Acute myeloid leukaemia (also known as acute myeloblastic leukaemia, acute myelogenous leukemia, acute granulocytic leukemia and AML) is the most common type of acute leukaemia in adults. Under normal conditions the bone marrow produces cells known as myeloblasts which, after maturation, become granulocytes, cells responsible for the body's defences against infection.

With AML, cells of the myeloid cell line (myeloblasts) proliferate in an abnormal way and progressively invade the bone marrow, interfering with the production of normal blood cells, leading to bone marrow failure and the infiltration of extramedullary tissue.

Sometimes AML is the final stage of other diseases such as myelodysplastic syndromes or chronic myeloproliferative syndromes. The incidence of the disease is high amongst patients with certain chromosome alterations such as Down syndrome and Fanconi Anemia.

AML may appear years after having received chemotherapy and/or radiotherapy for the treatment of another cancer. Such AMLs are called secondary.

AML is a disease that affects adults, although it can sometimes be found in children. This kind of leukaemia accounts for 40% of the leukaemias in the western world. Its incidence in Spain is estimated to be 15 new cases per million inhabitants per year.

The average age of patients with AML is 64 years of age, with most patients falling between the ages of 60 and 75 years of age.

The two most commonly used methods for classifying AML are the former 2006 French-American-British (FAB) system, and the World Health Organization (WHO) system.

The FAB classification divides AML into 8 subtypes, from M0 to M7, based on the kind of leukaemia cells and their degree of maturity. The classification is established by means of examining the appearance of the leukaemia cells with an optical microscope or with cytogenetic methods.

The 8 AML subtypes according to the FAB system are:

Tipo FAB	Definition	Frecuency
AML 0	Acute myeloid leukaemia without localised differentiation	2-5%
AML 1	Acute myeloid leukaemia without maturation	15-20%
AML 2	Acute myeloid leukaemia with maturation	25-30%
AML 3	Acute promyelocytic leukaemia (with t15;17 translocation)	10-15%
AML 4	Acute myelomonocytic leukaemia (AMML)	15-30%
AML 5	Acute monocytic leukaemia (AMoL)	10-15%
AML 6	Erythroleukemia	3-4%
AML 7	Acute megakaryocytic leukaemia	1%

The World Health Organisation's (WHO) classification attempts to be more useful than that of the FAB from the clinical point of view, classifying leukaemias on the basis of causal genetic/molecular alteration or the existence of other possible causal factors that affect prognosis. In spite of this, in our country doctors usually continued to use the FAB classification.

The 5 AML subtypes according to the WHO classification are:

1) AML with recurrent cytogenetic alterations, a group which comprises the following main subtypes::

• AML 8;21 translocation*
• AML with chromosome 16 inversion**
• APL (acute promyelocytic leukaemia) with 15;17 translocation***
• AML with 9;11 translocation
• AML with 6;9 translocation
• AML with inversion of chromosome 3
• AMKL (acute megakaryoblastic leukaemia) with 1;22 translocation

* Translocation is when a segment of a chromosome is attached to another chromosome, in this case part of chromosome 8 is attached to chromosome 21; this is indicated as t(8;21)

** An inversion means that a segment of the chromosome changes position within the same chromosome; this is indicated as inv(16).

*** These three kinds of leukaemia are considered to have a good prognosis due to their good response to treatment.

All these entities also describe their corresponding genetic mutation, while others describe mutations that do not correspond to a cytogenetic alteration. This is the case with NPM1, CEBPA and FLT3 mutations to which ever greater importance is being attributed since the first two seem to imply a favourable prognostic value, while FLT3 mutation has a clearly unfavourable value. Nowadays, therefore, equal value is given to chromosome and molecular alterations in order to establish treatment protocols.

2) AML with multilineage dysplasia

— Secondary to a myelodysplastic or myeloproliferative syndrome

— Non-secondary

3) AML related to prior therapy (also called secondary AML)

4) AML related to Down syndrome

5) Other AML, including, amongst others:

— AML, minimally differentiated*

— AML without maturation*

— AML with maturation*

— Acute myelomonocytic leukemia*

— Acute monoblastic or monocytic leukemia*

— Acute erythroid leukemia*

— Acute megakaryoblastic leukemia*

— Acute basophilic leukemia

— Acute panmyelosis with myelofibrosis

— Myeloid sarcoma

* Corresponds to FAB classification (from AML0 to AML7)

6) Acute leukaemia of ambiguous lineage

— Undifferentiated acute leukaemia

— Acute bilineal leukaemia

— Acute biphenotypic leukaemia

Given the acute nature of the disease, the interval between the appearance of the first symptoms and diagnosis is usually less than three months. The symptoms of patients with AML are the consequence of the anemia produced by red blood cell deficiency (fatigue, debility, dizziness, pallor); platelet deficiency (bruises, bleeding gums, nosebleeds, bleeding from other foci); and granulocyte 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 chemotherapy, 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 treatment for acute myeloid leukaemia is determined on a case by case basis bearing in mind the subtype of the disease, the age and general state of health of the patient, and later on, the patient's response to initial treatment.

The main aim of any leukaemia treatment, or treatment for any other malignant blood disease, is to achieve complete remission from the disease at the molecular level. There are consequently two phases of treatment: remission induction and post-remission or consolidation. The maintenance phase, consisting of low doses of chemotherapy, that is so effective for acute lymphoblastic leukaemia (ALL) is totally ineffective for AML.

Remission induction therapy is always based on intensive chemotherapy, consisting in the intravenous administration of various anti-cancer drugs with the aim of achieving the disappearance of leukaemia cells from the blood and from the bone marrow (complete remission), enabling the normal production of the other blood cells. A patient is considered to have achieved complete remission when the number of blasts in the bone marrow is lower than 5%. This clinical situation can usually be achieved after the first course of treatment although, occasionally, a second course of induction therapy may be necessary to achieve remission. Generally speaking, 70-80% of patients achieve complete remission.

This must be followed by post-remission or consolidation therapy, the aim of which is to destroy the residual leukaemia cells (minimal residual disease), which could at any moment start to reproduce and cause a relapse.

AML patients have three options for post-remission therapy:

• Consolidation chemotherapy
• Consolidation chemotherapy followed by autologous transplant (from patients themselves)
• Consolidation chemotherapy followed by allogeneic transplant (from a compatible donor)

The first option is the one chosen for patients with a favourable prognosis (low risk of relapse) and without minimal residual disease data. There is insufficient evidence to recommend chemotherapy on its own, or chemotherapy followed by autologous transplant. The choice between one option and the other depends on the patient's age and the availability or otherwise of a compatible brother or sister that would enable an allogeneic transplant to be performed in the event of relapse. Similarly, the optimum consolidation therapy procedure to follow and the number of cycles of chemotherapy to administer has not been fully established. Nevertheless, when there is to be a transplant, just one course of consolidation therapy is usually administered, but when there is to be no transplant, two or three courses of consolidation therapy are usually administered.

For some patients with AML subtypes considered to be high risk (high risk of relapse, or after a relapse), who are under the age of 65 a hematopoietic progenitor transplant (bone marrow, peripheral blood or umbilical cord blood) is indicated from a compatible donor (allogenic transplant), ideally a histocompatible brother or sister or, in the absence of such a donor, a compatible non-related donor, or unit of umbilical cord blood, found internationally through a donor registry.

For patients aged between 65 and 70 the decision whether to perform an allogenic transplant or not must be made on a case by case basis. In such cases, it is not the patient's age in itself that is important, but rather the patient's general state of health, tolerance to previous treatments, state of mind and the availability of a compatible sibling. In such cases transplants from non-related donors are not contemplated given their extremely poor results.

For patients over the age of 70, given their poor tolerance to intensive chemotherapy and the low probability of a positive response to such treatment, different therapeutic strategies must be adopted. The most frequent ones are low-level chemotherapy and the administration of hypomethylating agents, such as Decitabine and Azacytidine, in order to delay the progression of the disease as much as possible, with the least toxicity and best quality of life possible.

Treatment for secondary and post-myelodysplastic AML is no different from other AMLs, although the probability of achieving and maintaining complete remission is much lower given the higher resistance to chemotherapy. In such cases, if feasible, an allogenic transplant of hematopoietic progenitors is usually performed, since it is the therapeutic option that presents the best chance of a cure.

Patients with Down syndrome require specific, lower intensity, protocols on account of their special sensitivity to chemotherapy.

The prognosis for patients suffering from acute myeloid leukaemia varies considerably and depends on the age of the patient and the AML subtype they are suffering from. Advanced age, AMLs associated with previous treatments, or secondary to a myelodysplasia or myeloproliferative syndrome, the degree of initial leukocytosis, the presence of certain genetic/molecular anomalies, and slowness in achieving complete remission, amongst other factors, are considerations that indicate a poor prognosis.

Young patients with standard risk leukaemias who receive an allogenic transplant from a family member or non-related donor during their first compete remission have a 65-70% probability of cure, while patients of advanced age with a post-myelodysplastic or secondary leukaemia who do not achieve complete remission through induction chemotherapy, have practically no chance of finding a cure.

Special attention must be paid to this leukaemia because, over recent decades, thanks to scientific research, substantial improvements have been made in its treatment such that, from being an AML subtype with a very poor prognosis, it is now a disease that responds very well to treatment. This disease is characterised by a translocation between the chromosomes 15 and 17 [t(15;17)], which affects the retinoic acid receptor alpha receptor (RAR-α or RARA), and by its sensibility to all-trans retinoic acid (ATRA). It is for this reason that this kind of leukaemia receives a different treatment from those used for other AMLs.

It is responsible for 10-15% of all cases of AML. The average age of patients with AML-3 is 40 years of age.

● Symptoms and diagnosis

Given the acute nature of the disease, the interval between the appearance of the first symptoms and diagnosis is usually less than two months. As well as symptoms attributable to the anemia produced by red blood cell deficiency (fatigue, weakness, dizziness, pallor), up to 75% of patients present hemorrhages (bruising, oral mucosa, nosebleeds, and bleeding from any other focus, including the central nervous system). Hemorrhages are responsible for 60% of deaths during this initial phase of the disease. A third of patients may present fever on account of secondary intercurrent infections due to granulocyte deficiency. It is rare to observe growth of the lymphatic ganglions, the liver or the spleen.

As well as the basic blood and bone marrow tests (morphology, cell and immunophenotype count), that are performed for all leukaemias, for AML-3 special importance is attributed to cytogenetic and molecular biology analysis since 80% of patients present t(15;17) translocation and 99% the PML-RARα, gene, making it possible to have a reliable diagnosis that has important therapeutic implications.

In contrast with other leukaemias, with AML-3 it is not recommended to perform a lumbar puncture to determine whether the disease has affected the central nervous system.

● Treatment and prognosis

During initial treatment (induction) chemotherapeutic agents of the anthracycline class (daunorubicin or idarubicin) are used, as is the non-chemotherapeutic ATRA, belonging to the vitamin A family.

This treatment enables remission to be achieved in approximately 80-90% of patients affected by acute promyelocytic leukaemia. After remission patients must receive three courses of consolidation therapy, followed by maintenance treatment for two years, during which ATRA continues to be administered.

In the event of relapse, patients must be treated with ATRA and chemotherapy (or more recently with arsenic trioxide + ATRA) in order to later undergo an allogenic transplant of hematopoietic progenitors or an autogenic transplant, depending on the level of response and the availability or otherwise of a related donor.

90% of patients achieve complete remission with the induction treatment and 99% achieve molecular remission after consolidation therapy, with more than 85% having a life expectancy of five years, after which it is exceptional for there to be a relapse.

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

 

• Adult acute myeloid leukaemia treatment. National Cancer Institute.
  
  
• Acute myeloid leukaemia. Leukaemia and Lymphoma Society. Leukaemia and Lymphoma Society

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

 

• Bone marrow transplant guide. Fundación Josep Carreras

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

• Fertility and treatment information. Leukaemia and Lymphoma Society