation: report from the Bone Marrow Transplant Survivor Study. Blood 2005;105:4215-4222. 
10 Reece DE, Nevill TJ, Sayegh A, et al. Regimen-related toxicity and non-relapse mortality with high-dose 
cyclophosphamide, carmustine (BCNU) and etoposide (VP16-213) (CBV) and CBV plus cisplatin (CBVP) 
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