Acute leukaemias are a group of cancer diseases characterised by the malignant transformation and uncontrolled production of immature hematopoietic cells of the lymphoid line (acute lymphoblastic leukaemia, ALL) or myeloid line (acute myeloblastic leukaemia, AML).

With acute myeloid leukaemia, the cells of the myeloid line (myeloblasts) proliferate abnormally and progressively invade the bone marrow, interfering with the normal production of blood cells, leading to bone marrow failure and the infiltration of extramedullary tissues.

Acute leukaemias are the most frequent cancers during childhood and account for 32% of the cancers during this period (under 15 years of age). The lymphoid form is the most frequent and AML accounts for 20% of the leukaemias diagnosed during this stage of life. The annual incidence of AML during childhood is 8 cases per million children under the age of 15. (US Cancer Institute's Surveillance, Epidemiology and End Results (SEER) program). 

AML during childhood is most frequent before the age of two. Its incidence declines during school years and then increases progressively with age after adolescence.

The specific causes of most cases of childhood AML are not known. Only in a very small percentage of cases (around 5%), do acute childhood leukaemias develop in patients with an underlying genetic disorder that predisposes them to leukaemia such as, for example, Down syndrome or inherited bone marrow failure syndromes (Fanconi anemia and dyskeratosis congenita, amongst others).

The two most commonly used methods for classifying AML are the French-American-British (FAB) system, based on the leukaemia cell's microscopic characteristics and its expression of certain proteins (immunophenotype), and the new World Health Organization (WHO) system, which incorporates genetic and molecular information about the leukaemia cell and clinical information of prognostic interest.

In our country the most commonly used method is the FAB classification.

The WHO classification, updated in 2016, takes into account genetic and molecular aspects of the leukaemia cells. The most common cytogenetic alterations in AML are translocations; the attachment of a fragment of a chromosome to another chromosome (indicated as t). For example: t(8;21), a fragment of chromosome 8 has become attached to a part of chromosome 21; or, within the same chromosome, t(16;16). Chromosome inversions may also be observed when a segment of a chromosome changes direction within the same chromosome (this is indicated as inv).

The translocations and inversions detected in cytogenetic studies generate the rearrangement of the genes located in the affected regions of the chromosome. These are indicated by the names of the genes involved, so in the case of t(8;21) it will generate a rearrangement of the genes RUNX1 and RUNX1T1. Cytogenetic alterations have proved to be a very important prognostic factor and are used is most treatment protocols to determine their intensity.

In recent years, mutations have been described in one or various genes of the leukaemia cells of most patients. Some of them have proved to be of prognostic importance and of relevance when determining the intensity of treatment. Thus, the WHO's recent classification includes the mutations in NPM1 and CEBPA, which are associated with a more favourable prognosis.

Most childhood cases are classified within the AML group with recurrent genetic alterations or non-specific AML.

The clinical presentation of AML is variable and, in general, the symptoms diagnosed are due to the infiltration of the bone marrow, and other organs, by leukaemia cells. Although its initial presentation may be insidious, childhood AML is usually acute, with less than three months between the onset of symptoms and diagnosis.

The most common symptoms are the result of anemia caused by a deficiency in red blood cells (fatigue, debility, dizziness, pallor); platelet deficiency (bruises, petechiae, bleeding gums, nosebleeds, bleeding from other foci), and white blood cell deficiency (fever and infections).

Sometimes a growth can be observed of the lymphatic ganglions, the liver or the spleen. Specific symptoms of the infiltration of the central nervous system may also be observed (headaches, vomiting, drowsiness, etc.), skin (disseminated nodules or lumps), mucous membrane (inflammation of the gums), vision (blurred vision, blindness), amongst others.

As well as the basic blood and bone marrow tests that are performed for all leukaemias, cytogenetic tests (to detect specific chromosome anomalies) and molecular diagnoses (to detect specific genetic alterations), are also performed since they are of fundamental importance for categorising and classifying the disease. Certain genetic and molecular alterations are associated with a greater or lesser response to therapy, or a greater or lesser risk of relapse.

Studies must also be conducted to determine whether the disease has spread to the central nervous system by performing a lumbar puncture in order to analyse the cerebrospinal fluid it contains.

The prognosis for childhood AML has improved significantly over recent decades. This improvement is the result, in part, of the better classification and stratification of each patient into risk groups, which is to say, according to each individual's risk of relapse. This stratification makes it possible to apply adapted therapeutic strategies whereby more intensive therapies are employed for patients presenting high-risk prognostic factors, and lower-level therapies for those considered to have a low risk of relapse.

The final aim of the treatment is to achieve complete remission from the disease and that this remission be profound (at the molecular level) and permanent.

A distinction is to be drawn between two phases of treatment: induction, and post-remission (or consolidation), therapies. The maintenance phase with low doses of chemotherapy, used in the protocols for acute lymphoblastic leukaemia, have been abandoned in most protocols for AML, being considered to offer no additional benefit, except in the case of the subgroup of acute promyelocytic leukaemia (see below).

Treatment for childhood AML is always based on intensive chemotherapy; the intravenous administration of various cytostatic drugs (chemotherapy) over various courses of treatment. Normally, although this can vary according to the protocol being followed, 1 or 2 induction courses are administered, followed by 2-3 courses of consolidation.

The aim of the induction therapy is to eliminate the leukaemia cells in the blood, and most of the disease present in the bone marrow, thereby returning it to its normal function, something referred to as achieving complete remission. This clinical situation can usually be achieved after the first course of induction therapy, although it is sometimes necessary to administer two more courses of induction therapy to achieve this result. With the protocols currently in use, more than 85% of patients achieve complete remission after the induction therapy phase.

This is followed by post-remission, or consolidation, therapy, the aim of which is to eliminate any residual leukaemia cells (minimal residual disease), that could be responsible for a future relapse.

Chemotherapy specifically targeting the central nervous system directly must also be administered (intrathecal chemotherapy). These drugs are administered by means of lumbar puncture. The use of cranial radiotherapy has been removed from most protocols.

For some patients a transplant of hematopoietic progenitors (HPT) may be indicated as part of the consolidation treatment. Most present-day protocols no longer include autologous bone marrow transplant (from one's self) as part of the consolidation treatment for this disorder, but in cases in which it is indicated, it is recommended that the HPT be from a compatible donor, that is to say, an allogenic transplant, from either a related or a non-related donor.

HPT in cases of childhood AML is a subject that is under constant review. The indications for HTP for patients with AML during the first complete remission (patients who have not presented relapse) are controversial and are not the same in all countries. Generally speaking, this treatment is reserved for cases considered to be of high risk on account of the biological characteristics of the disease, or because of an unsatisfactory response to chemotherapy. Most patients who have suffered a relapse but achieve a second complete remission are candidates for HPT.

The chances for a cure are determined by the patient's characteristics, those of the disease (genetic/molecular alterations), the treatment administered and the patient's response to this treatment. In contrast with adults, when the patient's characteristics, such as advanced age or the co-existence of other disorders, may be of great importance, in the case of children, such factors are not relevant.

The rate of survival for children with AML has improved notably over recent years, approaching 65%. This improvement has been due to the increased intensity of chemotherapy, the improved classification of patients into risk groups, the implementation of more effective support measures such as better antibiotics, the ease with which blood and platelet transfusion may be sought, help with diet and specialised nursing, as well as a notable improvement in the selection of donors for carrying out HPT

For more quality information about childhood acute myeloid leukaemia you can consult the following websites:

• Childhood acute myeloid leukaemia treatment. National Cancer Institute.

• Chronic myelomonocytic leukaemia and juvenile myelomonocytic treatment. National Cancer Institute
  
  
• Guide for ALL patients and caregivers. Leukaemia & Lymphoma Society

• Información sobre la leucemia mielomonocítica crónica y la leucemia mielomonocítica juvenil. Leukaemia and Lymphoma Society

• Acute Promyelocytic
  Leukemia Facts. Leukaemia and Lymphoma Society
  
  
• Treatment of acute promyelocytic leukemia. Leukaemia and Lymphoma Society

There are other resources and links of interest that may be of use to patients with childhood acute myeloid leukaemia:

• Bone marrow traansplant guide. Fundación Josep Carreras

• Graft-versus-host disease. Leukaemia and Lymphoma Society