Acute leukemia - a heterogeneous group of clonal
neoplastic disorders of hematopoietic tissue, characterized by uncontrollable
proliferation, differentiation disorder and accumulation in bone marrow and
peripheral blood of immature hematopoietic cells.
Acute leukemia is 2-3% of malignant tumors
human. The incidence of acute leukemia is an average of 3-5 cases per
100 000 population. In 75% of cases the disease is diagnosed in adults, 25%
cases - in children. The average ratio of myeloid and lymphoid acute leukemia
It is 6: 1. In adult patients over the age of 40 years 80%
presented myeloid forms in children - 80-90% - lymphoid. Median
the age of patients with acute leukemia nelimfoblastnyh - 60-65 years old, sharp
lymphoblastic leukemia - 10 years.
There is a genetic risk factor of acute
myeloid leukemia. There are a large number of cases of family messages
disease, the risk of AML in the nearest relatives of the patient
three times higher. Several congenital conditions may
increase the likelihood of AML. Most often this is Down's syndrome, in which the probability is increased in AML
10 - 18 times.
(Tumor-causing agents) can be considered as etiological factors
AML, such as gasoline, tobacco smoking and ionizing radiation. The most important
risk factor is the age of 65 years.
The impact of individual
genetic characteristics of the organism, as well as the impact on the body of exogenous
factors manifested in the development of secondary acute myeloid leukemia,
make up 5-20% of all cases of AML. In particular, the AML may develop
people previously treated with various chemotherapy regimens on the
The presence in the previous phase
as myelodysplastic syndrome (MDS), the most common in the elderly
patients, is also an important risk factor for AML. antitumor
chemotherapeutic effects, especially alkylating agents, anthracyclines
epipodophylotoxins and increases the likelihood of development of the secondary
AML / secondary MDS. The highest probability of disease falls on the 3-5 year
after chemotherapy. The combined use of chemotherapy / radiation therapy also significantly
It increases the risk of secondary AML / secondary MDS. It should be noted that the secondary
leukemias / MDS not occur in all patients receiving anti
Acute leukemia is
the result of damage - mutations - in the genetic material clonogenic
hematopoietic cells. As a result of this happening at the molecular level
events leading to disruption of the cell cycle control, change
the processes of transcription and the production of a number of key regulatory proteins. malignant
cells in AML act myeloblasts,
incapable of maturation and differentiation as a result of impaired
genetic control and accumulate
in bone marrow. The cells were leukemic clone
interfere with activity of normal cells, displacing them from the bone marrow.
Currently, all sharp
leukemias are divided into myeloid and acute lymphoblastic leukemia.
WHO classification of acute myeloid leukemia is shown below.
WHO Classification of acute myeloid leukemia
|The name of the subspecies||Description|
characteristic genetic changes
Patients with AML subtype
usually high levels of remission and a better prognosis compared with other AML
AML with dysplasia
It includes patients with a prior myelodysplastic syndrome (MDS)
or Myeloproliferative disease (IIB)
which pass into AML. This subspecies of AML is more common in older people and
characterized by a poor prognosis.
MDS associated with previous treatment
AML includes patients receiving himiolechenie and / or radiation therapy, after
which originated with AML or MDS. Under these leukemias may be typical
changes in the chromosomes, the prognosis for them is often worse.
subject to the signs listed subspecies
AML subtypes that are not in the above.
The French-American-British classification (FAB)
system divides AML into 8 subtypes, M0 on the M7, based on the types of
cells - white blood cells predecessors, and on the degree of maturity changed
cells. Determination of malignant cells is carried out on the basis of
external signs under light microscopy and / or cytogenetics, identifying
deviations underlying changes in chromosomes. Different subtypes of AML
different prognosis and response to treatment. Despite the advantages of the WHO classification,
FAB system is still widely used. As there are eight FAB subtypes
acute myeloid leukemia
myeloid leukemia without maturation
myeloid leukemia with maturation of granulocytes
t (8; 21) (q22; q22),
t (6; 9)
or acute promyelocytic
|t (15; 17)|
inv (16) (p13q22),
combined with bone marrow eosinophilia
t (16; 16)
leukemia (M5a) or acute
monocytic leukemia (M5b) (M5b)
t (9; 11), t (11; 19)
leukemias, including erythrocyte leukemia (M6a) and very rare pure
erythroid leukemia (M6b)
|t (1; 22)|
The clinical picture of acute leukemia is determined by the severity of
Anemic - decrease in hemoglobin level and
erythrocyte count, which is manifested
weakness, decreased performance, drowsiness, symptoms
heart failure, heart beat,
weakness, shortness of breath, pale skin and mucous membranes, orthostatic
hypotension, secondary angina and myocardial infarction, intermittent
claudication, clinical respiratory failure in patients with chronic
broncho-pulmonary diseases (COPD).
Granulotsitopenicheskogo - infectious complications,
caused by decrease in the number of granulocytes in the blood, and high temperatures appears intoxication and
local clinic (necrotic angina, ulcerative stomatitis, osteomyelitis
jaw after tooth extraction) or generalized (sepsis, infective endocarditis)
most bacterial infections.
- Bleeding into the skin and mucous membranes, nasal and gingival bleeding,
gastrointestinal and renal bleeding, uterine bleeding, increased
bleeding during surgical procedures.
- Lymphadenopathy, splenomegaly, hepatomegaly, hyperplastic gingivitis,
bone pain, dysfunction of cranial nerves, headache, blurred
view, general and focal neurological
symptoms, headache, priapism.
- Weakness, loss of appetite, weight loss, sweating.
Diagnosis of acute leukemia
It is a step in the diagnosis of
Clinical analysis of blood by taking a blood sample from a vein. The blood sample
It determines the number of blood cells (erythrocytes, leukocytes and their subtypes, and
and platelets). Upon detection in the clinical analysis of blood for more than 20%
blast cells can be diagnosed with acute leukemia.
the absence of a sufficient blood for diagnostic amount of blasts, as well as
the exact purpose of verification of the diagnosis with the use of additional methods
Research shown holding aspiration bone marrow biopsy.
Bone marrow examination includes the study of bone marrow aspirate
(Analysis mielogrammy- cytology), in rare cases a trepanobiopsy
bone marrow for histological examination of the bone marrow.
As additional research methods to determine the version of an acute
leukemia and prognostic markers is conducted by:
study (mieloperiksidaza, esterase, glycogen)
research - the identification of chromosomal abnormalities, such as missing or
extra chromosome in bone marrow cells by standard analysis
or metaphase FISH method
in situ hybridization
situ - method based on the ability of
chromosomal DNA (target) under certain conditions of binding with small
DNA sequences (probes) that are complementary to this chromosomal DNA. at
accession to the probe produces a fluorescent substance the DNA analysis it
cell location in interphase cells). The results of cytogenetic
research is a diagnostic value and prognostic.
t (8; 21),
t (15; 17), inv (16)
revealed, +8, +21, +22, del (7q), del (9q), Violations of 11q23, all other
structural or numerical changes
research (genetic research is conducted to identify the specific
mutations that may influence the outcome of disease - such as, FLT3-tyrosine, CD117 gene for receptor synthesis liability
stem cell growth factor c-KIT, genes CEBRA,
BAALC, ERG, NPM1.
on tumor cells, differentiation antigens (CD) by flow cytometry (immunophenotyping).
Later in patients with acute
leukemia by repeated measurements of the bone marrow to
determine the effect of the therapy, complete remission and process step
(Remission, stabilization, progression).
Clinical stage and phase of the disease
stage - the time interval between the first clinical manifestations
disease diagnosis and achievement of first complete remission
clinical and hematological remission - the number of blasts in myelogram
decreases of less than 5%, no vnekostnomozgovye leukemic foci
lesions, while there should be no blast cells in the peripheral blood,
platelet count of 100 × 109 / L 2.5 x leukocytes
109 / l, granulocytes 1.0 x
109 / L, hemoglobin concentration 100 g / l.
Recently we introduced the concept of cytogenetic and molecular biological
minimal residual (residual) disease.
disease (bone marrow, vnekostnomozgovoy).
Before treatment is carried out a full clinical
patient survey to assess comorbidity status
cardiovascular, respiratory, genitourinary, central nervous system.
It includes a full biohiichesky blood count, coagulation, screening for
hepatitis B and C, HIV, herpes group viruses. Ultrasonic
abdominal X-ray of the chest issledoaanie / computer
tomography of the chest, ECG / echocardiography, CT / MRI of the head, inspection
neurologist, ophthalmologist, etc. All that is necessary for the correct choice of treatment and
prevention of complications.
AML patients depend on the type of disease, the prognostic factors, age
patient and concomitant pathology and can be divided into
potentially healing therapies and supportive care.
AML treatment is supportive care, which includes treatment of intercurrent infections, urine acid
diathesis, substitution therapy, blood components, as well as treatment
At the heart
maintenance treatment of patients with MDS is replacement therapy
blood components. In patients at low risk of AML anemia can be
basic clinical significant problem. replacement therapy
It alleviates the symptoms of anemia and therefore is an important method of treatment.
transfusion depends on the patient, the severity of anemia, as well as
comorbidity, especially great need for transfusion of components
blood with the development of bleeding in a patient. The result of substitution therapy
It is to increase the level of hemoglobin, which, studies show,
It has a positive correlation with the quality of life index.
platelets held in those cases where the number of platelets
very low and / or there are life-threatening bleeding. With the development of
bleeding disorders (disorders of blood clotting system, such as reduction of
fibrinogen or prothrombin complex factors) is carried out replacement
therapy or blood plasma components
recombinant preparty (NovoSeven, protrombopleks etc.)
Potentially healing therapies
To control the symptoms of the disease or cure AML used in younger patients
intensive chemotherapy to destroy most abnormal clone
cells and to achieve long-term remission. This method of treatment has
significant side effects such as hair loss, stomatitis appearance
mouth, nausea, vomiting, appearance of watery stools. Furthermore these side
phenomena, chemotherapy and has adverse effects on normal
cells that require a long stay in a hematologic
department. At this time, the patient produced red blood cell transfusions and
platelets, appointed antibacterials to combat
infection. If the induction chemotherapy provides adequate control over
abnormal cells (remission), the restoration of normal
blood cells to begin in a few weeks. However, even in cases
successful treatment of the disease can come back - recur.
- The only
known treatment that can cure the majority of patients with AML,
It is the transplantation of allogeneic (donor) hematopoietic stem
cells. It should be borne in mind that it is a complicated procedure associated with the risk of
early and late complications. The outcome of treatment depends on the degree of compatibility (HLA-compatible) donor and patient
(Recipient), as well as the availability of suitable donor cells (presence of
compatible blood brothers and / or sisters, the availability of donor bank). Therefore
way, there are strict indications and contraindications for this type of treatment:
It is suitable for those cases in which patients are able to move
transplantation of stem cells and have a suitable donor and responded to chemotherapy.
mechanisms for the development of MDS / AML secondary undertaken in recent years has shown,
that this disease is characterized by hypermethylation of the promoter region
oncosupressor of some genes, which leads to the "silence" of these genes and
tumor cell proliferation and transformation in AML. On the basis of this knowledge
so-called hypomethylating agents have been developed which facilitate
hypomethylation of DNA, causing the expression of previously "off" genes.
In May 2004, the Office
US the Food and Drug Administration (Food and Drug Administranion, FDA) has granted permission for the use of
injectable azacytidine (Vaydaza) for treating all types of IBC. In Russia,
the drug was approved for use in 2010, including for the treatment of both MDS and AML. The results showed that
azacitidine significantly extends the life of patients with acute myeloid leukemia,
which is not shown stem / intense transplantation
chemotherapy. The research shows that the survival rate of patients with AML without modern treatment is 1.6
months, whereas the life expectancy increases azacytidine in AML
11.1 months, having a favorable
safety profile. Besides,
drug, with sufficient training of medical personnel, can
applied as an outpatient.
According to accepted protocols in Russia, treatment of AML patients who did not
suitable for intensive
chemotherapy and secondary AML carried low-dose cytarabine, and / or
using maintenance therapy . such therapy
It improves the quality of life for patients but does not prolong their lives
in comparison with the natural history of the disease. While the use of
azacitidine in these patients can dramatically change the course
disease (Table 1).
1. The average overall survival for AML patients depending on treatment (indirect
|Without treatment||maintenance therapy||Low-dose cytarabine||azacitidine|
the number of blasts in myelogram 20-30%
The median survival of patients with AML (20-30% blasts)
receiving azacytidine, it increases to 24.5 months. In this group the differences
azacitidine maintenance therapy with groups and low-dose cytarabine
statistically significant (p = 0.045), regardless of age or karyotype, and
additional months of life up to 11.1 and 7.5, respectively (median
survival in the maintenance group is equal to 13.4, and in the low group
dose cytarabine - 17.0 months) (III phase of the study data analysis AZA-001) . After 2 years, 50.8% were alive in the group of patients
azacytidine, which is 2 times higher than in a comparison group (26.2%). For
comparison - patients with AML who are not receiving current therapy (natural
the disease) die within 7 weeks of diagnosis.
For patients with AML who are not
shows intensive chemotherapy / stem cell transplantation, treatment
azacytidine may be the only means of prolonging life and
helping achieve lasting remission. In the AZA-001 study group azacitidine treatment response
2000) reached 29% of patients (complete and partial response), 49% - achieved
hematologic improvement. The differences with comparison groups ( "maintenance
therapy, "" low-dose cytarabine ") are statistically significant (12% and 5, 31 and 25%
respectively). Time to disease progression was 14.1 month
group "azacitidine" and 8.8 months in the control group (p = 0.047). duration
hematologic response was equal to 13.6 months compared to azacytidine
5.2 months for traditional therapy (p = 0.002).
Patients with MDS and AML treated
azacytidine therapy there was a higher probability of independence from
RBC transfusions: 45% of patients became independent from
transfusions, while traditional modes - only 11% (p <0.0001).
Thus, treatment azacytidine AML patients (20-30% blasts)
not only accompanied by a higher life expectancy and overall
frequency compared to remission maintenance therapy and low-dose cytarabine,
but higher rates of hematologic improvement and independence from
transfusions. Patients with high-risk MDS azacytidine therapy
accompanied by an increase in the time to transformation to AML (17.8 months vs 11.5 months, p <0.001).
Azacitidine is included in the international treatment protocols
patients with myelodysplastic syndrome and AML in patients over 60 years.
USA: in the treatment guidelines of the National AML
oncology Network (National Cancer Comprehensive Network. NCCN. USA) (2010) azacitidine recommended for use in
patients older than 60 years who are not candidates for high-dose
chemotherapy. Recommendations are given with a high level of evidence.
grade 3-4 adverse reactions, developing during treatment with azacytidine,
includes hematologic (71.4%), including thrombocytopenia (85%), neutropenia
(91%) and anemia (5