Chronic myeloleukemia in children

Chronic myelogenous leukemia in children (CML) is a form of chronic leukemia characterized by increased and unregulated clonal proliferation of myeloid cells in the bone marrow, which manifests itself in the formation of a tumor consisting in the chronic phase of 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 gene BCR/ABL.

Chronic myelogenous leukemia in a child was described in the early 19th century as the first among other oncohematological diseases. In the mid-20th century, CML became the first oncological disease for which the molecular basis of pathogenesis was deciphered, and at the end of the 20th century, it was one of the first for which so-called point (target) therapy was developed, when the drug acts selectively on the molecular target in the tumor cell, which triggers the processes of uncontrolled reproduction.

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Epidemiology of chronic myelogenous leukemia in children

Chronic myelogenous leukemia is common in all age groups, but is most common in older children and adults. It is most common in people aged 50-60 years. The incidence is 1-2 per 100,000 population per year, and men are more often affected than women. In children, the incidence of CML is 0.1-0.5 per 100,000 children, 3-5% of all forms of leukemia. It is most common in children over 10 years of age.

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

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Causes of Chronic Myeloid 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 increased incidence of CML has been reported in survivors of the atomic bombing of Hiroshima and Nagasaki in 1945, as well as in patients with spondyloarthritis who received X-ray therapy.

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How does chronic myelogenous leukemia develop in children?

Chronic myelogenous leukemia in children is the first oncological disease in which a genetic defect known as the Philadelphia chromosome was proven. This aberration received its name from the place of discovery - the city of 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 connected. In this case, part of the BCR gene from chromosome 22 is connected to the tyrosine kinase gene (ABL) of chromosome 9. An abnormal BCR/ABL gene is formed, the product of which is abnormal tyrosine kinase - a protein with a molecular weight of 210 kDa (designated as p210). This protein activates a complex cascade of enzymes that control the cell cycle, thereby accelerating cell division, inhibits DNA restoration (reparation) processes. This leads to instability of the cell genome, making it susceptible to further mutations.

Symptoms of Chronic Myeloid Leukemia in Children

Symptoms of chronic myeloid leukemia in children vary depending on the phase of the disease the patient is in. The chronic phase is asymptomatic for a long time. Its only manifestation may be an enlarged spleen. The diagnosis during this period can be made using a general blood test. Patients experience weakness, increased fatigue, pain and a feeling of heaviness in the left hypochondrium, which especially increases after eating. Sometimes shortness of breath is observed, associated with a decrease in the excursion of the lungs, which is limited by a large spleen. Enlargement of the liver in the chronic phase of CML is secondary to an enlarged spleen and is not observed in all patients.

The acceleration phase (acceleration, progression of the disease) is clinically little different from the chronic phase. The spleen volume increases rapidly. Basophilia in the blood can be clinically manifested by reactions associated with the release of histamine (skin itching, feeling of heat, loose stools). This phase is characterized by periodic increases in body temperature, a tendency to infectious diseases. At the end of the phase, pain in the bones and joints may occur.

The blast crisis phase (terminal, blast phase) is similar to acute leukemia in its clinical manifestations. A pronounced intoxication syndrome develops. Anemic syndrome is associated with insufficient erythropoiesis. Hemorrhagic syndrome caused by thrombocytopenia is manifested by bleeding of the microcirculatory (petechial-spotted) type - multiple petechiae, ecchymoses, bleeding from the mucous membranes. Hyperplastic syndrome is manifested by an increase in the mass of the liver and spleen, blast infiltration in various organs and tissues, lymphadenopathy, bone pain. An enlarged liver comparable to an enlarged spleen is observed in CML only in the blast crisis phase; in previous periods, the spleen always exceeds the liver in volume. That is why an enlarged liver can be one of the unfavorable symptoms of the disease.

Juvenile type of chronic myelogenous leukemia

Usually appears in children under 2-3 years old and is characterized by a combination of anemic, hemorrhagic, intoxication, proliferative syndromes. In the anamnesis, and often on admission to the clinic, eczematous rashes are noted. Blood analysis reveals varying degrees of anemia (with a tendency to macrocytosis), thrombocytopenia, increased ESR and leukocytosis with a sharp shift up to myeloblasts (from 2 to 50% or more) with the presence of all transitional forms (promyelocytes, myelocytes, young, band neutrophils), pronounced monocytosis. Leukocytosis usually ranges from 25 to 80 x 10 /l. In the bone marrow - increased cellularity, suppression of the megakaryocytic germ; the percentage of blast cells is small and corresponds to that in the peripheral blood, but they all have signs of anaplasia. Characteristic laboratory signs of the juvenile form are also the absence of the Ph' chromosome in the bone marrow cell culture, a high level of fetal hemoglobin (30-70%), which distinguishes this form from the adult type of myeloid leukemia in children. In some children, the absence of one of the 7th pair of chromosomes is detected.

Adult-onset chronic myelogenous leukemia

Sometimes it is diagnosed during routine examinations, during blood tests in school-age children, i.e. the disease develops gradually. Adult chronic myeloid leukemia is twice as common as juvenile. It is believed that approximately 40% of patients with chronic myeloid leukemia do not have any clinical symptoms at the time of diagnosis and are diagnosed only hematologically. 20% of patients have hepatosplenomegaly, 54% have only splenomegaly. Sometimes chronic myeloid leukemia begins with weight loss, weakness, fever, chills. There are three phases of chronic myeloid leukemia:

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

During the acceleration period of the expanded clinical and hematological picture of the disease, general malaise, increased fatigue, weakness, enlarged abdomen, pain in the left hypochondrium, and pain when percussing the bones are usually observed. The spleen is usually very large. Hepatomegaly is less pronounced. Lymphadenopathy is usually minimal. Blood tests reveal moderate anemia, normal or increased platelet count, and hyperleukocytosis (usually more than 100 x 10 ⁹ /l). The leukocyte formula is dominated by promyelocytes and myelocytes, but there are also myeloblasts (about 5-10%) and metamyelocytes, band and segmented forms, i.e. there is no leukemic gaping. There are many forms of eosinophilic and basophilic series, lymphopenia, and increased ESR. In the bone marrow, against the background of increased cellularity, a slight increase in blast elements, pronounced metamyelocytic and myelocytic reactions are noted. During karyotyping, an additional small chromosome is found in the group of the 22nd pair in 95% of patients - the so-called Philadelphia chromosome (Ph'-chromosome) - the result of a balanced translocation of material between the 9th and 22nd chromosomes. During this translocation, a proto-oncogene is transferred, and it is this gene that causes the development of chronic myeloid leukemia. The Ph'-chromosome is found in 5% of children with acute lymphoblastic leukemia and 2% with AML.

Terminal exacerbation of chronic myelogenous leukemia occurs as an acute blast crisis with hemorrhagic syndrome and intoxication: gray-earthy skin color, generalized lymphadenopathy, bone damage, hyperthermia, not always associated with infection.

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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 (CMPD), which also includes chronic neutrophilic leukemia, hypereosinophilic syndrome (chronic eosinophilic leukemia), true polycythemia, essential thrombocythemia, chronic idiopathic myelofibrosis and unclassified CMPD, which are extremely rare in childhood. These are clonal (tumor) diseases in which the tumor substrate consists of mature, differentiated, functionally active cells of myeloid origin. In this case, there are no signs of dysplasia, hematopoietic insufficiency (anemia, thrombocytopenia, leukopenia). The main manifestations of the disease are associated mainly with hyperplastic syndrome (hepatosplenomegaly, tumor infiltration of organs), an increase in the number of certain (depending on the type of chronic hepatitis C) cells in a general blood test (erythrocytes, platelets, neutrophils, eosinophils).

The main characteristic of all CMPD is a chronic course, the duration of which in each specific case cannot be determined. The disease may progress further, symptoms of hematopoietic dysplasia appear in one or several germs. Maturation of blood cells is disrupted, new mutations appear, new immature tumor clones, which leads to a gradual transformation of CMPD into myelodysplastic syndrome, and then into acute leukemia. A more "benign" course is also possible with replacement of 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. Three phases are distinguished during the course of CML:

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

The chronic phase has all the features of chronic MPD. Hyperplasia of granulocytopoiesis and megakaryocytopoiesis in the bone marrow is manifested by changes in the general blood test in the form of leukocytosis with a shift to the left, accompanied by thrombocytosis. In the clinical picture during this period, an enlarged spleen is most characteristic.

The criteria for transition to the acceleration phase are:

• the appearance in a general blood test of blast cells >10% but <30%;
• the sum of blasts and promyelocytes in the general blood test is >20%;
• the number of basophils in the general blood test is >20%;
• decrease in platelet count to less than 100,000/μl, not related to therapy;
• increase in spleen size by 50% within 4 weeks;
• additional chromosomal aberrations (such as the 2nd Philadelphia chromosome, the disappearance of the Y chromosome, trisomy 8, isochromosome 17, etc.).

The criteria for transition to the blast crisis phase are:

• the number of blast cells in the general 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.

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Diagnosis of chronic myelogenous leukemia in children

In most cases, chronic myelogenous leukemia in children can be suspected based on a complete blood count. The anamnesis and clinical manifestations are usually not very specific. The greatest attention during examination should be paid to assessing the size of the spleen and liver. Changes in the complete blood count in CML differ at different periods of the disease.

In a biochemical blood test, the activity of lactate dehydrogenase, uric acid levels, and electrolytes are determined. These indicators are necessary to assess the intensity of cell decay processes, which is an integral part of any tumor process. An assessment is made of residual nitrogen indicators - urea and creatinine levels, as well as the activity of liver enzymes (ALT, AST, gamma-GTP, ALP), and the content of direct and indirect bilirubin.

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

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

Genetic testing of bone marrow should include karyotyping (standard cytogenetic testing), which involves morphological assessment of chromosomes in metaphase nuclei. This can not only confirm the diagnosis by detecting Philadelphia chromosome 1(9;22), but also additional aberrations, which are considered a criterion for the transition of the disease from the chronic phase to the acceleration phase.

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

Along with a puncture biopsy, a bone marrow trephine biopsy with subsequent histological examination of the biopsy is necessary for diagnosing CML. This allows one to assess the cellularity of the bone marrow and the degree of fibrosis, and to identify possible signs of dysplasia, which may be early signs of transformation.

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

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

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Differential diagnostics

Differential diagnostics of CML is performed with neutrophilic leukemoid reactions, which are often found in patients with severe bacterial infections. Unlike CML, the level of basophils never increases in the acute phase of inflammation, and leukocytosis is less pronounced. In addition, an enlarged spleen is not typical for patients with leukemoid reactions. For differential diagnostics of myeloproliferative disease and neutrophilic leukemoid reaction in the most complex controversial cases, it is recommended to determine alkaline phosphatase in neutrophils (detected in leukemoid reaction).

A final conclusion about the presence or absence of CML in a patient can be made based on a genetic study, determining the presence of the Philadelphia chromosome and the BCR/ABL gene.

Differential diagnostics of CML with other CMPZ is performed in adults. Due to the casuistic rarity of other CMPZ in the pediatric population, CML is differentiated only with juvenile myelomonocytic leukemia (JMML). This is a rather rare disease (frequency 1.3 per 1,000,000 children per year, or 2-3% of childhood leukemia). It occurs in children from 0 to 14 years old (in 75% of cases - up to 3 years). As with CML, uncontrolled proliferation of the granulocytic germ occurs, hepatosplenomegaly develops.

Until recently, JMML was considered a variant of CML in Russian literature. However, JMML is characterized by a fundamentally different, malignant course, instability to CML therapy, and an extremely unfavorable prognosis. In 2001, the WHO classification singled out JMML as a special group of myeloproliferative/myelodysplastic diseases, which, along with uncontrolled proliferation of cells of myeloid origin, are characterized by signs of dysplasia - defects in the differentiation of bone marrow cells. Unlike CML, JMML lacks the Philadelphia chromosome (or BCR/ABL gene). JMML is characterized by monocytosis in the peripheral blood (more than 1x109/l). The number of blasts in the bone marrow in JMML is less than 20%. To confirm the diagnosis of JMML, 2 or more of the following criteria are also required: increased fetal hemoglobin levels, the presence of immature granulocytes in the peripheral blood, leukocytosis greater than 10x10 ⁹ /l, detection of chromosomal aberrations (most often monosomy 7), hypersensitivity of myeloid precursors to the action of colony-stimulating factors (GM-CSF) in vitro.

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Treatment of chronic myelogenous leukemia in children

The principles of diet and regimen, organization of care for patients are the same as for acute leukemia. Splenectomy is not indicated. In blast crises, treatment is carried out according to the programs of therapy of acute myeloid leukemia. The juvenile variant is much more resistant to therapy, and its treatment scheme has not been developed. Treatment is prescribed according to the schemes of VAMP, CAMP, etc.

The first attempts to treat chronic myelogenous leukemia in children were made in the 19th century. The only medicine then was arsenic, which managed to shrink the tumor, reduce the size of the spleen and reduce leukocytosis for a short time. In the 20th century, the main drugs for the treatment of CML were hydroxyurea, cytarabine, myelosan, and interferon. With their help, it was possible to achieve not only hematological (absence of clinical symptoms and signs of the disease in the general blood test and bone marrow), but also cytogenetic (absence of the BCR/ABL mutation) remissions. However, the remissions were short-term, 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 acceleration phase to the chronic phase, increase the duration of the chronic phase, and prevent disease progression.

The introduction of the allogeneic hematopoietic stem cell transplantation (HSCT) method into practice has made it possible to achieve significant success in the treatment of CML. It has been shown that HSCT from an HLA-compatible related donor (brother or sister) at the beginning of the chronic phase of the disease allows achieving a cure in 87% of children. The results are somewhat worse with HSCT from an unrelated and (or) HLA-incompatible donor, when treating in the acceleration or blast crisis phases, as well as at later stages from the moment of diagnosis and against the background of conservative treatment.

The HSCT method allows not only to replace the patient's hematopoietic system affected by the tumor with a healthy one, but also to prevent relapse 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 benefit of using this method should be measured against the risk of complications of the HSCT procedure itself, which often lead to death.

New opportunities in the treatment of CML appeared after the introduction of BCR/ABL tyrosine kinase inhibitors into clinical practice at the beginning of the 21st century, the first of which (and so far the only one in Russia) is the drug imatinib (Gleevec). Unlike drugs for conservative treatment, selected empirically, in this case they use a molecular mechanism of action aimed at the key link in the pathogenesis of the disease - pathological BCR/ABL tyrosine kinase. It is this enzyme that is recognized as a substrate of the chimeric gene BCR/ABL, it triggers the processes of uncontrolled cell division and a failure in the DNA reparation system. This approach to the treatment of oncological diseases is called point (target) therapy.

Treatment of chronic myelogenous leukemia in children with imatinib allows most patients to achieve a stable complete hematological and cytogenetic response. However, over time, some patients develop resistance to the drug, which leads to rapid progression of the disease. To overcome resistance to imatinib, it will be possible to use other tyrosine kinase inhibitors (dasatinib, nilotinib, etc.), which are currently at the clinical trial stage. Drugs with other molecular targets in the pathogenesis of CML are also being developed, 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 acting on BCR/ABL were published.

While some adult patients have been given the option of forgoing HSCT in favor of tyrosine kinase inhibitors, this issue has not been fully resolved for children due to the time-limited action of imatinib. Multicenter studies currently underway will help clarify the role of HSCT and tyrosine kinase inhibitors, as well as other traditional CML drugs (interferon, hydroxyurea, etc.) in children.

Treatment of patients in the chronic phase and acceleration phase differs mainly in the doses of the drugs used. In the blast crisis phase, when the disease resembles acute leukemia, high-dose polychemotherapy is administered using a treatment regimen for acute lymphoblastic leukemia or acute non-lymphoblastic leukemia (depending on the predominant clone of blast cells). World experience shows that in the acceleration or blast crisis phase after preliminary conservative treatment, there is no alternative to HSCT. Despite the fact that in these periods of the disease, HSCT gives a significantly smaller effect compared to the results of its use in the chronic phase of CML.

Prognosis for Chronic Myeloid Leukemia in Children

The prognosis of the disease depends on many factors, including the age of manifestation, spleen size, blast count, platelet count, eosinophil count, and basophil count in the peripheral blood. In addition, therapy is currently considered an important prognostic factor. In published studies, the average survival time after confirmation of the diagnosis of CML ranges 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, which have only recently been introduced into clinical practice, which is expected to dramatically increase the survival time of CML patients.

The prognosis for the 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, recovery is possible for both forms of chronic myeloid leukemia.

Outpatient observation and recommendations

Chronic myelogenous leukemia in children is a chronic disease, so all patients should be monitored by a hematologist for life. Patients receiving imatinib therapy are examined once a week during the first 3 months of treatment, and once every 2 weeks thereafter. During a clinical examination, the size of the spleen is necessarily assessed, symptoms of CML and side effects of imatinib are identified. A complete blood count is prescribed, with determination of the reticulocyte level and white blood cell count, and a biochemical blood test with an assessment of lactate dehydrogenase activity.

Molecular genetic testing of peripheral blood leukocytes to determine the amount of the chimeric BCR/ABb gene is performed monthly. Bone marrow puncture with morphological and cytogenetic testing for early diagnostics of the transition from the chronic phase to the acceleration phase is prescribed once every 3 months. Bone marrow trepanobiopsy is required every six months to determine the degree of myelofibrosis. Monitoring in the third year of therapy and further is performed depending on the clinical, hematological and molecular genetic effect of the treatment.

After HSCT, patients are usually monitored in a specialized transplant center according to specially developed schemes depending on the HSCT method used. In addition to diagnostic and therapeutic procedures necessary to monitor the state of remission for the underlying disease, the viability of the transplant, infectious status, and activity of the immunological reaction "graft versus host" are assessed.

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