Leukemia in children

Childhood leukemia is a general term for malignant tumors arising from hematopoietic cells, which account for approximately 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 diagnosed with the disease per year.

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

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

The first description of a patient with leukemia was made by the French doctor Alfred Velpeau, who in 1827 treated a 63-year-old florist with severe weakness, fever, hepatosplenomegaly and stones in the urinary tract. Velpeau noted the similarity of this patient's blood to liquid oatmeal and suggested that the disease was associated with some "white blood corpuscles". The term "leukemia" (translated from Greek - "white blood") was introduced into scientific circulation in 1856 by the German pathologist Rudolf Virchow. Since Virchow was unable to explain the cause of the sharp increase in the number of white blood cells (leukocytes), he simply stated the picture he saw 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 to describe the disease - "leukemia" and "hemoblastosis", which, in their opinion, better corresponded to the essence of the disease, since leukemia does not occur in all patients, and the disease itself is associated not with blood, but with bone marrow. In other European languages, the traditional, Virchowian term "leukaemia" is still preserved.

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Epidemiology of leukemia in children

The incidence of acute leukemia in childhood is 2-5 cases per 100,000 children per year. Acute lymphoblastic leukemia (ALL) occurs in 75-85% of leukemia cases in children, making it the most common oncological disease in childhood. ALL occurs most frequently in children aged 2 to 5 years. Boys are slightly more likely to get sick than girls (1.3:1).

Acute nonlymphoblastic leukemia (ANLL) occurs with a frequency of 0.6-0.8 cases per 100,000 children and accounts for 18-20% of all leukemia in children. In adults, ANLL is the most common form of leukemia, accounting for 70% of cases. The average age of those affected is 60 years. In children, ANLL is more common in the first years of life, more often in boys.

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Causes of Leukemia in Children

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

All tumor cells have common biochemical, morphological, immunological characteristics, 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 vast majority of cases, it is impossible to find any etiologic factor in the disease in a specific patient. Only a few risk factors can be reliably discussed. It is known that the incidence of ALL in children increased sharply in Japan after the bombings of Hiroshima and Nagasaki. However, there is currently no evidence of the effect of low doses of radiation (for example, X-rays) on the development of acute leukemia. The use of radiation therapy, chemotherapy, in particular such drugs as etoposide, teniposide, cyclophosphamide (cyclophosphamide), procarbazine hydrochloride (procarbazine) for the treatment of any oncological disease leads to the development of acute leukemia (usually ALL) in some patients after 2-9 years, which has special properties. This fact made it possible to distinguish secondary ALL as a separate variant of acute leukemia according to the modern classification.

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

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

What causes leukemia in a child?

Symptoms of Leukemia in a Child

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

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

Hemorrhagic syndrome, which occurs according to the microcirculatory (petechial-spotted) type of bleeding. Its manifestations vary in severity: from small petechiae and ecchymoses on the skin and mucous membranes to large subcutaneous hemorrhages, severe bleeding from the mucous membranes (nasal, gastrointestinal, renal, uterine). The main characteristics of hemorrhages are the asymmetry of the lesion, the connection with the damaging agent by the place and time of occurrence. The cause of bleeding in leukemia is thrombocytopenia associated with the disappearance or suppression of megakaryocytes and insufficient production of platelets 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 leukemic infiltrates on the skin (leukemids), in various tissues and organs (chloromas or - a more modern term - myeloid sarcomas). Bone pain is a common symptom associated with blast infiltration of the bone marrow, osteoporosis and stretching of the periosteum. Enlarged lymph nodes are usually painless, dense, "cold", not fused with the surrounding tissues. When palpating the liver and spleen, a stony edge is determined, there may be pain due to stretching of the organ capsule.

Frequent infectious diseases occur due to a disruption in the production of leukocytes by the bone marrow. In this case, the child falls ill with severe bacterial, fungal, and viral infections without any apparent cause for his or her loved ones. The presence of several infectious foci in unrelated areas is typical (for example, pneumonia and felon, otitis and furunculosis).

Tumor intoxication: unmotivated increases in body temperature 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 leukemic process to the central nervous system (neuroleukemia). The clinical picture depends on the localization of the process; the lesion may often be completely asymptomatic. The most characteristic clinical signs are headache, dizziness, increased appetite with weight gain. There may be pain in the muscles of the extremities, cramps, vomiting, stiffness of the occipital muscles, Kerning and Brudzinsky symptoms, focal symptoms.

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

Generalized lymphadenopathy is more typical for various variants of ALL, as well as for M4 and M5 variants of AML. In T-linear ALL, there is more frequent damage to the lymphoid organs of the mediastinum (thymus and lymph nodes), the complication of which is obstruction of the respiratory tract, superior vena cava compression syndrome (swelling of the upper half of the body). Mature B-linear ALL is characterized by rapid growth of the tumor mass, and hyperplastic syndrome is more often manifested by an increase in lymphoid tissue in the head and neck area.

In the M2 variant of APL, chloromas occur more often than in other types of leukemia. In the M4 and M5 variants of APL, gingival hyperplasia is more often observed. In acute promyelocytic leukemia (leukemia t(15; 17) or M3 according to FAB), severe hemorrhagic syndrome occurs, associated primarily with coagulopathy and therefore accompanied by a hematoma type of bleeding. Manifestations of disseminated intravascular coagulation syndrome may also begin with the manifestation of the disease in the M4 variant of APL. The M4 variant is characterized by a more frequent presence of initial damage to the central nervous system - neuroleukemia. Arthralgia, serositis, and hemolytic anemia are characteristic of erythroblastic leukemia in the clinical picture. The megakaryoblastic variant of ONLL is characterized by myelofibrosis and osteosclerosis, which greatly complicates bone marrow puncture biopsy and makes the interpretation of the morphological examination of the puncture problematic.

Symptoms of Leukemia in Children

Classification of leukemia

As early as 1889, Ebstein suggested the polymorphism of leukemia and proposed dividing it into acute and chronic, and Naegeli in 1900 into lymphoid and myeloid. With the deepening of knowledge about the nature of the disease, the emergence of new methods of examining patients, and the comparison of treatment results, which previously seemed to be similar varieties of the same form of leukemia, it is becoming increasingly clear how large and heterogeneous a group of diseases is hidden under the name "leukemia".

The French-American-British classification (FAB), proposed in 1976, is still generally accepted in the world. It provides for the division of acute leukemias according to the morphological characteristics of tumor cells. Acute lymphoblastic leukemia and acute non-lymphoblastic leukemia are distinguished.

Acute lymphoblastic leukemia (ALL).

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

Acute nonlymphoblastic leukemia (ANLL).

• M0 - undifferentiated leukemia.
• Ml - myeloblastic leukemia without maturation.
• M2 - myeloblastic leukemia with maturation.
• M3 - promyelocytic leukemia.
• M4 - myelomonocytic leukemia and myelomonocytic leukemia with eosinophilia (M4eo).
• M5 - monoblastic leukemia (M5a) and monocytic leukemia (M5b).
• MB - erythromyelosis.
• M7 - megakaryoblastic leukemia.

Unfortunately, it turned out that the morphological features of tumor cells do not provide us with complete information about the varieties, expected prognosis, and do not always allow us to navigate the choice of treatment tactics for a specific patient. Therefore, in 2001, the World Health Organization (WHO) proposed a new classification of acute leukemia, which was supposed to reconcile clinicians and morphologists. Acute non-lymphoblastic leukemia (ANLL).

ONLL with characteristic genetic abnormalities:

• ONLL with translocation of chromosome 8 to chromosome 21, resulting in the formation of the AML1/ETO gene (t(8;21) (q22;22) AML1/ETO);
• ONLL with inversion or translocation of chromosome 16 (inv 16(p 13q22) or t( 16; 16)(p 13;q22) CBFp/MYHll);
• ONLL with translocation of chromosome 15 to chromosome 17 a(15;17)(r22;r12) PMb/rAra);
• ONLL with various anomalies of chromosome 11 (11 r23).
• ONLL with multilineage dysplasia:
• ONLL against the background of preleukemic disease (myelodysplastic syndrome or myeloproliferative disease);
• ONLL without proven preleukemic disease, but with dysplasia of at least 50% of cells, showing signs of several lines of myeloid differentiation.
• Therapy-associated ANLL is secondary ANLL. This type develops in patients who have previously received chemotherapy for some other oncological disease.
• ONLL, not included in the previous three groups, is classified according to the morphological criteria of the RAV classification, where 8 subtypes are distinguished. In this group, variants that occur separately (extremely rarely) in childhood are distinguished:
  • acute basophilic leukemia;
  • acute panmyelosis with myelofibrosis;
  • myeloid sarcoma.

Acute biphenotypic leukemia is distinguished separately, in which tumor cells bear morphological, cytochemical, immunological signs of myeloid and lymphoid differentiation lines or simultaneously B- and T-linear signs. The so-called bilinear variants, when the tumor consists of several independent clones of blast cells, are also included in this group of acute leukemia.

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

T-linear options:

• pro-T;
• pre-T;
• mature T.

B-linear options:

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

F is a mature B-cell variant that has b3-cell morphology according to FAB.

In addition, ALL with characteristic genetic abnormalities is distinguished.

• ALL with 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.

The WHO classification allows more precise identification of various therapeutic groups and determination of the disease prognosis. Variants of ONLL with t(8;21), t(15;17), inv 16 and approximately corresponding morphological variants according to FAB (M2, M3, M4eo) are characterized by a relatively favorable prognosis during polychemotherapy. At the same time, variants of ONLL with llq23 MLL, secondary ONLL, ONLL with multilinear dysplasia are characterized by an extremely poor prognosis, despite the chemotherapy conducted according to modern protocols.

In ALL, the least favorable prognosis is observed in cases of ALL with the Philadelphia chromosome and infantile ALL t(4;11), which occurs in the first year of life. At the same time, ALL t(12;21) and hyperdiploid variants, in which the number of chromosomes in tumor cells is increased, respond relatively well to treatment.

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How to recognize leukemia in children?

The diagnosis is based on the characteristic clinical picture, anamnestic data and laboratory tests. If acute leukemia is suspected, it is necessary to do a complete blood count with mandatory calculation of the white blood cell count. The main characteristics of the complete blood count for acute leukemia will also be signs indicating depression of normal hematopoiesis - anemia, thrombocytopenia, agranulocytosis (decreased levels of hemoglobin, erythrocytes, platelets and neutrophils). When calculating the white blood cell count, leukemic gaping is characteristic - the appearance of early granulocyte precursors (blasts, myeloblasts, promyelocytes), which are normally absent in the peripheral blood, and mature segmented neutrophils in the absence of late precursors, which can be present in a leukemoid reaction (band neutrophils, metamyelocytes). The appearance of blast cells in the leukocyte formula in the presence of anemia, thrombocytopenia, and agranulocytosis makes the diagnosis of acute leukemia obvious already during a general blood test, however, to confirm the diagnosis and determine the type of acute leukemia, a bone marrow biopsy is necessary.

Bone marrow examination is usually performed by a puncture biopsy of the anterior or posterior superior iliac spine. Sometimes a puncture of the upper third of the sternum (sternal puncture) is performed, and in children in the first weeks of life - a puncture of the calcaneus or tibial tuberosity. This produces liquid red bone marrow, which is subjected to morphological, cytochemical, immunological and genetic testing to establish the type of acute leukemia. When performing a biopsy, the principle of reference testing (conducting similar analyses in different, independent laboratories) should always be used.

Morphological (cytological) examination of bone marrow is a count of the number of hematopoietic cells (myelokaryocytes) with standard staining. Myelogram is the result of this count, it presents the percentage of bone marrow cell populations. The criterion for the diagnosis of acute leukemia is more than 30% leukemic (blast) cells (WHO criterion - more than 20%). Morphological examination also determines the structural features of blast cells, which, together with their cytochemical characteristics, underlies the RAB classification of leukemia.

Cytochemical examination is based on the detection of various lines of differentiation of blast cells by assessing the presence of various biochemical markers (mainly enzymes) in them. High myeloperoxidase (MPO) activity is specific for the myeloid, granulocytic line of differentiation. Lymphoblasts and megakaryoblasts are always MP O-negative. Monoblasts can be either MPO-positive or negative. The reaction to lipids with Sudan black is less specific, it is usually positive in the same cells as MPO. In rare cases, sudan-positive lymphoblasts are noted. Thus, MPO- and sudan-positive variants of leukemia include M1, M2, M3 and M4 variants according to FAB. The marker of the monocytic and megakaryocytic differentiation series is non-specific esterase (alpha-naphthyl esterase) inhibited by sodium fluoride, i.e. M4, M5 and M7 variants according to FAB can be considered NE-NaP-positive. Glycogen staining (PAS reaction) is used for differential diagnostics between ALL and ALL. In lymphoblasts, the PAS reaction appears as granules, while in cells of myeloid origin, diffuse staining of the cytoplasm is noted. There are other cytochemical tests, but this method does not allow determining all types of acute leukemia, distinguished by the WHO classification. Its main area of application is myeloid leukemia. In each specific case, the diagnosis of various types of acute leukemia can be made only on the basis of all research methods (morphological, cytochemical, immunological, genetic).

Immunological testing is of great importance, first of all, for determining ALL variants, as well as for differential diagnosis with AML variants. The method is based on determining membrane and cytoplasmic markers of leukemic cells of various differentiation lines and maturity stages using labeled monoclonal antibodies. The set of tumor cell markers determined using this method is called an immunophenotype. In recent years, the flow cytometry method has become most widely used to evaluate the results of immunophenotyping, allowing automatic counting of the number of labeled cellular elements and, thus, having a final conclusion on the day of bone marrow puncture. The international system of differentiation clusters (CD) of leukocyte antigens is used to evaluate the immunophenotype of blast cells. For the diagnosis of ALL, it is important to determine the so-called early markers present on undifferentiated lymphoblasts (CD34, CD10), and antigens of B-cell (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 modern classification. In case of ANLL, it is necessary to determine antigens of blood stem cells (CD34), myeloblasts and monoblasts (CD 13, CD33), megakaryoblasts (CD61), erythroblasts (glycophorin A) and other markers present on cells of different differentiation lines at different stages of maturity.

Genetic testing usually involves searching for the most characteristic and frequently occurring genetic abnormalities required to establish an accurate diagnosis according to the WHO classification. For this purpose, molecular genetic testing is used, which is based on the polymerase chain reaction (PCR) principle. Specific mutations (chimeric genes) are searched for. PCR allows not only to diagnose various types of leukemia, but also to evaluate the results of treatment, the so-called minimal residual disease (MRD), in a situation where a population of blast cells that are not distinguishable during morphological testing remains in the bone marrow. In some cases, standard cytogenetic testing (karyotyping) is used, which allows to evaluate the entire set of chromosomes. It is indispensable for diagnosing changes in the number of chromosomes, as well as for searching for rare aberrations. In addition, the fluorescent in situ hybridization (FISH) method is used, which allows to detect chimeric genes with high accuracy using DNA probes, using, for example, ready-made cytological preparations of bone marrow.

To detect damage to the central nervous system (neuroleukemia), it is also necessary to examine the cerebrospinal fluid; for this, a lumbar puncture is performed. The level of protein and glucose is determined, and a cytological examination of the sediment (cytosis) is performed. The detection of 5 or more blast cells per microliter is diagnostic. In the presence of characteristic neurological symptoms and the absence of a diagnostic number of tumor cells in the cerebrospinal fluid, a computer or magnetic resonance imaging of the head is performed to diagnose neuroleukemia.

To diagnose neuroleukemia, it is necessary to seek the help of specialist consultants (neurologist and ophthalmologist). In this regard, examination of the fundus is of fundamental importance. Characteristically, the differences in the color of the arteries and veins disappear. The veins are dilated, tortuous, full-blooded, the slow blood flow in them resembles the pouring of sand in an hourglass. The walls of the veins in the peripheral sections are covered with a whitish "sleeve", representing paravasal accumulations of blasts. Sometimes whitish nodules surrounded by a reddish border are found. Clouding of the retina, expansion of the boundaries of the optic nerve disc are often noted. Sometimes hemorrhages and the resulting retinal detachment can be seen.

Ultrasound examination (US) of the abdominal cavity and retroperitoneal space is performed on all patients with suspected acute leukemia. It allows to identify focal leukemic lesions of parenchymatous organs, enlarged lymph nodes and formation of chloromas in visceral tissue. Ultrasound of the testicles in boys is of great importance for diagnosing their lesions, since they can often become a source of relapse in the future.

Chest X-ray is used to diagnose damage to the lungs and lymphoid organs of the mediastinum.

Acute leukemia in children is a severe systemic disease, which affects all organs and systems of the body in one way or another. Therefore, to diagnose these lesions, all patients undergo a biochemical blood test with mandatory determination of residual nitrogen (uric acid, urea, creatinine), liver and pancreatic enzyme activity (ALT, AST, g-GTP, alkaline phosphatase, LDH, amylase), total protein concentration, direct and indirect bilirubin, electrolytes, acute phase response indicators (C-reactive protein, seromucoid). Of primary importance is the determination of cell breakdown indicators (potassium concentration, uric acid, LDH activity), which may indicate the presence of such a formidable complication as acute tumor lysis syndrome, which requires immediate treatment.

To determine severe systemic disorders, the condition of the heart muscle (electrocardiography, echocardiography), hemostasis system (coagulogram), and urinary system (general urine analysis) are also assessed. Studies of serum immunoglobulin levels, serological tests for a range of transfusion-associated infections (HIV, syphilis, hepatitis, SMU), as well as opportunistic infections (mycoplasma, chlamydia, herpes viruses, chickenpox, Epstein-Barr) are performed.

Differential diagnostics

Differential diagnostics are carried out, first of all, with the so-called leukemoid reactions, in which changes occur in the general blood test (precursor cells, atypical leukocytes, anemia are detected), and there may also be hepatosplenomegaly, lymphadenopathy. These changes are reactive manifestations of the disease (most often an infectious process).

Infectious mononucleosis is a disease caused by the Epstein-Barr virus. It is characterized by fever, hepatosplenomegaly, generalized lymphadenopathy, atypical mononuclear cells in the general blood test, anemia, and thrombocytopenia.

Generalized cytomegalovirus and other infections caused by opportunistic pathogens may occur with similar symptoms, which is especially typical for young children. In older children, differential diagnosis with tuberculosis often has to be made.

In severe septic processes, anemia, thrombocytopenia, leukocytosis with the appearance of precursor cells, up to blasts, may occur in the general blood test.

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

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

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

The peculiarity of reactive changes in the general blood test is the absence of a leukemic gap characteristic of acute leukemia, the precursor cells have a morphology different from the tumor. A detailed anamnesis, the appointment of additional, primarily serological studies can be a good help in conducting a differential diagnosis. In all doubtful cases, it is recommended to conduct a puncture biopsy of the bone marrow. It should be remembered that the detection of an infectious disease does not exclude the diagnosis of acute leukemia, but on the contrary, can be one of the symptoms that allow one to suspect it.

Diagnosis of leukemia in a child

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Treatment of leukemia in children

Treatment of acute leukemia in children should be carried out only in a specialized hospital, where there are the necessary technical capabilities: laboratory facilities, an intensive care unit or ward, equipment for blood transfusions, trained and qualified personnel.

The basis of treatment of acute leukemia in children is polychemotherapy, which, as in cases of treatment of other oncological diseases, is prescribed by the treatment protocol. The protocol is a set of rules that reflects the timing, doses, method and conditions of administration of a specific chemotherapy drug, defines a list of mandatory studies both for primary diagnostics and for evaluation of therapy effectiveness, monitoring the so-called minimal residual disease. The protocol also defines the timing and conditions of dispensary observation. Depending on the frequency of occurrence in the population of a particular form of oncological disease, there are international and national protocols that unite entire networks of hematological clinics. One of these clinics assumes responsibility for the research center for a certain nosological form of oncological disease and is engaged in the collection, scientific and statistical processing of information on the treatment of each specific patient, provides advisory assistance, reference revision of diagnostic tests, develops an update to the protocol based on the empirical experience gained and modern fundamental developments. Another important function of the research center is randomization of patients. Patients with similar diagnosis and clinical status receive different treatments at different stages of therapy. The treatment results of the resulting 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, dividing them by a number of signs into different therapeutic groups in accordance with risk factors. Different clinics use different protocols for the treatment of various forms of acute leukemia. Combinations of chemotherapy drugs, 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. are usually used. For the treatment of AML, anthracyclines (daunorubicin, idarubicin, mitoxantrone), antimetabolites (cytarabine, purinethol), alkaloids (etoposide), etc. are mainly used.

The classical principles of polychemotherapy for acute leukemia in children are the implementation of step-by-step therapy: induction of remission, consolidation, maintenance therapy, prevention or treatment of complications (for example, neuroleukemia).

The main goal of induction is to achieve clinical and hematological 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 drugs are usually used, aimed at combating minimal manifestations of the disease (residual tumor mass in the bone marrow, which cannot be detected by routine cytological examination and requires the use of molecular genetic methods). The disappearance of minimal residual disease characterizes molecular remission.

Maintenance therapy involves long-term use of low-dose chemotherapy drugs used to prevent early relapses of the disease. Currently, maintenance therapy is not used for all types of acute leukemia.

Treatment of neuroleukemia is a difficult task, since chemotherapy drugs, when administered orally or parenterally, poorly penetrate the blood-brain barrier. In patients without damage to the central nervous system, it is necessary to carry out prophylaxis of neuroleukemia, which consists of regular intrathecal administration of chemotherapy drugs during lumbar punctures and prophylactic cranial irradiation. Intrathecal administration of chemotherapy drugs followed by irradiation is also used to treat neuroleukemia. However, in this case, a special Ommaya reservoir is installed, which allows chemotherapy drugs to be administered into the central nervous system (directly into the ventricles of the brain) with greater frequency.

In recent years, special attention has been paid to the inclusion of alternative drugs, such as differentiating agents and monoclonal antibodies, in treatment protocols along with chemotherapy. For the treatment of acute promyelocytic leukemia [APML 1(15;17)], along with chemotherapy, a vitamin A derivative, tretinoin (ATRA), is used. It does not have a cytostatic effect, i.e., it 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 tretinoin in the treatment of APML 1(15;17) has made it possible to achieve an unprecedentedly high survival rate for myeloid leukemia - 85% in this group of patients.

In addition, monoclonal anti-CD20 antibodies (rituximab) are currently used to treat mature cell B-ALL, allowing tumor cells to be fixed to potentiate the effect of chemotherapy drugs on them. Other differentiating agents are being developed at the clinical trial stage - tyrosine kinase inhibitors (imatinib mesylate), histone acetylase inhibitors (depakine), monoclonal antibodies - anti-CD33 (gemtuzumab), anti-CD52 (alemtuzumab), interleukins and many others.

One of the main areas of development of therapeutic protocols is the development of methods for assessing the so-called minimal residual disease (MRD) - a condition in which a small population of tumor cells remains, undetectable by light microscopy. In this situation, the presence of blasts can only be determined using molecular methods. It is precisely at combating MRD that all therapy is aimed after the completion of the first stage - induction of remission. Standardization of MRD assessment methods allows for a new identification of risk groups of patients already at subsequent stages of polychemotherapy, and more effective prevention of relapse of the disease.

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

How is leukemia treated in children?

Prognosis of leukemia in children

Acute leukemia in children, like other oncological diseases, without specific treatment leads to a fatal outcome in 100% of cases. Assessing the results of modern therapy, they talk about a five-year survival rate, which can be general (excluding the occurrence of a relapse) and event-free (taking into account cases of relapse development). 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 also played by the clinical status of the patient at the time of diagnosis. In this case, the amount of leukocytosis in the peripheral blood, the presence or absence of neuroleukemia, and the age of the patient are important. For the general group of patients with ALL, event-free survival is 70%, for patients with ONLL - 50%.

Outpatient observation and recommendations are determined in each specific case by the treatment protocol and depend on the type of acute leukemia and the risk group. Outpatient observation must be carried out in a specialized hematological center. Its main principles: confirmation of disease remission, regular examinations, general blood test, and, if indicated, monitoring of minimal residual disease, functions of internal organs, and the state of the central nervous system.

Patients who have undergone HSCT undergo special follow-up. These patients require monitoring of the transplant condition (testing for chimerism - the presence of molecular markers of the donor's hematopoietic system), monitoring of the so-called "graft versus host" disease, and assessment of the infectious status (primarily regular screening for a range of viral infections).