Oncology:
Our other therapeutic areas

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      • There are different types of leukaemia, which are differentiated on the one hand according to the course of the disease and on the other hand according to the origin of the cells:

      a slowly progressing malignancy characterized by increased production of mature but dysfunctional B lymphocytes. The primary disease sites include peripheral blood, spleen, lymph nodes, and bone marrow1

      a slowly progressing malignancy characterized by excessive proliferation of white blood cells (WBCs; neutrophils, eosinophils and basophils) , mainly, but not exclusively, of the granulocytic series, in the bone marrow (BM) and circulating blood. In its initial stages, CML evolves very slowly2

      a very fast progressing malignancy characterized by clonal expansion of immature “blast cells” in the peripheral blood and bone marrow resulting in ineffective erythropoiesis (red blood cell development) and bone marrow failure.3

      a very fast progressing malignancy characterized by a clonal hematopoietic stem cell disorder of B or T cell origin.4

      Acute forms progress quickly and uncontrollably. Chronic forms are characterized by a generally slow course. In myeloid forms of leukaemia, myeloid cells, a specific form of white blood cells, degenerate. In lymphatic leukaemia, on the other hand, another type of white blood cell is affected, the so-called lymphocytes.

      what is cll

      Various cancers of the blood-forming system are referred to as leukaemia or blood cancer. The production of healthy blood cells is disrupted by too many non-functional white blood cells5.

      cll-1

      In leukaemia, there is an uncontrolled increase in white blood cells (called leukocytes). They play an important role in the immune system: healthy white blood cells are responsible for fighting off infections in the body6. If white blood cells degenerate in a not yet fully developed stage, they cannot fulfill their function in the body's own defence system. The more of these non-functional cells are in the bone marrow, in the blood or in the lymphatic system, the healthier white blood cells, red blood cells (erythrocytes) and blood platelets (thrombocytes) are displaced. The erythrocytes are responsible for transporting oxygen in the blood. The task of the platelets is to clot the blood5,12,13.

      Chronic lymphocytic leukaemia (CLL) is classified as a lymphoma as well as a leukaemia: Since it has its origin in the lymphatic organ system (lymph nodes, spleen, liver), it is a sub-form of lymphoma diseases7. In contrast to many other lymphomas, however, CLL is leukemic. This means that the degenerated cells are not only found in the lymphatic organs, but also in the bone marrow and blood5.

      CLL develops in the lymphatic system with a change in a single cell called a B lymphocyte. This cell multiplies slowly but uncontrollably. The cells created in this way are not functional. They live longer than healthy cells and can accumulate in the bone marrow. There they hinder the formation of healthy blood cells. Gradually, the changed cells can also affect other organs such as the liver or spleen5,8.

      cll-2
      facts and figures
      infographic-leukemia

      The symptoms that accompany chronic lymphocytic leukaemia (CLL) and how pronounced they are can vary widely. There are people who have only one symptom, others have several illness-related complaints. Often the disease does not cause symptoms at the beginning, so it is discovered by accident. It can take many years for the first signs to show up. Sometimes an accumulation of various complaints gives rise to further investigations5,9,10.

      symptoms and diagnoses

      Symptoms

      As a result of the proliferation of the diseased B lymphocytes; including fever of unknown cause, night sweats and unwanted weight loss (more than 10% of body weight in 6 months)10.

      symptoms-1

      Deficiency of red blood cells: leads to anemia; typical signs can be tiredness, paleness and declining performance.5,10,12

      Deficiency of healthy white blood cells: affects the body's defences; frequent infections, which may be more severe and heal more slowly than usual, can be the result.5,6,12

      Platelet Deficiency: manifests itself in an increased tendency to bleed; Wounds or injuries bleed more and bruises more often for no apparent reason.5,13

      As the disease progresses, the sick cells displace more and more healthy, functional blood cells. This can affect various body functions. In the advanced stages of chronic lymphocytic leukaemia (CLL), many sufferers notice a decrease in performance along with tiredness and paleness. The doctor then often finds an increased bleeding tendency, painless swelling of the lymph nodes or an enlarged spleen or liver.5,9,10

      Path to diagnosis5,9,10

      Because chronic lymphocytic leukaemia (CLL) usually does not cause symptoms in the early stages, it is often discovered by chance during a routine examination. Some sufferers seek medical advice due to unclear symptoms. These include, for example, declining performance, fatigue or weight loss. If CLL is suspected, the doctor can carry out various tests.

      doctor-leukemia

      The family doctor is often the first point of contact. Among other things, the general practitioner (GP) asks about complaints, existing illnesses or illnesses in the patient’s family. During the subsequent physical examination, the GP can determine whether the lymph nodes, spleen or liver are enlarged. A first blood count shows whether the number of white blood cells (leukocytes), especially those of lymphocytes, is increased. It also shows whether the amount of red blood cells and platelets is decreased. If these examinations confirm the suspicion of chronic lymphocytic leukaemia (CLL), the GP will refer the patient to the hematologist.

      The hematologist can confirm the diagnosis through further examinations and also determine the stage of the disease. This happens on the one hand with the help of special blood tests, on the other hand with imaging procedures and physical examinations.

      course of disease

      The course of chronic lymphocytic leukaemia (CLL) is slow to moderately rapid in most people. Many have no symptoms in the first few years after diagnosis and can live with the disease. Rapid progression of the disease is rare5,9,10. In order to better assess the individual course of the disease, the treating hematologist determines the stage of CLL. The spread of the disease in the body can be classified using the so-called Binet classification10,14. Three stages of chronic lymphocytic leukaemia are distinguished: Stages A and B are considered to be early stages of the disease, while C is an advanced stage. In addition to the involvement of the lymphatic system (lymph nodes, spleen and liver), the impairment of healthy blood formation is also taken into account when assessing the course of the disease10,14.

       

      Binet stages (most common used staging system in EU)10,14

      A

      Less than three lymph node regions involved, no anemia, no reduction in blood platelets and therefore no tendency to bleed

      B

      Three or more affected lymph node regions, no anemia, no reduction in blood platelets and therefore no tendency to bleed

      C

      Presence of anemia or a reduced number of blood platelets and thus an increased tendency to bleed; the number of affected lymph node regions does not matter

       

      course-of-disease-ilu

      Genetic tests can also help to better assess the disease and its individual course. This provides the doctor with further information on which therapy is most suitable. The right time and the intensity of the treatment can also be better estimated. The chromosomes (carriers of the genetic material) of the diseased B lymphocytes are examined as part of a so-called cytogenetic examination. A simple blood sample is sufficient for this. In this way, changes in the genome of the cancer cells can be determined. These can in part promote the survival of the cancer cells. For example, some people affected are missing a certain section of a gene (17p deletion) or certain genes are damaged (TP53 mutation)5,9-10,14-15. 

      treatment options

      Which chronic lymphocytic leukaemia (CLL) treatment is right for the patient and when it becomes necessary depends on various factors. The stage of the disease, the general condition, concomitant illnesses or the results of genetic tests all play a role5,9.

      Watch and wait

      Often times, if the patient is in the early stages of CLL and there are no symptoms, the condition is not an acute threat. CLL usually progresses very slowly. So far there are no sufficient, reliable study data that show that therapy at this early stage can positively influence the further course of the disease5. Therefore, the hematologist will probably refrain from treatment with medication at this stage. Instead, he/she will monitor the condition with regular check-ups. This strategy is called "watch and wait", translated as "Monitoren en wachten"5,16.

      For some people, this wait and see phase is an emotional challenge. Waiting for the next doctor's visit and the current findings can create uncertainty. Some people try to improve their general health by exercising, others find that communicating with other people affected, for example in a self-help group, can help to cope better with CLL).

      The situation is very different when the patient reaches the advanced stages of the disease, or when first symptoms occur. The treating hematologist will decide together with the patient when the right time has come to start treatment and which therapy is the right the patient.

      Aspects that may speak for a CLL treatment14:

      enlarged lymph nodes or a significantly enlarged spleen or liver

      a doubling of white blood cells (leukocytes) within six months

      a lack of healthy white blood cells, red blood cells, or platelets

      General symptoms such as significant weight loss, fever, night sweats, fatigue or a noticeable decrease in performance

       

      When we talk about actual treatment, there are different mode of actions that could be leveraged to threat CLL. Chemotherapy and targeted therapies such as antibodies or oral targeted therapies differ primarily in the way they act on the cancer cells. Chemotherapy intervenes in the division cycle of cancer cells. Even healthy, rapidly renewing cells can therefore be attacked by chemotherapy. Targeted drugs intervene in special cellular signaling pathways of tumor cells and thus in the disease process. Therefore, we distinguish several mono- or combination therapy options like oral targeted therapy (alone or in combination with a monoclonal antibody) and chemo immunotherapy (combination of monoclonal antibodies and chemotherapy). Less often used therapy options would be traditional chemotherapy and stem cell transplantation5,9-10,14.

      doctor-pills

      Oral targeted therapy

      Treatment options for CLL have improved significantly in recent years. In addition to the previous chemotherapy and antibody therapies, which are usually administered intravenously into the bloodstream, other drugs are now available that are taken as tablets or capsules. This novel oral targeted therapy blocks certain proteins that are responsible for cancer cell growth and survival5,9-10,14. 

      Chemo immunotherapy5,10,14,18

      Treatment options used for CLL include monoclonal antibodies as well as chemotherapy. A combination of the two forms of treatment is known as chemo-immunotherapy.

      Antibodies are proteins that are important for the body's defences. They attach themselves to intruders such as viruses and bacteria or the body's own damaged structures and identify them. This allows them to be recognized and broken down by the immune system. Monoclonal antibodies also follow this principle. These are targeted antibodies that are produced using biotechnological processes. They are able to activate the body's natural defence processes against specific diseases.19

      The anti-CD20 antibodies can be used to treat CLL. Depending on the active ingredient, it can be used as chemo-immuno or in combination with an oral targeted therapy. Anti-CD20 antibodies recognize the so-called CD20 antigen. This molecule is located on the surface of the B lymphocytes and is involved in cell growth. The antibody especially docks to the cancer cell, triggers a reaction of the immune system against this cell and thus cell death.20

      chemo-immunotherapy
      iv-chemotherapy

      Treatment with cytostatics is called chemotherapy. These drugs particularly inhibit cells that divide quickly and uncontrollably, such as cancer cells. As a result, the number of cancer cells decreases, and blood formation can take place again. The aim of chemotherapy is to achieve the best possible remission and thus to ease the symptoms caused by the disease. Successful treatment can lead to a dormant phase of the disease. During this time no therapy is necessary for the time being.

      Chemotherapy for CLL can be taken as tablets or given as an infusion. Outpatient therapy is possible in both cases. This means that no long hospital stay is required for the duration of the treatment, but only for the short time of the individual infusions. Chemotherapy for CLL usually lasts six months. Several treatment cycles are carried out during this time. Depending on the therapy, a break in treatment of a few days or weeks can sometimes be planned. During this time, the healthy blood cells, which can also be damaged by chemotherapy, have an opportunity to recover. 

      Which substances are used depends, among other things, on the general condition, the individual expectations of the therapy or possible concomitant diseases. 

      Allogenic stem cell transplantation

      Stem cell transplantation is a treatment option less frequently used for CLL, however it could be viable. In this treatment option, patients are first treated with high dosages of chemotherapy and/or radiotherapy to treat the leukaemia. The stem cells given to the patient have the function to rebuild and restore the damaged bone marrow of the patient. Often allogenic stem cell transplantation is used, meaning that the source of the stem cells is not the patient itself, but a suitable donor21,22.

       

      Under development

      1. Mukkamalla SKR, Taneja A, Malipeddi D, master SR. Chronic lymphoctic leumia. https://www.ncbi.nlm.nih.gov/books/NBK470433/ . Updated march 7, 2021. Accessed July 2021
      2. Minciacchi VR, Kumar R, Krause DS. Chronic Myeloid Leukemia: A Model Disease of the Past, Present and Future. Cells. 2021 Jan 10;10(1):117. doi: 10.3390/cells10010117. PMID: 33435150; PMCID: PMC7827482.
      3. Vakiti A, Mewalwalla P. Acute Myeloid Leukemia. https://www.ncbi.nlm.nih.gov/books/NBK507875/. Updated July 2021. Accessed July 2021
      4. Onciu M. Acute lymphoblastic leukemia. Hematol Oncol Clin North Am. 2009 Aug;23(4):655-74. doi: 10.1016/j.hoc.2009.04.009. PMID: 19577163.
      5. National Cancer Institute. Chronic Lymphocytic Leukemia Treatment (PDQ®); http://www.cancer.gov/types/leukemia/patient/cll-treatment-pdq.  Accessed March 2021
      6. National Cancer Institute. leukocyte (PDQ®); https://www.cancer.gov/publications/dictionaries/cancer-terms/def/leukocyte accessed March 2021
      7. National Cancer Institute. lymphoma (PDQ®); https://www.cancer.gov/types/lymphoma accessed March 2021
      8. National Cancer Institute. Lymph node (PDQ®); https://www.cancer.gov/publications/dictionaries/cancer-terms/def/lymph-node accessed March 2021
      9. https://www.allesoverkanker.be/chronische-leukemie accessed March 2021
      10. Michael Hallek. Chronic lymphocytic leukemia: 2020 update on diagnosis, risk stratification and treatment; https://doi.org/10.1002/ajh.25595
      11. Posch ML, Prince SA, Thompson K, Modi F, Jordan J. Chronic Lymphocytic Leukemia of the Aortic Valve: A Case Report. Cureus. 2021 Jan 6;13(1):e12517. doi: 10.7759/cureus.12517. PMID: 33564521; PMCID: PMC7863072
      12. National Cancer Institute. erythrocyte (PDQ®); https://www.cancer.gov/publications/dictionaries/cancer-terms/def/erythrocyte accesses March 2021
      13. National Cancer Institute. thrombocyte (PDQ®); https://www.cancer.gov/publications/dictionaries/cancer-terms/def/thrombocyte accesses March 2021
      14. Michael Hallek et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL; Blood (2018) 131 (25): 2745–2760.; https://doi.org/10.1182/blood-2017-09-806398
      15. National Cancer Institute. DNA (PDQ®); https://www.cancer.gov/publications/dictionaries/cancer-terms/def/dna accessed March 2021
      16. https://www.allesoverkanker.be/watchful-waiting-bij-chronische-lymfatische-leukemie-cll accessed March 2021
      17. https://www.allesoverkanker.be/doelgerichte-therapie-bij-chronische-lymfatische-leukemie-cll accessed March 2021
      18. https://www.allesoverkanker.be/chemotherapie-bij-chronische-lymfatische-leukemie-cll accessed March 2021
      19. National Cancer Institute. antibody (PDQ®); https://www.cancer.gov/publications/dictionaries/cancer-terms/def/antibody accessed March 2021
      20. National Cancer Institute. Monoclonal antibodies (PDQ®); https://www.cancer.gov/about-cancer/treatment/types/immunotherapy/monoclonal-antibodies accessed March 2021
      21. https://www.allesoverkanker.be/stamceltransplantatie-bij-chronische-lymfatische-leukemie-cll accessed April 2021
      22. https://www.allesoverkanker.be/stamceltransplantatie accessed April 2021

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