Acute myeloid leukemia

Content

  • WHO Classification of acute myeloid leukemia
  • The French-American-British classification
  • Clinical picture
  • Diagnosis of acute leukemia
  • Clinical stage and phase of the disease
  • Treatment


  • Acute myeloid leukemiaAcute 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.

    Some carcinogens
    (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
    other malignancies.

    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
    treatment.

    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
    AML with
    characteristic genetic changes
    • AML
      a translocation between chromosomes 8 and 21 [t (8; 21)] (ICD-O
      9896/3); RUNX1 / RUNX1T1
    • AML
      inversions in chromosome 16 [inv (16)] (ICD-O
      9871/3); CBFB / MYH11
    • AML
      a translocation between chromosomes 15 and 17 [t (15; 17)] (ICD-O
      9866/3); ARRK; PML-
      protein

    Patients with AML subtype
    usually high levels of remission and a better prognosis compared with other AML
    subspecies.
    AML with dysplasia
    several shoots
    This subspecies
    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.
    AML and
    MDS associated with previous treatment
    This subspecies
    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.
    AML without
    subject to the signs listed subspecies
    It includes
    AML subtypes that are not in the above.



    The French-American-British
    classification

    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
    AML.

    Subspecies Name Cytogenetic changes
    M0 Minimally differentiated
    acute myeloid leukemia
    M1 Acute
    myeloid leukemia without maturation
    M2 Acute
    myeloid leukemia with maturation of granulocytes
    t (8; 21) (q22; q22),
    t (6; 9)
    M3 promyelocytic,
    or acute promyelocytic
    leukemia (APL)
    t (15; 17)
    M4 Acute
    myelomonocytic leukemia
    inv (16) (p13q22),
    del (16q)
    M4eo myelomonocytic
    combined with bone marrow eosinophilia
    inv (16)
    t (16; 16)
    M5 Acute monoblastny
    leukemia (M5a) or acute
    monocytic leukemia (M5b) (M5b)
    del (11q),
    t (9; 11), t (11; 19)
    M6 Acute erythroid
    leukemias, including erythrocyte leukemia (M6a) and very rare pure
    erythroid leukemia (M6b)
    M7 Acute
    megacaryoblastic leukemia
    t (1; 22)
    M8 Acute basophilic
    leukosis



    Clinical picture

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

    • 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.
    • hemorrhagic
      - Bleeding into the skin and mucous membranes, nasal and gingival bleeding,
      gastrointestinal and renal bleeding, uterine bleeding, increased
      bleeding during surgical procedures.
    • proliferous
      - Lymphadenopathy, splenomegaly, hepatomegaly, hyperplastic gingivitis,
      bone pain, dysfunction of cranial nerves, headache, blurred
      view, general and focal neurological
      symptoms, headache, priapism.
    • intoxication
      - Weakness, loss of appetite, weight loss, sweating.



    Diagnosis of acute leukemia

    1. Acute myeloid leukemiafirst
      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.
    2. at
      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.
    3. AT
      As additional research methods to determine the version of an acute
      leukemia and prognostic markers is conducted by:
    • cytochemical
      study (mieloperiksidaza, esterase, glycogen)
    • cytogenetic
      research - the identification of chromosomal abnormalities, such as missing or
      extra chromosome in bone marrow cells by standard analysis
      or metaphase FISH method
      (Fluorescence
      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.
    Exodus Deviations 5-year survival relapse
    Favorable t (8; 21),
    t (15; 17), inv (16)
    70% 33%
    Satisfactory Not
    revealed, +8, +21, +22, del (7q), del (9q), Violations of 11q23, all other
    structural or numerical changes
    48% 50 %
    • Molecular-biological
      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.
    • Study
      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

    • Primary-active
      stage - the time interval between the first clinical manifestations
      disease diagnosis and achievement of first complete remission
    • total
      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
      remission.
    • Stage
      minimal residual (residual) disease.
    • relapse
      disease (bone marrow, vnekostnomozgovoy).
    • terminal
      stage.



    Treatment

    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.

    Therapies
    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.


    Supportive and
    symptomatic therapy

    basis
    AML treatment is supportive care, which includes treatment of intercurrent infections, urine acid
    diathesis, substitution therapy, blood components, as well as treatment
    comorbidity.

    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.

    Frequency
    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.

    Transfusion
    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

    1. Acute myeloid leukemiaTo 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.
    2. 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.
    3. Study
      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 [1]. 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).

    Table
    1. The average overall survival for AML patients depending on treatment (indirect
    comparatives).

    Without treatment maintenance therapy Low-dose cytarabine azacitidine
    AML is
    including
    AML with
    the number of blasts in myelogram 20-30%
    1.6 13.4 17.0 24.5

    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) [2]. 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.

    Acute myeloid leukemiaFor 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
    (IWG criteria
    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.

    TO
    grade 3-4 adverse reactions, developing during treatment with azacytidine,
    includes hematologic (71.4%), including thrombocytopenia (85%), neutropenia
    (91%) and anemia (5

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