Author: Dipl. Biol. Maria Yiallouros, erstellt am: 2010/02/04, Reviewer: Prof. Dr. med. Günter Henze, English Translation: Dr. med. Gesche Tallen, Last modification: 2011/08/10 doi:10.1591/poh.patinfo.all.kurz , Kurz-URL: www.kinderkrebsinfo.de/ALL_kurzinformation

General information

Acute lymphoblastic leukaemia (ALL) is a malignant disease that arises from transformed cells of the haematopoietic system. ALL 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 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 ALL, 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 ALL 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.

ALL can rapidly progress. 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 80 % of childhood leukaemia, acute lymphoblastic leukaemia (ALL) is the most frequent leukaemia in children and adolescents, and it accounts for about one third of all cancers in this age group.

According to the German Childhood Cancer Registry in Mainz, about 500 children and teenagers aged between 0 and 14 years are newly diagnosed with ALL in per year. Counting all paediatric patients up to 19 years of age, the incidence is about 550-600 new diagnoses per year.
In general, ALL can develop in every age group. The frequency of childhood ALL is highest during the first five years of life, with boys being slightly more affected than girls.

Classification of acute lymphoblastic leukaemia

ALL is mainly characterised by a malignant transformation of lymphocyte precursor cells (lymphoblasts). This transformation can happen during every stage of cell maturation (differentiation), thereby affecting various subtypes of lymphocytes as well as their precursors. Accordingly, there are different forms of ALL, such as those arising from B-lymphocyte precursor cells (B-ALL) or from T-lymphocytes and their precursor cells (T-ALL). In cases of malignant transformation during early development of the lymphocyte, the resulting ALL is marked with the prefix ”pre–“.

In fact, various subtypes of childhood ALL, such as pre-pre-B-ALL (pro-B-ALL), common ALL, pre-B-ALL, pre-T-ALL and T-ALL, to name a few, have been characterised so far, the courses and prognoses of which can differ significantly. Current treatment strategies for children and adolescents with ALL consider these different subtypes. Therefore, children and adolescents with ALL do not all receive the same treatment.

Causes

The causes of acute lymphoblastic leukaemia (ALL) still have to be elucidated. It is known so far that the disease arises from the malignant transformation of precursor lymphocytes, 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, ALL 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 acute leukaemia than their healthy peers. Also exposure to ionising irradiation or X-ray, certain genotoxic chemicals and drugs as well as 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 ALL has been identified yet.

Symptoms

The symptoms of most children and adolescents with ALL 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 ALL.

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 ALL complain about bone pain, most often in the back and in the long bones of the arms and legs, which is a result of bone marrow replacement by leukaemic cells. 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 ALL. 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 ALL. 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.

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 ALL and an acute myeloid leukaemia (AML), but also to define the subtype of ALL. Knowing the subtype is important for optimal treatment planning, because the different forms of ALL 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, bones or brain), primary diagnostics are completed by imaging, such as 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 interpret 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, the latter of which 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 patients with ALL 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 (like ALL subtype, extension of disease) 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 ALL treatment.

Patients with mature B-ALL are excluded from the treatment concepts recommended for all the other ALL-subtypes. Instead, they are treated according to the protocols for children and adolescents with mature B-cell non-Hodgkin-lymphomas, which you can find here.

Treatment courses

In general, treatment of childhood ALL (except mature B-cell ALL) is comprised of various 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. This treatment phase usually takes five to eight weeks.
2. Consolidation therapy: Consolidation follows induction therapy and takes about two to four months. It includes courses of intensive chemotherapy, however, partially with different agents than those used during induction. With consolidation therapy, the patient should get rid of the remaining leukaemia cells (maintain remission) and thus have a minimised risk of developing recurrent disease. An important component of consolidation is the prophylactic treatment of the central nervous system (CNS-directed therapy), by which spread of leukaemia cells to the CNS is supposed to be prevented. CNS-treatment includes the application of anticancer drugs into the spinal canal via a lumbar puncture (intrathekal chemotherapy). For most ALL patients with CNS-involvement, radiotherapy of the cranium is recommended in addition to intrathekal chemotherapy in order to prevent further spread of leukaemic cells within the CNS.
3. Reinduction therapy: This phase consists of alternating courses of polychemotherapy, the intensity of which is comparable to that of induction therapy. Reinduction is to ensure complete destruction of leukaemia cells, and thus minimise the risk of developing recurrent disease. Reinduction might take weeks to months, with intensive treatment courses alternating with chemotherapy pauses.
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 until a total treatment time of two years has been achieved.

Currently open national and international clinical trials

In Germany, Austria, Switzerland and many other European countries, diagnostics and treatment of almost all children and adolescents with first diagnosis of acute lymphoblastic leukaemia (ALL) are performed according to standardised and controlled protocols, which are continuously being optimised based on the current status of medical knowledge. Since numerous treatment centres in different countries are involved in these therapy optimising studies, they are also called “multicentred” and “cooperative” clinical trials.

The following list shows the currently open national and international clinical trials for children and adolescents with acute lymphoblastic leukaemia (B-ALL). Please note, that these protocols do not include patients with mature B-cell ALL. The current management algorithm for children with mature B-cell ALL is identical with the one provided by the treatment protocl for patients with mature B-cell Non-Hodgkin-Lymphom‎a.

• Trial AIEOP-BFM ALL 2009, an international, multicentric therapy optimising trial for the treatment of children and adolescents between 1 and 18 years of age with first diagnosis of ALL. Many treatment centres throughout Germany, as well as in Austria, Switzerland, Italy, the Czech Republic, Israel and Australia are participating in this trial. The coordination centre of trial AIEOP-BFM ALL 2009 is located at the University Hospital of Schleswig-Holstein, Campus Kiel, Germany. The study coordinator and chair is Prof. M. Schrappe, MD, PhD. The protocol of trial AIEOP-BFM ALL 2009 is based on the experiences obtained with trial AIEOP-ALL BFM 2000, which has been closed in 2010.
• Trial CoALL-08-09 (CoALL is the abbreviation for "cooperative ALL"), a multicentric therapy optimising trial of the GPOH‎ for treatment of children and adolescents with first diagnosis of ALL. Since its opening in October 2010, various treatment centres have participated in this trial, the protocol of which is a bit different from AIEOP 2009. The study coordinator and chair is Prof. M. Horstmann, MD, PhD, at the University of Hamburg in Germany.
• Trial INTERFANT-06, an international multicentric trial for infants up to 1 year of age with first diagnosis of ALL or of a certain ALL-subtype called biphaenotypic ALL. The German trial coordination centre is located at the University Hospital of Schleswig-Holstein, Campus Kiel, Germany. The study coordinator and chair is Prof. M. Schrappe, MD, PhD.
• Trial EsPhALL, an international trial for patients with Philadelphia chromosome-positive ALL, who are already enrolled in BFM-, COALL- or INTERFANT-trials, respectively. (Chair: Prof. M. Schrappe, MD, PhD, University of Schleswig-Holstein, Campus Kiel, Germany).
• Trial ALL-SZT BFM 2003, a multicentric trial for the treatment and therapy optimisation of paediatric patients with ALL and eligible for allogeneic stem cell transplantation. This trial is open for patients who are enrolled in an ALL BFM- (or ALL-REZ BFM, respectively) or in the CoALL trial. The trial coordination centre is located at the St. Anna Children's Hospital in Vienna, Austria. Chairperson is Christina Peters, MD, PhD.
• Trial ALL-REZ BFM 2002, a multicentric therapy optimising trial for treatment of children and adolescents with first relapse of an ALL. More than 100 centres in Germany, Austria, Switzerland are participating. The study coordination centre is located at the Dpt. of Paediatric Oncology/Haematology, Charite, University Medicine Berlin, Campus Virchow, Berlin, Germany. Chair is Prof. G. Henze, MD, PhD, Dr. hon. and the study coordinator is A. von Stackelberg, MD, PhD.

The major goal of all these trials is to further improve the treatment and reduce the side-effects for patients with childhood (relapsed) ALL. Furthermore, specific knowledge of the disease is intensified by associated research projects, the results of which will determine future treatment protocols.

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 lymphoblastic leukaemia (ALL) have significantly improved. Today’s modern diagnostic procedures and the use of intensive, standardised polychemotherapy protocols combined with optimised supportive care regimens result in 5-year survival rates of currently about 87 %.

However, for children with unfavourable prognostic factors, such as high white blood cell counts at diagnosis and/or nonresponse to therapy and/or a certain ALL-subtype, survival rates are considerably lower than 87 %.

About 90 of the 550 – 600 children and adolescents (every seventh patient) newly diagnosed with ALL in Germany per year develop(s) recurrent disease. Recurrent disease most frequently appears during the first two to three years, while they are rather rare after five years following first diagnosis of ALL. Prognosis is significantly worse in case of relapse. Some patients, for example those with late relapses, however, might profit from stem cell transplantation following high-dose chemotherapy. The 5-year-survival rates for patients with first relapse of childhood ALL are currently about 35 – 40 %. The major goal of the currently active ALL treatment protocols as well as of future studies is to identify ways to further improve prognosis for children and adolescents with ALL or ALL 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 ALL. They do not predict individual outcomes. Acute leukaemias can show unpredictable courses, in both patients with favourable and patients with unfavourable preconditions.