The bone marrow produces the blood cells. 
Leukemia usually affects the production of white blood cells, that is, cells that fight viruses, bacteria and fungi to prevent infections .
The immature cells (blasts) found in the case of leukemia do not function like normal and mature cells.
Blasts are immature cells from which they derive:

  1. White blood cells (leukocytes),
  2. Red blood cells (red cells or erythrocytes),
  3. Platelets

In the case of acute myeloid leukemia, the blasts:

  1. They continue to grow,
  2. Entopem the bone marrow and infer with the production of normal cells.

The consequences are the difficulties:

  1. To combat infections,
  2. To block bleeding ,
  3. To transport oxygen.

 

Acute leukemia
is a proliferative disease characterized by rapid growth of immature blood cells .

This buildup prevents the bone marrow from producing healthy blood cells.
Immediate treatment is necessary because of the rapid progression and accumulation of malignant cells that:

  1. Enter the bloodstream,
  2. They spread to other organs.

If left untreated, the patient may die within a few months or even weeks.
There is a severe variant of acute leukemia which is called fulminant leukemia, in this case:

  1. The course is very fast,
  2. Usually the death of the individual occurs in a short time.

Acute leukemia is characterized by:

  • Increased blood cells ,
  • Interruption of differentiation – the cells produced by the bone marrow are immature or undifferentiated blasts.

It was previously called acute nonlymphocytic leukemia.
Also known as acute myelogenous leukemia (AML), it occurs more often in adults than in children.
Studies show that AML occurs mainly in males than in females.

 


Acute lymphocytic leukemia

This type of leukemia affects lymphoid cells (lymphocytes) that accumulate:

  1. In bone marrow,
  2. In the lymph nodes and in the lymphatic tissue.

Lymphatic tissue forms the immune system. 
Also known as lymphoblastic or acute lymphoid leukemia, it is the most common type of leukemia in children. This disease also affects adults, especially those 65 years or older.
It is a lymphocyte tumor characterized by overproduction and the continual multiplication of malignant immature white blood cells in the bone marrow.

 


Child Leukemia

Similar to adult leukemia, childhood leukemia can be:

  1. Acute,
  2. Chronic.

However, in children, leukemia is mainly acute.
Acute childhood leukemia is classified into 3 categories:

  1. Acute lymphocytic leukemia (ALL);
  2. Acute myeloid leukemia (AML);
  3. Hybrid leukemia.

In ALL the problem begins in the cells that form the lymphocytes, while in the AML the problem begins in the non-lymphocytic cells that form:

  1. White blood cells,
  2. Red blood cells,
  3. Platelets.

Hybrid leukemia is a combination of ALL and LMA, in which lymphocyte and non-lymphocytic progenitor cells are affected.
ALL represents the most frequent type of childhood leukemia, up to 70% incidence of childhood leukemia.
The remaining 30% consists of LMA and hybrid leukemia.
A rare form called juvenile myelomonocytic leukemia (JMML) occurs in young children younger than 4 years. It can be acute or chronic.

 

Symptoms of acute myeloid leukemia (AML)

The AML spreads rapidly in the blood and bone marrow.

Symptoms

Localized or diffuse lymphadenomegaly ( swollen lymph nodes ) is present in 14% of cases.
Massive generalized lymphadenomegaly is present in about 25% of patients with the M4-M5 (monocytic component) form.
A parotid lymph node is affected in the right image.
The patient suffers from  acute extramedullary myeloid leukemia , with accumulation of neoplastic cells in the skin or other organs.

 

Early symptoms of leukemia

The first signs and symptoms of leukemia are:

  1. Constant fatigue ,
  2. Weight loss,
  3. Fever or chills ,
  4. Frequent infections.

 

Symptoms of leukemia in children

Depending on the number of leukemic cells, children have different symptoms.

These children appear pale, weak, and anemic.
In addition, other symptoms include:

The decrease in red blood cell count also causes pallor of the skin along with swollen lymph nodes due to excess white blood cells in the blood.

 

Classification (FAB) of LMA

In 1970, a group of French, American, and British specialists divided acute myeloid leukemia into subtypes, from M0 to M7, based on the type of cell that developed leukemia and the maturation of cells.

Subtype FAB Name
M0 Undifferentiated acute myeloblastic leukemia
M1 Acute myeloid leukemia with minimal maturation
M2 Acute myeloid leukemia with maturation
M3 Acute promyelocytic leukemia (APL)
M4 Acute myelomonocytic leukemia with eosinophilia
M5 Acute monocytic leukemia
M6 Acute erythroid leukemia
M7 Acute megakaryoblastic leukemia

The blasts of the M0 have no sign of differentiation, so they are absolutely immature.
Starting from M1 to M3, the differentiation is interrupted at several levels, the explosions of:

  1. M1 are at a fairly undifferentiated stage,
  2. M2 are in an intermediate stage,
  3. M3 are more differentiated.

The presence of the granules is a typical sign of differentiation, in particular the granules are observed in M2, but not in M1.

 


Treatment for acute myeloid leukemia

Because there are many different forms of acute myeloid leukemia, it is difficult to identify the appropriate target therapy .
There are about 200 translocations and known chromosomal mutations, but some are more frequent than others.
One of the mutations most commonly found in AML is tandem internal duplication of FMS-like tyrosine kinase 3   (FLT3-ITD).
This mutation is present in about 25% of all patients suffering from AML and is associated with an unfavorable prognosis.
Source : Acute myeloid leukemia: the challenge of capturing disease variety. Löwenberg B – Hematology Am Soc Hematol Educ Program. 2008; (): 1-11

Usually the doctor proposes a treatment with different types of drugs together.
Treatment includes:

 

Chemotherapy

Combinations of cytarabine (AraC) and anthracyclines are the initial treatment for acute myeloid leukemia.
A high dose of AraC is now standard therapy in patients <60 years.
Source : Current and emerging therapies for acute myeloid leukemia – Robak T1, Wierzbowska A – Clin Ther. 2009; 31 Pts. 2: 2349-70 .
Cytarabine (AraC) is effective against acute myeloid leukemia because it binds to the hENT1 receptor that is present in tumor cells.
After some chemical reactions inside the cell, this drug acts on the DNA blocking the synthesis and repair of cellular genetic material.

Dosage of chemotherapy drugs

  1. Daunorubicin (60 or 90 mg / m2 on days 1, 2 and 3),
  2. Idarubicin (10-12 mg / m2 on days 1, 2 and 3).

These drugs should be given in combination with a continuous infusion of cytarabine for seven days (100 mg / m2 / day for one week.)
The goal of chemotherapy is complete remission (CR), ie:

  • Less than 5% of blasts in the bone marrow aspirate sample, nucleated cells ≥ 200 (without Blasts with Auer bodies or persistence of extramedullary disease),
  • Neutrófilos (ANC) > 1000 / μL,
  • Platelets ≥ 100,000 / μl.

 

Inhibitors of tyrosine kinase 3 (FLT3) similar to FMS

Several inhibitors of the small molecules FLT3 have been developed with mixed results.
First-generation drugs include inhibitors of different kinases, such as:

  1. Midostaurina,
  2. Lestaurtinib,
  3.  Tandutinib,
  4. Sunitinib,
  5. Sorafenib.

When used individually, they have limited antileukemic activity that shows:

  1. A transient only reduction of blasts (immature cells) in the blood and bone marrow,
  2. An increase in toxicity.

 

Differentiation therapy

The problem of acute myeloid leukemia is the blockade of the differentiation program, therefore, a differentiating therapy is necessary.
Treatment of immature cells is performed with:

  1. Retinoic acid (a derivative of vitamin A), and in particular the ATRA (all-trans-retinoic) form, is recognized by RARα receptors (the retinoic acid receptor alpha) and the blasto becomes a granulocyte,
  2. Vitamin D3 – in this case the blasts become monocytes.

FonteFLT3 inhibitors in AML: are we there yet? – Sudhindra A, Smith CC – Curr Hematol Malig Rep. 2014 Jun; 9(2):174-85.

 

Allogeneic stem cell transplantation

This is the most common type of transplant for the treatment of AML.
In an allogeneic transplant, stem cells come from a person who is not the patient, usually a donor who has a bone marrow compatible with that of the patient.

In AML, allogeneic transplantation is preferable to autologous (with cells from the same person).
Leukemia is a disease of the blood and bone marrow, so by placing the cells in the patient, there is a risk of transplanting malignant (leukemic) cells.

 


Does acute myelogenous leukemia have a cure? The prognosis

The prognosis depends on:

  1. Age of the patient , over 60 years the prognosis is worse,
  2. Type of chromosomal alteration .

From 2003 to 2009, the 5-year survival rates for children were:

  • ALL: 91.7% for children and adolescents under 15 years of age and 92.6% for children under 5 years of age.
  • LMA: 64.8% for children and adolescents under 15 years of age.

Survival statistics  have improved  significantly over the last five decades.

Despite significant progress in the treatment of AML:

  1. From 20% to 40% of patients do not receive complete remission with chemotherapy,
  2. From 50% to 70% of patients develop a relapse within 3 years.

Approximately 60% -70% of adults with AML have complete remission after medical therapy.
More than 25% of adults with AML (about 45% of those with complete remission) survive for 3 years or more.
Rates of remission in AML in adults are inversely related to age , with an expected remission rate of more than 65% for people under 60 years of age.
The data show that, in older patients, the duration of remission is lower.
Other unfavorable prognostic factors are:

  1. Involvement of the central nervous system,
  2. Systemic infection at the time of diagnosis,
  3. High number of white blood cells (> 100,000 / mm3),
  4. AML caused by treatment,
  5. Previous blood diseases.

FonteMyint H, Lucie NP: The prognostic significance of the CD34 antigen in acute myeloid leukaemia. Leuk Lymphoma 7 (5-6): 425-9, 1992.

The AML associated with a tandem internal duplication of the FLT3 gene (FLT3 / ITD mutation):

  1. It has a worse prognosis,
  2. The frequency of recurrence is greater.

FonteYanada M. et al.: Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations for acute myeloid leukemia: a meta-analysis. Leukemia 19 (8): 1345-9, 2005

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