acute myeloid leukemia. What is adult acute myeloid leukemia and who does it affect?

Adult acute myeloid leukemia
What is adult acute myeloid leukemia and who does it affect?

Acute myeloid leukemia (also known as acute myeloblastic leukemia, acute myelogenous leukemia, acute granulocytic leukemia, or AML) is the most common type of acute leukemia in adults. Under normal conditions the bone marrow produces cells called myeloblasts that, after maturing, become granulocytes, cells responsible for the body's defense against infections.

In AML, the cells of the myeloid line (myeloblasts) proliferate abnormally, progressively invading the bone marrow, interfering with the production of normal cells in the blood, causing medullary insufficiency and infiltrating extramedullary tissues.

Occasionally, AML is the final stage of other diseases such as myelodysplastic syndromes or chronic myeloproliferative syndromes. Its incidence is very high among patients with certain chromosomal alterations such as Down syndrome or Fanconi anemia.

AML may appear years after receiving chemotherapy and / or radiotherapy for the treatment of another neoplasm; these AML are called secondary.

AML is an adult disease, although it can occasionally be seen in children. This type of leukemia accounts for 40% of all leukemias in the Western world. Its incidence in our country is estimated at 15 new cases per million inhabitants and year.

The median age of patients with AML is 64 years and the majority of patients are in the range of 60-75 years.
Types of acute myeloid leukemia

The two most commonly used schemes to classify AMLs are the old FAB system of 2006 and the new system of the WHO (World Health Organization).

The FAB classification (Franco-Anglo-American) divides the AML into 8 subtypes, from M0 to M7, based on the type of leukemic cells and their degree of maturity. This classification is established by examining the appearance of leukemic cells under an optical microscope or by cytogenetic techniques.

The 8 AML subtypes according to the FAB system classification are:
Type FAB Definition Frequency
AML 0 Acute myeloid leukemia without localized differentiation 2 - 5%
AML 1 Acute myeloid leukemia without maturation 15 - 20%
AML 2 Acute myeloid leukemia with maturation 25 - 30%
AML 3 Acute promyelocytic leukemia (with translocation t15; 17) 10 - 15%
AML 4 Acute myelomonocytic leukemia (AML) 15 - 30%
AML 5 Acute monocytic leukemia (LMoA) 10 - 15%
LMA 6 Erythroleukemia 3 - 4%
AML 7 Acute megakaryocytic leukemia 1%

The classification of the World Health Organization (WHO) tries to be more useful than the FAB from the clinical point of view, classifying the leukaemias based on the genetic / molecular causal alteration or the existence of other possible causal factors with prognostic impact. Despite this, in our country it is common for medical teams to continue using the FAB classification.

The 5 subtypes of AML according to the WHO classification are:

1) AML with recurrent cytogenetic alterations, a group in which, in a schematic way, the main subtypes are included:

    AML with translocation 8; 21 *
    AML with inversion of chromosome 16 **
    The promyelocytic with translocation 15; 17 ***
    AML with translocation 9; 11
    LMA with translocation 6; 9
    AML with inversion of chromosome 3
    AML (megakaryoblastic) with translocation 1; 22


A translocation is the displacement of a segment from one chromosome to another chromosome, so in this case part of chromosome 8 is located in 21, it is indicated as t (8; 21)

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

*** These three varieties of leukemia are considered good prognosis because of their good response to treatment.

In all these entities, their corresponding genetic mutation has also been described, while in others, mutations have been described that do not correlate with a cytogenetic alteration. This is the case of mutations NPM1, CEBPA and FLT3 to which it is increasingly being given greater relevance since the first two seem to provide a favorable prognostic value while the FLT3 mutation has a clearly unfavorable value. Therefore, nowadays, both chromosomal and molecular alterations are evaluated to establish treatment protocols.

2) AML with multiline dysplasia

- Secondary to a myelodysplastic or myeloproliferative syndrome

- No secondary

3) AML related to previous treatments (also called secondary AML)

4) AML related to Down Syndrome

5) Other AML, including:

- LMA minimally differentiated *

- LMA without maturation *

- LMA 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

* They correspond to the FAB classification (from LMA0 to LMA7)

6) LA with line ambiguity

- The undifferentiated LA

- LA bilinear

- Bifenotypic LA
Symptoms and diagnosis

The interval between the appearance of the first symptoms and the diagnosis is usually less than 3 months due to the acute nature of the disease. The symptoms of patients with AML are a consequence of the anemia produced by the deficit of red blood cells (feeling tired, weak, dizzy, pale); of platelet deficiency (bruising, bleeding of the gums, nasal or any other focus); and the deficit of granulocytes (fever and infections). Sometimes the growth of the lymph nodes, the liver or the spleen can be observed. Specific symptoms of infiltration of the central nervous system (headache, vomiting, drowsiness, etc.), skin (disseminated nodules or areas of thickened skin), mucous membranes (inflammation of the gums), ocular (blurred vision, blindness) may also be observed. ), among other.

In addition to basic studies in blood and bone marrow to be performed in all leukemia, cytogenetic studies (to detect specific chromosomal abnormalities) and molecular studies (to detect specific gene alterations), since they are essential to classify and classify the disease. Certain genetic or molecular alterations are accompanied by a greater or lesser sensitivity to chemotherapy treatment and a higher or lower risk of recurrence.

It should also be studied if the disease has spread to the central nervous system by performing a lumbar puncture in order to analyze the cerebrospinal fluid that bathes this system.
The treatment

The treatment of acute myeloid leukemia will be determined in each case taking into account the subtype of the disease, the age, the general condition of the patient and, subsequently, the response to the initial treatment.

The main objective of any treatment in leukemias or other haematological malignancies is to achieve complete remission of the disease at the molecular level. For this reason, there are 2 treatment phases: induction to remission and post-remission or consolidation. The maintenance phase with low doses of chemotherapy so effective in acute lymphoblastic leukemia (ALL) is totally ineffective in AML.

The phase of induction to remission is always based on intensive chemotherapy, consisting of the administration of various antineoplastic agents intravenously in order to achieve the disappearance of leukemic cells from the blood and bone marrow (complete remission), allowing the production normal of the other blood cells. It is considered that a patient has achieved complete remission when the number of blasts in the bone marrow is less than 5%. This clinical situation is usually achieved after the first treatment cycle, although it may sometimes be necessary to administer two cycles of induction to achieve remission. Overall, 70-80% of patients will achieve complete remission.

Subsequently, a post-remission or consolidation treatment must be carried out with the purpose of destroying the residual leukemic cells (minimum residual disease) that at any time could begin to reproduce and cause a relapse.

In patients with AML, there are three options for post-remission treatment:

    Consolidation chemotherapy
    Consolidation chemotherapy followed by autologous transplantation (from the patient)
    Consolidation chemotherapy followed by allogeneic transplantation (from compatible donor)

The first option is the choice in patients with favorable prognosis (low risk of recurrence) and no residual minimal disease data. There is not enough evidence to recommend chemotherapy alone or chemotherapy followed by auto-TPH. The decision between one or another option usually depends on the age of the patient and the availability or not of a compatible sibling that allows an allogeneic transplant in case of recurrence of the disease. Similarly, the optimal regimen to be used for consolidation and the number of chemotherapy cycles to be administered are not well established. However, when a transplant is to be performed, a single consolidation cycle is usually administered, whereas when transplant is not performed, two or three cycles tend to be administered.

In some patients with AML subtypes considered high risk (high risk of relapse of the disease or after a relapse), and with ages less than 65 years, it is indicated to perform a transplant of hematopoietic progenitors (bone marrow, peripheral blood or umbilical cord blood) from a compatible donor (allogeneic transplant), ideally a histocompatible sibling or, failing that, a non-related compatible voluntary donor located globally or an umbilical cord blood unit.

In patients between the ages of 65 and 70, the decision to perform an allogeneic transplant should be made individually. In these cases the important thing is not the age itself, but the general condition of the patient, tolerance to previous treatments, their mood and the availability of a compatible sibling (in these ages the possibility of performing a transplant is not considered). of a non-family donor due to its very poor results).

In patients older than 70 years, given the poor tolerance to intensive chemotherapy and the low probability of response of elderly patients' AML (more resistant to treatment), different therapeutic strategies should be adopted. The most used are chemotherapies at low doses or the use of hypomethylating agents, such as Decitabine or Azacitidine, which are intended to delay the progression of the disease to the maximum, causing the least toxicity and the best possible quality of life.

The treatment of secondary and post-myelodysplastic AML does not differ from the rest of the AML, although the likelihood of achieving a complete, sustained remission is much lower due to its greater resistance to chemotherapies. In these cases, if feasible, it is common to perform an allogeneic transplant of hematopoietic progenitors because it is the therapeutic approach with greater curative possibilities.

Patients with Down syndrome, due to their special sensitivity to chemotherapy, require specific protocols of lesser intensity.
The prognosis

The prognosis of patients affected with acute myeloid leukemia varies substantially depending on the age and subtype of the AML. Advanced age, AML related to previous or secondary treatments to myelodysplasia or myeloproliferative syndrome, the degree of initial leukocytosis, the presence of certain genetic / molecular anomalies, as well as the slowness in obtaining complete remission, among others, constitute parameters of an unfavorable forecast.

Thus, young patients with standard risk leukaemias who receive a family allogeneic or unrelated donor transplant in first complete remission have a probability of healing of up to 65-70%, while an elderly patient with a post-leukemia - myelodysplastic or secondary that does not reach complete remission with induction chemotherapy, has practically no cure options.
Specific subtype: Acute promyelocytic leukemia (AML-3)

We must pay special attention to this leukemia because in recent decades, thanks to scientific research, it has obtained a substantial improvement in its treatment, going from being a subtype of AML with very poor prognosis to being a disease that responds very good to the treatment. This disease is characterized by a translocation between chromosomes 15 and 17 [t (15; 17)], which affects the retinoic acid receptor alpha (RAR-α or RARA), and its sensitivity to holo-transretinoic acid (ATRA) . That is why this type of leukemia receives a different treatment than that used in the rest of the AML.

It represents 10 - 15% of all AML. The median age of patients with AML-3 is 40 years.

● Symptoms and diagnosis

The interval between the appearance of the first symptoms and the diagnosis is usually less than two months due to the acute nature of the disease. In addition to symptoms attributable to anemia caused by red blood cell deficiency (feeling tired, weak, dizzy, pale), hemorrhages are usually present in up to 75% of patients (bruising, oral and nasal mucosa, or any other another focus, including the central nervous system). Hemorrhages are responsible for 60% of deaths in this initial phase of the disease. One third of patients may have fever due to intercurrent infections secondary to the lack of granulocytes. It is rare to see growth of lymph nodes, liver or spleen.

In addition to the basic studies in blood and bone marrow (morphology, count and immunophenotype) to be performed in all leukemia, in the AML-3, cytogenetics and molecular biology acquire special relevance since 80% of patients have the t (+) translocation ( 15; 17) and 99% the PML-RARα gene, which make it possible to establish a safety diagnosis with important therapeutic implications.

Unlike in other leukemias, it is not recommended to perform a lumbar puncture in order to analyze if the disease has affected the central nervous system.

● Treatment and prognosis

In the initial (induction) treatment, a chemotherapeutic agent of the class of anthracyclines (daunorubicin or idarubicin) and a non-chemotherapeutic drug, ATRA, belonging to the family of vitamin A are used.

This treatment allows to achieve remission in approximately 80-90% of patients affected by acute promyelocytic leukemia. After remission, they must receive three consolidation cycles and then carry out maintenance treatment for two years during which the ATRA continues to be administered.

In the case of a relapse, patients should be treated with ATRA and chemotherapy (or more recently with arsenic trioxide + ATRA) to receive an allogeneic hematopoietic stem cell transplant or a self-transplant, depending on the degree of response and availability or not a family donor.

90% of patients achieve complete remission with induction treatment and 99% reach a molecular remission after consolidation, with an expected survival at 5 years of over 85%, with recurrences being exceptional after this time.
+ info

For more information, you can consult the following web pages:

- National Cancer Institute of the United States - Acute myeloid leukemia in adults
- American Cancer Society - Treatment of acute promyelocytic leukemia
- MedlinePlus: Acute myelogenous leukemia in adults
Meet AML patients

Read the testimony of people who suffer or have suffered from this disease.
Support and help

If you have acute myeloid leukemia or the patient is a family member, you can access the forum of patients and ex-patients of the Josep Carreras Foundation, a group of people who support and advise to live this situation in the best possible way. You can access the forum from here.