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CLL special consultation
Laboratory
Therapy and research in the Department of Internal Medicine III
All stages and forms of CLL are treated in the Department of Internal Medicine III. One focus here is the realisation of clinical studies. The aim of these clinical trials is to improve the standard therapies currently available and to research individual risk factors on the way to personalised medicine. Based on an improved understanding of the biology of the disease (see below), more and more targeted treatment approaches are being developed today (Fig. 1). The Department of Internal Medicine III participates intensively in the clinical trials of the German CLL Study Group (DCLLSG) and industry partners and is the reference laboratory within the DCLLSG. A number of studies are coordinated from Ulm and the centre has been instrumental in the approval of several new drugs for the treatment of CLL and other lymphoproliferative diseases. Patient care takes place either in the special outpatient clinic, the early clinical trials unit (ECTU) or on one of the specialist wards and in the day clinic.
An important focus of the Department of Internal Medicine III is research into the principles of disease development and progression. To this end, malignant cells are analysed for the presence of chromosomal changes (chromosomes are the packaging units of DNA that contain genetic information). It is known that several of these changes occur frequently in CLL and in some cases also have an impact on the response to therapy (Fig. 2). Furthermore, the constant development of new technologies enables us to research previously unknown chromosomal and genetic changes. Important focal points are the question of how various genetic changes and other biological factors such as the "microenvironment" and downstream signalling pathways as well as apoptosis regulation contribute to the disease or, for example, resistance to therapy. At the same time, we are trying to develop new targeted therapeutic approaches.
Both clinical trials and basic research are carried out in close collaboration with German or international study groups. The aim is for the results of this research to contribute to finding even more effective and tolerable therapies in the future that are tailored to the specific characteristics of individual patients.
Clinical studies
Further information on the active studies can be found at
Description of the disease
Basic information
With an incidence of approx. 5/100,000, CLL is the most common adult leukaemia in the western world. The disease mainly affects older people, although around 20% of patients are younger than 55. The gender distribution is m:w = 2:1. CLL is characterised by the accumulation of morphologically mature but functionally incompetent lymphocytes in bone marrow, blood, lymph nodes and other organs, predominantly in the lymphatic system (Fig. 3). As the disease progresses, haematopoiesis is suppressed and organ functions are impaired. The prognosis varies from individual to individual, with survival times ranging from months to decades. The stage according to Binet or Rai is of prognostic significance, although newer laboratory diagnostic markers (thymidine kinase (TK), ß2-microglobulin (ß2-MG), genomic aberrations, gene mutations (e.g. in TP53, ATM, ATM2) and other markers (e.g. in TP53, ATM2) allow a more precise diagnosis.(e.g. in TP53, ATM, NOTCH1, SF3B1, BIRC3, etc.), the mutation status of the variable parts of the immunoglobulin genes (IGHV) and surrogate markers such as ZAP-70 provide an improved prognosis assessment.
Signs of illness
Symptoms and findings
The majority of patients are symptom-free at diagnosis (incidental finding), some patients notice an enlargement of the lymph nodes. In the advanced stages of the disease, general symptoms (B symptoms), bleeding, a tendency to infection and autoimmune phenomena (especially autoimmune cytopenia) often occur. In the course of the disease, a highly malignant transformation ("Richter syndrome") with an unfavourable prognosis may occur.
Confirmation of diagnosis
The diagnosis is made according to WHO criteria from the blood (clonal B cell lymphocytosis due to mature lymphocytes of >5/nl, immunophenotype: CD5+, CD19+, CD23+, CD79a+, CD20(+), sIgM/D(+), CD10-, FMC7-, CD103-, Cyclin-D1-, CD79b-).
Classification and staging
Staging
Staging at diagnosis is classified according to Binet and Rai and is of prognostic significance
Therapeutic options
In CLL, studies are active for almost all situations (age, stage, previous therapy, etc.), particularly within the framework of the German CLL Study Group (DCLLSG) (Fig. 4). Every patient should have the opportunity to be treated in a trial. This will not only lead to continuous improvement in treatment, but also ensure the best possible quality of treatment for each individual patient. The new, chemotherapy-free treatment options with substances that specifically target the leukaemia cells ("targeted therapy" according to the lock-and-key principle) are playing an increasingly important role in these studies.
An overview of the currently recruiting studies is available on the website of the German CLL Study Group http://www.dcllsg.de/.
In addition to the DCLLSG studies, other international studies, some of them company-initiated, are also active with innovative substances (e.g. BTK, PI3K and BCL2 inhibitors as well as other new targeted substances, etc.).
The currently active CLL studies at the Department of Internal Medicine III can be found on the website of the study centre. Outside of trials, treatment should be stratified according to age, concomitant diseases, genetics (in particular 17p deletion and TP53 mutation, as well as IGHV mutation status, etc.), stage, disease activity and, if applicable, previous therapy/response.
Patients with CLL in stage Binet A are initially observed outside of trials ("watch-and-wait" strategy) and only treated in the event of progression (see below).
Treatment is generally indicated in stage Binet C or Binet B with symptoms (B symptoms, organomegaly, impending organ complications) or with active disease. Currently available conventional treatment methods are palliative in nature; potentially curative approaches such as allogeneic stem cell transplantation are being trialled and should be carried out in studies.
For younger patients, the standard therapy consists of a fludarabine combination (FC) or bendamustine with the addition of antibodies (rituximab). When selecting the therapy (chlorambucil, fludarabine, FC+/- rituximab), the focus should be less on calendar age and more on comorbidity and the therapy goal (efficacy and side effects). However, this therapy is increasingly being replaced by new, chemotherapy-free treatments such as BTK, PI3K and BCL2 inhibitors and their combinations. These substances are already the standard therapy for patients whose CLL has a 17p deletion or TP53 mutation or who are not suitable for chemotherapy due to concomitant diseases.
The next treatment should be chosen depending on the response to the previous therapy. In the case of remissions of > 2-3 years, the primary therapy can be repeated. However, an escalation of therapy is often advisable or necessary in order to achieve remission again.
In recent years, CLL has been one of the pacesetters in the development of new, targeted therapies, which are often superior to conventional chemotherapy in terms of efficacy and tolerability. These developments are currently being continued in studies with combination therapy using these new substances as well as other new developments, with the aim of being able to offer all patients the most effective and tolerable treatment individually.