Acute myeloid leukemia


  • Classification of WHO sharp myeloid leukemia
  • Franco-American-British classification
  • Clinical picture
  • Diagnosis of sharp leukemia
  • Clinical stages and phases of the disease
  • Treatment

  • Acute myeloid leukemiaSharp leukemia — Heterogeneous group of clonal
    Tumor diseases of the hematopoietic fabric characterized uncontrolled
    proliferation, disruption of differentiation and accumulation in the bone marrow and
    peripheral blood of immature hematopoietic cells.

    Acute leukemia is 2-3% malignant tumors
    man. The incidence of sharp leukemia is an average of 3-5 cases on
    100,000 population. In 75% of cases, the disease is diagnosed in adults, 25%
    Cases — in children. The average ratio of myeloid and lymphoid sharp leukemia
    is 6: 1. In adult patients over the age of 40 years of 80% of cases
    presented by myeloid forms, in children — 80-90% — lymphoid. Median
    age patients with acute nonlimfoblastic leukemia — 60-65 years old, sharp
    lymphoblastic leukemia — 10 years.

    There is a genetic probability of developing acute
    Myeloid Leukoza. There are a large number of family cases reports
    Diseases, the likelihood of an IML for the nearest relatives of the patient
    three above. A number of innate states can
    increase the likelihood of Oml. Most often it is Down Syndrome, in which the probability of an IML is raised in
    10 — 18 times.

    Some carcinogens
    (causing tumors agents) can be considered as etiological factors
    OML, such as gasoline, smoking tobacco and ionizing radiation. Most important
    Risk factor is older than 65 years.

    The influence of individual
    The genetic features of the body, as well as the impact on the body of exogenous
    Factors manifests itself in the development of secondary acute myeloid leukemia,
    components of 5-20% of all cases of IML. In particular, the IML may develop
    People previously undergoing treatment with various chemotherapy modes
    Other malignant formations.

    The presence of the preceding phase in
    the form of myelodsplastic syndrome (MDS) most common in the elderly
    patients, too, is an important risk factor Oml. Antitumorian
    Chemotherapeutic effects, especially alkylating drugs, anthraciklines
    and epipodophillexins, increases the probability of the development of secondary
    OML / secondary MDS. The highest probability of the disease falls for 3-5 years
    After chemotherapy. Combined application of chemo / radiation therapy is also significantly
    Increases the risk of secondary IML / secondary MDS. It should be noted that secondary
    leukemia / MDS arise not in all patients receiving antitumor

    Acute leukemia is
    Consequently damage — Mutations — In the genetic material of the clone
    Hooping cell. As a result, the molecular level occurs
    Events leading to a violation of control over the cell cycle, change
    Transcription Processes and Products of a number of key proteins-regulators. Malignant
    Meloblasts protrude cells with OML,
    incapable of ripening and differentiation as a result of impaired
    genetic control and accumulating
    in bone marrow. Lakeclone cells
    interfere with the activities of normal cells, pushing them from bone marrow.

    Currently all sharp
    leukemia is taken to divide on myeloid and sharp lymphoblastic leukemia.
    The classification of the WHO sharp myeloid leukemia is presented below.

    Classification of WHO sharp myeloid leukemia

    Name subspecies Description
    Oml S
    characteristic genetic changes
    • Oml
      with translocations between chromosome 8 and 21 [t (8; 21)] (ICB-O
      9896/3); Runx1 / Runx1t1
    • Oml
      Inversion in chromosome 16 [Inv (16)] (ICB-O
      9871/3); CBFB / myH11
    • Oml
      with translocations between chromosome 15 and 17 [t (15; 17)] (ICB-O
      9866/3); Arrk; PML-

    In patients with such a subspecies of the IML
    Usually high levels of remission and the forecast is better comparatively with the OML of others
    Oml with dysplasia
    Several Rostkov
    This subspecies
    Includes patients with preceding myelodsplastic syndrome (MDS)
    or myeloproliferative disease (MPB),
    which go to the IML. This subspecies of the IML is more common in the elderly and
    Differs unfavorable outlook.
    Oml I
    MDS associated with previous treatment
    This subspecies
    OML includes patients receiving chemistry and / or radiation treatment after
    which came the IML or MDS. With these leukemia, there may be characteristic
    Changes in chromosomes, the forecast for them is often worse.
    Oml, N
    subject to the signs of listed subspecies
    Oml subspecies that are not included in those listed above.


    Franco-American-British classification (Fab)
    The system shares an IML to 8 subspecies, from M0 by M7, based on the types
    cells — leukocyte predecessors, and on the degree of maturity of the changed
    cells. Determination of malignant cells are carried out on the basis
    external signs with light microscopy and / or cytogenetically, detecting
    underlying deviations of changes in chromosomes. Different subspecies of the IML
    Different forecast and response to treatment. Despite the advantages of the WHO classification,
    Fab system is still widely used. By Fab there are eight subtypes

    Subspecies Name Citogenetic changes
    M0 Minimally differentiated
    Acute myeloblastic leukemia
    M1 Spicy
    Myeloblastic leukemia without ripening
    M2 Spicy
    Myeloblastic leukemia with ripening of granulocytes
    T (8; 21) (Q22; Q22),
    t (6; 9)
    M3 Promelocyrtar,
    Or acute promelocyrtar
    leukemia (op floor)
    t (15; 17)
    M4 Spicy
    Myelomocytic leukemia
    Inv (16) (P13Q22),
    DEL (16Q)
    M4EO Myelonocital
    Combined with bone marrow eosinophilia
    Inv (16),
    t (16; 16)
    M5 Acute monoblastic
    leukemia (M5A) or acute
    Monocystary leukemia (M5B) (M5B)
    DEL (11Q),
    t (9; 11), t (11; 19)
    M6 Spicy erythitoid
    leukemia, including erythrocytarian leukemia (M6A) and very rare clean
    Erythitoid leukemia (M6B)
    M7 Spicy
    Megakaryoblastic leukemia
    T (1; 22)
    M8 Acute basophilic

    Clinical picture

    The clinical picture of acute leukemia is determined by severity
    Basic syndromes:

    • Anemic — reduced hemoglobin levels and
      the number of erythrocytes, which manifests itself
      weakness, decrease in working capacity, drowsiness, manifestations
      heart failure, heartbeat,
      weakness, shortness of breath, pallor of skin and mucous membranes, orthostatic
      hypotension, secondary angina and myocardial infarction, intelligent
      Chromota, clinic of respiratory failure in patients with chronic
      Broncho-pulmonary diseases (COPD).
    • Granulocyteopenic — Infectious complications,
      due to a decrease in the number of granulocytes in the blood, which is manifested by high temperature and intoxication, as well as
      Local clinic (necrotic districts, ulcerative stomatitis, osteomyelitis
      Jaws after the extraction of the tooth) or generalized (sepsis, infectious endocarditis),
      more often bacterial, infection.
    • Hemorrhagic
      — Hemorrhage in skin and mucous, nasal and gum bleeding,
      Gastrointestinal and renal bleeding, uterine bleeding, elevated
      Bloodfaction during operational interventions.
    • Proliferative
      — Lymphadenopathy, Splenomegaly, Hepatomegaly, Hyperplastic Gingivitis,
      Pains in the bones, disorders of the function of the cranial brain nerves, headache, violations
      vision, general and focal neurological
      symptomatics, headache, priapism.
    • Inxication
      — Weakness, decline in appetite, weight loss, sweating.

    Diagnosis of sharp leukemia

    1. Acute myeloid leukemiaFirst
      Step in diagnostics is
      Clinical analysis of blood by taking blood sample from veins. In blood sample
      The number of blood cells (erythrocytes, leukocytes and their subtypes is determined, and
      Also platelets). When discovery in clinical analysis of blood more than 20%
      Blast cells can be diagnosed with acute leukemia.
    2. At
      the absence of sufficient blood to diagnose the number of blasts, as well as
      The purpose of accurate verification of the diagnosis using additional methods
      Studies are shown to conduct an aspiration biopsy of the bone marrow.
      The study of the bone marrow includes a study of bone marrow aspirate
      (Analysis of my cellogram-cytological examination), in rare cases, spendpalobiopsy is carried out
      bone marrow for a histological study of the bone marrow.
    3. IN
      quality of additional research methods to determine the variant of acute
      leukemia and prognostic markers are carried out:
    • Cytoochemical
      Research (myeloperixidase, eserase, glycogen)
    • Cytogenetic
      study — detection of chromosomal anomalies, such as absent or
      Additional chromosomes in bone marrow cells by standard analysis
      Metafaz or FISH method
      In. hybridization
      situMethod based on the ability
      chromosomal DNA (target) to contact under certain conditions with small
      DNA sequences (probes), complementary this chromosomal DNA. At
      Accession to the fluorescent substance probe produce DNA analysis by its
      location of cells in interphase cells). The results of cytogenetic
      Studies are worn both diagnostic importance and prognostic.
    Exodus Deviation 5-year survival Recurious frequency
    Favorable T (8; 21),
    T (15; 17), inv (16)
    70% 33%
    Satisfactory Not
    Revealed, +8, +21, +22, Del (7Q), DEL (9Q), violations 11Q23, all other
    Structural or Numerical Changes
    48% fifty %
    • Molecular biological
      research (genetic research is carried out to identify characteristic
      mutations that can affect the outcome of the disease — For example, FLT3-tyrosine kinase, CD117 gene, retired for the receptor synthesis
      Stem cell growth factor C- Kit, Cebra genes,
      Baalc, ERG, NPM1.
    • Study
      On tumor cells of differential antigens (CD) by flow cytometry (immunophenotyping).

    In the future in patients with sharp
    leukemia re-studies of bone marrow in order to
    Determine the effect of therapy, the completeness of the remission achieved and the process stage
    (remission, stabilization, progression).

    Clinical stages and phases of the disease

    • Primary-active
      stage — time interval between first clinical manifestations
      Diseases, diagnosis and the first full remission
    • Full
      Clinical hematological remission — The number of blast cells in myelogram
      Decreases less than 5%, there are no extra-visa leukemic foci
      lesions, while in peripheral blood should not be blast cells,
      Number of platelets 100×109 / l leukocytes 2.5 x
      109 / l, granulocytes 1.0 x
      109 / l, hemoglobin level of 100 g / l.
      Recently, the concept of cytogenetic and molecular biological
    • Stage
      minimum residual (residual) disease.
    • Recurd
      Diseases (bone marrow, extraotic surge).
    • Terminal


    Before starting treatment, a complete clinical
    Patient examination to assess the state of concomitant pathology
    Cardiovascular, respiratory, urogenital systems, central nervous system.
    It includes a complete biochemical blood test, coagulogram, examination on
    Hepatitis B and C, HIV, Viruses of the Herpes Group. Ultrasound of organs
    Abdominal cavity, chest x-ray study / Computer
    Tomography of chest, ECG / Echo Cardiography, CT / MRI head, inspection
    neurologist, oculist and t.D. All this is necessary for the right choice of treatment and
    Preventing complications.

    Treatment methods
    Patients with IML depend on the type of disease, prognostic factors, age
    the patient, as well as related pathology and can be divided into
    Potentially healing therapeutic methods and supporting therapy.

    Supporting I
    Symptomatic therapy

    OML treatment is supportive therapy, which includes the treatment of intercurrent infections, uricultural
    diathesis, replacement therapy with blood components, as well as treatment
    Concomitant pathology.

    Based on
    Supporting therapy of patients with MDS lies replacement therapy
    Blood components. Patients with low risk of development Oml anemia can be
    Main clinical meaningful problem. Replacement therapy
    facilitates symptoms of anemia and, therefore, is an important treatment.

    transfusions depends on the state of the patient, the severity of anemia, as well as
    concomitant pathology, especially the need for overflowing components
    blood when developing in patient bleeding. The result of substitution therapy
    is an increase in hemoglobin level, which studies show,
    has a positive correlation with a quality quality indicator.

    platelet mass is carried out in cases where the number of platelets
    extremely low and / or there are hazardous bleeding. Under development
    Coagulopathy (violations in the blood coagulation system, for example, level reduction
    Fibrinogen or prothrombin complex factors) conduct replacement
    Therapy of blood plasma components or
    recombinant prepartes (Novosvlen, PromromBoplex and PR.)

    Potentially healing therapeutic methods

    1. Acute myeloid leukemiaTo control the symptoms of the disease or cure of the IML in young patients use
      Intensive chemotherapy to destroy the clone of pathological
      cells and reach long remission. This treatment method has
      Significant side effects, such as hair loss, the appearance of stomatitis
      oral cavity, nausea, vomiting, appearance of liquid stool. In addition to these side
      phenomena, chemotherapy has adverse effects and healthy
      cells that require a long stay in hematological
      Departments. At this time, the patient is carried out over-blood cell and
      thrombocyte mass, antibacterial drugs are prescribed to combat
      infection. If induction chemotherapy provides adequate control over
      pathological cells (state of remission), then restoration of normal
      Blood cells should begin within a few weeks. However, even in cases
      Successful treatment disease can be returned — recur.
    2. The only one
      known method of treatment capable of healing most patients with OML,
      is the transplantation of allogeneic (donor) hematopoietic stem
      cells. It should be borne in mind that this is a complex risk-related procedure
      early and late complications. The outcome of treatment depends on the degree of compatibility (HLA compatibility) of the donor and the patient
      (recipient), as well as on the availability of suitable donor cells (availability
      Compatible blood brothers and / or sisters, availability of donor bank). Thus
      The way there are strict testimony and contraindications for this type of treatment:
      It is suitable for those cases when patients are able to transfer
      Stem cell transplantation and have a suitable donor and answered chemotherapeutic treatment.
    3. Study
      The mechanisms of development of MDS / secondary IML, undertaken in recent years showed,
      that for this pathology is characterized by hypermetilization of the promoter region
      some genes-oncosuppressors, which leads to «Silence» These genes I
      Proliferation of tumor cells and transformations in the IML. On the basis of these knowledge
      The so-called hypometaling agents that contribute were developed
      DNA hypomettylation, causing expression earlier «Disabled» Genov.

    In May 2004, management
    USA for food and drug control (Food and Drug Administranion, FDA) issued permission to use
    Injection preparation Azacytidin (Vaidaza) for the treatment of all types of MDS. In the Russian Federation
    The drug was approved for use in 2010, including for the treatment of both MDS and IML. The results of the study showed that
    Azacytidin reliably prolongs life to patients with acute myeloid leukemia,
    Scheduled stem cell transplantation / intensive
    chemotherapy. The studies show that the survival rate of patients with an OML without modern treatment is 1.6
    months, while Azacytidin increases lifespan with IML
    11.1 months, possessing favorable
    Safety profile. Besides,
    the drug, with sufficient qualifications of medical personnel, may
    Apply Ambulator.

    According to the protocols adopted in Russia, the treatment of patients IML, which are not
    Suitable for intensive
    chemotherapy and secondary OML is carried out by low doses of cytarabine and / or with
    using supporting therapy [one]. Such therapy
    Improves the quality of life of patients, but does not increase their life
    in comparison with the natural course of the disease. While use
    Azacitidine in this category of patients can radically change the flow
    Diseases (Table 1).

    one. The average total survival in the patients of the IML, depending on therapy (indirect
    Comparative data).

    Without treatment Supporting therapy Low doses of cytarabin Azacytidin
    Oml, including
    Oml S
    The number of blasts in myelogram 20-30%
    1,6 13,4 17.0 24.5

    Median survival of patients with OML (20-30% of blasts),
    receiving azacytidine, increases to 24.5 months. At the same time, the differences in the group
    Azacytidine with groups of supporting therapy and low doses of cytarabin
    statistically reliable (p = 0.045), regardless of age or karyotype, and
    Optional months of life are 11.1 and 7.5 respectively (median
    survival in the supporting therapy group equals 13.4 and in the low group
    Doses of cytarabin — 17.0 months) (analysis of data research III phase AZA-001) [2]. After 2 years, 50.8% of patients in the group were alive
    Azacitidine, which is 2 times more than in comparison groups (26.2%). For
    Comparison — Patients with an OML who do not receive modern therapy (natural
    The course of the disease) die within 7 weeks from the diagnosis.

    Acute myeloid leukemiaFor patients with an IML, not
    Intensive chemotherapy / stem cell transplantation, treatment
    azacytidine may be the only means of life prolonging and
    helping to achieve long remission. In the AZA-001 study in the Azacitidine group to therapy response
    (Criteria IWG
    2000) reached 29% of patients (full and partial answer), 49% — achieved
    Hematological improvement. Differences with comparison groups («Supportful
    therapy», «Low doses of cytarabin») Statistically reliable (5 and 12%, 31 and 25%
    respectively). Time to the progression of the disease was 14.1 months in
    Group «Azacytididine» and 8.8 months in comparison groups (p = 0.047). Duration
    The hematological response was 13.6 months on the azacytidine in comparison with
    5.2 months on traditionally used therapy (p = 0.002).

    In patients with MDS and IML who received
    Therapy ascitidine was observed a higher probability of independence from
    Transfusions of the erythrocyte mass: 45% of patients became independent from
    Hemotransphus, while on traditional modes — Only 11% (P < 0.0001).

    Thus, the treatment of ascitidine of patients Oml (20-30% of blasts)
    accompanied not only by a higher life expectancy and total
    Remissary frequency compared to supporting therapy and low doses of cytarabina,
    but also higher hematological improvement and independence
    Transfusions. Patients with MDS High Risk Azacytidine Therapy
    accompanied by an increase in time before transformation into an OML (17.8 months VS 11.5 months, p<0.001).

    Azacytidin is included in the International Protocols for Treatment
    Patients with myelodsplastic syndrome and IML in patients over 60 years.

    USA: in the National Oml Treatment Guide
    Oncological network (National Cancer Comprehensive Network, NCCN, USA) (2010) Azacytidine is recommended for application
    patients older than 60 years who are not candidates for highly visible
    Chemotherapy. Recommendations are given with a high level of evidence.

    undesirable phenomena of 3-4 degrees developing against the background of the treatment of azacytidine,
    treat hematologic (71.4%), including thrombocytopenia (85%), neutropenia
    (91%) and anemia (5

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