Chronic myelogenous leukemia in children

Chronic myeloid leukemia in children (XML) is a form of chronic leukemia characterized by increased and unregulated clonal proliferation of myeloid cells in the bone marrow, which is manifested by the formation of a tumor consisting of a chronic phase from mature granulocytes and their precursors.

The disease is associated with the formation of the so-called Philadelphia chromosome - translocation t (9; 22), with the formation of a chimeric BCR / ABL gene.

Chronic myeloid leukemia in a child was described in the early XIX century. The first among other oncohematological diseases. In the middle of XX century. CML was the first oncological disease, which deciphered the molecular basis of pathogenesis, and at the end of the 20th century. - one of the first for which the so-called point (targeted) therapy is developed, when the drug acts selectively on a molecular target in a tumor cell that triggers uncontrolled reproduction.

[1], [2]

Epidemiology of chronic myelogenous leukemia in children

Chronic myelogenous leukemia is common in all age groups, but is most frequent in older children and in adults. The most common occurs at the age of 50-60 years. The incidence of 1-2 per 100 population per year, more often men suffer than women. In children, the incidence of CML is 0.1 -0.5 per 100 children's children's LLC, 3-5% of all forms of leukemia. It is more common in children older than 10 years.

The incidence of chronic myelogenous leukemia is 0.12 per 100,000 children per year, i.e. Chronic myeloid leukemia accounts for 3% of all leukemias in children.

[3], [4], [5], [6],

Causes of chronic myelogenous leukemia in children

The cause of chronic myelogenous leukemia in children is unknown. The only described risk factor for CML is ionizing radiation. For example, an increase in the occurrence of CML is observed in people who survived the atomic bombing of Hiroshima and Nagasaki in 1945, as well as in patients with spondyloarthritis who received X-ray therapy.

[7], [8], [9], [10], [11]

How does chronic myelogenous leukemia develop in children?

Chronic myelogenous leukemia in children is the first oncological disease in which a genetic breakdown, known as the Philadelphia chromosome, was proven. The aberration was named after the discovery site in Philadelphia, USA, where in 1960 it was first seen and described by Peter Nowell (University of Pennsylvania) and David Hungerford (Fox Chase Cancer Center).

As a result of this translocation, parts of chromosomes 9 and 22 are joined. At the same time, part of the BCR gene from chromosome 22 is connected to the tyrosine kinase (ABL) gene of the 9th chromosome. An abnormal BCR / ABL gene is produced, the product of which is an abnormal tyrosine kinase - a protein with a molecular weight of 210 kDa (denoted as p210). This protein activates a complex cascade of enzymes that control the cell cycle, thereby accelerating cell division, inhibiting DNA repair (repair) processes. This leads to instability of the cell's genome, making it susceptible to further mutations.

Symptoms of chronic myelogenous leukemia in children

Symptoms of chronic myelogenous leukemia in children vary depending on the phase of the disease in which the patient is. The chronic phase is asymptomatic for a long time. The only manifestation of it can be an increase in the spleen. The diagnosis in this period can be made using a general blood test. Patients with weakness, fatigue, pain and a feeling of heaviness in the left hypochondrium, especially worse after eating, are noted. Sometimes there is shortness of breath, associated with a reduction in the lung excursion, which is limited to a large spleen. The increase in the liver in the chronic phase of CML is secondary to the increase in the spleen and is not observed in all patients.

The phase of acceleration (acceleration, progression of the disease) is clinically little different from the chronic phase. The spleen increases rapidly. Basophilia in the blood can clinically manifest as reactions associated with the release of histamine (itching, heat, liquid stool). This phase is characterized by periodic rise in body temperature, a tendency to infectious diseases. At the end of the phase, pain in the bones and joints can occur.

Phase blast crisis (terminal, blast phase) in clinical manifestations is similar to acute leukemia. Developed intoxicated syndrome. Anemic syndrome is associated with inadequate erythropoiesis. Hemorrhagic syndrome caused by thrombocytopenia is manifested by bleeding in the microcirculatory (petechial-spotted) type - multiple petechiae, ecchymosis, bleeding from the mucous membranes. Hyperplastic syndrome manifests itself in the form of an increase in the mass of the liver and spleen, blast infiltration in various organs and tissues, lymphadenopathy, pain in the bones. The increase in the liver compared with an enlarged spleen is noted with CML only in the blast crisis phase, in previous periods the spleen by volume always exceeds the liver. That is why enlarging the liver can be one of the unfavorable symptoms of the disease.

Juvenile type of chronic myelogenous leukemia

Usually occurs in children up to 2-3 years old and is characterized by a combination of anemic, hemorrhagic, intoxication, proliferative syndromes. In an anamnesis, and often when entering the clinic, eczematous rashes are noted. In the analysis of blood, anemia (with a tendency to macrocytosis), thrombocytopenia, an increase in ESR and leukocytosis with a sharp shift up to myeloblasts (from 2 to 50% and more) with all the transitional forms (promyelocytes, myelocytes, juveniles, stabs) are found to varying degrees. Pronounced monocytosis. Leukocytosis usually ranges from 25 to 80 x 10 / L. In the bone marrow - increased cellularity, oppression of the megakaryocytic germ; the percentage of blast cells is small and corresponds to that in the peripheral blood, but all of them are signs of anaplasia. Characteristic laboratory features in the juvenile form are also the absence of the Ph'-chromosome in the culture of bone marrow cells, a high level of fetal hemoglobin (30-70%), which distinguishes this form from the adult type of myeloid leukemia in children. Some children show absence of one of the 7th pair of chromosomes.

Adult type of chronic myelogenous leukemia

Sometimes it is diagnosed with routine examinations, blood tests in children of school age, i.e., the disease develops gradually. The adult type of chronic myelogenous leukemia occurs twice as often as the juvenile type. It is estimated that approximately 40% of patients with chronic myelogenous leukemia at the time of diagnosis do not have any clinical symptoms and they have a hematologic diagnosis. Hepatosplenomegaly is observed in 20% of patients, in 54% - only splenomegaly. Sometimes chronic myelogenous leukemia begins with loss of body weight, weakness, fever, chills. There are three phases of chronic myelogenous leukemia;

1. slow, chronic (lasts about 3 years);
2. Acceleration (lasts about 1-1.5 years), but with appropriate treatment the disease can be returned to the chronic phase;
3. the final (terminal aggravation, the phase of rapid acceleration, lasting 3-6 months and usually ending with death).

During the acceleration of an expanded clinical hematological picture of the disease, general malaise, fatigue, weakness, an enlarged abdomen, pain in the left hypochondrium, painfulness when tapping on bones are usually noted. The spleen is usually very large. Hepatomegaly is less pronounced. Lymphadenopathy is usually minimal. When analyzing blood, moderate anemia, normal or increased platelet count and hyperleukocytosis (usually more than 100 x 10 ⁹ / L) are found. The leukocyte formula is dominated by promyelocytes, myelocytes, but there are both myeloblasts (about 5-10%) and metamyelocytes, stab and segmented forms, that is, there is no leukemia. Many forms of the eosinophilic and basophilic series, lymphopenia, and ESR are increased. In the bone marrow against the background of increased cellularity, there is a slight increase in blast elements, a pronounced metamyelocytic and myelocytic reaction. When karyotyping, 95% of patients have an additional small chromosome in the 22nd pair - the so-called Philadelphia chromosome (Ph'-chromosome) - the result of a balanced translocation of the material between the 9th and 22nd chromosomes. With this translocation, the protooncogene is transported, it is this gene that causes the development of chronic myelogenous leukemia. Ph'-chromosome is found in 5% of children with acute lymphoblastic leukemia and 2% with AML.

Terminal exacerbation of chronic myelogenous leukemia proceeds according to the type of acute blast crisis with hemorrhagic syndrome and intoxication: gray-earthy skin color, generalized lymphadenopathy, bone damage, hyperthermia, not always associated with infection.

[12], [13], [14]

Classification of chronic myelogenous leukemia

According to the modern classification adopted by the World Health Organization in 2001, chronic myelogenous leukemia in children is included in the group of chronic myeloproliferative diseases (KMPP), which also includes extremely rare in childhood chronic neutrophilic leukemia, hypereosinophilic syndrome (chronic eosinophilic leukemia), true polycythemia, essential thrombocythemia, chronic idiopathic myelofibrosis and unclassifiable CMPZ. These are clonal (tumor) diseases, in which the tumor substrate consists of mature, differentiated, functionally active cells of myeloid origin. At the same time there are no signs of dysplasia, insufficiency of hematopoiesis (anemia, thrombocytopenia, leukopenia). The main manifestations of diseases are associated mainly with hyperplastic syndrome (hepatosplenomegaly, tumor infiltration of organs), an increase in the number of cells (depending on the variant of the CMPZ) cells in the general blood test (erythrocytes, platelets, neutrophils, eosinophils).

The main characteristic of all KMMP is a chronic current, the duration of which in each specific case can not be determined. In the future, the disease can progress, there are symptoms of hematopoiesis dysplasia for one or more sprouts. The maturation of blood cells is broken, new mutations appear, new immature tumor clones, which leads to gradual transformation of CMPZ into myelodysplastic syndrome, and then to acute leukemia. There may also be a more "benign" course with replacement of the bone marrow with connective tissue (myelofibrosis) and myeloid metaplasia of the spleen.

The mechanisms of development of chronic myelogenous leukemia in children are well studied. In the course of CML, three phases are distinguished:

• chronic phase;
• acceleration phase;
• blast crisis.

The chronic phase has all the characteristics of the KMMP. Hyperplasia of granulocytopoiesis and megakaryocytopoiesis in the bone marrow is manifested by changes in the general blood analysis in the form of leukocytosis with a left shift accompanied by thrombocytosis. In the clinical picture during this period, the increase in spleen is most characteristic.

The criteria for transition to the accelerating phase are:

• appearance in the general analysis of blood blast cells> 10%, but <30%;
• the amount of blasts and promyelocytes in a general blood test> 20%;
• number of basophils in the general blood test> 20%;
• a decrease in the number of platelets less than 100,000 / mm3, not associated with therapy;
• increase in spleen size by 50% for 4 weeks;
• additional chromosome aberrations (such as the 2nd Philadelphia chromosome, disappearance of the Y chromosome, trisomy 8, isochromosome 17, etc.).

Criteria for the transition to the blast crisis phase are:

• the number of blast cells in the total blood test and / or in the bone marrow exceeds 30%;
• blastic infiltration of organs and tissues outside the bone marrow, liver, spleen or lymph nodes.

[15], [16], [17], [18]

Diagnosis of chronic myelogenous leukemia in children

In most cases, chronic myelogenous leukemia in children can be suspected on the basis of a general blood test. Anamnesis and clinical manifestations, as a rule, are of little specificity. The greatest attention during examination should be given to the evaluation of the size of the spleen and liver. Changes in the general analysis of blood in CML differ during different periods of the course of the disease.

In the biochemical blood test, the activity of lactate dehydrogenase, uric acid levels, electrolytes is determined. These indicators are necessary for an estimation of intensity of processes of disintegration of cells - an integral component of any tumor process. The indices of residual nitrogen - urea and creatinine levels, as well as the activity of liver enzymes (ALAT, ASAT, gamma-GTP, APF), the content of direct and indirect bilirubin are evaluated.

To establish the final diagnosis of chronic myelogenous leukemia in children, it is necessary to conduct bone marrow studies - puncture biopsy and trepanobiopsy. The material collected at the puncture is subjected to cytological and genetic studies.

In the myelogram (cytological analysis of bone marrow) in the chronic phase, hyperplasia of granulocyte and megakaryocytic germs of hemopoiesis is revealed. In the acceleration phase, an increase in the content of immature forms is noted, the appearance of blasts, the number of which does not exceed 30%. The picture of the bone marrow in the blast crisis phase resembles that of acute leukemia.

Genetic examination of the bone marrow should include karyotyping (standard cytogenetic study), in which a morphological evaluation of chromosomes in metaphase nuclei is made. Not only can the diagnosis be confirmed by detecting the Philadelphia chromosome 1 (9; 22), but also additional aberrations that are considered the criterion for the transition of the disease from the chronic phase to the accelerating phase.

In addition, a molecular genetic study using in situ hybridization (FISH) and a multiplex polymerase chain reaction can detect not only the chimeric BCR / ABL gene, which confirms the diagnosis of CML, but also to determine the various splicing variants (the molecular features of the BCR / ABL gene, specific points where the fusion of chromosomes 9 and 22 occurred).

Along with puncture biopsy for the diagnosis of CML it is necessary to conduct bone marrow trepanobiopsy with a subsequent histological examination of the biopsy specimen. This allows us to evaluate the cellularity of the bone marrow and the degree of fibrosis, to identify possible signs of dysplasia, which may be early signs of transformation.

Determination of antigens of the main histocompatibility complex (HLA-typing) in the patient and his family members (siblings and parents) is carried out among the primary diagnostic measures to determine the potential donor of hematopoietic stem cells.

Among the necessary studies for CML include ultrasound examination of the abdominal cavity organs and retroperitoneal space, electrocardiography, chest X-ray.

[19]

Differential diagnostics

Differential diagnosis of CML is carried out with neutrophilic leukemoid reactions, which are often found in patients with severe bacterial infections. Unlike CML, the acute phase of inflammation never increases the level of basophils, less pronounced leukocytosis. In addition, for patients with leukemoid reactions, spleen enlargement is uncharacteristic. To perform differential diagnosis of myeloproliferative disease and neutrophilic leukemia reaction in the most difficult disputable cases, the determination of alkaline phosphatase in neutrophils is recommended (revealed in the leukemoid reaction).

A final conclusion about the presence or absence of a patient with CML can be made on the basis of genetic research, determination of the presence of the Philadelphia chromosome and the BCR / ABL gene.

Differential diagnosis of CML with other CMPs is performed in adults. In connection with the casuistic rarity of other KMMP in the children's population, CML is differentiated only with juvenile myelomonocytic leukemia (JMML). This is a rather rare disease (frequency of 1.3 per 1,000,000 children per year, or 2-3% of children's leukemias). It occurs in children from 0 to 14 years (in 75% of cases - up to 3 years). As with CML, uncontrolled proliferation of granulocyte germ proceeds, hepatosplenomegaly develops.

In the domestic literature until recently, YUMML was considered as a variant of CML. However, YMML differs from the fundamentally different, malignant course, the instability to CML therapy and the extremely unfavorable prognosis. WHO classification in 2001 singled out YUMML as a special group of myeloproliferative / myelodysplastic diseases, for which along with uncontrolled proliferation of cells of myeloid origin, there are signs of dysplasia - defects in differentiation of bone marrow cells. In contrast to CML at YUMML there is no Philadelphia chromosome (or BCR / ABL gene). For YMML, monocytosis in the peripheral blood (more than 1x109 / l) is characteristic. The number of blasts in the bone marrow at YUMML is less than 20%. To confirm the diagnosis of YMML, two or more of the following criteria are also required: an increase in the level of fetal hemoglobin, the presence of immature granulocytes in the peripheral blood, leukocytosis more than 10x10 ⁹ / l, the detection of chromosomal aberrations (most often - monosomy 7), the hypersensitivity of myeloid precursors to the action of colony-stimulating factors GM-CSF) in vitro.

[20], [21], [22], [23], [24], [25]

Treatment of chronic myelogenous leukemia in children

The principles of diet and regime, organization of care for patients are the same as in acute leukemia. Splenectomy is not indicated. In cases of blast crises, treatment is carried out according to the programs for acute myeloid leukemia. The juvenile variant is much more resistant to therapy, and the scheme of its treatment is not worked out. Prescribe treatment according to the schemes of VAMP, CAMP and others.

The first attempts to treat chronic myelogenous leukemia in children were made back in the XIX century. The only remedy was arsenic, with which it was possible to shorten the tumor for a short time, reduce the size of the spleen and reduce the leukocytosis. In the XX century. The main drugs for the treatment of CML have become hydroxyurea, cytarabine, myelosan, interferon. With their help, it was possible to obtain not only hematological (absence of clinical symptoms and signs of disease in the general analysis of blood and bone marrow), but also cytogenetic (absence of mutation BCR / ABL) remission. However, remissions were short-lived, and the disappearance of the mutant gene was noted in a small percentage of cases. The main goal of such therapy was to transfer from the accelerated phase to the chronic phase, increase the duration of the chronic phase, prevent the progression of the disease.

The introduction of the method of allogeneic transplantation of hematopoietic stem cells (TSCC) made it possible to achieve significant success in the treatment of CML. It was shown that carrying out TSCS from an HLA-compatible related donor (brother or sister) at the onset of the chronic phase of the disease makes it possible to achieve a cure in 87% of children. The results are somewhat worse for TSCS from an unrelated and (or) HLA-incompatible donor, during treatment in the acceleration or blast crisis phase, and also at a later date from the time of diagnosis and against conservative treatment.

The TSCS method allows not only to replace the hematopoietic hemopoietic system of the patient with a healthy one, but also to prevent the recurrence of the disease, using the activation of antitumor immunity based on the immunological phenomenon of "graft-versus-leukemia". It should be noted, however, that the use of this method should be commensurate with the risk of complications of the TSCC procedure itself, often leading to death.

New opportunities in the treatment of CML appeared after the introduction at the beginning of the XXI century. In the clinical practice of BCR / ABL-tyrosine kinase inhibitors, the first of which (and so far only in Russia) is imatinib (glivec). Unlike preparations for conservative treatment that have been selected empirically, in this case a molecular mechanism of action is used, aimed at the key link in the pathogenesis of the disease, pathological BCR / ABL tyrosine kinase. This enzyme is recognized as a substratum of the chimeric BCR / ABL gene, it triggers the processes of uncontrolled cell division and malfunction in the DNA repair system. This approach in the treatment of cancer is called point (targeted) therapy.

Treatment of chronic myelogenous leukemia in children with imatinib allows the majority of patients to achieve persistent full hematologic and cytogenetic response. However, over time, some patients develop resistance to the drug, which leads to a rapid progression of the disease. To overcome the resistance to imatinib, other tyrosine kinase inhibitors (dasatinib / nilotinib, etc.), which are currently at the stage of clinical trials, may be used in the near future. They also develop drugs with other molecular targets in the pathogenesis of CML, which will make it possible to make CML therapy multidirectional in the future. In 2005, the first encouraging data on vaccination with a special vaccine on BCR / ABL was published.

While for some adult patients a decision has been made to abandon TSCC in favor of treatment with tyrosine kinase inhibitors, this issue has not been finally resolved for children due to the limited duration of imatinib. To clarify the role of TSCA and tyrosine kinase inhibitors, as well as other traditional drugs for the treatment of CML (interferon, hydroxyurea, etc.) in children, multicenter studies currently under way will allow.

Treatment of patients in the chronic phase and the phase of acceleration differs mainly in the doses of the drugs used. During the phase of blast crisis, when the disease resembles the picture of acute leukemia, high-dose polychemotherapy is performed using the scheme of treatment of acute lymphoblastic leukemia or acute non-lymphoblastic leukemia (depending on the prevailing clone of blast cells). World experience shows that in the phase of acceleration or blast crisis after preliminary conservative treatment there is no alternative to TSCC. Despite the fact that during these periods of the disease course the TSCC gives a significantly smaller effect in comparison with the results of its application to the chronic phase of CML.

Prognosis for chronic myelogenous leukemia in a child

The prognosis of the disease depends on many factors, including the age of the manifestation, the size of the spleen, the number of blasts, platelets, eosinophils and basophils in peripheral blood. In addition, currently an important factor in the prognosis is considered ongoing therapy. In published studies, the average life expectancy after confirmation of the diagnosis of CML varies from 42 to 117 months. It should be noted that these studies did not take into account the use of tyrosine kinase inhibitors for the treatment of CML in clinical practice only in recent years, which is expected to dramatically increase the life expectancy of CML patients.

Prognosis for juvenile type is unfavorable - patients die in the first year of treatment. In the adult type, the duration of the disease is several years. Some patients live 10 years or more. After successful bone marrow transplantation and total radiation therapy in both forms of chronic myelogenous leukemia, recovery is possible.

Dispensary observation and recommendations

Chronic myelogenous leukemia in children is a chronic disease, so all patients should be monitored for life by a hematologist. Examinations of patients receiving imatinib therapy are carried out once a week for the first 3 months of treatment, in the subsequent period - 1 time in 2 weeks. When a clinical examination is necessary to assess the size of the spleen, identify the symptoms of CML and the side effects of imatinib. Assign a general blood test, with the determination of the level of reticulocytes and the leukocyte formula, and a biochemical blood test with an assessment of lactate dehydrogenase activity.

Molecular genetic study of peripheral blood leukocytes with determination of the amount of chimeric BCR / ABb gene is carried out monthly. Puncture of the bone marrow with morphological and cytogenetic studies for early diagnosis of the transition of the chronic phase to the accelerating phase is prescribed 1 time in 3 months. Every six months, bone marrow trepanobiopsy is required to determine the degree of myelofibrosis. Observation at the third year of therapy is further carried out depending on the clinical-hematological and molecular-genetic effect of the treatment.

After TSCS, patients are usually observed in a specialized transplantation center according to specially developed schemes, depending on the TSCT method used. In addition to the diagnostic and treatment procedures necessary to monitor the state of remission for the underlying disease, evaluate the consistency of the transplant, the infectious status, the activity of the immunological reaction "graft versus the host."

[26], [27], [28],