Quality Assurance on Diagnosis and Therapy of Secondary Immunodeficiencies (SID) in Patients With Chronic Lymphocytic Leukemia (CLL) or Multiple Myeloma (MM) in Germany (QS-SID)
Conditions: Secondary Immunodeficiencies (SID)
Sponsor: AIO-Studien-gGmbH

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Title of the 
Study 
Quality assurance on diagnosis and therapy of sec-
ondary immunodeficiencies (SID) in patients with 
chronic lymphocytic leukemia (CLL) or multiple 
myeloma (MM) in Germany (QS-SID) 
NCT Number 
NCT04172467 
Date: 
5/16/2019 
Version 
V2.1 
 
 

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Quality assurance on diagnosis and therapy of  
secondary immunodeficiencies (SID) in patients with  
chronic lymphocytic leukemia (CLL) or multiple myeloma (MM) 
SYNOPSIS 
 
Scientific project lead  
Prof. Dr. Hartmut Link (AGSMO / AIO AG Supportivtherapie) 
Title of the study 
Quality assurance on diagnosis and therapy of secondary immunodefi-
ciencies (SID) in patients with chronic lymphocytic leukemia (CLL) or 
multiple myeloma (MM). 
Background  
SIDs and resulting infection complications are a concomitant phenome-
non of cancer patients, particular common in patients with CLL or MM. 
Especially hypogammaglobulinaemia is associated with the underlying 
disease as well as the anti-neoplastic therapy (CD19, CD20, CD52 antibod-
ies, kinase and mTOR inhibitors, chemotherapy and immunotherapeutic 
agents) and its co-medication. Therefore, the European Conference on In-
fections in Leukemia (ECIL) recently published a position paper on infec-
tions associated with different immunotherapeutic and molecular tar-
geted agents. [1]  Since infections are an important cause of morbidity and 
mortality, the adequate diagnostic and therapy of SIDs regarding individ-
ual risk factors are essential to ensure quality of treatment.  
Guidelines [GL] on CLL[2], MM[3], the DGHO GL on therapy-induced sec-
ondary immunodeficiencies[4] as well as the German Bundesärztekammer 
(BÄK)[5] recommend an immunoglobulin-replacement therapy (IgRT) in 
patients with clinically relevant susceptibility to infections. Clinical rele-
vance is defined as ≥ 3 bacterial infections within one year or a sepsis.  
Primary objective 
The aim of the study is to examine the monitoring of immunoglobulin lev-
els (IgG, IgA, IgM; timing/interval/modus) and the therapy of hypogam-
maglobulinaemia in clinical routine in patients with systemic therapy of 
CLL or MM in Germany.  
To this end, a nationwide representative survey is to be conducted to ob-
serve the current practice of infections prophylaxis in hospitals and office-
based physicians. 
Secondary objective 
Explorative analysis of correlations between type of antineoplastic ther-
apy (CD229/CD20/CD52 antibodies, kinase and mTOR inhibitors, chemo-
therapy, immunotherapy), stage of disease and additional risk factors 
(age, comorbidities, neutrophil and lymphocyte counts) and the occur-
rence of hypogammaglobulinaemia, the number and severity of infec-
tions and mortality. 
Hypotheses 
The recommendations on immunoglobulin replacement therapy (IgRT) 
of the BÄK and national guidelines for CLL and MM therapy are imple-
mented insufficiently in clinical routine. 
Guideline adherent prophylaxis and therapy is associated with fewer 
and less serious infections. 
Intervention(s) 
no interventions  

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Target criteria /  
Endpoints 
Infections prior, during and after antineoplastic therapy (up to one year 
after begin of therapy) 
Immunoglobulin level (IgG, IgA, IgM) prior, during and after anti-neo-
plastic therapy 
IgRT in accordance to the recommendations of BÄK and guidelines 
Infection free survival according to IgG Substitution 
Study design 
Retrospective, representative registry. 
Treatment structure analysis and recruitment (phase 1): 
In a first step, data on care facilities, that treat patients with CLL or MM 
in Germany is obtained.  
In phase 1 all centers in Germany that potentially treat patients with the 
CLL or MM are contacted and data of its facility care level and its num-
ber of treated patients is recorded using a one-sided pen-to-paper form. 
In addition, the willingness of care facilities to become involved in pa-
tients’ documentation is elicited (phase 2). 
Patient documentation (phase 2) 
To achieve a reliable, representative sample of patients treated in Ger-
many, the distribution of cases to be documented is specified in the in-
dividual indications amongst the facilities involved. This is done using 
the facilities' data on patient numbers and treatment structure obtained 
in phase I: 
The participating centers are assigned to clusters based on key distin-
guishing features (facility type, care level and number of patients 
treated). This sample is modulated according to the previous treatment 
structure analysis. By taking this approach, the actual percentages of the 
various care facilities in an indication area can be reflected proportion-
ally in the patient documentation sample.  
In phase 2 a multiple-page electronic case record form (eCRF) is com-
pleted in order to collect the original patient and treatment data, which 
are relevant to the purpose of the study. All data is gathered retrospec-
tively and anonymously using the patient files. Patient and disease re-
lated variables (age, general condition according to the Eastern Cooper-
ative Oncology Group (ECOG), relevant comorbidity, staging and rele-
vant mutations), systemic antineoplastic treatment (chemotherapy, an-
tibodies, kinase-inhibitors, relevant co-medication etc.) are recorded. 
Also, data on diagnosis of Ig-levels (IgG, IgA, IgM), therapy of secondary 
immunodeficiencies as well as the number and severity of occurred in-
fections and their treatment is collected. Clusters for classification of in-
fections will be developed (e.g. life-threatening, need for hospitaliza-
tion). 
In order to ensure data quality, the scientific project lead will provide 
training for two employees of the commissioned institute on matters re-
garding the content of the study. This knowledge will be incorporated 
into the programming of the user interface and the patient databases so 
that the program will check for completeness and, as far as possible, 
plausibility, on the basis of defined requirements and constraints. These 
checks accompany the process of entering data into the eCRF and allow 
for validating data instantly. If inconsistencies, mistakes or omissions are 

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detected, data will be validated by an integrated query management 
system. 
Physicians questionnaire (phase 3) 
In an additional step and alongside the patient documentation, the at-
tending physicians in participating centers will be surveyed (phase 3) on 
their competency profile, their assessment of guideline quality and their 
approach to avoid infections of CLL and MM patients. 
Population 
Inclusion criteria: Patients with CLL or MM who started an anti-neo-
plastic systemic therapy between July 1st 2017 and June 30th 2018. The 
observation period for documented patients has to cover at least 12 
months after beginning systemic therapy. 
Exclusion criteria: Patient in terminal phase of the disease, life expec-
tancy less than three months 
Statistics 
The primary analysis for all target criteria is performed in accordance 
with the intention-to-treat-principle (ITT). The descriptive statistics com-
prise absolute and relative frequencies for qualitative characteristics, 
e.g. Binet-classification. For continuous characteristics such as age, loca-
tion parameter with respective measures of dispersion are calculated 
(mean with standard deviation, median with interquartile range as well 
as the minimum and maximum). The Kaplan-Meier method is used to 
estimate the time-related number of infections (differentiated by sever-
ity) and mortality; the log-rank test is used to check the equality of the 
distributions.  
Two-sided 95% confidence intervals are given for the effect estimate.  
Subgroup analysis are planned for different type of antineoplastic ther-
apy and patent related risk factors as well as site related characteristics 
(certified vs. non-certified, hospitals vs. office-based). In order to ad-
dress the problem of inflation of type I errors (false-positive or α-errors) 
by multiple testing, the p-values of pairwise comparison were adjusted 
using the Bonferroni-Holm or Benjamini-Hochberg procedure to control 
the family-wise error rate (FWER) respectively the false discovery rate 
(FDR) (depending on issue). 
Sample size calculation 
To generate valid, reliable and representative data on infections, sec-
ondary immune deficiencies 1200 patients should be documented (550 
CLL patients and 650 MM patients). 
The sample size is calculated on the basis of the yearly incidence of the 
underlying disease (CLL and MM) and the rate of infections of patients 
with these indications under systemic therapy. The sample should rep-
resent 10% of yearly incidence to generate sufficient data on the diag-
nosis and therapy of infections and secondary immunodeficiencies. 
disease 
yearly incidence 
in Germany [6] 
sample size 
rate of 
SID[7-11] 
Chronic lympho-
cytic leukemia (CLL) 
~ 5.500 
~ 550 
20-85%  
Multiple myeloma 
~ 6.500 
~ 650 
25-60% 
Total 
~ 12.000 
~ 1200 
 
Duration of study 
2019/20 

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Number of sites 
About 100 centers, hospitals and office-based hematology practices  
Ethics /  
Data protection  
Data is collected retrospectively and completely anonymously from pa-
tent record. Data only includes the documentation of clinical routine; no 
additional study-related treatments or examinations are conducted. 
Only authorized personnel in the practices or hospitals, which are sub-
ject to an obligation to secrecy, will be able to view the original docu-
ments. Participation of the centers is therefore not dependent on ob-
taining informed consent from the patients.  
Data protection while entering data into the eCRF is guaranteed by the 
eCRF itself, which is compliant to the “standard requirements for GCP-
compliant data management in multi-national clinical trials”. Further-
more, data protection is guaranteed because all participating centers 
are given an individual access code to compose a personal combination 
of user name and password. SSL encryption prevents unauthorized ac-
cess to the data as it is being entered. 
 
STUDY MANAGEMENT  
 
Institution 
Function 
Contact 
AGSMO / 
AIO 
 
 
AIO-Studien-gGmbH 
 
Institute MMF 
 
Scientific project lead  
 
 
 
Legal sponsor 
 
Logistic, data collections, pro-
gramming, analysis and statis-
tics  
Prof. Dr. Hartmut Link  
(Speaker of AG Supportive Therapy of 
AIO, AGSMO board member) 
 
Dr. Anette Hipper 
 
Markus Kerkmann 
Laura Holtmann 
 
LITERATURE  
 
1. 
Maschmeyer, G., et al., Infections associated with immunotherapeutic and molecular 
targeted agents in hematology and oncology. A position paper by the European Conference 
on Infections in Leukemia (ECIL). Leukemia, 2019. 
2. 
Leitlinienprogramm Onkologie (Deutsche Krebsgesellschaft, D.K., AWMF):, S3-Leitlinie zur 
Diagnostik, Therapie und Nachsorge für Patienten mit einerchronischen lymphatischen 
Leukämie (CLL). 2018. 
3. 
Wörmann, B., et al. Leitlinie Multiples Myelom. Onkopedia 2018; Available from: 
https://www.onkopedia.com/de/onkopedia/guidelines/multiples-
myelom/@@view/html/index.html. 
4. 
Na I-K, Hensel M, Maschmeyer G, Scheibenbogen C, Wehr C, Wolff D, et al. Immundefekte, 
sekundär. Schwerpunkt: Therapieinduzierte Immundefekte in der Hämatologie und 
Onkologie Onkopedia: DGHO; 2019 Available from: 
https://www.onkopedia.com/de/onkopedia/guidelines/immundefekte-
sekundaer/@@guideline/html/index.html. 
5. 
Beirats, V.d.B.a.E.d.W., Querschnitts-Leitlinien (BÄK) zur Therapie mit Blutkomponenten und 
Plasmaderivaten, in 4. überarbeitete und aktualisierte Auflage 2014. 2014, 
Bundesärztekammer. 

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6. 
Krebs in Deutschland. 2012, Robert Koch-Institut, Epidemiologie und 
Gesundheitsberichterstattung. 
7. 
Reiser, M., et al., Management of patients with malignancies and secondary 
immunodeficiencies treated with immunoglobulins in clinical practice: Long-term data of the 
SIGNS study. Eur J Haematol, 2017. 99(2): p. 169-177. 
8. 
Raanani, P., et al., Immunoglobulin prophylaxis in chronic lymphocytic leukemia and multiple 
myeloma: systematic review and meta-analysis. Leuk Lymphoma, 2009. 50(5): p. 764-72. 
9. 
Tadmor, T., M. Welslau, and I. Hus, A review of the infection pathogenesis and prophylaxis 
recommendations in patients with chronic lymphocytic leukemia. Expert Rev Hematol, 2018. 
11(1): p. 57-70. 
10. 
Mauro, F.R., et al., Clinical relevance of hypogammaglobulinemia, clinical and biologic 
variables on the infection risk and outcome of patients with stage A chronic lymphocytic 
leukemia. Leuk Res, 2017. 57: p. 65-71. 
11. 
Barmettler, S., et al., Association of Immunoglobulin Levels, Infectious Risk, and Mortality 
With Rituximab and Hypogammaglobulinemia. JAMA Netw Open, 2018. 1(7): p. e184169.