Chronic lymphocytic leukaemia (CLL)

Chronic lymphocytic leukaemia (CLL) is characterised by an uncontrolled proliferation of apparently mature but non-functional lymphocytes (a specific type of white blood cell that is an important component of the immune system) in the bone marrow and blood. As the disease progresses, these abnormal cells multiply in the blood, bone marrow, lymph nodes, spleen and other organs, resulting in health problems due to the suppression of healthy organs and their functions or the suppression of normal haematopoiesis in the bone marrow.

Chronic lymphocytic leukaemia is the most common leukaemia in adults. In Germany, around 5600 new cases of the disease occur every year. The risk of developing CLL increases with age. The disease peaks at around 65 years of age. However, around 20 % of patients are younger than 50.

The cause of CLL is still unknown. A clear connection with radiation, toxins or other environmental factors has not been shown. However, organic solvents increase the risk of developing CLL. The disease is caused by genetic changes ("genetic defect") in a blood cell. These genetic defects develop in an originally normal blood cell, which then degenerates and multiplies. It is not a hereditary change. However, the risk of developing CLL is slightly increased in first-degree relatives of CLL patients.

In the vast majority of patients today, CLL is diagnosed at an early stage of the disease, usually by chance during a routine health check or blood test. As the disease progresses, symptoms such as swelling of the lymph nodes, reduced performance, pallor, shortness of breath (due to a reduction in red blood cells), bleeding events (due to a reduction in platelets) or infections (due to a reduction in normal white blood cells) lead to the diagnosis. In addition, B-symptoms (fever, night sweats with change of clothes and unintentional weight loss) can occur during the course of the disease. As any organ can be affected by CLL, patients' symptoms can be very varied and sometimes atypical.

Medical history and physical examination

During a medical consultation, all symptoms (including the absence of symptoms) and relevant previous illnesses are enquired about. A physical examination, which primarily involves palpation of any swelling of the lymph nodes or enlargement of the liver and spleen, will provide an initial assessment of the spread of the disease.

Laboratory tests

First and foremost, blood tests are required to establish the diagnosis of CLL. In addition, the blood tests provide information about the general state of health, in particular the function of other organs such as the liver or kidneys, as well as concomitant diseases or complications that may have already occurred. Blood tests also provide important information for predicting the course of the disease (molecular cytogenetics, molecular genetics, protein expression such as ZAP-70). Following appropriate information and written consent from the patient, a small amount of blood can be collected at the same time for scientific analyses. This ultimately serves to gain scientific knowledge and helps to further improve the treatment of CLL. Bone marrow aspiration is not usually required for diagnosis, but may be necessary in certain situations during the course of the disease.

Further examinations

Ultrasound examinations of the liver, spleen and lymph nodes are required to assess the function of important organs and to determine the exact spread of the disease. If necessary, a computerised tomography scan can also be carried out to assess the exact spread of the disease. A lung function test, ECG or ultrasound examination of the heart may be necessary to check organ functions.

In order to assess the course of the disease for an individual patient and to advise on the best possible treatment strategy, CLL must be precisely subclassified. In recent years, it has been possible to identify various subgroups that are associated with very different disease courses. To this end, examinations of genetic changes (IGHV mutation status, genomic aberrations using FISH, mutation analyses of genes such as TP53, ATM, NOTCH1, SF3B1, etc.) and protein molecules (CD38, ZAP-70) are carried out. In addition to the clinical appearance of the disease, these factors allow a better assessment of the future course of the disease and the most promising treatment options. In many cases, no treatment is required in the early stages of the disease. However, it is possible to estimate whether the disease will progress rapidly and whether treatment may become necessary or which treatment offers the best prospects of success.

The choice of treatment depends on the age and general condition of the patient, the clinical spread (stage) of the disease, any concomitant diseases and the individual patient's wishes and risk profile (in particular molecular markers, see above). There are a number of options available for the treatment of CLL, but with the exception of stem cell transplantation from a family or unrelated donor, it is not curable with the therapies currently available. In recent years, the treatment of CLL has changed dramatically, with new specific inhibitors almost completely replacing conventional chemotherapy. The choice of therapy depends on concomitant diseases, genetic changes and age. If possible, therapy should always be carried out within the framework of clinical trials.

Watch and wait treatment

This form of treatment is usually chosen if the disease is at an early stage without symptoms. In studies, treatment of patients in the early stages has so far shown no improvement over an initial wait-and-see approach and starting treatment when problems occur. In this context, it is important to know that CLL patients often have disease courses in which no symptoms or threatening complications occur for many years or even decades. Current therapy studies are investigating whether early therapy based on a patient's individual risk leads to an improvement after all.

"Small molecule" inhibitors

BTK, PI3K and BCL2 inhibitors offer the possibility of chemotherapy-free therapy and have thus revolutionised the treatment of CLL. These drugs show excellent efficacy in patients with a poor genetic profile. They are drugs that specifically attack important key molecules in the CLL cells and thus lead to cell death. In addition to their high effectiveness, they are characterised by good tolerability and can also be used in older patients. The introduction of the various inhibitors has significantly improved the treatment options, even in the event of a recurrence of the disease.

Antibodies

Like small molecule inhibitors, antibodies are drugs that specifically target CLL cells and are a very effective treatment. Antibodies that are directed against the surface molecule CD20, which is found on CLL cells, can be combined with both small molecule inhibitors and conventional chemotherapy. In exceptional cases, antibody therapy alone may also be considered.

Chemotherapy

Conventional chemotherapy can usually effectively suppress CLL, but in most cases it is inferior to therapy with the new inhibitors. It is only considered in individual cases for patients with a very good risk profile, but even in this group it is no better than the "small molecule" inhibitors.

Stem cell transplantation

In a small group of selected patients, stem cell transplantation can be carried out with foreign ("allogeneic", either from siblings or foreign donors) stem cells. These procedures offer the chance of more permanent disease control, possibly even a cure, but on the other hand are associated with more side effects and risks compared to conventional chemotherapy. Very individual counselling is required here. Due to the comparatively high risk of this treatment strategy, it is only recommended for patients with a very unfavourable, therapy-resistant course of CLL or certain high-risk genetic characteristics.

Therapy studies

In therapy studies, new forms of treatment - new drugs or combinations of drugs - are investigated in patients. Over the last few decades, this has led to important advances in the diagnosis and treatment of CLL. For this reason, the treatment of CLL should take place within the framework of clinical trials. Participation in a "trial" offers the patient not only the availability of new, innovative active substances, but also standardised therapy monitoring with regular review of the course of the disease by internationally recognised experts. There is always a range of clinical trials available that offer the most promising treatment options in various disease situations.

Supportive therapy

The lack of healthy blood cells can lead to infections, bleeding or weakness and fatigue. It may therefore be necessary to transfuse blood products and administer antibiotics. Further supportive measures (treatment of pain or administration of immunoglobulins) depend on the individual course of treatment.

Intensive research is being conducted worldwide on the development of new markers for prognosis assessment and drugs for treatment. The aim is to personalise the treatment of CLL patients. To this end, research projects and therapy studies are being conducted in which the most innovative measures for risk assessment and treatment are applied. These measures are intended to maximise the prospects of quality of life, disease control and possibly a cure for each individual patient.