Leukaemia

Under we understand a of white blood cells (leukocytes). Risk factors for are ionizing radiation, certain chemicals and viruses, as well as genetic disposition.

In general, there is an excessive multiplication of leukocytes‘ sub-groups, i.e. white blood cells in the bone marrow. They are, however, immature and incapable of function. At the same time, a normal haematopoiesis is suppressed and there is a lack of normal blood cells. This results in fatigue, pallor, and palpitations caused by anemia, as well as an increased tendency to infections and bleeding because of the lack of mature white blood cells and platelets.

Diagnosis is determined by blood tests (differential blood count), for the exact typology of leukaemic cells a bone marrow examination is needed. Sampling is done from sternum or pelvic bone.

There are different forms, the most important yet provides the disease history. An acute and chronic is distinguished.

Acute has a rapid course and without treatment leads to death in a short period of time. A massive multiplication of cells occur, which are then stored in various organs (particularly the liver, spleen, meninges). In addition, the symptoms listed above occur quickly – due to lack of normal blood cells.

Acute lymphocytic / lymphoblastic (ALL) occurs 80% in childhood. Acute myelogenous (AML) is more common in adults. The treatment happens in the form of chemotherapy, if possible, by means of bone marrow transplantation.

Chronic s have a slow pace with longer stable phases. Chronic lymphocytic (CLL) usually occurs after the age of 45, chronic myelogenous (CML) a little earlier. CML is characterized by the shift to the formation of blasts, appearing after a certain time, which corresponds to the transition into an acute . The treatment focuses – apart from immunotherapy – according to the disease symptoms.

A bone marrow transplant promises the best prognosis, whereas the good results are achieved with chemotherapy, especially in children.

GENERAL

means “white blood”. This indication comes from the increased number of white blood cells in the blood, occurring in some forms of . This large number of white blood cells results, in stationary blood, to visible whitish limbo over the settling of the red blood cells.

is a collective term for diseases, which occur from malignant () changes in one or more of the different types of white blood cells (leukocytes) in the blood-forming organs. Malignant cells multiply pretty uncontrollably, do not mature and therefore can not perform the functions of healthy cells. Following the multiplication without restrain, the malignant leukocytes species in hematopoietic bone marrow extends, possibly also in other organs. From there, the cells transfer into blood. Different types of are described in detail in the following paragraphs. In doing so, especially the chronic and acute is being distinguished.

BLOOD PRODUCTION

In the blood of a healthy person various cell types circulate that fulfill different tasks and go through various development stages. At the same time the dying blood cells are constantly being replaced by new blood cells. Possible excessive production is prevented by various control mechanisms. New formation of blood cells occurs in the bone marrow, especially in the spine.

Red blood cells (erythrocytes)

From certain bone marrow stem cells, during various stages of maturation, red blood cells are developed, which, after the completion of the ripening process, go from the bone marrow into the blood, and there they fulfill the role of transporting oxygen from the lungs into various body cells and the role of removing CO2 from the tissues into the lungs. Erythrocytes have an average life expectancy of about 100 to 120 days.

White blood cells (leukocytes)

Similarly, different types of white blood cells are developed from the stem cells through different stages of maturation in the bone marrow and lymphoid organs, such as lymph nodes, thymus and spleen, which fulfill various tasks of immunity of the organism to eliminate disease agents and waste products there and in the blood. Leukocytes have a life expectancy of 3 to 120 days, but in the blood only about 1 day. White blood cells (leukocytes), are, according to their appearance, divided into three groups. Granulocytes are with 60-70% of leukocytes the largest sub-group. Other types of leukocytes are lymphocytes with 20-30% and monocytes with 2-6%. Each of these sub-groups fulfills a different function.

Platelets (thrombocytes)

The platelets (thrombocytes) are developed from specialized stem cells that are also stored in the bone marrow, through various development stages, which transfer from the bone marrow into the blood, and serve there for blood clotting. Their function is important for sealing blood vessels following injuries. Thrombocytes have an average life expectancy of approximately 7 to 11 days.

FREQUENCY

In Germany and other industrial countries about 8-11 people per 100 000 population fall ill each year from leukaemia.

CAUSES

The causes of are not yet clearly explained. Known factors that increase the risk of are:

• the exposure to ionizing radiation, for example, at explosions of nuclear bombs, at the reactor’s disasters such as Chernobyl, torotrast (radioactive x-ray contrast agent, which is now no longer used) and at radiation therapy: the risk of is doubled at a whole-body dose 1 Gy in adults and already at 30 mGy in fetuses
• some chemicals (e.g. cytostatics, benzene, etc.).
• Some viruses, for example. HTLV I (HTLV means Human T-cell Vius and causes a form of that mainly occurs in adults in southern Japan and the Caribbean)
• genetic (determined by genotype) factors are co-responsible for the development of , it is evident, for example, Philadelphia chromosome association with CMV; an increased risk of remains also with other syndromes with changes in genotype, such as, at trisomy 21 (Down syndrome); because there is a genetic trait, people have in close kinship (identical twins) with the patient with an increased risk of this disease

LOCALISATION

At the malignant cells multiply in the bone marrow and there they push away the healthy stem cells that are needed for the production of healthy blood and immune cells (see above). Malignant cells mostly occur in the blood, as well as in lymphoid tissues, which serve to the immunity of the organism, such as, lymph nodes, spleen, and other. Rarely, malignant cells are found also in other tissues.

SYMPTOMS

With the extension of malignant cells in the bone marrow, the production of normal blood cells increasingly distorts. This reduces the number of normal blood cells. At the same time, leukemic cells can not that have passed into the blood, mostly because of their immaturity fulfill the role of normal mature leukocytes (white blood cells).

Consequences may be:

Anemia (lack of red blood cells) associated with:

• paleness
• tiredness
• tachycardia (increased heart rate)
• underperforming and dyspnea (shortness of breath) during exercise

Thrombocytopenia (platelet deficiency) associated with:

• petechiae (punctate bleeding into the skin without external causes)
• nose bleeds
• hematoma (bruising) after insignificant traumas (minimumal injuries)
• bleeding gums
• rarely: gastrointestinal bleeding, hemoptysis (coughing up blood), cerebral hemorrhage (in the brain)

Granulocytopenia (lack of viable white blood cells) associated with:

• fever
• mildew, specific type of fungal infections e.g. in the oral cavity
• pyogenic (pus) skin infections
• more rarely with: pneumonia (pneumonia), meningitis (inflammation of the meninges), pyelonephritis (inflammation of the renal pelvis)

In addition to bone marrow infiltration by leukemic cells can infiltrate other organs namely resulting in irritation symptoms such as, irritation of the meninges when attacking the meninges (meningoencephalomyelopatia), as also a result of enlargement and reduction of function of infected organs, like spleen.

DIAGNOSIS

The important means of diagnosis is so called blood count. It more precisly examines microscopically the blood components. The frequency of various blood cells is calculated. In the so-called differential blood count, there are furthermore proportions of different types as well as stages of maturity of white and red blood cells determined. The changes in the frequency of certain blood cells lead then in addition to the clinical picture to diagnosis.

If the number of leukocytes (white blood cells), erythrocytes (red blood cells) and thrombocytes (platelets) normal, then is with 95% of probability excluded.

When leukaemia occurs, there is often a decreased number of platelets (tombocytopenia), red blood cells (anemia) and possibly white blood cells (granulocytopenia). The acute , and the acute shift of chronic myeloid is characterized by a gap (Hiatus leucaemicus) in the of granulocytes maturation. Doing so, there is at the prevalence of immature and mature granulocytes a reduced number of intermediate stages.

At the acute myeloid there are also, under the microscope, so called Auer rods recognised, these are typical small changes inside the white blood cells.

Because the disease is localized in the bone marrow, an important diagnostic mean of bone marrow examination, which is taken out with a needle out of the sternum (sternal puncture) or a sample is taken (biopsy) from the crest of the pelvic bone. The proof of at least 30% of immature cells (blasts) in the bone marrow confirmes the diagnosis.

Breakdown criteria

There are various forms of , which can be divided very differently. Breakdown criteria are:

• acute or chronic: Breakdown occurs on the basis of clinical history. Doing so, the slow (chronic) progressions, in the short period of time, may “experience” apparent accelerations. Then we talk about acute shifts.
• myelogenous or lymphocytic: Breakdown based on morphological, cytochemical and immunochemical criteria. Then it is differentiated according to similarity of malignant () cells with healthy cells.
• mature cells or immature cells: The level of distinction of leukaemic cells serves as a breakdown criterion.
• subleukaemic or aleukaemic and leukaemic: I tis differentiate based on the number of leukocytes in the blood count. Subleukaemic and aleukaemic refers to a decreased number of white blood cells and leukaemic an increased number of these cells.

VARIOUS FORMS OF – ACUTE FORMS OF

Acute s are malignant diseases of hematopoietic stem cells with the multiplication of immature cells, so-called blasts, in the bone marrow and usually also in the blood. Moreover, other organs may be affected too. Infestation of spleen leads to an increasement of this body organ (splenomegaly), the infestation of the lymph nodes to their enlargement, the infestation of the brain or the nerves leads to the respective functions disruptions and to the irritation occurrence. The infestation of oral cavity occurs too. In the advanced stages, there are leukemic infiltrates, i.e. the accumulation of leukemic cells, in various organs, such as, lungs, kidneys, or brain.

The frequency of acute

In western industrialized countries, including the Federal Republic of Germany, about 4 people per 100 000 population fall ill each year.

Symptoms of acute

• In a short time general symptoms occur such as, feeling battered, fever and night sweats.
• Symptoms, caused by changes in normal hematopoiesis (blood-formation), include the tendency to infections, anemia, and enhanced bleeding tendency.
• Swollen lymph nodes occur in 30%.
• Liver enlargement (hepatomegaly) occurs less frequently than the enlargement of the spleen (splenomegaly) and is more common in children than in adults.

Prognosis of acute

Without an intensive therapy the disease happens to be fatal within a short time.

BREAKDOWN OF ACUTE : ACUTE LYMPHATIC / LYMPHOBLASTIC (ALL)

ALL frequency

Leukemias in childhood are mostly the acute s. While 80% of them is ALL. ALL are so the most common malignant diseases in childhood. 80% of acute s in later life, in the adult age, are on the other hand AML (see below). ALL occurs predominantly in children and adolescents with a peak frequency between 2nd and 5th year of age.

ALL causes

The causes are malignant (pernicious) changes in stem cell of lymphocytes (= a subgroup of leukocytes). Change in genotype occurring at ALL is already detectable in newborns, who get the ALL in few years later. However, not every child with such change in genotype becomes ill with ALL. This suggests that in addition to the changes described in the genotype also other obtained factors, or outside influences play a certain role.

ALL symptoms

Mostly fever, sore throat and a general feeling of being battered develop quickly. In addition to the general symptoms of acute , extremely frequently the infestation of the meninges (meningiosis leucaemica) occurs at ALL, with the accumulation of leukaemic cells on the eye background. It can be manifested by headache, vomiting and meningism. There are often pains in joints, bones and abdomen. Typical signs are pallor of the skin, swelling of the lymph nodes and skin bleeding.

ALL diagnosis

ALL diagnosis is usually determined from a blood sample. In the blood count, respectively in the differential blood count there are striking quantitative changes of different kinds of blood cells. For diagnosis, in addition to cell morphology, i.e. apart from the phenotype of cells under a microscope, the imunocytological methods (= breakdown based on monoclonal antibodies) are mainly used.

The diagnosis is confirmed by the bone marrow examination. Several types are differentiated (L1 to L3) ALL based on morphology (appearance) of the cells.

ALL therapy

ALL therapy is primarily based on the deployment of cytostatic drugs – drugs that disrupt cell division – under chemotherapy. Generally they are deployed in the combined therapies according to the previously specified schemes that can achieve a cure rate of 70 to 80%.

The first, so called remission induction treatment is to reduce the number of malignant cells by at least a power of ten. This is at the ALL in children reached in 95%. By the following, so called consolidation treatment other leukaemic cells should be destroyed. So called remitting conservative chemotherapy lasts at least 2-3 years. Its aim is to complete remission, i.e. complete regression of the disease associated with normalization of blood count and bone marrow, and with the disappearance of other disease manifestations.

At the bone marrow transplantation, after mortifying the contaminated bone marrow of the patient the healthy bone marrow cells from a donor are transferred. “Sick” bone marrow is mortified through chemotherapy with high doses and through the whole body irradiation. In doing so, all leukaemic cells must be captured. Donor cells are then administered as an infusion and they settle in the bone marrow of the recipient. The problem is temporary weakness due to the lack of immunity of the organism because of the own production lack of leukocytes at the time between the killing of the own bone marrow and the “growth” of the transplanted bone marrow of the donor. The patient must therefore, at the time of the weakening of the body after the destruction of own immune system, including malignant () leukocytic cells and rebuilding of an intact immune system through the bone marrow of the donor, protect himself mainly against germs. Any, at any other time, harmless germ could, at the time of missing immune system, destroy the body and kill the patient. This critical phase, therefore, the patient must spend in a sterile environment in specific departments.

Another problem is the necessity of a suitable bone marrow donor. Bone marrow transplant in a builds up a whole new immune system in the patient‘s body. Transplanted bone marrow has some of the characteristics of the bone marrow donor. Newly built immune system “does not know” that it is no longer in the donor , but in another organism (in the recipient organism = patient). If the donor and the recipient differentiate too much, a new immune system considers the recipient for a “stranger” and attacks his body. Finding a bone marrow donor with – possibly – equivalent tissue properties as the patient’s, is therefore very important, however, unfortunately also very expensive and difficult. More recent efforts therefore, apart from others, lead to the fact to sort the healthy stem cells from the bone marrow cells in the laboratory, where they are artificially reproduced and given to the patient as available “donor” bone marrow. It would be perfect, because the donor and recipient would be then identical. Using this method, several difficulties needs to be resolved, such as, reliable separation of healthy stem cells from malignant () altered cells. Since it is, at ALL, the prognosis for a long time after 1 remission very good, the bone marrow transplantation is carried out only after relapse (disease recurrence).

Cranial radiation follows after the diagnosis of meningitis. However, it may be done also prophylactically, because at ALL there are often infestations of the meninges (meningiosis leucaemica); these are also a source of complications and recurrences. In addition, the mediastinal tumours are irradiated (big tumour nodes between the two lungs) – usually subsequent to chemotherapy.

Additional therapeutic measures include replacement of blood cells, i.e. erythrocytes and thrombocytes transfusion, initiation of new leukocytes creation by the administration of G-CSF and GM-CSF, prophylaxis against infections, respectively infection treatment.

ALL prognosis

ALL leads, if untreated, in a few months, to death. By cytostatic therapy (i.e. chemotherapy) can be achieved, in contrast, often years lasting remission (regression) and healing.

After 5 years 80% of children suffering from ALL still live and approximately 60% of the treated adolescents and adults, after 10 years, still 50%.

Later consequences

Later consequences of the therapy may be organ damage in the brain, lungs, and hormone producing organs and on the liver, as well as an increased risk of metastasis. Patients are often infertile. These side effects of therapy are more than outweighed by the apparent improvement in the prognosis. Current efforts lead towards the less harmful therapy at the same level of success.