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The term "malignant lymphoma" is used to summarise a group of malignant diseases in which there is a rapid and uncontrolled proliferation of cells of the lymphatic system. The lymphatic system normally serves as a defence against pathogens and is found in lymph nodes, but also in the spleen, tonsils, bone marrow and many other organs. In many cases, a swelling of a lymph node is therefore the typical manifestation of this disease, but sometimes these diseases can also occur in other organs (such as the brain, skin or intestines).

Malignant lymphomas are not a uniform group of diseases. There are at least 30 different subtypes. There is a current classification by the World Health Organisation (WHO), but this is constantly being updated and expanded. The three most important groups of lymphomas, some of which differ considerably in terms of treatment and prognosis, are defined below.

1. Hodgkin's disease
2. indolent (or low-malignant) non-Hodgkin's lymphomas, which primarily include follicular lymphoma
3. Aggressive non-Hodgkin's lymphomas, especially diffuse large cell lymphoma.

Malignant lymphomas are rare compared to so-called solid tumours (such as lung cancer or breast cancer). However, there has been an increase in the incidence over the last 10 to 15 years. The age of onset varies for different types of lymphoma. In the case of indolent lymphomas, most patients are over 60 years old. In the case of aggressive lymphomas, there are many patients who are significantly younger. Hodgkin's disease typically also occurs in young people (20-40 years), but there is a second age peak in patients over 60.

In most cases, the cause of malignant lymphomas is not known. As a rule, there is no familial clustering, i.e. the disease is not hereditary. Environmental toxins and radioactive irradiation can play a role, but in many cases a causal link is difficult to establish.

In a small group of lymphomas, however, there are indications of the cause. For example, the Ebstein-Barr virus plays a role in lymphomas that occur in patients who have a reduced immune system due to an HIV infection or after a transplant. Other viruses such as the hepatitis C virus, the so-called Kaposi's sarcoma-associated herpes virus or the HTLV virus have also been identified as triggers of very rare types of lymphoma. Gastric inflammation caused by a bacterium (Helicobacter pylori) plays an important role in low-malignant gastric lymphoma. These findings are partly used for therapy: in some cases, antibiotic therapy alone (in the case of gastric lymphoma) or viral therapy can lead to an improvement or even cure of the disease.

The swelling of a lymph node in the neck, armpits or groin is the most common symptom for which patients with lymphoma consult a doctor for the first time. Lymph node enlargement or enlargement of the spleen in the abdomen is often found as an incidental finding during an ultrasound examination, or in the chest as an incidental finding during an X-ray examination of the lungs. However, as in principle any other organ can be affected, completely different symptoms may be in the foreground, e.g. seizures in the case of lymphomas of the brain or bone fractures in the case of bone lymphomas or skin rashes in the case of skin lymphomas.

Patients with low-malignant lymphomas usually feel well and the lymphoma is often discovered more or less by chance. In the case of aggressive lymphomas or Hodgkin's disease, general symptoms often occur, which are medically referred to as "B symptoms". Patients are often tired and exhausted, lose a lot of weight even though they eat normally, sweat profusely at night, which makes it necessary to change their nightgown or the entire bed linen, or have a fever without any signs of infection.

Today, malignant lymphomas are categorised according to the histological picture (histology), the composition of the surface proteins (immunohistochemistry), genetic and molecular genetic aspects and clinical aspects. An international classification is provided by the World Health Organisation (WHO) and is revised at regular intervals. The subdivision of malignant lymphomas is very complex: more than 30 forms with further subtypes are differentiated.

To simplify matters, however, the subdivision into Hodgkin's disease, the low-malignant and the highly malignant forms of non-Hodgkin's lymphomas is sufficient. The next chapter ("Treatment options") is also subdivided on this basis.

In most cases, staging is based on the Ann Arbor classification, which distinguishes between four different stages. In stage 1, one lymph node localisation is affected. In stage 2, several lymph nodes on one side of the diaphragm are affected. In stage 3, lymph nodes on both sides of the diaphragm are affected. Stage 4 refers to diffuse organ involvement (e.g. if the bone marrow is also affected). The suffix "B" indicates the presence of symptoms such as fever, night sweats and weight loss; the suffix "A" indicates the absence of these symptoms. The suffix "E" indicates the presence of lymphoma outside the lymph nodes (e.g. stomach, lungs, skin, testicles).

Similar to the various diseases, there are major differences in the treatment of malignant lymphomas. What all non-Hodgkin's lymphomas have in common is that they are systemic diseases, i.e. surgery on a lymph node does not make sense as the lymph cells have quickly spread throughout the body and continue to grow elsewhere. Similarly, radiotherapy alone is usually not useful. Chemotherapy is therefore the most important measure, but it is adapted to the disease, age and general condition of the patient. There are therefore options ranging from mild chemotherapy (e.g. tablets that are taken at home) to very intensive procedures (e.g. high-dose chemotherapy, in which so-called blood stem cells are collected from the patient, frozen and given back to enable the bone marrow to recover quickly).

The treatment options for the three most common groups (see above) are discussed below.

1. hodgkin's disease

The treatment results for Hodgkin's disease are excellent. Thanks to the new therapy protocols, a cure can be achieved in over 90% of cases, even in advanced stages. Therapy is based on the stage of the disease and a number of well-defined risk factors (e.g. haematopoietic sedimentation rate, the number of affected areas, the diameter of a manifestation in the chest). In this way, three risk groups (low, medium and high risk) are defined. Standard therapy for low-risk groups is short-term chemotherapy (2 cycles, duration 2 months) and post-radiation, for medium-risk groups somewhat longer chemotherapy (4 cycles, duration 4 months) and post-radiation and finally for high-risk groups intensive chemotherapy (8 cycles, duration 6-8 months). However, the good treatment results are clouded by the relatively frequent late complications of such treatment. For example, 10-15% of cured patients have to reckon with other tumours caused by chemotherapy and radiotherapy after 15-20 years. For this reason, modern study protocols endeavour to reduce the intensity of treatment as far as possible and to reduce such late complications.

If the disease relapses, many patients can achieve a permanent remission with high-dose chemotherapy and stem cell transplantation. If this is not possible, there are a number of experimental therapy options (other chemotherapies, immunotherapies, antibody therapies). For young patients who have also failed high-dose chemotherapy, a so-called allogeneic transplant (stem cell transfer from a related or unrelated donor) is also a possible option.

2. Low-malignant non-Hodgkin's lymphomas

The treatment strategy for low-malignant lymphomas differs significantly from that of other lymphomas. In many cases, patients do not need therapy for years. Studies have shown that there are no advantages to starting treatment early. In general, the disease cannot be cured at an advanced stage, but it is often possible to achieve remission over many years. Therefore, chemotherapy is only started when a patient feels symptoms of the disease (e.g. when lymph nodes press on other organs, when B-symptoms occur). If symptoms are present, the standard therapy today is a combination of chemotherapy and the antibody rituximab. Antibodies are the body's own proteins with which the immune system can defend itself against pathogens. Nowadays, however, it is also possible to produce antibodies that are directed against lymphoma cells (but also against other cancer cells, e.g. in breast cancer). On average, 6 cycles of treatment with chemotherapy and antibodies are required. Unfortunately, in most cases a relapse occurs after some time (usually years), so that low-malignant lymphomas are considered incurable. Nevertheless, many patients with this type of lymphoma can live well and without symptoms.

Patients with relapses of follicular lymphoma receive maintenance treatment with the antibody Rituximab every 3 months for 2 years. This maintenance therapy will probably also be authorised for patients after the first therapy in the middle of 2010.

Only in a small proportion of patients with a localised stage are attempts made to achieve a cure through early radiotherapy.

In the event of a relapse, renewed chemotherapy leads to a remission. In young patients, however, the option of high-dose chemotherapy with stem cell transplantation should also be discussed. This intensive treatment method generally achieves a longer response than "normal" chemotherapy.

Radioimmunotherapy is a new option that has only been authorised in Germany since 2004. Here, an antibody against lymphoma cells is administered as an infusion, which is coupled with a highly radioactive particle (yttrium). This allows the radioactive particle to be delivered directly to the tumour and targeted irradiation to be carried out. This option is particularly suitable for older patients for whom a stem cell transplant is not an option.

There are also a number of experimental approaches that can be considered for patients for whom conventional therapy methods are not an option

3. highly malignant non-Hodgkin's lymphomas

In the case of highly malignant lymphomas, similar to Hodgkin's disease, attempts are made to achieve a sustained remission and, if possible, a cure through rapid intensive therapy. The standard for over 30 years has been chemotherapy according to the so-called CHOP scheme (each letter is an abbreviation for different substances: cyclophosphamide, doxorubicin, vincristine, prednisone). For some years now, this chemotherapy has been combined with the antibody rituximab (see chapter on low-malignant lymphomas). As a rule, 6-8 cycles of this R-CHOP therapy are administered. In certain cases, local radiotherapy is also useful, for example if a lymph node was particularly large at the start of treatment or if organs other than lymph nodes were affected.

In the event of a relapse, high-dose chemotherapy with stem cell transplantation of the patient's own stem cells is the first option for young patients. If a relapse nevertheless occurs, a stem cell transplant from a related or unrelated donor is also an experimental but nevertheless sensible measure.

In older patients, other chemotherapy combinations and sometimes local radiotherapy are usually considered. However, the chances of a cure are increasingly low after the first or second relapse

4 Other non-Hodgkin's lymphomas

Due to the more than 30 different subtypes and the different localisations (brain, stomach, etc.), there are treatment protocols in specific situations that differ from the options described above. It is not possible to describe them all in this short section.

Mantle cell lymphoma, for example, has a special status. For a long time it was thought to be a low-malignant lymphoma due to its microscopic appearance. It then turned out that the prognosis for this disease was particularly poor with conventional therapy. For this reason, young patients are immediately recommended high-dose chemotherapy with stem cell transplantation. For older patients or patients for whom such therapy is not an option, a combination of the monoclonal antibody Rituximab and conventional chemotherapy is recommended.

For some types of lymphoma, a dramatic improvement in the chances of recovery has been achieved over the last 30 years. In Hodgkin's disease, many studies are currently focussing on reducing side effects and long-term complications and improving the quality of life during treatment. However, the prognosis for patients with aggressive lymphomas in so-called high-risk situations is unsatisfactory, especially if the first therapy has not responded. The prognosis for young patients with low-grade malignant lymphomas in relapses is similarly unsatisfactory, as is the prognosis for patients with mantle cell lymphoma.

Current developments are focussed on the best combination and timing of standard therapies. In addition, attempts are being made to minimise the side effects of intensive therapies such as stem cell transplantation from related or unrelated donors, so that this previously risky approach is available to as many patients as possible. Finally, a whole series of new drugs are being developed. On the one hand, the possibility of producing antibodies against tumour cells and coupling these with effective substances (radioactive particles or cytotoxins) has created an exciting new therapeutic option. With increasing knowledge of the molecular processes in tumour cells, it is possible to produce drugs that specifically interfere with the metabolism of the tumour cell but not that of the healthy cell (e.g. bortezomib or temsirolimus in mantle cell lymphoma).