Leukemia in children

Leukemia in children is a common name for malignant tumors originating from the hematopoietic cells, which account for about 1/3 of all oncological morbidity in children. Oncological morbidity (leukemia, lymphomas and solid tumors) in Ukraine is about 15 cases per year per 10,000 children and adolescents, which in absolute figures is more than 15,000 children newly infected per year. 

The incidence of leukemia in different regions varies from 4 to 5 per 100,000 children under the age of 15 with a peak at the age of 3.5-4 years. At the same time, 75% of patients - children with acute lymphoblastic (ALL); 15-20% - with acute non-lymphoblastic leukemia (ONL); 1-3% - with chronic myeloid leukemia (CML); the rest - with non-identifiable variants of acute leukemia (AL).

Acute leukemia is a heterogeneous group of tumorous diseases of the blood system (hemoblastoses), in which primary damage to the bone marrow occurs by tumor cells that have hematopoietic origin, suppression of normal hematopoiesis and infiltration of various tissues and organs, and tumor cells.

The first description of the patient leukemia was made by the French doctor Alfred Velpault, who in 1827 treated a 63-year-old florist with severe weakness, fever, hepatosplenomegaly and stones in the urinary tract. Velpo noted the similarity of this patient's blood to liquid oatmeal and suggested that the disease is associated with certain "white blood corpuscles". The term "leukemia" (translated from Greek as "belokorie") was introduced into scientific usage in 1856 by German pathologist Rudolf Virchow. Since Virchow failed to explain the reason for the sharp increase in the number of white blood cells (leukocytes), he simply stated the picture he had seen in the peripheral blood. After some data on the pathogenesis of the disease were obtained in the 1920s, Soviet scientists (Ellerman, Kassirsky) proposed new terms for the description of the disease - "leukemia" and "hemoblastosis", which, in their opinion, were more in line with the essence of the disease, after all The disease is not found in all patients, and the disease itself is associated not with blood, but with the bone marrow. In other European languages, to date, the traditional, Virkhian term "leukaemia" is preserved.

[1], [2], [3], [4], [5], [6], [7]

Epidemiology of leukemia in children

Frequency of occurrence of acute leukemia in childhood is 2-5 cases per 100 LLC of child population per year. In this case, acute lymphoblastic leukemia (ALL) occurs in 75-85% of cases of leukemia in children, which makes it the most common oncological disease in childhood. With the highest frequency, ALL is found in children aged 2 to 5 years. Several boys are more likely to get sick compared to girls (1.3: 1).

Acute non-lymphoblastic leukemia (ONLL) occurs with a frequency of 0.6-0.8 cases per 100 000 children and makes up 18-20% of all leukemias in children. In adults, ONLL is the most common form of leukemia, accounting for 70% of cases. The average age of the sick is 60 years. In children, ONLL is more common in the first years of life, more often in boys.

[8], [9], [10], [11], [12], [13], [14], [15], [16], [17]

The causes of leukemia in children

It is known that acute leukemia is a "clonal" disease. The mutation occurring in the hematopoietic cell leads to a failure of its differentiation at the stage of the most immature forms (so-called blasts) with their further proliferation. In this case, a malignant tumor is formed, which replaces the bone marrow and prevents normal blood formation. Tumor cells (blasts) emerge from the bone marrow into the bloodstream and with its current spread throughout the body, causing leukemia infiltration of various tissues and organs. Penetration of the blasts through the blood-brain barrier with subsequent infiltration by blast cells of the membranes and brain substance is called neuroleukemia.

All tumor cells have unified biochemical, morphological, immunological signs, which proves their common origin from one mutated cell. The main question is what are the causes of this somatic mutation, as well as the inability of the body's defense systems to resist the tumor process.

In the overwhelming majority of cases, it is impossible to find any etiological factor in the disease in a particular patient. We can only say that there are several risk factors. It is known that the incidence of ALL in children has increased dramatically in Japan after the bombing of Hiroshima and Nagasaki. However, at present there is no evidence of the effect of small doses of radiation (eg X-rays) on the development of acute leukemia. The use of radiotherapy, chemotherapy, in particular preparations such as etoposide, teniposide, cyclophosphamide (cyclophosphamide), procarbazine hydrochloride (procarbazine), in some patients after 2-9 years leads to the development of acute leukemia (usually ONLL) ), which has special properties. This fact made it possible to distinguish secondary ONLL into a separate variant of acute leukemia according to the modern classification.

B-cell ALL is associated with an infection caused by the Epstein-Barr virus. The role of other viruses, in particular retroviruses that cause leukemia in laboratory animals, and are responsible for the development of adult T-leukemia, has not been proven in the genesis of acute leukemia in children.

More often acute leukemia occurs in people suffering from certain genetic diseases. These are, first of all, DNA repair diseases, such as Fanconi anemia, Bloom's syndrome, Nijmegen syndrome and others. At primary immunodeficiencies (ataxia-telangiectasia of Louis-Barr, X-linked agammaglobulinemia, severe combined immune deficiency, etc.), first of all antitumor immunity suffers, which leads to the development of malignant neoplasms. More often than on average in the population, acute leukemia occurs in children with other genetic diseases, such as Down's disease.

What causes leukemia in a child?

Symptoms of leukemia in children

Clinical symptoms of acute leukemia in children are highly variable and consist of symptoms resulting from tumor replacement of the bone marrow (and cessation due to this normal hematopoiesis), as well as symptoms of blasts (tumor cells) of organs and tissues. When assessing the clinical status of the patient, the following syndromes are distinguished.

Anemic syndrome: general weakness, fatigue, pallor of the skin, systolic murmur in the apex of the heart, as a consequence of anemia due to insufficient formation of red blood cells in the bone marrow. This leads to the development of hemic hypoxia.

Hemorrhagic syndrome, which proceeds through a microcirculatory (petechial-spotted) type of bleeding. Its manifestations are different in severity: from peteches and ecchymoses on the skin and mucous membranes to large subcutaneous hemorrhages, heavy bleeding from the mucous membranes (nasal, gastrointestinal, renal, uterine). The main characteristics of hemorrhages - the asymmetry of the lesion, the connection with the damaging agent at the place and time of occurrence. The cause of bleeding in leukemia is thrombocytopenia associated with the disappearance or suppression of megakaryocytes and inadequate platelet production in the bone marrow, which is completely replaced by tumor cells.

Hyperplastic syndrome: enlargement of the liver and spleen (hepatosplenomegaly), lymph nodes (lymphadenopathy), the appearance of leukemia infiltrates on the skin (leukemids), in various tissues and organs (chloromas or - more modern term - myeloid sarcomas). Bone pain is a common symptom associated with bone marrow infiltration, osteoporosis, and stretching of the periosteum. The enlarged lymph nodes are usually painless, dense, "cold", not soldered to surrounding tissues. When palpation of the liver and spleen determine the stony edge density, there may be soreness by stretching the capsule of the organ.

Frequent infectious diseases occur due to impaired production of bone marrow leukocytes. At the same time, a child becomes ill without serious bacterial, fungal, or viral infections, visible to his close relatives. Characteristic of several infectious foci in unrelated areas (for example, pneumonia and panaritium, otitis and furunculosis).

Tumor intoxication: unmotivated body temperature rises without visible foci of infection, loss of appetite, weight loss, asthenia of the central nervous system.

Neurological symptoms of leukemia in children may indicate the spread of the leukemia process in the central nervous system (neuroleukemia). The clinical picture in this case depends on the localization of the process, often the lesion can be generally asymptomatic. The most characteristic clinical signs: headache, dizziness, increased appetite with weight gain. There may be pain in the muscles of the limbs, cramps, vomiting, stiff neck, symptoms of Kerning and Brudzinsky, focal symptomatology.

Along with the described signs, characteristic for all types of acute leukemia in general, its various variants have their own clinical features, which, however, do not contradict the general signs of the disease.

For various variants of ALL, as well as for M4 and M5 variants of ONL, generalized lymphadenopathy is more common. With T-linear ALL, lesions of the lymphoid organs of the mediastinum (thymus and lymph nodes) occur, the complication of which is airway obstruction, the upper vena cava compression syndrome (edema of the upper half of the trunk). A mature B-linear ALL is characterized by a rapid increase in the tumor mass, and the hyperplastic syndrome is more often manifested by an increase in lymphoid tissue in the region of the head and neck.

When M2 variant of ONLL, chlorides appear more often than other types of leukemia. With M4 and M5 variants, ONLL is more often noted for gingival hyperplasia. In acute promyelocytic leukemia (leukemia t (15; 17) or M3 according to FAB) there is a severe hemorrhagic syndrome, associated primarily with coagulopathy and therefore accompanied by a hematomic type of bleeding. With manifestations of the syndrome of disseminated intravascular coagulation, manifestation of the disease can also begin in the M4 variant of ONLL. The M4 variant is characterized by a more frequent presence of an initial lesion of the central nervous system - neuroleukemia. For erythroblast leukemia, the clinical picture is characterized by arthralgias, serosites, hemolytic anemia. For the megakaryoblastic variant ONLL, myelofibrosis and osteosclerosis are characteristic, which greatly complicates the bone marrow puncture biopsy, making the interpretation of the morphological examination of the punctate problematic.

Symptoms of leukemia in children

Classification of leukemia

As far back as 1889, Ebstein suggested the polymorphism of leukemias and proposed to divide them into acute and chronic ones, and Nagely in 1900 - to lymphoid and myeloid. With the deepening of knowledge about the nature of the disease, the emergence of new methods of examining patients, comparing the results of treatment, which previously looked like similar varieties of the same form of leukemia, it becomes increasingly clear how large and diverse the group of diseases is concealed under the name "leukemia".

Until now, the Franco-American-British classification (FAB), proposed as far back as 1976, is generally accepted in the world. It provides for the division of acute leukemia by the morphological characteristics of tumor cells. Isolate acute lymphoblastic leukemia and acute non-lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL).

• L1 - ALL with the morphology of small lymphoblasts.
• L2 - ALL with the morphology of large polymorphic lymphoblasts.
• L3 - ALL with the morphology of large polymorphic lymphoblasts with vacuoles.

Acute non-lymphoblastic leukemia (ONLL).

• M0 is undifferentiated leukemia.
• Ml - myeloblastic leukemia without maturation.
• M2 - myeloblastic leukemia with maturation.
• M3 - promyelocytic leukemia.
• M4 - myelomonocytic leukemia and myelomonocytic leukemia with eosinophilia (M4o).
• M5 is monoblastic leukemia (M5a) and monocytic leukemia (M5b).
• Mb - erythromyelosis.
• M7 is megakaryoblastic leukemia.

Unfortunately, it turned out that the morphological signs of tumor cells give us far from complete information about the varieties, the expected prognosis, do not always allow us to orient ourselves in the choice of therapeutic tactics for a particular patient. Therefore, the World Health Organization (WHO) in 2001 proposed a new classification of acute leukemia, which was supposed to bring together clinicians and morphologists. Acute non-lymphoblastic leukemia (ONLL).

ONLL with characteristic genetic abnormalities:

• ONLL with the translocation of chromosome 8 to chromosome 21, which results in the formation of AML1 / ETO (t (8; 21) (q22; 22) AML1 / ETO gene);
• ONLL with inversion or translocation of chromosome 16 (inv 16 (p 13q22) or t (16; 16) (p 13; q22) CBFp / MYHll);
• ONLL with the translocation of chromosome 15 to the chromosome 17a (15; 17) (r22; r12) PMB / rAra);
• ONLL with various anomalies of the chromosome 11 (11 r23).
• Multi-line dysplasia:
• ONLL on the background of a course of preleukemic disease (myelodysplastic syndrome or myeloproliferative disease);
• ONLL without a proven preleukemic disease, but with a dysplasia of at least 50% of the cells, which has the signs of several lines of myeloid differentiation.
• ONLL, associated with therapy, is a secondary ONLL. This type develops in patients who have previously received chemotherapy for any other cancer.
• ONLL, not included in the previous three groups, is classified according to the morphological criteria of the RAV classification, where 8 subtypes are allocated. In this group, separate variants (extremely rare) in childhood are singled out:
  • acute basophilic leukemia;
  • acute panmyelosis with myelofibrosis;
  • myeloid sarcoma.

Isolated acute biphenotypic leukemia, in which tumor cells carry morphological, cytochemical, immunological signs of the myeloid and lymphoid lines of differentiation, or both B- and T-linear characters. To the same group of acute leukemia include the so-called bilinear variants, when the tumor consists of several independent clones of blast cells.

Acute lymphoblastic leukemia (ALL) is divided into variants according to the immunological characteristics of lymphoblasts that respond to malfunction at different stages of differentiation into T or B lymphocytes.

T-linear versions:

• pro-T;
• pre-T;
• mature T.

B-linear variants:

• pro-B;
• pre-pre-B (or general);
• pre-B;

F is a mature B-cell variant that has the morphology of b3 cells by FAB.

In addition, ALL is isolated with characteristic genetic abnormalities.

• ALL with the Philadelphia chromosome t (9; 22) (q34; ql 1) BCR / ABL.
• ALL with translocation t (4; l 1) (q21; q23) MLL / AF4.
• ALL with translocation t (12; 21) TEL / AM L.

Classification of the WHO makes it possible to more accurately distinguish different therapeutic groups, determine the prognosis of the disease. The variants of ONL with t (8; 21), t (15; 17), inv 16, and approximately corresponding morphological variants according to FAB (M2, M3, M4o) are characterized by a relatively favorable prognosis for polychemotherapy. At the same time, variants of ONLL with llq23 MLL, secondary ONLL, ONLL with multiline dysplasia are characterized by extremely poor prognosis, despite the ongoing chemotherapy according to modern protocols.

With ALL, the least favorable prognosis is noted in cases of ALL with the Philadelphia chromosome and the infant ALL (t; 4; 11) that occurs in the first year of life. Moreover, ALL t (12; 21) and hyperdiploid variants, in which the number of chromosomes is increased in tumor cells, are relatively not amenable to treatment.

[18], [19], [20], [21], [22], [23], [24]

How to recognize leukemia in children?

The diagnosis is based on a characteristic clinical picture, anamnestic data and laboratory studies. If you suspect a sharp leukemia, you need to make a general blood test with a mandatory count of the leukocyte formula. The main characteristics of the general blood test for acute leukemia will also be signs indicative of depression of normal hematopoiesis, anemia, thrombocytopenia, agranulocytosis (reduction of hemoglobin, erythrocyte, platelet and neutrophil levels). When calculating the leukocyte formula, leukemia is characterized by the appearance of early precursors of granulocytes (blasts, myeloblasts, promyelocytes) that are not normal in peripheral blood and mature segment neutrophils in the absence of late progenitors that may be present in the leukemia reaction (stab neutrophils, metamyelocytes). The appearance of blast cells in the leukocyte formula in the presence of anemia, thrombocytopenia, agranulocytosis makes the diagnosis of acute leukemia obvious already in the general blood test, but to confirm the diagnosis and determine the variant of acute leukemia, a bone marrow biopsy is necessary.

The bone marrow examination is usually performed by puncture biopsy of the anterior or posterior upper iliac spine. Sometimes puncture of the upper third of the sternum (sternal puncture) is performed, and in children of the first weeks of life - a puncture of the heel or tuberosity of the tibia. In this case, a liquid red bone marrow is obtained, which is subjected to morphological, cytochemical, immunological and genetic studies to establish the variant of acute leukemia. When carrying out a biopsy, the principle of reference research should always be used (carrying out similar analyzes in different, independent laboratories).

Morphological (cytological) examination of the bone marrow is a calculation of the number of hematopoietic cells (myelokaryocytes) under standard color. Myelogram is the result of this calculation, it shows the percentage of cellular populations of bone marrow. Criterion for the diagnosis of acute leukemia is more than 30% of leukemia (blast) cells (WHO criterion is more than 20%). Morphological examination also determines the features of the structure of blast cells, which, together with their cytochemical characteristics, is the basis of the RAV classification of leukemia.

The cytochemical study is based on the identification of different lines of differentiation of blast cells by estimating the presence in them of various biochemical markers (mainly enzymes). The high activity of myeloperoxidase (MPO) is specific for the myeloid, granulocyte line of differentiation. Lymphoblasts and megacaroblasts are always MP O-negative. Monoblasts can be both MPS-positive and negative. The response to lipids with Sudan by black is less specific, it is usually positive in the same cells as the MPO. In rare cases, Sudan-positive lymphoblasts are noted. Thus, MPS, and Sudan-positive variants of leukemia include M1, M2, M3 and M4 variants according to FAB. The marker of monocytic and megakaryocytic differentiation series is nonspecific esterase (alpha-naphthyl esterase) inhibited by sodium fluoride, that is, NE-N-P-positive M4, M5 and M7 variants according to FAB can be considered. For differential diagnosis between OLL and ONLL, glycogen coloration (PAS reaction) is used. In the lymphoblasts, the PAS-reaction appears in the form of granules, while in the cells of myeloid origin the diffuse staining of the cytoplasm is noted. There are other cytochemical tests, but this method allows you to determine not all the varieties of acute leukemia, highlighted by the WHO classification. Its main field of application is myeloid leukemia. In each specific case, the diagnosis of various variants of acute leukemia can be made only on the basis of all methods of investigation (morphological, cytochemical, immunological, genetic).

Immunological research is of paramount importance, first of all, for the determination of ALL variants, as well as for differential diagnosis with ONLL variants. The method is based on the determination of membrane and cytoplasmic markers of leukemia cells of different lines of differentiation and stages of maturity using labeled monoclonal antibodies. The totality of markers of the tumor cell, determined with the help of this method, is called the immunophenotype. In recent years, the method of flow cytometry has become the most widely used for the evaluation of the results of immunophenotyping, which makes it possible to automatically count the number of labeled cellular elements and, thus, to have a definitive conclusion on the day of bone marrow puncture. To assess the immunophenotype of blast cells, an international system of differentiation clusters (CDs) of leukocyte antigens is used. For the diagnosis of ALL, it is important to determine the so-called early markers present on undifferentiated lymphoblasts (CD34, CD10), and the B-cell antigens (CD19, CD20, CD22) and T cell (CD3, CD5, CD7, CD4, CD8) differentiation lines. Based on the immunophenotype, a final diagnosis of the ALL variant can be made in accordance with the current classification. With ONLL it is necessary to determine the antigens of blood stem cells (CD34), myeloblasts and monoblasts (CD 13, CD33), megakaryoblasts (CD61), erythroblasts (glycophorin A) and other markers available on cells of different lines of differentiation at different stages of maturity.

Genetic research usually searches for the most characteristic and frequently occurring genetic abnormalities required to establish an accurate WHO diagnosis. To do this, use molecular genetic research, which is based on the principle of polymerase chain reaction (PCR). Search for specific mutations (chimeric genes). PCR allows not only to diagnose various variants of leukemia, but also to evaluate the results of treatment, the so-called minimal residual disease (MPI), in a situation where the population of blast cells that is not distinguishable in morphological research remains in the bone marrow. In some cases, a standard cytogenetic study (karyotyping) is used, which allows to evaluate the whole set of chromosomes. It is indispensable for diagnosing changes in the number of chromosomes, as well as for finding rare aberrations. In addition, the method of fluorescence in situ hybridization (FISH) is used, which allows the detection of chimeric genes with high accuracy using DNA probes, using, for example, ready cytological preparations of the bone marrow.

To identify the lesion of the central nervous system (neuroleukemia), it is also necessary to study the cerebrospinal fluid; for this, a lumbar puncture is done. Determine the level of protein, glucose, conduct cytological examination of the sediment (cytosis). Diagnostic is the detection of 5 blast cells and more in a microliter. If there is a characteristic neurological symptomatology and no diagnostic number of tumor cells in the cerebrospinal fluid, a computer or magnetic resonance imaging of the head is performed to diagnose neiroleicemia.

For the diagnosis of neuroleukemia, it is necessary to resort to the help of specialist consultants (neurologist and ophthalmologist). Fundamentally important in this regard is the examination of the fundus. Characteristic disappearance of differences in the color of the arteries and veins. The veins are enlarged, crimped, full-blooded, the slowed flow of blood in them resembles the pouring of sand in the hourglass. The walls of the veins in the peripheral segments are covered with a whitish "liner" representing paravassal accumulations of blasts. Sometimes they find whitish nodules, surrounded by a reddish rim. Often noted opacification of the retina, widening the boundaries of the optic disc. Sometimes you can see hemorrhages and the retinal detachment caused by them.

Ultrasound examination (ultrasound) of the abdominal cavity organs, retroperitoneal space is performed by all patients with suspected acute leukemia. It allows to identify focal leukemic lesions of parenchymal organs, enlargement of lymph nodes and formation of chlorine in visceral tissue. Of great importance is ultrasound of the testes in boys for the diagnosis of their lesions, since in the future they can often become a source of relapse.

To diagnose the lesions of the lungs and lymphoid organs sreddosteniya use chest X-ray.

Acute leukemia in children - a serious systemic disease, in which one way or another the damage to all organs and systems of the body. Therefore, for the diagnosis of these lesions, all patients undergo a biochemical blood test with mandatory determination of residual nitrogen (uric acid, urea, creatinine), hepatic and pancreatic enzymes (ALAT, ASAT, g-GTP, AFP, LDH, amylase), total protein concentration , direct and indirect bilirubin, electrolytes, acute phase response (C-reactive protein, seromucoid). At the same time, determination of cell decay parameters (concentration of potassium, uric acid, LDH activity) is of paramount importance, which may indicate the presence of such a formidable complication as acute tumor lysis syndrome requiring immediate treatment.

To assess severe systemic disorders, an assessment is also made of the state of the heart muscle (electrocardiography, echocardiogram), hemostasis system (coagulogram), urinary system (general urine analysis). Serum immunoglobulin levels, serological tests for the spectrum of infections associated with transfusions (HIV, syphilis, hepatitis, SMU), as well as opportunistic infections (mycoplasma, chlamydia, herpes, varicella, Epstein-Barr viruses) are performed.

Differential diagnostics

Differential diagnosis is carried out, first of all, with the so-called leukemoid reactions, in which there are changes in the general analysis of blood (detecting progenitor cells, atypical leukocytes, anemia), and also hepatosplenomegaly, lymphadenopathy. These changes are reactive manifestations of the disease (most often the infectious process).

Infectious mononucleosis is a disease caused by the Epstein-Barr virus. It is characterized by fever, hepato-splenomegaly, generalized lymphadenopathy, in the general blood test - atypical mononuclears, anemia, thrombocytopenia.

Generalized cytomegalovirus and other infections caused by opportunistic pathogens can occur with similar symptoms, which is especially characteristic of young children. At an older age, a differential diagnosis with tuberculosis is often necessary.

In case of severe septic process, anemia, thrombocytopenia, leukocytosis with the appearance of progenitor cells, up to the blasts in the general blood test, can occur.

With a number of systemic diseases of connective tissue, primarily systemic lupus erythematosus, panniculitis, pancytopenia may occur in combination with fever, hepatosplenomegaly, hemorrhagic rash.

Other systemic diseases of the blood are aplastic anemia, chronic myelogenous leukemia in the stage of blast crisis, etc. Pancytopenia can be accompanied by a severe course of B12 and folic-deficient megaloblastic anemia. Similar manifestations of hemorrhagic syndrome and thrombocytopenia also occur with idiopathic thrombocytopenic purpura, sometimes together with posthemorrhagic anemia and lymphadenopathy (reactive infectious origin). Pancytopenia can accompany the course of the aplastic crisis, and anemia and leukocytosis with the appearance of early precursors - the course of the hemolytic crisis with various hemolytic anemia.

Pancytopenia with the detection in the bone marrow of blast cells can occur when metastasizing solid tumors.

The peculiarity of reactive changes in the general blood analysis is the absence of a leukemia dip characteristic for acute leukemia, the progenitor cells have a morphology different from the tumor one. Good help in conducting a differential diagnosis can be a detailed collection of anamnesis, the appointment of additional, primarily, serological studies. In all doubtful cases, it is recommended to perform a bone marrow biopsy. It should be remembered that the detection of an infectious disease does not exclude the diagnosis of acute leukemia, but, conversely, may be one of the symptoms that allow him to be suspected.

Diagnosis of leukemia in children

[25], [26], [27]

Treatment of leukemia in children

Treatment of acute leukemia in children should be performed only in a specialized hospital, where for this purpose there are necessary technical facilities: laboratory base, department or intensive care unit, equipment for blood transfusion, trained and qualified personnel.

The basis for the treatment of acute leukemia in children is polychemotherapy, which, like in the cases of treatment of other oncological diseases, is prescribed by a medical protocol. The protocol is a set of rules, which reflects the timing, dose, method and conditions for the introduction of a specific chemotherapy drug, a list of mandatory studies for both primary diagnosis and evaluation of the effectiveness of therapy, tracking the so-called minimal residual disease. The protocol also determines the terms and conditions for dispensary observation. Depending on the frequency of occurrence in a population of some form of cancer, there are international and national protocols that integrate entire networks of hematological clinics. One of these clinics assumes the responsibility of the research center for any specific nosological form of the cancer and collects, scientifically-statistically processed information on the treatment of each individual patient, provides advice, reviews diagnostic tests, develops an updated protocol based on the empirical evidence experience and modern fundamental developments. Another important function of the research center is the randomization of patients. Patients with a similar diagnosis and clinical status receive different treatment at different stages of therapy. The results of treatment of the obtained groups are compared and the data obtained are used to improve the protocol.

The modern approach includes specific treatment of various variants of acute leukemia in children, their division according to a number of signs on different therapeutic groups in accordance with risk factors. In different clinics, different protocols are used to treat certain forms of acute leukemia. Differences in chemotherapy combinations, doses and methods of their administration differ. At various stages of ALL therapy, glucocorticoids (prednisolone, dexamethasone, methylprednisolone), alkaloids (vincristine), anthracyclines (daunorubicin), enzymes (beta-asparaginase), antimetabolites (methotrexate, mercaptopurine, thioguanine, cytarabine), alkylating agents cyclophosphamide, ifosfamide), etc. Anthracyclines (daunorubicin, idarubicin, mitoxantrone), antimetabolites (cytarabine, purinethol), alkaloids (etoposide), etc. Are used for the treatment of ONL.

Classical principles of polychemotherapy of acute leukemia in children - phased therapy: induction of remission, consolidation, maintenance therapy, prevention or treatment of complications (eg, neuroleukemia).

The main goal of induction is to achieve clinical-hematologic remission-the disappearance of clinical symptoms of the disease and blast cells from the bone marrow (less than 5% in the myelogram).

The next stage is consolidation, during which other combinations of chemotherapy are usually used to combat minimal manifestations of the disease (a residual tumor mass in the bone marrow that can not be detected by routine cytological research and molecular genetics methods should be used). The disappearance of a minimal residual disease characterizes molecular remission.

Supportive therapy implies the long-term use of chemotherapy in low doses, which are used to prevent early relapse of the disease. Currently, maintenance therapy is not used in all cases of acute leukemia.

Treatment of neuroleukemia is not an easy task, because chemotherapy, when administered orally or parenterally, does not penetrate poorly through the hemato-encephalic barrier. In patients without lesions of the central nervous system, it is necessary to prevent neuronal leukemia, which consists of regular intrathecal injections of chemotherapeutic agents during lumbar punctures and preventive cranial irradiation. For the treatment of neuroleukemia, intrathecal injections of chemotherapeutic agents with subsequent irradiation are also used. However, at the same time, a special reservoir of Ommaya is installed, which allows the introduction of chemotherapy drugs into the central nervous system (directly into the ventricles of the brain) at a higher frequency.

In recent years, special attention has been paid to the inclusion of alternative drugs, such as differentiating agents and monoclonal antibodies, in the treatment protocols along with chemotherapy. For the treatment of acute promyelocytic leukemia [ONLL 1 (15; 17)], along with chemotherapy, a derivative of vitamin A - thretonine (ATRA) is used, which does not possess a cytostatic effect, i.e. Does not kill tumor cells, but allows them to mature, differentiate and subsequently undergo apoptosis, like all non-tumor cells in the body. The use of threotinin in the treatment of ONLL 1 (15, 17) allowed to achieve an unprecedented high survival rate for myeloid leukemias - 85% in this group of patients.

In addition, at present, monoclonal anti-SE20 antibodies (rituximab) are used to treat the anti-cell B-ALL, allowing the detection of tumor cells to potentiate the effect of chemotherapy on them. Other differentiating agents, tyrosine kinase inhibitors (imatinib mesylate), histone acetylase inhibitors (depakin), monoclonal antibodies-anti-SEZZ (gemtuzumab) anti-SE52 (alemtuzumab), interleukins, and many others, are being developed at the stage of clinical trials.

One of the main directions in the development of therapeutic protocols is the development of methods for the evaluation of the so-called minimal residual disease (MRD), a condition in which a small population of tumor cells remains that is not discernible for light microscopy. In this situation, it is possible to determine the presence of blasts only with the help of molecular methods. It is on the fight with the MRB that all therapy is targeted after the completion of the first stage - the induction of remission. Standardization of methods for evaluating MPD allows to differentiate patients' risk groups in the next stages of polychemotherapy, and more effectively to prevent the recurrence of the disease.

For the treatment of a number of variants of acute leukemia, mainly relapses and primary patients from high-risk groups, allogeneic transplantation of hematopoietic stem cells - TSCS (bone marrow, peripheral blood stem cells, cord blood) is used. The indications and peculiarities of the TSCC method are also determined in each specific case by the treatment protocol and depend on the variant of acute leukemia, the risk group, the presence of a related donor, the degree of histocompatibility of the transplant. The main principle of action is myeloablation (radical removal of bone marrow of a recipient containing tumor cells), as well as activation of antitumor immunity based on the phenomenon of "graft-versus-leukemia".

How is leukemia treated in children?

Prognosis of leukemia in children

Acute leukemia in a child, like other cancers, without specific treatment leads to 100% of deaths. Estimating the results of modern therapy, they speak of a five-year survival rate, which may be general (without recurrence) and event-free (given the occurrence of relapse). The main factor determining these indicators is the biology of the tumor, primarily its genetic variant, as well as morphological, immunological variants, as mentioned above. A certain role is played also by the clinical status of the patient at the time of diagnosis. In this case, the importance of leukocytosis in peripheral blood, the presence or absence of neuroleukemia, as well as the age of the patient. For the general group of patients with ALL, event-free survival is 70%, for patients with ALL, 50%.

Clinical follow-up and recommendations are determined in each case by the treatment protocol and depend on the variant of acute leukemia and the risk group. Clinical follow-up should be performed in a specialized hematology center. Its main principles: confirmation of remission of the disease, regular examinations, delivery of a general blood test, according to indications - control of the minimal residual disease, the functions of internal organs, the state of the central nervous system.

In a special way, dispensary observation is carried out in patients with TSCA. These patients need to monitor the condition of the transplant (carrying out analyzes for chimerism - the presence of molecular markers of the donor's hematopoietic system), monitoring the so-called "graft-versus-host disease", assessing the infectious status (primarily, regular screening for the spectrum of viral infections).