Author: Dipl. Biol. Maria Yiallouros, erstellt am: 2010/02/02, Reviewer: Prof. Dr. med. Ursula Creutzig, English Translation: Dr. med. Gesche Tallen, Last modification: 2011/04/20 doi:10.1591/poh.patinfo.aml.kurz , Kurz-URL: www.kinderkrebsinfo.de/AML_kurzinformation

General information

Acute myeloid (or nonlymphocytic) leukaemia (AML) represents a malignant disease that arises within the haematopoietic system. AML usually originates from the bone marrow and is characterised by the production of too many white blood cells (leukocytes).

Healthy white blood cells (like all healthy cells) have an inner clock that determines their life span. Healthy white blood cells originate from their precursors in the bone marrow, they divide, mature, die and are replaced by new cells. In a patient with AML, most of the white blood cells have lost their inner clock. They divide without a limit and most of them do not mature, and thus not function properly. As a consequence, the bone marrow is getting more and more crowded with dysfunctional white blood cells, while the healthy bone marrow cells, such as red blood cells and platelets, are losing their room, and thus, they become lesser and lesser. Therefore, anaemia, frequent infections and bleeding can be first symptoms of acute leukaemia.

Since AML is primarily not limited to a certain region of the body, but can spread from the bone marrow into the blood and the lymphatic system, thereby affecting various complete organ systems, it represents, like all leukaemias, a malignant systemic disease – cancer.

AML can progress rapidly. The spread of leukaemia cells and the resulting damage to other body parts cause fatal diseases, which - without the appropriate treatment – are lethal within a few weeks or months.

Epidemiology

Comprising about 20 % of childhood leukaemia, acute myeloid leukaemia (AML) is, following acute lymphoblastic leukaemia (ALL), the second most frequent leukaemia in children and adolescents. AML accounts for about 5 % of all cancers in this age group.

According to the German Childhood Cancer Registry in Mainz, about 90 children and teenagers aged younger than 15 are newly diagnosed with AML in per year. Counting all paediatric patients up to 19 years of age, the incidence is about 110 new diagnoses per year.
In general, AML can develop in every age group. The frequency of childhood AML is highest during the first two years of life, with boys being slightly more affected than girls. After that, incidence decreases and remains stable throughout childhood. It shows a mild increase again during adolescence. During adulthood, and particularly beyond age 55, there is a dramatic increase in the incidence of AML.

Classification of acute myeloid leukaemia

AML originates from bone marrow precursors of the various cells our blood is made of, including red blood cells (erythrocytes), white blood cells (leukocytes like granulocytes or monocytes) and platelets (thrombocytes). AML is mainly characterised by a malignant transformation of granulocyte precursor cells (myeloblasts). However, AML can also derive from immature monocytes, young red blood cells or platelets and even from the very young precursors of all of them (the so-called myeloid cells).

Taken together, AML represents a heterogeneous group of haematologic malignancies that arise within bone marrow precursor cells of different type and stage of development. Accordingly, different forms of AML, such as acute myeloblastic or monocytic leukaemia and many more, including various mixed forms, have been identified. Historically, the classification of AML was mainly based on how the cells looked like under the microscope (morphologic criteria), and which bone marrow precursor they derived from. Today, subsets of AML are also defined by the alterations that can be found in the genetic material of the malignant cells (cytogenetic characteristics).

Historically, the classification of AML was mainly based on how the cells looked like under the microscope (morphologic criteria), and which bone marrow precursor they derived from. Today, subsets of AML are also defined by the alterations that can be found in the genetic material of the malignant cells (cytogenetic characteristics).

In fact, various subtypes of childhood AML have been characterised so far, the courses and prognosis of which can differ significantly. Current treatment strategies for children and adolescents with AML consider these different subtypes. Therefore, children and adolescents with AML do not all receive the same treatment.

Causes

The causes of acute myeloid leukaemia (AML) still have to be elucidated. It is known so far that the disease arises from the malignant transformation of precursor blood cells in the bone marrow, and also, that this transformation can be associated with genetic alterations of these cells. Why these genetic alterations exist and why they cause the disease in some children but not in others, is not known yet. Most certainly, AML is caused by a specific combination of many genetic and also environmental factors.

It is also known, that children with certain inherited or acquired immunodeficiencies as well as young patients with chromosomal alterations (such as Down syndrome or Fanconi anaemia) have a higher risk of developing leukaemia than their healthy peers. Also (prenatal exposition to) ionising irradiation or X-ray and to certain genotoxic chemicals and drugs, prenatal exposition to parental nicotine or alcohol abuse, and maybe certain viruses have been reported to play a role in the development of leukaemia. However, for most of the patients, no specific risk-factor for the development of AML has been identified yet.

Symptoms

The symptoms of most children and adolescents with AML develop within only a few weeks and their range is exceptionally large. The young patients may suffer only minor symptoms or life-threatening complications due to depletion of normal bone marrow cells and other organ dysfunction based on the space occupying effects of the spreading leukaemic cells. Therefore, the production of red and white blood cells as well as of platelets is reduced in patients with AML.

As a consequence, these young patients often show symptoms like fatigue and pallor, caused by the lack of red blood cells (anaemia), which are responsible for oxygen transport to body cells. The lack of sufficient white blood cells with their role of combatting intruding pathogens goes along with frequent bacterial infections, and thus fever. A further symptom are bleedings, such as gum or mucosal, due to insufficient blood coagulation based on the lack of platelets.

A lot of children with AML complain about bone pain, most often in in the back and in the long bones of the arms and legs, which is a result of bone marrow replacement by leukaemic blasts. These often spread to liver, spleen, and lymph nodes where they occupy space, thereby causing organ enlargement and abdominal pain. Overall, every organ can be affected by AML, including skin and mucosa. In cases of central nervous system involvement, patients may suffer from nausea, headaches, nerve palsies and impaired vision.

However, a child or teenager showing any of the symptoms described above does not necessarily suffer from AML. A lot of these symptoms, such as fever, fatigue or headaches are also regularly seen with common childhood diseases like common colds and other viral infections. Nevertheless, if symptoms persist or increase, it is strongly recommended to present the child or teenager to a paediatrician. If acute leukaemia is diagnosed, treatment should begin as soon as possible.

Diagnosis

If the paediatrician thinks that the young patient’s history, physical exam and possibly even results from blood tests and/or imaging are suspicious of acute leukaemia, the young patient should immediately be referred to a hospital with a childhood cancer program (paediatric oncology unit), where further diagnostics can be initiated and performed by childhood cancer specialists.

These tests serve to confirm or rule out the suspected diagnosis and usually include specific blood work. Also, bone marrow tests are necessary to obtain further information on the disease. Thanks to modern laboratory techniques, such as immunological and molecular genetic methods, it has not only become possible to differentiate between an AML and an acute lymphoblastic leukaemia (ALL), but also to define the subtype of AML. Knowing the subtype is important for optimal treatment planning, because the different forms of AML do not only have different cellular and genetic characteristics, but also differ in their responses to treatment and in prognosis.

To assess a possible spread of the disease to other organs (like liver, spleen, lymph nodes, skin, bones or brain), primary diagnostics are completed by imaging. Imaging may include an ultrasonography of the belly and lymph nodes, chest radiographs, magnetic resonance imaging of the belly, pelvis, testes, and a bone scan. To find or rule out possible central nervous system involvement, magnet resonance imaging (MRI scans) of the brain and spine, and also a lumbar puncture to search for leukaemic cells in the cerebrospinal fluid are usually performed.

To prepare the patient for the intensive treatment, several organ functions must be checked, since certain anticancer agents have specific side-effects that can affect specific organs. To have an initial assessment later helps to detect and appropriately interprete potential functional changes. These preparatory diagnostics usually include various tests of the heart and brain function as well as a variety of different blood tests that will give information on the functional status of the liver, bone marrow, and the kidneys and will determine the patient’s blood group.

However, not every patient needs the full check-up. Your caregivers will inform you and your child, which diagnostic procedures are individually required in your case and why.

Treatment

In case of suspected or confirmed diagnosis of acute lymphoblastic leukaemia (ALL), the patient should be admitted to a children's hospital with a paediatric oncology program as soon as possible. Only there, the diagnostics and treatment provided by highly qualified professionals who are experienced with and specialised on kids and teens with cancer can be guaranteed.

Treatment options

Treatment of AML consists of intensive multiagent chemotherapy, sometimes combined with radiation of the brain and spine (craniospinal radiotherapy) and/or stem cell transplantation. Intensity and duration of treatment have to be determined individually for each patient, based on the patient’s individual risk-factors that influence the course of the disease, response to treatment, and thus prognosis. This strategy is called risk-adapted therapy.

The major goal of treatment is to eliminate all leukaemic cells in the body, thereby providing recovery for the bone marrow to appropriately function as a blood producing organ again. In order to prevent or adequately manage the side effects of the intensive therapy, specific supportive care regimens have been established and now represent an important and efficient component of AML treatment.

Treatment courses

In general, therapy of childhood AML is comprised of various treatment phases, duration, drug combinations and goals of which are quite different. Major treatment elements are:

1. Induction therapy: Induction consists of alternating courses of intensive chemotherapy with various anticancer agents (polychemotherapy). Induction aims at achieving remission, i. e. eliminating most of the leukaemia cells in a relatively short period of time.
2. Consolidation therapy: Consolidation follows induction therapy. It also includes courses of intensive chemotherapy, however, partially with different agents and higher dosages than those used during induction. With consolidation therapy, the patient should get rid of the remaining leukaemia cells and thus have a minimised risk of developing recurrent disease.
3. Treatment of the central nervous system (CNS-directed therapy): CNS-directed therapy is recommended for all patients with AML, also those, whose CNS (brain and/or spine) is not affected by the disease. CNS-directed therapy is therefore considered either a prophylactic or a therapeutic treatment, by which spread of leukaemia cells to or within the CNS is supposed to be prevented or stopped, respectively. CNS-treatment includes the application of anticancer drugs into the spinal canal via a lumbar puncture (intrathekal chemotherapy). If the CNS is definitely involved, radiotherapy of the cranium is recommended in addition to intrathekal chemotherapy.
4. Maintenance therapy: Maintenance therapy consists of a less intense polychemotherapy that is mostly given orally while the children are out-patients. The goal of performing maintenance therapy is to fight all leukaemia cells that might have survived the intensive treatment over a long period of time, usually about a year after cessation of intensive therapy.

Some patients, for example children with high numbers of leukaemia cells (high white blood cell counts) at diagnosis or patients with severe involvement of other organs, receive a so-called pretreatment prior to the induction therapy. Also, patients with Down syndrome or acute promyelocytic leukaemia are treated on the basis of specific treatment concepts.

The overall treatment time for patients not receiving stem cell transplantation is about one and a half years. It is longer in cases of nonresponse to therapy or recurrent disease.

Therapy optimising clinical studies

In Germany, diagnostics and treatment of almost all children and adolescents with first diagnosis of acute myeloid leukaemia (AML) are performed according to a standardised and controlled study protocol, that is continuously being optimised based on the current status of medical knowledge. With many treatment centers being involved in this kind of standardised treatment, such studies are also called “multicentred” and “cooperative”, and most often many countries participate.

The current protocol, AML-BFM 2004, is used by the majority of childhood cancer centres in Germany, Switzerland, Austria, and the Czech Rebublic. The study centre is localised at the Department of Paediatric Oncology and Haematology, Medical School Hannover, Germany (study coordinator: Prof. Dr. med. Dirk Reinhard). Comparable standardised treatment approaches have also been developed for patients with AML relapse.

Prognosis

Thanks to the immense progress in diagnostics and treatment during the last three decades, the chances of cure for children and adolescents with acute myeloid leukaemia (AML) have significantly improved. Today’s modern diagnostic procedures and the use of intensive, standardised polychemotherapy protocols associated with optimised supportive care regimens result in 5-year survival rates of about 60 %. However, this also means that in almost 40 % of the young patients the disease cannot be controlled. One reason is nonresponse to therapy, which means that the patient does not attain remission following the intensive treatment phase. About 10 % of patients are affected by nonresponse.

Furthermore, there are high incidences of recurrent disease, with about 30 % of the 110 children and adolescents diagnosed with AML in Germany per year suffering a relapse. Prognosis is significantly worse in case of relapse, in particular, if the disease comes back early, such as within a year after achievement of the first remission. In about one third of patients with relapsed AML, however, longterm disease-free survival can be achieved by intensive polychemotherapy followed by stem cell transplantation.

The major goal of the current AML treatment protocol, AML-BFM 2004, as well as of future studies is to identify ways to further improve prognosis for children and adolescents with AML or AML relapse, respectively.

Note: The survival rates mentioned in the text above are statistical values. Therefore, they only provide information on the total cohort of patients with childhood AML. They do not predict individual outcomes. Acute leukaemias can show unpredictable courses, in both patients with favourable and patients with unfavourable preconditions.