Acute lymphoblastic t cell leukemia lifespan. Acute lymphoblastic leukemia: causes, symptoms, treatment. Acute lymphoblastic leukemia treatment

Acute lymphoblastic leukemia is a type of leukemia that results from acquired damage to the DNA of developing cells in the bone marrow. In 80% of all leukemia cases in children, it is the acute leukemia type that appears.

This disease comes from the precursors of the line of B and T lymphocytes or T. This group also includes high-grade lymphoma.

Causes of acute lymphoblastic leukemia

It is often very difficult to determine the reasons for this type of leukemia.

Factors that increase the likelihood of this disease occurring:

• high doses of radiation, as evidenced by data obtained from the example of people who survived the explosion of an atomic bomb in Japan;
• impact chemical substances , such as benzene, heavy metals or mustard gas;
• genetic mutations;
• autosomal mechanisms, for example, hormonal or endocrine, immunological.

Acute lymphoblastic leukemia results from the tumor transformation of hematopoietic stem cells and the expansion of malignant “cellular organelles” that displace normal cells from bone marrow, which leads to progressive dysfunction of the bone marrow.

The prognosis for treatment of the disease worsens before the age of 2 years and over 10 years. In adults, acute lymphoblastic leukemia appears mainly before the age of 30 years.

Depending on the number of blasts in the peripheral blood, the degree of expansion and infiltration of the liver and spleen, the so-called risk index. Based on this index, 3 groups of patients are distinguished: group low risk, medium risk group and high risk group.

Symptoms of acute lymphoblastic leukemia

When the cardiovascular system is invaded, heart rhythm disturbances and symptoms of heart failure may occur. Hematuria may indicate urinary tract occupation.

Blood and bone marrow tests that confirm the presence of blasts in the peripheral blood can make the diagnosis of acute lymphoblastic leukemia.

In addition, this type of leukemia is characterized by thrombocytopenia (decreased number of platelets in the blood), anemia (decreased amount of hemoglobin), decreased granulocyte count, accelerated erythrocyte sedimentation reaction, increased uric acid levels and a surge in LDH activity.

All children are examined at the onset of the disease cerebrospinal fluid. In addition, karyotype studies are performed to detect possible chromosomal abnormalities, as well as immunophenotype studies.

Treatment of acute lymphoblastic leukemia

Treatment should begin immediately after diagnosis. It leads to remission, that is, a state in which there are no blasts in the blood and bone marrow.

Children are treated in specialized hematology centers. Before starting treatment, a blood transfusion is given. Antibiotics may also be prescribed. To achieve complete remission, chemotherapy (vincristine, anthracycline, prednisolone, L-asparginase) along with multiple drug therapy and sometimes radiation therapy.

The next step is consolidation of remission, which aims to eliminate the disease. Treatment lasts several weeks and also consists of the use of cytostatics. In addition, the treatment uses means of protecting the central nervous system.

After completion of consolidation, it is necessary to periodically monitor the patient's health status, examine the bone marrow and blood levels. blood cells. Currently, the treatment is very effective and 70% of patients achieve remission, and in children treatment success is observed even in 98% of cases.

If the bone marrow begins to function properly, the patient feels better, and the number of cancer cells decreases, the patient is prepared for a bone marrow transplant.

Bone marrow transplantation consists of transplanting bone marrow stem cells into the recipient's blood. The donor of bone marrow or stem cells obtained from peripheral blood can be a genetically identical twin, brothers and sisters, with appropriate tissue compatibility.

It is also possible to transplant the patient's own stem cells obtained from cord blood at birth, peripheral blood or bone marrow. Stem cells give rise to all blood cell lines: white blood cells, red blood cells and platelets.

Prognosis for acute lymphoblastic leukemia

Unfortunately, in a certain percentage of patients there is relapse of the disease and the appearance of blast cells in the bone marrow, central nervous system, and testicles. Relapse may occur soon after treatment or later long time. In case of recurrence within the central nervous system, aggressive intrathecal intensive treatment and radiation are used.

IN last years The prognosis for lymphoblastic leukemia has improved significantly. The percentage of people who achieve remission is more than 70%, and with intensive chemotherapy - more than 90%. The prognosis is worse in older people and depends on the subtype of acute lymphoblastic leukemia. An unfavorable prognosis occurs in the presence of the Philadelphia chromosome and age over 35 years.

Which can be cured by consulting a doctor. To do this on time, you need to know everything about the disease down to the smallest detail.

What is acute lymphoblastic leukemia?

Acute lymphoblastic form is considered the most common among (approximately 80%).

Most often it affects boys under 6 years of age and young men; girls are affected several times less often.

Lymphoblastic leukemia affects the lymph nodes, bone marrow, thymus gland, and internal organs such as the spleen.

If the disease recurs after chemical therapy, the central nervous system is involved in its process.

In essence, lymphoblastic leukemia is a malignant disease of the hematopoietic system, which is characterized by the rapid and uncontrolled proliferation of lymphoblasts (immature lymphoid cells).

Causes

The exact causes of the disease have not been established. Currently, scientists can only identify provoking acute lymphoblastic leukemia factors, which include:

• Infectious diseases suffered during infancy.
• Received chemotherapy, radiation therapy and treatment with ionizing radiation.
• A stillbirth that the mother had previously.
• Biological mutagens and their Negative influence on a pregnant woman.
• The baby's weight at birth is more than 4 kg.
• Genetic pathologies of the child, for example, Down syndrome, immunodeficiency and the like.
• Availability malignant neoplasms in the family history.

Scientists believe that the disease develops due to a combination of several of these factors, as well as a predisposition to it.

Symptoms and signs

Lymphoblastic leukemia is characterized by the presence of certain syndromes:

• Intoxicating. Characterized by usual signs intoxication, that is, weakness, fever and quick loss weight.
• Hyperplastic. Peripheral lymph nodes are enlarged; upon palpation, painful conglomerates of a dense texture are revealed. The joints hurt and swell, there is pain in the bones and bone fractures. If the infiltrate has penetrated the liver and spleen, severe pain in the abdominal area.
• Anemic. The skin becomes painfully pale, the mucous membranes of the mouth bleed, tachycardia appears and hemorrhagic syndrome(bloody vomiting, hemorrhages, ecchymosis).

Also observed individual symptoms. So, in boys, the testicles and kidneys may become enlarged and painful. Extensive hemorrhages in the retina and lung tissue are often observed. Respiratory failure and swelling appear optic nerve. Elements of an infiltrating nature may appear on the skin, which hurt on palpation.

Diagnostics

Diagnosis begins with collecting anamnesis, including family history, and analyzing symptoms. Afterwards tests and examinations are prescribed:

• General and biochemical tests blood. Show the level of hemoglobin, leukocytes and erythrocytes, the presence of thrombocytopenia, kidney and liver damage. Myelocytes and metamyelocytes are also found in the blood if there is no intermediate form of maturation.

The photo shows a blood picture in acute lymphoblastic leukemia

• Myelogram. It is carried out in 3 stages. First, a morphological cytology analysis is taken, showing hypercellularity of the bone marrow and infiltration of blast cells. Cytochemical analysis is then performed, followed by immunophenotyping to determine the cell type.
• Spinal puncture showing the presence of damage to the central nervous system by leukemia cells.
• Ultrasound. Determines the degree of magnification lymph nodes and the size of the affected organs.
• Chest X-ray to see if the mediastinum is enlarged.

If the patient is prescribed chemotherapy, additional tests, for example, urine tests, ECG and echocardiography.

Treatment

The main thing is chemotherapy, which is divided into three stages:

• Induction. The duration takes approximately several weeks, and is carried out until a stable remission is achieved. It is chemotherapy using cytostatics. Medicines destroy leukemic cells and restore hematopoiesis. Vincristine, glucocorticosteroids, asparaginase, anthracycline and others can be used as drugs. Statistics show that in more than 85% of cases it is possible to achieve stable remission.
• Consolidation. Lasts up to several months. Aimed at destroying remaining pathogenic cells. The most commonly prescribed medications are methotrexate, 6-mercaptopurine, vincristine, prednisolone, cytarabine, asparaginase and other drugs. To increase the effect, it is recommended to administer the drugs intravenously.
• Maintenance therapy. The duration is several years. Therapy is aimed at maintaining remission and eliminating the risk of relapse. The patient is prescribed 6-mercaptopurine and methotrexate.

Depending on response to treatment, patient age and concomitant diseases Other medications may be prescribed. For example, taking multivitamins or antibiotics. In rare cases, a bone marrow transplant is required.

Acute lymphoblastic leukemia (ALL) is characterized by malignant growth of lymphoid cells. As already noted, this clinical and hematological form of leukemia accounts for up to 80% of total number acute leukemia in children.

CLASSIFICATION. In 1976, the Franco-American-British Cooperation Group (FAB Group) attempted to clarify morphological classification acute leukemia and proposed criteria for identifying types of tumor cells based on cytomorphological and cytochemical studies.

According to the morphological criteria of blast cells, acute lymphoblastic leukemia is divided according to three cell types into LI, L2 and L3. Their characteristics are presented in table 126.

Table

It should be noted that some patients with ALL have mixed cell populations. This served as the basis for identifying two more intermediate types - L1/L2 and L2/L1, in the designation of which the predominant population is indicated in the first place.

Cytochemically, an enzyme is detected in most lymphoblasts - terminal deoxynucleotidyl transferase, a rather rare DNA polymerase. This enzyme is very rarely detected in blasts in acute non-lymphoblastic leukemia (Table 127). In addition, lymphoblasts contain clumpy accumulations of glycogen, which are detected by staining with Schiff's reagent (positive PAS/or RABD reaction). In ALL, peroxidase-positive and Sudan black-staining granules are absent in the cytoplasm.

Table 127

In recent years, morphological variants have been described in the group of patients with acute lymphoblastic leukemia, depending on the immunological characteristics of proliferating cells and the presence of surface markers. Modern immunological phenotyping is carried out based on the determination of differentiation antigens on the cell surface using a panel of rabbit monospecific antisera and monoclonal antibodies.

ALL is regarded as a heterogeneous group of malignant proliferations consisting of immature cells of the lymphoid lineage that have stopped at various stages differentiation.

Depending on the presence of different markers and the degree of differentiation of leukemia cells, they distinguish O-cell (non-T, non-B), early pre-B-cell (CALLA-negative), pre-B-cell, B-cell, pre-T -cellular and T cell species acute lymphoblastic leukemia (Table 128).

Table 128

Note. t-DNT - terminal deoxynucleotidyl transferase; CALLA - ALL common antigen; clg - cytoplasmic Ig; slg - membrane Ig; TA - antigen thymus; E - receptor for sheep erythrocytes

O-cell (non-T, non-B) acute lymphoblastic leukemia: the development of leukemic cells is blocked at very early stages, and therefore the leukemic clone is represented by early lymphoid precursors (Fig. 94). However, most researchers believe that non-T and non-B acute lymphoblastic leukemias can be attributed to the malignant transformation of B-lymphocyte precursors, since these cells express antigens of early B-cell differentiation.

Early pre-B cell ALL is represented by pre-B cells that have t-deoxynulkeotidyltransferase (t-DNT) activity but are unable to synthesize common acute lymphoblastic leukemia antigen CALLA or immunoglobulins.

Pre-B-cell ALL is represented by cells that have t-DNT activity and are capable of synthesizing CALLA and cytoplasmic immunoglobulins.

B-cell ALL is characterized by cells that do not have t-DNT activity and often do not express CALLA, but these cells synthesize complete immunoglobulin molecules that are expressed on their surface.

Pre-T-cell ALL is represented by cells that express thymus antigens on the surface, but are negative for the sheep erythrocyte receptor (CD2 molecule).

T-cell ALL: The malignant cells belong to the mature T-cell lineage and are positive for the sheep red blood cell receptor.

CLINICAL MANIFESTATIONS. Acute leukemia in children develops gradually. A thorough survey of patients’ parents indicates that long before a diagnosis is made, clinical signs of somatic distress are identified in children, which are initial signs diseases. In the clinical picture of acute lymphoblastic leukemia in children, four periods are distinguished: initial, period full development illness, remission period and terminal period.

Initial period. During this period, the clinical manifestations of the disease are not specific; there are no pathognomonic signs of acute leukemia.

Patients experience lethargy, decreased appetite (sometimes up to anorexia), fast fatiguability, headaches, sometimes pain in bones and joints, in the stomach.

Often there is an increasing pallor of the skin due to gradually developing anemia.

Very often there is an increase in body temperature, from subfebrile to high numbers (37.4-39.2 ° C). Moreover, the temperature curve often becomes wrong kind. Hyperthermia is, as a rule, causeless and is caused by endogenous pyrogen, a product of leukemia cells.

These symptoms often serve as a reason to consult a doctor, but the diagnosis of acute leukemia is established correctly only in 15% of children. IN initial period disease, it is very important to suspect the presence of acute leukemia and refer the child for a blood test and bone marrow puncture.

The duration of the pre-diagnostic period, unfortunately, averages 1.5-2 months. That is why it is very important to pay attention to the most minor symptoms that can help in establishing a diagnosis.

Among other manifestations in the initial period of acute leukemia, prolonged bleeding after tooth extraction is noted. Therefore, in all cases where there is this symptom, you should definitely order a blood test and refer the child for consultation, indicating the purpose of this consultation.

High period. It is characterized by a combination of the following main syndromes: a) proliferative; b) anemic; c) hemorrhagic; d) neurotoxic; d) lesions skeletal system and other body systems.

Proliferative syndrome includes enlargement of peripheral lymph nodes and sometimes mediastinal lymph nodes. Most often, a generalized enlargement of the peripheral lymph nodes is observed, among them the anterior and posterior cervical, submandibular, and less often the axillary and inguinal ones are enlarged. The sizes of lymph nodes vary from 0.5-1 to 6-8 cm, but, as a rule, they form conglomerates - dense, painless (if there are no infectious complications).

In parallel with the enlargement of the lymph nodes, an enlargement of the liver and spleen is observed, which upon palpation have a dense consistency and a smooth surface.

Sometimes children with acute leukemia have a pronounced Mikulicz symptom complex - symmetrical swelling of the lacrimal and salivary glands due to the proliferation of lymphatic tissue in them.

Anemic syndrome is characterized by pallor of the skin and mucous membranes, weakening of heart sounds, the presence of systolic murmur, lethargy, weakness, and headache. Availability of this syndrome caused by the development and increase of anemia.

Hemorrhagic syndrome is characteristic feature acute leukemia and is manifested by hemorrhages on the skin, mucous membranes, nosebleeds, bleeding from gastrointestinal tract in the form of melena, less often - hematuria. The appearance of this syndrome is due to the occurrence of thrombocytopenia and a violation of the blood clotting process.

Damage to the skeletal system in patients with acute leukemia manifests itself in the form of flying pain in the joints. Damage to the skeletal system is caused by the appearance of foci of destruction in the bones of the skull, tubular bones, pelvic bones, ribs, and spine.

Neuroleukemia is the presence of proliferation of leukemic cells in the membranes of the brain, spinal cord, in the substance of the brain, in the nerve trunks and in the ganglia of the autonomic nervous system. It is a consequence of metastasis of blast cells into the central nervous system.

There are two possible ways for leukemia cells to enter the central nervous system:

Contact - from the bones of the skull and spine to the hard meninges, cranial and spinal nerves;

Diapedetic - from overcrowded vessels soft shell into the cerebrospinal fluid and into the brain substance through the perivascular spaces.

Clinically, neuroleukemia is characterized by symptoms of meningoencephalitis, damage to the cranial nerves, roots and peripheral nerves. In particular, the child experiences lethargy, drowsiness, headache, vomiting, stiff neck and positive symptom Kernig, sometimes paresis and paralysis, decreased vision and other symptoms.

In addition, during the height of the disease, damage to the intestines, kidneys, and respiratory organs is often noted due to the occurrence of specific infiltrates in these organs. There is also a decrease in indicators of immunological reactivity, changes in the ratio of various subpopulations of lymphocytes and their functional activity. Clinically, this is manifested by the presence of a duration of persistent infection caused by opportunistic microorganisms.

DIAGNOSIS. Confirm by mandatory examination of peripheral blood and bone marrow puncture (myelogram).

In the peripheral blood of patients, anemia is found (i.e., the hemoglobin content is less than PO g/l and the number of erythrocytes is less than 3.5-10/l), thrombocytopenia (the number of platelets is less than 150-10/l), changes in the number of leukocytes (more often - leukocytosis in varying degrees of severity) and accelerated ESR (within 40-60 mm/h).

When researching leukocyte formula the appearance of leukemic cells - lymphoblasts (within 15-20% or more) and the presence of mature lymphocytes - up to 75-80% are observed. The number of monocytes and eosinophils in patients with acute lymphoblastic leukemia changes little, and the content of neutrophils is reduced to 10-15%.

This picture of the leukocyte formula is characterized as a “leukemic failure”, when there are blast cells and mature forms of cells, in particular lymphoblasts and lymphocytes, but there are no transitional forms of lymphopoiesis cells.

An evaluation of the myelogram is always necessary to clarify the diagnosis of the disease. The myelogram in patients with acute lymphoblastic leukemia is characterized by a predominance of blast cells with a sharp decrease (up to complete disappearance) of cells of neutrophil, erythroid and platelet lineages.

Thus, these clinical and laboratory signs allow us to establish the diagnosis of acute lymphoblastic leukemia in children.

DIFFERENTIAL DIAGNOSTICS. Acute leukemia must be differentiated from leukemoid reactions in severe bacterial infections, medicinal disease, poisoning. Unlike leukemia, such patients do not have a pronounced proliferative syndrome or bone damage; in the bone marrow and peripheral blood, as a rule, all transitional elements between blasts and mature forms are present to one degree or another. Sometimes it is difficult to differentiate acute leukemia from infectious mononucleosis, infectious lymphocytosis. The clinical picture in most cases makes it possible to differentiate these diseases (sore throat, fever, hepatosplenomegaly, painful on palpation and enlarged lymph nodes are typical for mononucleosis), but the final judgment is still made on the basis of morphology: abundant basophilic cytoplasm, the absence of nuclear changes characteristic of leukemia allow diagnosis mononucleosis. In all in doubtful cases it is necessary to do a myelogram, which is indicated for any unknown origin anemia, thrombocytopenia, pancytopenia, hepatosplenomegaly, generalized enlargement of lymph nodes.

TREATMENT. Currently, the most effective treatment programs are those developed by pediatric hematologists in Germany and Austria. One of such progressive programs is the German program for the treatment of acute lymphoblastic leukemia ALL-BFM-90 (Berlin-Frankfurt-Müster).

The basic principle of treatment under the BFM program is intensive polychemotherapy for 6 months and maintenance for up to 2 years.

Treatment of acute leukemia is divided into two phases. In the first phase - induction of remission - they achieve a reduction in the number of blast cells to single ones in the bone marrow preparation. With this destruction of leukemia cells, it is possible to restore normal hematopoiesis and disappear clinical symptoms diseases. During the induction of remission, the proliferating subpopulation of leukemic cells sharply decreases, leaving cells that are mainly outside the mitotic cycle. These cells are able to enter the mitotic cycle, multiply and cause a relapse of the disease.

In the second phase of treatment, remission is prolonged and the proliferation of remaining leukemia cells is slowed down or stopped. The ideal treatment result is the complete destruction of the leukemia population.

In the second phase, consolidation therapy is carried out, aimed at prolonging remission, as well as reinduction - anti-relapse treatment, and finally maintenance treatment in the intervals between reductions and consolidation.

The most complete destruction and eradication of leukemia cells is achieved by using treatment programs that include drugs of different directions of action that affect leukemia cells in different phases of the mitotic cycle.

It has been established that the mitotic cycle of human cells consists of four main phases: G1 - presynthetic, S - DNA synthesis, G2 - premitotic and M - mitosis. The resulting daughter cells begin to divide again and enter the cell cycle or remain outside the cycle in the resting phase (GO). G1 accounts for 30-40% of the cycle time, S - 30-50%, G2 - 5-10% and M phase - 10% of the cycle time.

Most known anti-leukemia drugs affect mainly the dividing population of leukemia cells, while many leukemia cells are outside the generation cycle. Thus, according to available data, from 20-80 to 83-97% of all leukemia cells are in the G0 phase. Therefore for successful treatment patients with acute leukemia, it is important to use a rational combination, simultaneous and sequential, of chemotherapy drugs that affect cells in different phases cell cycle (Fig. 95).

Rice. 95.

Presynthetic phase (RNA and protein synthesis); S - phase of DNA synthesis; G2 - premitotic phase; M - mitosis phase; GO - resting phase

In the G1 phase and DNA synthesis (S-phase), the most active drugs are those involved in DNA synthesis, which leads to rapid cell death - rubomycin, adriamycin, methotrexate, amethopterin, daunoblastin. Asparaginase, cytosar/cytabarine, mercaptopurine, and vincristine act in the DNA synthesis phase.

In the mitosis phase, the most active are cyclophosphamide and prednisolone. These same drugs affect cells in the resting phase (GO).

In addition, it turned out that the anti-leukemia drugs used in some cases alter the cell cycle. Therefore, the concept of synchronizing therapy for acute leukemia has now been put forward. Its essence lies in trying to bring leukemia cells to a single functional stage, and then influencing them in the phase of greatest sensitivity to drugs. Of course, this problem is extremely difficult and is still far from being resolved. But the accumulated experience indicates the possibility of achieving, albeit partially, temporal synchronization under the influence of the use of cytostatic agents.

However, when starting treatment for leukemia, you should firmly remember the “golden” rule: “it is easier to prevent a complication than to treat it.” Absolutely necessary are:

A) daily change of linen, hygienic baths for the patient;

B) disinfection of staff hands, hair washing and two daily showers for caregivers.

Performing only these procedures dramatically reduces the risk of infectious complications.

Treatment is also started against the background of intestinal decontamination (colistin, polymyxin, nystatin). Toilet and treatment (with methylene blue) of the oral cavity are required.

When choosing a treatment protocol, it is necessary to determine the risk group. To do this, you must first establish the risk factor (Fig. 96). It is calculated using a nomogram. When using a nomogram, points on scale 1 and 2 are determined, then a straight line is connected and the point of its intersection with scale 3 is marked; then the points on scales 3 and 4 are connected by a straight line. The point of its intersection with scale 5 determines the risk factor.

There are indexes up to 0.8, from 0.8 to 1.2 and more than 1.2.

1 - absolute number blast cells in the blood before treatment;

2 - dimensions of the liver (in cm from under the edge of the costal arch);

3 - auxiliary scale;

4 - size of the spleen;

5 - risk factors

The standard risk group is established if: 1) RF
To classify a patient as a standard risk group, all six criteria must be met (Table 129).

The average risk group meets the following criteria: 1) RF > 0.8; 2) the number of blasts in the peripheral blood on the 8th day, after a 7-day prednisolone prophase, does not exceed 1000 in 1 μl; 3) there are no t (9; 22) translocations and/or BCR-ABL recombinations; 4) complete remission on the 33rd day of treatment.

To classify a patient as an average risk, he must meet all four criteria.

The high-risk group is distinguished by: 1) the presence of blasts in the peripheral blood on the 8th day, after a 7-day prednisolone prophase, more than 1000 in 1 μl; 2) the presence of translocation t (9; 22) and/or BCR-ABL recombination; 3) lack of complete remission on the 33rd day of treatment.

Table 129

*After 7 days of taking prednisone

The presence of at least one of the above criteria places the patient at high risk.

Basic conditions for starting this protocol: good general state sick; absence of infections; leukocytes - more than 1.5 10 / l; granulocytes - more than 0.5 10 / l; platelets - more than 60 10/l.

6-Mercaptopurine is prescribed at the rate of 25 m per 1 sq. m for 8 weeks.

Methotrexate (MTX) is prescribed at a dose of 1 g per 1 square meter. m: 1/10 of the total dose is administered over 30 minutes; 9/10 of the total dose is administered over 35.5 hours by continuous infusion. It is prescribed on the 8th, 22nd, 36th, 50th days from the start of protocol M.

Leucovorin is given at the rate of 15 mg per 1 square meter. m intravenously, bolus or orally in tablets at 42, 48 and 54 hours from the start of MTX administration. The dose of leucovorin is calculated using a special table depending on the level of MTX in the blood serum. If at the 54th hour the level of MTX in the serum is more than 0.25 mmol/l, then additional administration of leucovorin is required, calculated according to the table (the norm of MTX in the blood serum is 0.2 mmol/l).

MTX is administered intralumbarally 2 hours after the start of intravenous infusion of MTX in an age-specific dosage.

The first phase of protocol II (Fig. 99) is carried out two weeks after protocol M.

The conditions for starting Protocol II are: ongoing complete remission; good general condition of the patient; absence of infections; leukocytes - more than 2.5 10/l; granulocytes - more than 1 10/l; platelets - more than 100 10/l.

Dexamethasone 10 mg per 1 sq. m orally from the 1st to the 21st day from the start of the protocol, then the dose is reduced every three days by 1/3 of the complete withdrawal.

Vincristine - 1.5 mg per 1 sq. m of intravenous injections at intervals of one week ( maximum dose- 2 mg per 1 sq. m).

Adriamycin (ADR) - 30 mg per 1 sq. m, infusion over 1 hour. Before the 1st and 3rd appointments, it is necessary to conduct an ECG and echocardiographic study: if there are signs of decreased myocardial contractile function, further use of ADR should be discontinued.

L-Asparaginase - 10,000 units per 1 sq.m., infusion over 1 hour on days 8, 11, 15, 18.

Phase II. Conditions for starting phase II of protocol II: good general condition; absence of infections; normal age-related serum creatinine levels; leukocytes - more than 2-10/l; granulocytes - more than 0.5 10 / l; platelets - more than 50 10/l.

Cyclophosphamide - 1000 mg per 1 sq. m, infusion over 1 hour on the 36th day from the start of the protocol. Diuresis control and cystitis prevention are the same as in Protocol I.

6-Thioguanine (6-TG) - 60 mg per 1 sq. m orally on days 36-49, for a total of 14 days. Cytosar (ARA-C) - 75 mg per 1 m2 intravenously daily in two blocks every 4 days; on days 39, 40, 41, 45, 46, 47, 48. It is advisable not to interrupt the ARA-C block. If you need to reschedule or interrupt the ARA-C block, you should also stop taking 6-TG. Missed 6-TG prescriptions should be increased to the planned total dose of 840 mg per 1 square meter. m.

This is a group of heterogeneous malignant neoplasms from lymphoid precursor cells (lymphoblasts) that have certain genetic and immunophenotypic characteristics.

Acute lymphoblastic leukemia is the most common leukemia in childhood and adolescence. The peak incidence occurs between the ages of 1 and 6 years. They occur with damage to the bone marrow, lymph nodes, spleen, thymus, and other organs.

Causes of acute lymphoblastic leukemia:

The genetic basis for the development of acute lymphoblastic leukemia is changes in the structure of chromosomes, i.e. chromosomal aberrations. In leukemia, specific or primary and nonspecific chromosomal aberrations are distinguished. Primary ones include translocations, deletions, inversions, and amplifications of chromosome regions containing oncogenes, cell receptor genes, and growth factor genes. Such changes can form new DNA sequences and the appearance of new properties in the cell, the formation of a specific clone. Secondary chromosomal aberrations appear at the stage of tumor progression as a result of changes in the formed clone. Moreover, similar aberrations can be observed in various types of leukemia. Thus, the Philadelphia chromosome can be detected in both acute and chronic leukemia.

The reasons for the development of acute lymphoblastic leukemia in children have not yet been precisely established, but there is evidence of great importance infectious diseases in infancy, exposure to various physical (for example, X-ray diagnostics, ionizing radiation), the action of chemical mutagens. when exposed to benzene, among patients receiving cytostatic immunosuppressants (imuran, cyclophosphamide, leucaran, sarcolysin, mustargen, etc.), biological (viral) mutagens on the mother’s body during pregnancy. A connection has also been proven between many congenital chromosomal abnormalities and the development of acute leukemia.

Pathogenesis:

In the bone marrow, peripheral blood and other organs, tumor cells of the lymphoblast type are found with PAS-positive granules in the cytoplasm, which do not react to peroxidase, esterases and do not contain lipids.

In 2/3 of cases, cytogenetic abnormalities in the form of polyploidy, the Philadelphia chromosome and reciprocal translocation between chromosomes are found in tumor cells.

Cytogenesis of acute lymphoblastic leukemia is associated with T- and B-lymphocyte precursors. T-cell leukemias account for 10-15% of cases in European countries. B-cell leukemias predominate.

Based on the immunological phenotypes of tumor cells, several forms of lymphoblastic leukemia are distinguished, which is important for the choice of therapy and prognosis. Predominant B-lymphoblastic leukemias represented by early, intermediate and later versions, differing in the expression of CD10 paraglobulin, surface immunoglobulin and terminal dioxynucleotide transferase activity. Markers of T-lymphoblastic leukemia are CD7 and T-receptor antigens.

Symptoms of acute lymphoblastic leukemia:

There are two types of acute lymphoblastic leukemia: B-linear and T-linear, depending on the type of cells - lymphoid precursors.

All leukocytes in the human body are divided into 2 types - granulocytic and agranulocytic (granular and non-granular), these two groups, in turn, are divided into eosinophils, basophils, neutrophils (granulocytic), and lymphocytes (B- and T-type) and monocytes (agranulocytic). In the process of maturation and development (differentiation), all cells go through several stages, the first of which is the blast stage (lymphoblasts). Due to damage to the bone marrow by a tumor, lymphocytes do not have time to develop enough to fully perform their functions. protective functions. For the most part, acute lymphoblastic leukemia affects B lymphocytes (in about 85% of cases), which are responsible for the formation of antibodies in the body.
Clinical signs acute lymphoblastic leukemia
Syndrome - weakness, fever, malaise, weight loss. Fever may also be associated with the presence of a bacterial, viral, fungal or protozoal (less commonly) infection, especially in children with neutropenia (less than 1500 neutrophils per 1 μl).
Hyperplastic syndrome is an enlargement of all groups of peripheral lymph nodes. Infiltration of the liver and spleen leads to their enlargement, which may manifest as abdominal pain. Pain and aches in the bones may occur due to leukemic infiltration of the periosteum and joint capsule and tumor increase in bone marrow volume. At the same time, on radiographs one can detect changes characteristic of leukemic infiltration, especially in the tubular bones, near large joints.
Anemic syndrome - pallor, weakness, bleeding of the oral mucosa, hemorrhagic syndrome on the skin, pallor. Weakness occurs as a result of intoxication.
is associated with both thrombocytopenia and intravascular thrombosis (especially with hyperleukocytosis) and leads to the appearance of petechiae, ecchymoses on the skin and mucous membranes, hemorrhages, melena, and vomiting with blood.
In boys, initial testicular enlargement may be detected (5-30% of cases of primary ALL). These are painless, dense, unilateral or bilateral infiltrates. This happens especially often with hyperleukocytosis and the T-cell variant of ALL.
Respiratory disorders associated with enlarged mediastinal lymph nodes, which can lead to respiratory failure. This sign is characteristic of T-linear ALL.
Hemorrhages in the retina and swelling of the optic nerve may occur. Leukemic plaques may be detected in the fundus.

Due to severely reduced immunity, any damage to the skin is a source of infection; paronychia, felons, infected and injection marks may appear.

Quite rare complications may include kidney damage as a result of infiltration (clinical manifestations may be absent) and effusion due to impaired lymphatic drainage between the endocardium and epicardium.

Diagnostics:

To make a diagnosis of acute lymphoblastic leukemia, the content of blast cells in the bone marrow must be more than 30%. If the content of blast cells in the blood exceeds 30%, the diagnosis can be made without a bone marrow examination.

Treatment of acute lymphoblastic leukemia: in various ways treatment of patients with adult ALL.

Some treatments are standard (currently used) and some new treatments are being tested in clinical trials. A clinical trial is a research study designed to improve a standard treatment or obtain information about the results of new treatments for cancer patients. If clinical trials show that new way treatment is better than the standard treatment, the new treatment may subsequently become the standard treatment. Patients can also take part in clinical trials. Some clinical trials can only enroll patients who have not received any treatment.

Treatment for adult acute lymphoblastic leukemia usually occurs in two stages.

Stages of treatment for adult acute lymphoblastic leukemia:

Remission-induction therapy. The goal of this stage of treatment is to destroy leukemia cells in the blood and bone marrow and achieve remission.

Post-remission therapy. This is the second stage of treatment. It begins as soon as remission is achieved. The goal of post-remission therapy is to destroy the remaining leukemia cells, which may not be active, but may subsequently begin to grow and this will lead to relapse. This stage is also called continuation of remission therapy.

Therapeutic and prophylactic therapy of the central nervous system is usually carried out at each stage of treatment. Because chemotherapy drugs are taken orally or injected intravenously, medicinal substance often cannot destroy leukemia cells that have entered the central nervous system (brain and spinal cord). Leukemia cells take refuge (hide) in the central nervous system. Intrathecal chemotherapy and radiation therapy can destroy leukemia cells that have entered the central nervous system, thereby preventing relapse of the disease. This type of treatment is called therapeutic and preventive therapy of the central nervous system.

Today there are four standard treatment methods:

Chemotherapy.

Chemotherapy is a method of treating cancer with potent chemotherapy drugs. Chemotherapy drugs can stop and destroy the growth of cancer cells, preventing their separation and penetration into other tissues and organs. For chemotherapy, medications may be taken orally (in the form of tablets, capsules) or given intravenously or intramuscular injections. The drug enters the bloodstream, spreads throughout the body and affects cancer cells (systematic chemotherapy). When chemotherapy drugs are injected directly into the spine (intrathecal chemotherapy), organ, or cavity (such as the abdomen), the drug primarily targets cancer cells in those areas (regional chemotherapy). Combination chemotherapy is a treatment that uses more than one cancer chemotherapy drug. The method of using chemotherapy depends on the type and stage of cancer.

Intrathecal chemotherapy can be used to treat adult ALL, which tends to spread to the brain and spinal cord. Therapy used to prevent cancer cells from spreading in the body and reaching the brain or spinal cord is called CNS treatment. Intrathecal chemotherapy is carried out in combination with conventional chemotherapy, in which medications taken orally or by injection.

Intrathecal chemotherapy. Antineoplastic agents are injected into the intrathecal cavity of the spinal canal, where the cerebrospinal fluid is located (CSF is shown in blue in the figure). There are two different ways administration of chemotherapy drugs. The first method, shown at the top of the figure, is to administer the drug in the Ommaya reservoir. (A convex container that is inserted into the ventricles of the brain. The container holds the bulk of the drug so that the drug can slowly flow into the brain through small tubes). Another method, shown at the bottom of the figure, injects the drug directly into the cerebrospinal fluid in spinal column at lumbar level. The procedure is carried out under local anesthesia.

Radiation therapy.

Radiation therapy is a method of treating cancer that uses harsh x-ray radiation or other types of radiation to kill cancer cells or prevent the growth of cancer cells. There are two types of radiation therapy. Radial external therapy – special apparatus focuses radiation into the tumor area. Internal radiation therapy is the use of radioactive substances hermetically sealed in needles, capsules, rods or catheters that are placed directly in or near the tumor. External beam radiation therapy can be used to treat adult ALL, which tends to spread to the brain and spinal cord. This is called therapeutic and preventive therapy of the central nervous system.

Chemotherapy followed by stem cell transplantation.

Chemotherapy is given before stem cell transplantation. Stem cell transplantation is used to replace abnormal blood-forming cells with healthy ones. Stem cells (immature blood cells) are taken from the blood or bone marrow of the patient or donor, frozen and stored. Once chemotherapy is completed, the stored stem cells are thawed and given to the patient through stem cell infusions. The transplanted stem cells take root and help restore bone marrow cells that produce blood cells.

Tyrosine kinase inhibitor therapy.

Anti-cancer drugs called tyrosine kinase inhibitors are used to treat some types of adult ALL. The drug blocks an enzyme, tyrosine kinase, that promotes development from stem cells large quantity leukocytes (granulocytes or blast cells). Currently, two such drugs are used: Imatinib (Gleevec) (imatinib mesylate) (Gleevec) and Dasatinib.

Several new treatments are being tested in clinical trials.

This section describes treatments that are in clinical trials. It is impossible to talk about all the new treatments that are being studied. Clinical trial information is available on the NCI website

Biological therapy

Biological therapy is a treatment method that uses immune system patient in the fight against cancer. Substances that are produced in the body or that are synthesized in the laboratory are used to stimulate or restore natural defense mechanisms and fight cancer. This type of cancer treatment is also called biotherapy or immunotherapy.

Patients can also take part in clinical trials.

For some patients, participation in clinical trials is best choice. Clinical trials are part of the research process. The purpose of clinical trials is to determine whether a new treatment is safe and effective or better than the standard treatment.

Many of the current standard treatments are based on the results of early clinical trials. Patients participating in clinical trials may receive standard treatment or undergoing a new treatment.

Patients who take part in clinical trials make a major contribution to research and help improve future treatments. Even if the results of clinical trials do not indicate the effectiveness of a new treatment method, they often provide answers to very important questions and help move research one step forward.

Patients can participate in clinical trials before, during, and after they begin treatment.

Some clinical trials can only enroll patients who have not received any treatment. Patients whose disease does not respond to treatment can also participate in clinical trials. There are also clinical trials that explore new ways to prevent recurrence or treat side effects resulting from cancer treatment.

Conducting a re-examination.

Some tests that were done to diagnose cancer or the stage or form of the disease may be repeated. Sometimes tests are repeated to monitor the effectiveness of treatment. The decision to continue, change, or stop treatment is based on the results of these tests.

Some tests need to be done from time to time and after the end of treatment. Test results may show a change in the patient's condition or the presence of a relapse of the disease. Sometimes such tests are called control tests.

Blood cancer is a diagnosis that is scary for any adult to hear. But it’s much worse when this disease affects a child. Unfortunately, blood cancer or leukemia is a fairly common disease among young patients. Acute lymphoblastic leukemia is more common in children than other forms of leukemia.

Damage to the hematopoietic system in ALL is malignant. About 60-70% of reported cases occur in childhood(2-6 years).

What is ALL

Acute lymphoblastic leukemia is an oncological disease that occurs in children preschool age. It can also occur in an adult in the form of a late relapse, when a case of leukemia has already been established in the medical history. Having similar clinical manifestations at the initial stage of development, it can easily be confused with viral and cold infections.

Lymphoblastic leukemia is characterized by the uncontrolled formation of young forms of lymphocytes - lymphoblasts and prolymphocytes. At cancer lymphocytes are not produced, so the bone marrow, in an attempt to restore balance, releases immature forms of cells into the peripheral blood (shift to the left).

The appearance of blast cells in any type of disease indicates not only serious violations in the hematopoietic organs, but also about an unfavorable prognosis in the treatment of the patient. Due to a violation of the structure of deoxyribonucleic acid, chromosomal abnormalities develop, and prolymphocytes do not mature.

Forms

Lymphocyte cells are presented in two forms in the body: small and large. The larger forms are –NK cells. The uniqueness of these lymphocytes lies in their ability to destroy cancerous formations. Small forms, in turn, are represented by T- and B-lymphocytes.

1. T-lymphocytes are classified as: T-helpers, T-killers and T-suppressors. Their main task is to carry out phagocytosis - devouring bacteria and viruses. T-lymphocytes are produced in the bone marrow and mature in the thymus and thymus. 20% of cases of lymphocytic leukemia are of the T-cell type. It is detected at the age of 15 years, when the formation of the thymus gland ends.
2. B lymphocytes play an important role in the formation of immune antibodies. B lymphocytes mature in lymphoid tissue. Children are susceptible to the B-cell form of lymphocytic leukemia. At the age of 3-4 years, activation of the bone marrow in the production of B-lymphocytes is observed (humoral immunity is formed).

B-cell lymphocytic leukemia differs in type:

• pre-pre-B-cell;
• B-II-cellular;
• pre-B cell;
• B-mature cell.

When diagnosing acute lymphocytic leukemia in children, it is important to determine the type of B-cell phenotype, since a specific treatment algorithm has been developed for each subtype. In both cases, the red bone marrow suffers. The work in the formation of cells is disrupted - they do not perform their main functions, moreover, infected with cancer, and carrying cancer cells on the surface of the membrane, T and B lymphocytes lead to inhibition of cells of another series - erythropoiesis.

Stages of the disease

1. initial stage. Characterized by the development of anemia, but in early period disease hemoglobin does not drop to critical levels low rates(30 -50g/l). The number of platelets and red blood cells decreases. White blood cells begin to grow rapidly.
2. Expanded stage. The main feature of the advanced stage is leukocytosis. The number of leukocytes reaches 250-300*10/9/l. A leukemic failure is recorded (the predominance of cancer cells and immature forms of cells of the leukocyte series) and a leukemic window (there is no division of cells from young to mature forms).
3. Remission. In the peripheral blood, blast cells disappear, the level of leukocytes decreases, and all forms of the leukocyte series appear. In bone marrow analysis, blast levels are stable, but not more than 5%.
4. Relapse. Return of the disease to a more or less pronounced degree clinical manifestations. At this stage, the issue of additional treatment measures or treatment in other ways is decided.
5. Terminal stage . Therapeutic measures did not lead to the expected results. Hematopoiesis is completely inhibited, cell formation stops. The terminal stage leads to fatal outcome, patients do not survive.

Reasons for the development of pathology in children

The causes of leukemia in children and adults have not yet been identified. However, there is an assumption that acute lymphocytic leukemia in children may be caused by a lymphoid virus.

Supposed causes of the development of ALL in children:

• viral infections of the mother during pregnancy;
• antisocial lifestyle of a pregnant woman;
• mother's age at the time of conception;
• immunodeficiency;
• radiography of a pregnant woman;
• exposure to radiation on the fetus;
• chromosomal diseases (Down syndrome, cyalkia).

Common causes of ALL:

• weight over 4 kg;
• illnesses suffered in infancy;
• hereditary predisposition.

Among the most common causes of the development of not only lymphocytic leukemia, but also other types of leukemia, there are radiation and carcinogenic effects on the human body (both mother and father).

Symptoms and signs

Symptoms directly depend on the stage of the disease, and at an early stage they have a general clinical picture With viral infection: dizziness, malaise, fever, lethargy and fatigue.

The main symptoms of acute lymphocytic leukemia in a child include:

1. Anemia syndrome. Due to the inadequate production of hemoglobin by red blood cells, the body does not receive enough oxygen. This is expressed in lack of appetite, dizziness, low-grade fever. The skin is pale and dry. Pre-fainting conditions are characteristic when hemoglobin is less than 80 g/l.
2. Hemorrhage syndrome. Due to a decrease in the quantitative and qualitative properties of platelets, small dots (bruises) appear on the skin and mucous membranes. Sometimes vomiting with blood appears.
3. Sprawl syndrome(hyperplastic symptom). Cancer cells, making it difficult to work internal organs, lead to an enlargement of the spleen, liver, and lymph nodes. Due to the proliferation of bone marrow, swelling of the joints appears.

Signs of lymphoblastic type leukemia are associated with a decreased immune response:

• pain in the limbs, the body aches from pain;
• permanent colds(angina, bronchitis);
• difficulties with breathing rhythm due to enlarged lymph nodes;
• formation of abscesses and boils;
• the appearance of leukemia - brown formations on the skin - appear as confirmation of the advanced process of ALL.

Diagnostic measures

Diagnosis of acute lymphoblastic leukemia consists of studying blood parameters, bone marrow and clinical manifestations of leukemia.

1. Taking blood for a detailed analysis with counting shaped elements. Biochemical and cytochemical studies to clarify the phenotype of ALL.
2. Radiography and ultrasonography organs abdominal cavity and chest.
3. Myelogram. Study of red bone marrow puncture to determine the composition of the CSF and count the formed elements. IN exceptional cases A spinal cord biopsy is performed to determine neuroleukemia.
4. Genetic examination. The detection of chromosome 22 in a CSF specimen makes it possible to determine the correct treatment tactics.
5. Other studies: urine analysis, ECG, fluorography, MRI of extremities.

Basic treatment methods

A treatment algorithm has been created for the treatment of blood cancer. For each patient it is set individually, has 5 general stages: prophase, induction, consolidation, reduction, maintenance treatment. Treatment for lymphocytic leukemia lasts about 2 years.

Chemotherapy is the main method of fighting cancer.

Radiation therapy is aimed at irradiating the nervous system. This is a preparatory stage before a bone marrow transplant.

Accompanying therapy is to protect the child from intoxication and side effects after chemotherapy.

1. Conservative medicine at acute leukemia prescribed only at the stage of remission, in other cases conservative method treatment leads to death.
2. Surgical intervention. Stem cell transplantation is the only way to cure a child with lymphocytic leukemia with the 22nd chromosome. In other cases, a bone marrow transplant is performed when the disease returns (relapse).

There are no alternative treatments for leukemia other than supportive care.

Rehabilitation after treatment

The recovery process after acute lymphoblastic leukemia is long and difficult, and the earlier the disease is diagnosed, the faster and better it will be overcome.

For children, the prognosis is favorable - about 90% are completely cured. Relapses occur in only 5% of the young population, but can be treated with a bone marrow transplant. Statistics show that timely treatment of leukemia in a child leads to a 100% guarantee of recovery, which cannot be said about the adult population.