There is swelling with CML. Chronic myeloid leukemia - clinical picture, diagnosis, treatment. Chronic myeloid leukemia: stages

Diagnosis(CML) in most cases is easy to establish or, in any case, suspect based on characteristic changes in the blood picture. These changes are expressed in a gradually increasing leukocytosis, small at the beginning of the disease (10-15 10 9 / l) and reaching huge numbers as the disease progresses without treatment - 200-500-800 10 9 / l and even more.

Simultaneously with the increase in the number leukocytes characteristic changes in the leukocyte formula are noted: an increase in the content of granulocytes to 85-95%, the presence of immature granulocytes - myelocytes, metamyelocytes, with significant leukocytosis - often promyelocytes, and sometimes single blast cells. A very characteristic increase in the content of basophils to 5-10%, often with a simultaneous increase in the level of eosinophils to 5-8% (“eosinophil-basophil association”, not found in other diseases) and a decrease in the number of lymphocytes to 10-5%.

Sometimes the number of basophils reaches significant figures - 15-20% or more.

In literature 15-20 years ago in such cases, the disease was designated as a basophilic variant of chronic myeloid leukemia, which occurs in 5-8% of patients. An eosinophilic variant has been described, in which there are always 20-40% eosinophils in the blood. Currently, these variants are not isolated, and an increase in the number of basophils or eosinophils is considered a sign of advanced disease.

In most patients, the number of platelets up to 400-600 10 9 / l, and sometimes more - up to 800-1000 10 9 / l, rarely even higher. The content of hemoglobin and red blood cells can remain normal for a long time, decreasing only with very high leukocytosis. In some patients, at the onset of the disease, even a slight erythrocytosis is observed - 5.0-5.5 10 12 l.

Study bone marrow punctate detects an increase in the number of myelokaryocytes and the percentage of immature granulocytes with an increase in the myeloid/erythroid ratio to 20-25/1 instead of the normal 3-4/1. The number of basophils and eosinophils is usually increased, especially in patients with high content these cells in the blood. As a rule, it is noted a large number of mitotic figures.

In some patients, more often with significant hyperleukocytosis, in the bone marrow punctate blue histiocytes and cells resembling Gaucher cells are found. These are macrophages that take up glucocerebrosides from decaying leukocytes. The number of megakaryocytes is usually increased, as a rule, they have signs of dysplasia.

At morphological study no changes are detected in the structure of granulocytic cells in CML compared to normal ones, however, with electron microscopy Asynchronism is revealed in the maturation of the nucleus and cytoplasm: at each stage of granulocyte maturation, the nucleus lags behind the cytoplasm in its development.

From cytochemical features A sharp decrease or complete disappearance of alkaline phosphatase in neutrophils in the blood and bone marrow is very characteristic.

At trepanobiopsy pronounced hyperplasia of the myeloid germ, a sharp decrease in fat content are detected, in 20-30% of patients already at the onset of the disease there is one or another degree of myelofibrosis.
Morphological study spleen detects infiltration of the red pulp by leukemic cells.

Of the biochemical changes, the characteristic one is increase in vitamin B12 content in blood serum, which sometimes exceeds normal by 10-15 times and often remains elevated during clinical and hematological remission. Another significant change is an increase in uric acid levels. It turns out to be high in almost all untreated patients with significant leukocytosis and can increase even more during cytostatic therapy.

In some patients there is constant increased uric acid levels leads to the formation of urate urinary stones and gouty arthritis, deposition of uric acid crystals in tissues ears with the formation of visible nodules. The vast majority of patients have high serum lactate dehydrogenase levels.

Start diseases in most cases it is almost or completely asymptomatic. Usually, when changes in the blood have already appeared, the spleen is not enlarged. As the disease progresses, it progressively increases, sometimes reaching enormous sizes. Leukocytosis and spleen size do not always correlate with each other. In some patients, the spleen occupies the entire left half of the abdomen, descending into the small pelvis, with leukocytosis 65-70 10 9 /l, in other patients with leukocytosis reaching 400-500 10 9 /l, the spleen protrudes from under the edge of the costal arch by only 4-5 cm. Large spleen sizes are especially characteristic of CML with high basophilia.

With pronounced splenomegaly The liver is usually enlarged, but always to a much lesser extent than the spleen. Enlarged lymph nodes are not typical for CML; they sometimes occur in terminal stage disease and is caused by infiltration of the lymph node with blast cells.

Complaints weakness, a feeling of heaviness, sometimes pain in the left hypochondrium, sweating, low-grade fever appear only with a detailed clinical and hematological picture of the disease.

U 20-25% of patients with CML It is detected by chance, when there are still no clinical signs of the disease, and there are only mildly expressed hematological changes (leukocytosis and a small percentage of immature granulocytes in the blood), which are detected during a blood test done for another disease or during a preventive examination. The absence of complaints and clinical symptoms sometimes leads to the fact that characteristic but moderate changes in the blood, unfortunately, do not attract the doctor’s attention, and the true onset of the disease can only be established retrospectively when a patient presents with an already pronounced clinical and hematological picture of the disease.

Confirmation diagnosis of CML is the detection in blood and bone marrow cells of a characteristic cytogenetic marker - the Ph chromosome. This marker is present in all patients with CML and is not found in other diseases.

Chronic myeloid leukemia- first cancer, in which specific changes in chromosomes were described in humans and the molecular mechanisms underlying the development of the disease were deciphered.

In 1960 two cytogenetics from Philadelphia in the USA, P. Nowell and D. Hungerford found a shortening of the long arm of one of the chromosomes of the 21st pair in all the CML patients they examined. Based on the name of the city where the discovery was made, this chromosome was called the Philadelphia, or Ph-chromosome. In 1970, using a more advanced chromosome staining technique, T. Caspersson et al. They found that in CML there is a deletion of the long arm of one of the chromosomes, not the 21st, but the 22nd pair. Finally, in 1973, a major discovery was made, which became the starting point in the study of the pathogenesis of CML: J. Rowley showed that the formation of the Ph chromosome is due to reciprocal translocation (mutual exchange of part of the genetic material) between chromosomes 9 and 22.

With such translocations Most of the long arm of chromosome 22 is transferred to the long arm of chromosome 9, and a small terminal part of the long arm of chromosome 9 is transferred to chromosome 22. As a result, a characteristic cytogenetic anomaly occurs - elongation of the long arm of one of the chromosomes of the 9th pair and shortening of the long arm of one of the chromosomes of the 22nd pair. It is this chromosome from the 22nd pair with a shortened long arm that is designated as the Ph chromosome.

It has now been established that Ph chromosome- t(9;22)(q34;q11) is found in 95-100% of metaphases in 90-95% of CML patients. In approximately 5% of cases, variant forms of the Ph chromosome are detected. Most often these are complex translocations involving chromosomes 9, 22 and some third chromosome, and sometimes additional 2 or 3 chromosomes. With complex translocations there are always the same molecular changes as with the standard t(9;22)(q34;q11). Standard and variant translocations can be simultaneously detected in the same patient in different metaphases.

Sometimes there is a so-called masked translocation with the same molecular changes as in typical cases, but not determined by conventional cytogenetic methods. This is due to the transfer of smaller chromosome sections than during standard translocation. There are also cases described when t(9; 22) is not detected during a conventional cytogenetic study, but using FISH or RT-PCR (real-time PCR) it is possible to establish that in a typical region of chromosome 22 there is a gene rearrangement that is standard for CML - the formation chimeric gene BCR-ABL. Studies of such cases have shown that sometimes there is a transfer of a region of chromosome 9 to chromosome 22, but there is no translocation of a region of chromosome 22 to chromosome 9.

In the initial period cytogenetic study of chronic myeloid leukemia There were two variants of it: Ph-positive and Ph-negative. Ph-negative CML was first described by S. Krauss et al. in 1964. The authors found Ph-negative CML in almost half of the patients they observed. Subsequently, as research methods improved, the proportion of Ph-negative CML steadily decreased. It is now recognized that true Ph-negative (BCR-ABL-negative) CML does not exist, and previously described observations in most cases were related to BCR-ABL-positive CML, but with a type of chromosomal rearrangement that could not be detected by known at that time using cytogenetic methods.

Thus, received to present time data suggest that in all cases of CML there are changes in chromosomes 9 and 22 with the same rearrangement of genes in a certain region of chromosome 22. In cases where characteristic cytogenetic changes cannot be detected, we are talking about other diseases similar to CML in clinical manifestations (splenomegaly) and blood picture (hyperleukocytosis, neutrophilia). Most often it is chronic myelomonocytic leukemia(CMML), which in the 2001 WHO classification refers to diseases that have both myeloproliferative and myelodysplastic features. In CMML, the number of monocytes in the blood and bone marrow is always increased.

With chronic myeloid leukemia, many patients have translocations involving chromosome 5: t(5;7), t(5;10), t(5;12), in which fusion genes are formed involving the PDGFbR gene located on chromosome 5 (gene for the b-receptor of growth factor produced by platelets, - platelet-derived growth factor receptor b). The protein produced by this gene has a domain with the function of tyrosine kinase, which is activated during translocation, which often causes significant leukocytosis.

In the presence of leukocytosis, neutrophilia and young forms of granulocytes in the blood, dysplasia of all myelopoiesis sprouts, but the absence of monocytosis, the disease, according to the WHO classification, is designated as atypical CML, also considered under the heading of myelodysplastic/myeloproliferative diseases. In 25-40% of cases, this disease, like other forms of myelodysplastic syndromes, ends in acute leukemia. No characteristic cytogenetic changes are detected.

Chronic myeloid leukemia is a process of mutation of pluripotent cells, and further uncontrolled proliferation of granulocytes. According to statistics, myeloid leukemia accounts for 16% of all hemoblastoses in the middle age group of people, as well as 8% for all other age groups. The disease usually manifests itself after 31 years of age, and peak activity occurs at 45 years of age. Children under 12 years of age rarely get sick.

Chronic myeloid leukemia affects men and women equally. It is difficult to recognize the course of the disease, because the process is initially asymptomatic. Myeloid leukemia is often detected on late stages and then the survival rate decreases.

According to ICD-10, the disease is classified: C 92.1 – Chronic myelocytic leukemia.

Causes of chronic myeloid leukemia

The pathogenesis of myeloid leukemia originates in myelosis. As a result of certain factors, a tumor-producing clone of the cell appears, which is able to differentiate into white blood cells, which are responsible for maintaining immunity. This clone actively reproduces in the bone marrow, excluding healthy sprouts hematopoiesis. The blood is saturated with neutrophils in equal quantities with red blood cells. This is where the name comes from – leukemia.

The human spleen should act as a filter for these clones, but due to their large number, the organ cannot cope. The spleen is pathologically enlarged. The process of metastasis formation and spread to neighboring tissues and organs begins. Appears acute leukemia. Damage occurs to liver tissue, heart, kidneys and lungs. Anemia worsens, and the condition of the body leads to death.

Experts have found that CML is formed under the influence of the following factors:

• Exposure to radiation.
• Viruses.
• Electromagnetic fields.
• Chemical substances.
• Heredity.
• Taking cytostatics.

Stages of pathology development

It is customary to distinguish three main stages of the disease:

1. Initial – due to a slight growth of the spleen, as well as an increase in leukocytes in the blood. At this stage, patients are monitored without prescribing specific treatment.
2. Expanded – dominate Clinical signs. The patient is prescribed specialized medications. Myeloid tissue, located in the myelosis and spleen, increases. Rarely does the lesion affect lymphatic system. There is a proliferation of connective tissue in the bone marrow. Severe infiltration of the liver. The spleen becomes denser. When palpated, intense pain occurs. After a splenic infarction, friction sounds of the peritoneum against the affected area are heard. Possible increase in temperature. High probability of damage to neighboring organs: stomach ulcer, pleurisy, eye hemorrhage or pneumonia. A huge amount of uric acid, formed during the breakdown of neutrophils, contributes to the formation of stones in the urinary canals.
3. Terminal – platelet levels decrease and anemia develops. Complications appear in the form of infections and bleeding. Leukemoid infiltration causes damage to the heart, kidneys and lungs. The spleen occupies most of the abdominal cavity. Dense, painless, raised areas appear on the skin. pink spots. This is what a tumor infiltrate looks like. Lymph nodes enlarge due to the formation of sarcoma-type tumors in them. Sarcoid type tumors can appear and develop in any human organ or even bone. Signs of subcutaneous hemorrhage appear. A high content of leukocytes provokes the development of hyperleukocytosis syndrome, in which the central nervous system is damaged. Also observed mental disorders and blurred vision due to swelling of the optic nerve.

A blast crisis is an acute deterioration of myeloid leukemia. The condition of the patients is serious. They spend most of their time in bed, unable to even roll over. Patients are severely malnourished and may suffer from severe pain in the bones. The skin acquires a bluish tint. Lymph nodes are stony and enlarged. The abdominal organs, liver and spleen, reach their maximum size. Severe infiltration affects all organs, causing failure, leading to death.

Symptoms of the disease

The chronic period lasts on average up to 3 years, in isolated cases – 10 years. During this time, the patient may not suspect the presence of the disease. Rarely pay attention to unobtrusive symptoms, such as fatigue, decreased ability to work, feeling full belly. On examination, an increase in the size of the spleen is revealed and increased level granulocytes.

In the early stages of CML, a decrease in hemoglobin in the blood may be observed. Normochromic anemia appears. In chronic myeloid leukemia, the liver enlarges, as does the spleen. Enlargement of red blood cells occurs. In the absence of medical control, the disease accelerates its development. The transition to a deterioration phase may be indicated either by tests or general state patient. Patients quickly get tired, suffer from frequent dizziness, and bleeding becomes more frequent, which is difficult to stop.

Treatment in later stages does not reduce the level of leukocytes. The appearance of blast cells is observed, and their functions change (a characteristic phenomenon for a malignant tumor). In patients with CML, appetite is reduced or completely absent.

Diagnostic measures

The specialist conducts a thorough examination of the patient and records anamnesis in the medical history. Next, the doctor prescribes clinical tests and other blood tests. The first indicator is an increase in granulocytes. For a more accurate diagnosis, a small amount of bone marrow is collected and histology studies are performed.

The final point in the diagnosis is determined by a reverse transcription polymerase chain reaction test for the presence of the Philadelphia chromosome.

Chronic myeloid leukemia can be confused with diffuse myelosclerosis. For an accurate determination, an X-ray examination is performed to determine the presence or absence of areas of sclerosis on flat bones.

How is myeloid leukemia treated?

Treatment of chronic myeloid leukemia is carried out in the following ways:

• Bone marrow transplantation.
• Irradiation.
• Chemotherapy.
• Resection of the spleen.
• Removing leukocytes from the blood.

Chemotherapy is carried out with such drugs as: Sprycel, Myelosana, Gleevec, etc. The most effective method considered a bone marrow transplant. After the transplant procedure, the patient must remain in the hospital under the supervision of doctors, because Such an operation destroys the entire human immune system. After some time, complete recovery occurs.

Chemotherapy is often supplemented with radiation if it does not have the desired effect. Gamma radiation affects the area where the diseased spleen is located. These rays prevent the growth of abnormally developing cells.

If it is impossible to restore the function of the spleen, it is resected during the blast crisis. After surgery, the overall development of pathology slows down, and drug treatment increases effectiveness.

The leukapheresis procedure is carried out at the highest possible level of leukocytes. The procedure is similar to plasmapheresis. Using a special device, all leukocytes are removed from the blood.

Life expectancy with chronic myeloid leukemia

The majority of patients die in the second or third stage of the disease. Approximately 8-12% die after diagnosis of chronic myeloid leukemia in the first year. After the final stage, survival is 5-7 months. In case of a positive outcome after the terminal stage, the patient can survive for about a year.

According to statistics, the average life expectancy of patients with CML in the absence of the necessary treatment is 2-4 years. The use of cytostatics in treatment prolongs life to 4-6 years. Bone marrow transplantation prolongs life much more than other treatments.

Myeloid leukemia is not an independent disease, but refers to a condition characterized by increased and uncontrolled growth of myeloid lineage cells in the red bone marrow and their accumulation in the bloodstream.

Leukemia is also popularly called blood cancer, but the term is not correct. Nosologically, it is customary to distinguish two diseases associated with this condition - chronic (CML) and acute myeloid leukemia (AML).

In AML, massive division of myelopoiesis precursor cells (blasts) occurs, which cannot differentiate into mature ones. According to WHO statistics, AML accounts for about 80% of all other types of leukemia. According to surveillance data, the disease most often affects patients under 15 and after 60 years of age. In terms of gender, AML is less common in women.

Unlike AML, in CML malignant cells retain the ability to differentiate into mature forms. About 15% of all cases of leukemia are CML. The annual incidence is approximately 1.6 per 100,000 population. Most often, the disease affects patients in the age group 20-50 years. In gender ratio, men get sick more often than women, approximately 1.5:1.

Classification

In addition to the classical ICD, there are several classifications that allow you to obtain an accurate description of the pathological process. For acute myeloid leukemia, the most relevant is the French-American-British (FAB) classification, based on the type and maturity of the cells from which leukemia develops.

According to the hematological classification, chronic myeloid leukemia has about 5 main subtypes.

According to the International Classification of Diseases, 10th revision (ICD-10), each subtype of the disease should be assigned a specific code:

C92.0 – Acute myeloid leukemia.

C92.1 – Chronic myeloblastic leukemia.

C92.2 – Atypical chronic myeloid leukemia.

C92.4 – Acute promyelocytic leukemia.

C92.5 – Acute myelomonocytic leukemia.

C92.7 – Other myeloblastic leukemia.

C92.9 – Myeloblastic leukemia, unspecified.

C93.1 – Chronic myelomonocytic leukemia.

Causes and risk factors for developing AML

Acute myeloid leukemia is caused by damage to the DNA of developing cells of the myeloid lineage of the bone marrow, which subsequently provokes abnormal production of blood components. In AML, the bone marrow produces immature cells called myeloblasts. These abnormal cells cannot function properly and, when dividing and growing excessively, begin to crowd out healthy bone marrow elements.

In most cases, it is unclear what causes the DNA mutation, but several factors have been found to contribute to the development of AML, including antecedent hematological disorders, hereditary causes, environmental exposure and drug influence. However, most patients with new-onset AML do not have an identifiable cause for their disease.

Antecedent hematological disorders. The most common cause of development is myelodysplastic syndrome (MDS). It is a bone marrow disease of unknown etiology that most often occurs in older patients and presents with progressive cytopenia over months or years. There are also gradations of risk in patients with this syndrome. For example, patients with refractory anemia with ringed sideroblasts have a significantly lower risk of developing AML than patients with MDS with increased amount blast cells.

Congenital disorders. TO congenital diseases Predisposing patients to the development of AML include Bloom's syndrome, Down's syndrome, congenital neutropenia, Fanconi anemia and neurofibromatosis. Typically, these patients develop acute myeloid leukemia from childhood, but can also appear in adulthood.

In clinical studies, it was noted that the risk of spreading AML increases significantly with regular exposure to benzene. This chemical is used as a solvent in various industries (chemical and oil refineries, as well as in the production of rubber and footwear). Benzene is found in glue, cleaning products, paints and cigarette smoke. Exposure to formaldehyde is also associated with AML, but the exact impact is not yet known.

Chemotherapy. Patients who have previously undergone chemotherapy are more likely to develop AML. Some drugs are closely associated with the development of secondary leukemia (Mechlorethamine, Procarbazine, Chlorambucil, Melphalan, Etoposide, Teniposide and Cyclophosphamide).

The risk increases if the patient receives radiation therapy at the same time as taking these chemotherapy drugs. Secondary leukemias occur approximately 10 years after treatment for Hodgkin's disease, non-Hodgkin's lymphoma, or childhood acute lymphocytic leukemia. Secondary leukemias can also occur after treatment for breast, ovarian, or other cancers.

Exposure to radiation. Influence high level exposure is known factor risk of AML, as well as acute lymphoblastic leukemia. This was first noted among Japanese survivors of the nuclear bombing of Hiroshima and Nagasaki. Within 6-8 years after the tragic events, many Japanese people showed signs of acute myeloid leukemia.

Adverse radiation exposure can be observed during radiation therapy for cancer treatment, as well as with some types of diagnostic studies(radiography, fluoroscopy, computed tomography).

The causes are unknown, but it has been noted that men suffer from AML more often than women. Also, the disease is more common in people of the Caucasian race. Unproven risk factors include living in an area with high electromagnetic radiation, exposure to pesticides, bleaches and hair dyes.

Causes and risk factors for developing CML

U healthy person The cells of the body contain 23 pairs of chromosomes in their nucleus. In people suffering from CML, a disorder in the structure of chromosomes occurs in the bone marrow cells, which consists of moving a section from the 22nd chromosome to the 9th. The ultra-short 22nd chromosome, also called the Philadelphia chromosome (after the city where it was first discovered), is present in the blood of 90% of people suffering from CML.

Against the background of these chromosomal changes, new genes are formed that begin to overproduce the enzyme tyrosine kinase. Subsequently, a large amount of tyrosine kinase leads to abnormal division of bone marrow cells, which contributes to the development of chronic myeloid leukemia. Abnormal white blood cells do not develop or die as normal, but they divide in large numbers, crowd out healthy blood cells, and damage bone marrow.

The exact causes of AML have not yet been elucidated. It is now generally accepted that acute myeloid leukemia develops against the background of the accumulation of mutations in the precursor cells of myelopoiesis. With some exceptions, factors that increase the risk of developing CML are similar to AML.

Weakened immunity. Clinical researches showed that people suffering from immunosuppression, such as AIDS, are 3 times more likely to develop CML compared to the general population. The adverse effects of cytostatic drugs have also been noted in people forced to take them after organ transplantation. In this case, the risk increases by 2 times.

The reasons are not fully understood, but after statistical analysis it turned out that patients with inflammatory diseases intestinal diseases, such as ulcerative colitis or Crohn's disease, have a higher chance of developing CML compared to the general population.

Pesticides. A number of studies have provided evidence that men exposed to pesticides on a daily basis (farmers, agricultural workers) have an increased risk of developing chronic myeloid leukemia. When compared to the general population, the risk increases by approximately 40%.

Gender, age and other risk factors. As with AML, CML is more likely to affect Caucasian men. There were 4 studies that noted the adverse effects of obesity. Excess weight increases the likelihood of getting sick by about 25%.

Symptoms

Most clinical manifestations and signs of myeloid leukemia, both acute and chronic, are associated with the displacement of healthy bone marrow sprouts by abnormal cells. For this reason, 4 main syndromes are distinguished during the course of diseases:

• Anemic. A decrease in the number of red blood cells causes fatigue, increased heart rate, pallor and shortness of breath.
• Immunodeficient. The lack of normal white blood cell production makes patients more susceptible to infection because the abnormal cells lack the mechanisms to promote a full immune response.
• Intoxicating. Early signs myeloid leukemia are often nonspecific and may be similar to flu or other symptoms colds. Common symptoms include: fever, fatigue, weight loss, loss of appetite, shortness of breath, anemia, petechiae (spots on the skin caused by bleeding), bone and joint pain.
• Hemorrhagic. Decreased platelet synthesis leads to mild bruising or bleeding with minor injury.

In addition, with CML, in more than 50% of cases, an enlarged spleen is observed. It can reach such large sizes that it begins to compress the abdominal organs. An enlarged spleen sometimes accompanies AML, but usually the process is slow and painless.

Due to leukocyte infiltration, some patients experience swelling of the gums. In rare cases, the primary symptom of AML is the formation of a dense leukemic mass or tumor (chloroma) outside the bone marrow. Very rarely, AML causes enlarged lymph nodes and paraneoplastic inflammation of the skin.

Stages

Current separation chronic lymphocytic leukemia by phase allows doctors to more competently plan treatment and predict the outcome of the disease.

Chronic phase	Blood and bone marrow contain less than 10% blast cells. The phase can last for several years, but without adequate treatment the disease will progress and move on to the next stages of development. Approximately 90% of patients with CML are diagnosed in the chronic phase. Clinical manifestations may be present. They are usually expressed in the form general weakness and slight weight loss, the abdomen may increase due to splenomegaly.
Acceleration phase	A unified definition for this phase has not yet been developed, but the main criterion for the transition is considered to be an increase in the number of blasts from 10 to 19% or more than 20% of basophils in the peripheral blood. Basophils sometimes contain cytogenetic changes in addition to the Philadelphia chromosome.
Blast crisis	Its course resembles acute myeloid leukemia. In this phase, the number of blasts containing additional genetic changes increases to 20 percent or more. In 25% of cases, blasts may appear as immature cells in acute lymphocytic leukemia or acute myeloid leukemia. Clinical manifestations in this phase are expressed in the form of fever, enlarged spleen and weight loss.

Standards have not yet been developed for determining the staging of acute myeloid leukemia, but it is customary to distinguish 3 key phases based on general flow diseases.

Newly diagnosed AML	The phase corresponds to newly diagnosed leukemia, which has not been specifically treated before. It is possible that the patient was previously prescribed medications for symptoms of the disease (fever, bleeding), but not to suppress the growth of abnormal cells. At this stage of the course, up to 20% of blast cells are detected.
Remission	The phase means that the patient received appropriate treatment, against the background of which the blood test returned to normal. The main criterion for remission is the presence of less than 5% of blast cells in the aspirate and their absence in the peripheral blood and cerebrospinal fluid.
Relapse	Clinical manifestations and pathological changes in peripheral blood and aspirate returned after treatment.

The most common types of myeloid leukemia

About 25% of all cases of AML are due to maturing acute myeloblastic leukemia (M2). The subtype is characterized by the movement of part of the 8th chromosome to the 21st. On both sides of the splice, a new set of DNA is formed from fragments that previously encoded the RUNX1 and ETO proteins. Then these two sequences are connected and begin to encode one big squirrel called M2 AML, which allows the cell to divide unhindered.

The most common type of CML is chronic granulocytic leukemia. That is, any pathological factor that provokes changes in the chromosome set affects blast cells, from which granulocytes are then formed. This form of CML occurs in approximately 95% of cases.

Diagnostics

Several tests may be ordered to confirm the diagnosis of leukemia. Diagnostics also allows you to determine the type of disease and, based on the data obtained, select best method treatment. The basis of the diagnostic process when confirming the diagnosis of acute or chronic myeloid leukemia is laboratory research methods.

Complete blood count (CBC). In most patients, a preliminary diagnosis of myeloid leukemia is made after OAC. The essence of the test is to count blood cells (erythrocytes, leukocytes, platelets). OAC is often carried out as part of a regular medical examination. People suffering from CML will have a marked increase in white blood cell counts (usually due to granulocytes) associated with thrombocytosis and basophilia. In addition, elements of immature leukopoiesis are observed in the blood formula. When other bone marrow sprouts are suppressed, the number of red blood cells decreases in patients. Due to the increase total number Leukocyte leukemia is also sometimes called leukemia.

Aspiration and biopsy. No specific tumor markers have been found to identify myeloid leukemia, so in most cases they are diagnosed by a combination of biopsy and aspiration. This is the only sure way to confirm the diagnosis. An aspiration is a procedure that uses a thin needle to remove the liquid part of the bone marrow, while a biopsy takes a sample of the solid part. These 2 procedures are very similar and are often performed simultaneously to obtain more accurate information about the condition of the bone marrow.

A typical site for aspiration and biopsy is the iliac crest of the pelvis. After the pick up biological material a specialist in the field of pathological anatomy conducts a detailed examination of the obtained samples. One of the main criteria indicating AML in a patient is the presence of more than 20% blasts in the blood and aspirate.

The test involves testing leukemia cells for certain genes, proteins and other factors that indicate they are malignant. Based on this study, individualized targeted therapy may be developed in the future.

Genetic research. Allows you to determine the genotype of AML and select the optimal treatment option for the patient. In addition, the test results can be used in the future to monitor the treatment process.

Cytogenetic study. A type of genetic testing that is used to analyze a cell's chromosomes. Sometimes this test can be done on peripheral blood cells, but tissue samples obtained from the bone marrow are needed to make an accurate diagnosis.

After treatment for CML is initiated, cytogenetic and/or molecular testing is repeated on a different bone marrow sample to re-enumerate the number of cells containing the Philadelphia chromosome and evaluate the effectiveness of chemotherapy.

For most patients, the presence of the Philadelphia chromosome and the BCR-ABL hybrid gene is the main marker indicating the presence of CML. In a small number of patients, the Philadelphia chromosome is not detected by conventional tests, even despite the presence of the BCR-ABL hybrid gene and an increase in the number of blood cells. However, the treatment tactics in this case will be the same as in patients with a detectable Philadelphia chromosome.

Imaging research methods. They are prescribed to evaluate the effect of leukemia on other parts of the body. For example, computed tomography and ultrasonography sometimes used to view and measure the size of the spleen in patients with leukemia.

How fast is it developing?

No specific techniques have been developed to predict the duration of the chronic phase and the onset of blast crisis in CML. However, it is generally accepted that unfavorable factors sharp increase leukocyte level, hepatosplenomegaly, increased percentage of blasts in the red bone marrow. The same applies to AML.

Features of the course and treatment in special categories of patients

The course of the disease does not differ much depending on age and gender. The only factors that need to be taken into account are the weight and age of the patients, as these characteristics affect the dosage of the drugs.

Pregnancy. During pregnancy, the diagnosis of myeloblastic leukemia is very rare, approximately 1 in 300,000 cases. Moreover, if timely treatment is not started, there is a high probability of spontaneous abortion. In addition, an increased level of blast cells in the blood can cause intrauterine growth retardation, provoke premature birth or lead to intrauterine fetal death.

Despite the presence of a hematoplacental barrier that protects the fetus from the effects of chemotherapy, early stages termination of pregnancy may be recommended. If the diagnosis was made in the 2-3rd trimester, then, as a rule, the rest of the pregnancy is completed under the guise of chemotherapy. In addition, breastfeeding must be stopped during chemotherapy courses.

Treatment

When treating myeloid leukemia, the creation of optimal therapeutic tactics requires the cooperation of several specialists. It is especially important that the patient is under the supervision of an oncologist and/or hematologist.

Treatment options depend on several factors, including the phase of the disease, expected side effects, patient preference, and overall health.

Targeted therapy. This is a type of treatment that specifically affects the genes of malignant cells, their proteins and the tissue environment that promotes the growth and survival of leukemia. Targeted therapy blocks the growth and spread of malignant cells while limiting damage to healthy tissue.

The prescription of targeted drugs for AML directly depends on the specificity of the mutations that have arisen in malignant cells. For example, Midostaurin (Rydapt) is indicated for patients with a mutation of the FLT3 gene (25-30% of cases). Enasidenib (IDHIFA) is recommended for people with relapsed or refractory IDH2-mutated AML.

In CML, the target for the active substances is the enzyme tyrosine kinase BCR-ABL. There are 5 main drugs called tyrosine kinase inhibitors (TKIs): Imatinib (Gleevec), Dasatinib (Sprycel), Nilotinib (Tasigna), Bosutinib (Bosulif), and Pontinib (Iclusig). All 5 drugs can stop the BCR-ABL enzyme from working, which causes CML cells to die quickly.

It is important to note that men and women should avoid conceiving while taking TKIs. Otherwise, there is a high risk of spontaneous abortion, intrauterine fetal death, or the birth of a child with severe malformations. In addition, patients may develop idiopathic myelofibrosis as a side effect of CML therapy.

Chemotherapy. Drugs from this group are prescribed to destroy malignant cells by suppressing their ability to grow and divide. The form of drug administration can be in the form of intravenous, subcutaneous injection or in the form of tablets. A chemotherapy regimen usually consists of a specific number of cycles given over a given period of time. The patient can take 1 drug or several at the same time.

This is the main treatment for AML. Due to the frequent development of complications healing process It is quite difficult, so chemotherapy courses must be carried out in specialized hospitals. In the treatment of patients, it is customary to distinguish 4 phases:

1. Induction of remission.
2. Consolidation.
3. Intensification.
4. Maintenance therapy (2-5 years).

The most commonly used combination is Cytarabine (Cytosar-U) and an anthracycline drug such as Daunorubicin (Cerubidine) or Idarubicin (idamycin). Some older people cannot take these drugs, and Decitabine (Dacogen), Azacitidine (Vidaza), and/or low-dose Cytarabine may be used instead.

As a rule, 2-5 courses of chemotherapy are necessary to achieve remission, after which the patient enters the consolidation phase and is prescribed several more procedures. Maintenance therapy begins approximately a week after the end of the consolidation period. If modern protocols are followed, stable remission can be achieved in 60%, and recovery in 30% of patients.

As a rule, for CML, hydroxyurea drugs (Droxia, Hydrea) are prescribed, which effectively reduce the number of white blood cells. Chemotherapy can return blood counts to normal within a few days or weeks while reducing the size of the spleen. However, hydroxyurea preparations do not reduce the content of cells with the Philadelphia chromosome and do not have such a pronounced effect in the blast crisis phase. Although hydroxyurea has relatively few side effects, most patients with newly diagnosed CML are recommended to take Imatinib or another TKI. This means that patients do not need hydroxyurea or only use it for a short period.

Stem cell/bone marrow transplantation. This medical manipulation, in which the patient's diseased bone marrow is replaced with hematopoietic stem cells from a healthy donor. The method is considered the most effective way to treat both types of leukemia. There are 2 types of stem cell transplant:

• allogeneic – transplantation from a compatible donor (usually a relative);
• autologous – transplantation of one’s own bone marrow.

The success of transplantation is influenced by the phase of the disease, the results of previous treatment, the patient's age and general condition. Although transplantation is the only method that can guarantee complete recovery in CML, due to the high risk of side effects, it is used less frequently than TKIs.

Immunotherapy. The method enhances the body's natural defense mechanisms to activate them to fight myeloid leukemia. Immunotherapy involves the use of drugs based on immunocomponents produced in laboratory or natural conditions. Interferon (Alferon, Infergen, Intron A, Roferon-A) is an effective group of drugs that can reduce the number of white blood cells, and in some cases even reduce the number of cells containing the Philadelphia chromosome.

Before Imatinib became available, interferon therapy was the mainstay of treatment for chronic phase CML. Currently, Interferon is not recommended as a first-line drug because a number of studies have shown that TKIs work better and cause fewer side effects. Moreover, unlike TKIs, Interferon is safe to take during pregnancy.

New treatment methods. Most major hematological and cancer centers is actively involved in clinical trials aimed at increasing the incidence of successful recovery from myeloid leukemia. When consulting with a doctor, it is necessary to clarify the possibility of participating in research projects to receive experimental treatment.

Promising techniques currently being tested include:

• combinations of Imatinib with other drugs;
• development of new schemes for the use of ITC;
• creation of vaccines against BCR-ABL;
• development of new methods of stem cell transplantation aimed at reducing side effects.

Traditional treatment. Myeloid leukemias are very serious illnesses, characterized by high mortality and great difficulties in treatment. For this reason, the use folk remedies will be ineffective or even harmful for the patient. Patients, if desired, can take decoctions made from pumpkin, blueberries or birch buds, but only in addition to the main treatment.

Rehabilitation

The protocols do not provide for a specific rehabilitation program, but to improve the patient’s well-being, courses of physical therapy may be recommended, medicinal baths, oxygen therapy, psychological support and balanced diet. It is important that the patient during rehabilitation period was under the supervision of a specialist who would understand the patient’s condition and be able to eliminate side effects from therapy.

Relapse

In most cases, patients with acute myeloid leukemia develop a relapse after chemotherapy. In such cases, autologous stem cell transplantation is recommended. A number of hematology centers that adhere to this treatment tactic in the second remission or at the beginning of the first relapse achieve patient recovery in 25-50% of cases.

Such high results were achieved because many patients retained their stem cells during the first remission, after which a successful transplant took place. Harvesting stem cells after relapse is not as effective, as less than half of patients receiving chemotherapy will achieve a second remission. The most optimal solution for patients who do not have previously preserved stem cells is allogeneic transplantation.

If the patient does not have the opportunity to undergo a stem cell transplant, then in such cases the main treatment strategy will be to prescribe high-dose chemotherapy.

Resistant flow

Most patients achieve remission (no signs or symptoms) after initial treatment for AML. But in some patients, small areas of mutated cells remain in the body even after a full course of chemotherapy. Over time, the number of damaged cells will increase until they are detected in tests or until symptoms return. This condition is called resistant leukemia.

After completion of treatment, the doctor must provide the patient with personal information about possible risk development of resistant myeloid leukemia.

Complications

Myeloid leukemia has a huge number of complications that develop both during the course of the underlying disease and as a result of taking chemotherapy. However, the greatest concern for doctors, due to the increased risk of death and decreased quality of life, is the following three:

• Because of pathological increase the number of immature blast cells displaces normal blood sprouts, which leads to disruption of the body's immune mechanisms.

• Bleeding. Due to pathological changes in the blood coagulation system, people with AML are more susceptible to sudden internal bleeding.
• Infertility. Many drugs used in the treatment of AML, as side effect cause sterility. As a rule, it is temporary, but in some cases it can be permanent.

Prognosis (life expectancy)

In AML, the prognosis is determined by the type of cells involved in the pathological process, the age of the patient and the adequacy of the treatment provided. Standard modern therapeutic techniques increase survival in adult patients (up to 60 years), but in older patients this figure is much lower.

The life expectancy of patients suffering from CML does not exceed 3.5 years from the date of diagnosis. The blast crisis phase poses a particular danger to life. It accounts for 85% of all deaths due to CML. Timely and appropriate treatment allows the patient to increase survival by an average of 5-6 years from the moment the disease is diagnosed.

Diet

Patients suffering from blood diseases are prescribed table No. 11. The emphasis in nutrition should be on meat, chicken eggs, milk, cheese and kefir. Also, to replenish the loss of vitamins, regular consumption of vegetables and fruits is necessary. The total daily calorie content should reach at least 4500 kcal.

Prevention

There is no specific prevention of myeloid leukemia. We can only advise people at risk to avoid contact with benzene, pesticides and radioactive elements. One of the goals of follow-up after treatment is to regularly check for relapse. Therefore, it is recommended to undergo an annual preventive examination, which necessarily includes a general blood test.

Treatment of myeloid leukemia in Israel

According to statistics on the treatment of acute myeloid leukemia in Israel, in 90% of cases patients achieve stable remission, and more than half of them end in complete recovery.

In Israeli clinics, therapy for hematological diseases is based on advanced medical technologies, a huge practical experience specialists and modern protocols to increase patient survival.

Testing for myeloid leukemia is carried out in hematology departments of clinics or in specialized medical centers. Diagnostics include the following:

• Initial examination of the patient and collection of information about the history of the disease, the dynamics of its development and symptoms.
• Laboratory research methods, including hemogram and biochemical analysis blood. Cytogenetic testing is also performed to identify genetic changes and microscopically evaluate the state of chromosomes in blood cells, bone marrow and lymph nodes.
• A lumbar puncture involves taking bone marrow samples and helps identify the presence of abnormal cells. As a rule, the fence is made from lumbar region under local anesthesia using a special puncture needle.
• Bone marrow biopsy is the main method for diagnosing leukemia. It confirms the diagnosis and determines the type of disease. The doctor collects tissue under local anesthesia, or intravenous sedation can be used if the patient wishes.
• Ultrasonography indicates enlarged lymph nodes in the abdominal area, and also allows you to evaluate the structure and size of the liver, spleen and kidneys.

In addition to this diagnostic standard, the doctor may prescribe additional methods research, and also refer for consultation to other specialists.

Among the modern treatment methods in Israel, the following are used:

• Chemotherapy aimed at suppressing the growth and division of malignant cells. The technique is based on the principles of increasing efficiency and reducing the risk of side effects.
• A method of monoclonal therapy based on the use of special antibodies that selectively attack atypical cells.
• Stem cell transplantation is the most radical method treatment, which in most cases completely eliminates the disease.
• Targeted therapy based on the principle of targeting directly at a malignant cell without damaging healthy tissues of the body.

An individual approach to each patient and the use of the latest technologies are the main principles of treatment used in Israeli clinics. Such tactics can significantly increase the patient’s chances of recovery, as well as improve the prognosis for future quality of life.

Best hospitals in Israel

Medical Center "Herzliya". Experienced hematologists guarantee their patients effective treatment for leukemia. Herzliya Private Hospital is Israel's leading medical institution, providing its patients with first-class medical care and the best standards of treatment that can be found. Treatment of hematological diseases at Herzliya Medical Center is based on the latest scientific developments, which allow you to achieve impressive results at all stages of the disease and meet the most stringent patient safety standards. In a private hospital medical center“Herzliya” has created all the conditions for diagnosis and treatment of any level of complexity.

Specialists offer their patients modern chemotherapy protocols, bone marrow transplantation, as well as other therapeutic techniques that allow them to achieve maximum results in the treatment of leukemia. The main goal of doctors is to improve the survival rate and quality of life of patients. At the Assuta Clinic, patients receive individualized treatment based on genetic information about the type of hematological pathology. The hospital has a group of experts who are constantly testing new ways to combat leukemia. This means that Assuta Hospital patients can participate in clinical trials of new treatment protocols, which is not available in other hospitals.

Until recently, it was generally accepted that chronic myeloid leukemia was a disease that was more common in older men. Now doctors have come to the conclusion that both women and men have an equal chance of becoming victims of this disease. Why does this disease occur, who is at risk, and can it be cured?

Essence of the disease

In the human body, the bone marrow is responsible for the processes of hematopoiesis. Blood cells are produced there - red blood cells, platelets and leukocytes. The hemolymph contains the most leukocytes. They are responsible for immunity. Chronic myeloid leukemia leads to a failure of these processes.

In a person suffering from this type of leukemia, the bone marrow produces pathological leukocytes - oncologists call them blasts. They begin to multiply uncontrollably and leave the bone marrow before they have time to mature. Essentially, these are “immature” leukocytes that cannot perform protective functions.

Gradually they spread through the vessels to all human organs. The content of normal white blood cells in the plasma gradually decreases. The blasts themselves do not die - the liver and spleen cannot destroy them. Due to the lack of leukocytes, the human immune system stops fighting allergens, viruses and other negative factors.

Causes of the disease

In the vast majority of cases, chronic myeloid leukemia is caused by a gene mutation – a chromosomal translocation, which is commonly called the “Philadelphia chromosome”.

Technically, the process can be described as follows: chromosome 22 loses one of the fragments, which fuses with chromosome 9. A fragment of chromosome 9 attaches to chromosome 22. This causes a malfunction of genes, and then the immune system.

Experts say that the occurrence of this type of leukemia is also influenced by:

• exposure to radiation. After the nuclear attack on Hiroshima and Nagasaki, the incidence of CML in residents of Japanese cities increased significantly;
• exposure to certain chemicals - alkenes, alcohols, aldehydes. Smoking has a negative effect on the condition of patients;
• taking certain medications - cytostatics, if cancer patients take them along with undergoing radiation therapy;
• radiotherapy;
• hereditary genetic diseases - Klinefelter syndrome, Down syndrome;
• diseases of viral origin.

Important! CML mainly affects people over 30-40 years of age, and their risk of developing the disease increases with age, up to 80 years of age. It is diagnosed very rarely in children.

There is, on average, one to one and a half cases of this disease per 100 thousand inhabitants of the Earth. In children, this figure is 0.1-0.5 cases per 100 thousand people.

How does the disease progress?

Doctors distinguish three stages of development of chronic myeloid leukemia:

• chronic stage;
• acceleration stage;
• terminal stage.

The first phase usually lasts two to three years and is most often asymptomatic. The manifestation of this disease is atypical and may not differ from a general malaise. The disease is diagnosed accidentally, for example, when a person comes for a general blood test.

The first signs of the disease are general malaise, a feeling of fullness in the abdomen, heaviness in the left hypochondrium, decreased ability to work, low hemoglobin. Upon palpation, the doctor will find an enlarged spleen due to the tumor, and a blood test will reveal an excess of granulocytes and platelets. Men often experience long, painful erections.

The spleen enlarges, the person experiences problems with appetite, quickly becomes full, and feels pain radiating to the back in the left side of the abdominal cavity.

Sometimes in the initial phase the function of platelets is disrupted - their level increases, blood clotting increases. A person develops thrombosis, which is associated with headaches and dizziness. Sometimes the patient experiences shortness of breath with even minimal physical exertion.

The second, accelerated stage occurs when a person’s general condition worsens, symptoms become more pronounced, and laboratory tests record changes in blood composition.

The person loses weight, becomes weak, experiences dizziness and bleeding, and the temperature rises.

The body produces more and more myelocytes and white blood cells, and blasts appear in the bones. The body reacts to this by releasing histamine, so the patient begins to feel fever and itching. He begins to sweat heavily, especially at night.

The duration of the acceleration phase is from one to one and a half years. Sometimes a person begins to feel unwell only in the second stage and goes to the doctor when the disease has already progressed.

The third, terminal phase occurs when the disease enters the acute stage.

A blast crisis occurs in chronic meyloid leukemia, when cells with pathology almost completely replace healthy ones in the organ responsible for hematopoiesis.

The acute form of chronic myeloid leukemia has the following symptoms:

• severe weakness;
• temperature rise to 39-40 degrees;
• a person begins to rapidly lose weight;
• the patient feels joint pain;
• hypohidrosis;
• hemorrhages and bleeding.

Acute myeloid leukemia often leads to splenic infarction - the tumor increases the risk of splenic rupture.

The number of myeloblasts and lymphoblasts is growing. Blasts can turn into malignant tumor– myeloid sarcoma.

Chronic myeloid leukemia at the third stage is incurable, and only palliative therapy will prolong the patient’s life by several months.

How to diagnose the disease?

Since the disease initially has nonspecific symptoms, it is often discovered almost by accident when a person comes, for example, to take a general blood test.

If there is a suspicion of oncology, a hematologist must not only conduct a survey and examine him The lymph nodes, but also palpate the abdomen to see if the spleen is enlarged and if there is a tumor in it. To confirm or refute suspicions, the subject is sent for an ultrasound of the spleen and liver, as well as a genetic study.

Methods for diagnosing chronic myeloid leukemia:

• general and ;
• bone marrow biopsy;
• cytogenetic and cytochemical research;
• Ultrasound of the abdominal organs, MRI, CT.

A general detailed blood test allows you to trace the dynamics of the development of all its components.

At the first stage, it will determine the level of “normal” and “immature” white blood cells, granulocytes and platelets.

The acceleration phase is characterized by an increase in the level of leukocytes, an increase in the proportion of “immature” leukocytes to 19 percent, as well as a change in the level of platelets.

If the proportion of blasts exceeds 20 percent and the platelet count decreases, then the third stage of the disease has arrived.

Biochemical analysis will help determine the presence in the blood of substances that are characteristic of this disease. This is about uric acid, vitamin B12, transcobalamin and others. Biochemistry determines whether there are malfunctions in the functioning of lymphoid organs.

If a person has chronic myeloid leukemia in the blood, the following occurs:

• significant increase;
• the predominance of “immature” forms of leukocytes - blast cells, myelocytes, pro- and metamyelocytes.
• increased content of baso- and eosinophils.

A biopsy is necessary to determine the presence of abnormal cells. The doctor uses a special needle to collect brain tissue (a suitable place for puncture is the femur).

Cytochemical testing allows one to distinguish chronic myeloid leukemia from other types of leukemia. Doctors add reagents to the blood and tissue obtained from a biopsy and see how the blood cells behave.

Ultrasound and MRI give an idea of ​​the size of the abdominal organs. These studies help differentiate the disease from other types of leukemia.

Cytogenetic research helps to find abnormal chromosomes in blood cells. This method allows not only to reliably diagnose the disease, but also to predict its development. To detect an abnormal or “Philadelphia” chromosome, the hybridization method is used.

Treatment of the disease

Treatment of chronic myeloid leukemia has two main goals: to reduce the size of the spleen and to stop the bone marrow from producing abnormal cells.

Hematologic oncologists use four main treatment methods:

1. Radiation therapy;
2. Bone marrow transplantation;
3. Splenectomy (removal of the spleen);
4. Leukapheresis.

Depends on the individual characteristics of the patient’s body, as well as on the severity of the disease and symptoms.

In the early stages of treating leukemia, doctors prescribe drugs to their patients to strengthen the body, vitamins and a balanced diet. A person must also adhere to a work and rest schedule.

In the first stages, if the level of leukocytes increases, doctors often prescribe busulfan to their patients. If this gives results, the patient is transferred to maintenance therapy.

In late phases, doctors use traditional drugs: Cytosar, Myelosan, Dazanitib, or modern drugs like Gleevec and Sprycel. These drugs target the oncogene. Together with them, patients are prescribed interferon. It should strengthen the human immune system.

Carefully! The doctor prescribes the regimen and dosage of medications. The patient is prohibited from doing this on his own.

Chemotherapy usually comes with side effects. Taking medications often leads to digestive upset, causes allergic reactions and convulsions, reduces blood clotting, provokes neuroses and depression, and leads to hair loss.

If the disease is in a progressive phase, hematologists prescribe several drugs at the same time. The duration of intensive chemotherapy depends on how quickly laboratory values ​​return to normal. Typically, a cancer patient must undergo three to four courses of chemotherapy per year.

If taking cytostatics and chemotherapy do not produce results, and the disease continues to progress, the hematologist refers his patient to radiation therapy.

Indications for it are:

• an increase in tumor in the bone marrow;
• enlarged spleen and liver;
• if blasts enter the tubular bones.

The oncologist must determine the regimen and dose of radiation. The rays affect the tumor in the spleen. This stops the growth of oncogenes or completely destroys them. Radiation therapy also helps relieve joint pain.

Irradiation is used at the accelerated stage of the disease.

Bone marrow transplantation is one of the most effective ways treatment. It guarantees long-term remission for 70 percent of patients.

Bone marrow transplantation is a fairly expensive treatment method. It consists of several stages:

1. Donor selection. The ideal option is when a close relative of a cancer patient becomes a donor. If he does not have brothers and sisters, then he has to be looked for in special databases. This is quite difficult to do, since the chances that foreign elements will take root in the patient’s body are less than if a family member became the donor. Sometimes it becomes the patient himself. Doctors can transplant peripheral cells into his bone marrow. The only risk is associated with the high probability that blasts will get there along with healthy leukocytes.
2. Preparing the patient. Before surgery, the patient must undergo chemotherapy and radiation. This will kill a significant portion of the pathological cells and increase the chances that the donor cells will take root in the body.
3. Transplantation. Donor cells are injected into a vein using a special catheter. They first move through the vascular system, then begin to act in the bone marrow. After transplantation, the doctor prescribes antiviral and anti-inflammatory drugs so that the donor material is not rejected.
4. Working with the immune system. It is not immediately possible to understand whether donor cells have taken root in the body. Two to four weeks should pass after the transplant. Since the person’s immunity is at zero, he is ordered to stay in the hospital. He receives antibiotics and is protected from contact with infectious agents. At this stage, the patient’s body temperature rises, and chronic diseases may worsen.
5. Post-transplantation period. When it is clear that foreign leukocytes have been accepted bone marrow, the patient's condition improves. On full recovery it takes several months and even years. All this time, a person must be observed by an oncologist and receive vaccinations, since he the immune system will not be able to cope with many diseases. A special vaccine has been developed for people with weakened immune systems.

Transplantation is usually performed in the first stage.

Removal of the spleen, or splenectomy, is used in the terminal stage if:

• there has been an infarction of the spleen, or there is a threat of rupture;
• if the organ has enlarged so much that it interferes with the functioning of neighboring abdominal organs.

What is leukapheresis? Leukocytopheresis is a procedure aimed at clearing pathological leukocytes. A certain amount of the patient's blood is forced through a special machine, where cancer cells are removed from it.

This treatment usually complements chemotherapy. Leukapheresis is performed when the disease progresses.

Survival Projections

The healing of a cancer patient and his life expectancy depend on several factors.

The likelihood of recovery depends on the stage at which chronic myeloid leukemia was diagnosed. The sooner this is done, the better.

The chances of healing are reduced if the abdominal organs are seriously enlarged and protrude from under the edges of the costal arch.

Negative signs include leukocytosis, thrombocytopenia, and an increase in the content of blast cells.

The more manifestations and symptoms a patient has, the less favorable the prognosis will be.

With timely intervention, remission occurs in 70 percent of cases. After healing, the chances are high that the patient will live for several more decades.

Death most often occurs in the accelerated and terminal stages; about seven percent of patients with chronic myeloid leukemia die in the first year after they were diagnosed with CML. The causes of death are severe bleeding and infectious complications due to weakened immunity.

Palliative therapy at the last stage after blast crisis prolongs the patient’s life, at most, by six months. The life expectancy of a cancer patient is calculated in a year if remission occurs after a blast crisis.

In July of this year, the Office of Sanitary Supervision of Quality food products and the US Drug Administration (FDA) for the first time in the history of domestic pharmaceuticals assigned orphan status to a Russian experimental drug. It was a drug for the treatment of chronic myeloid leukemia. MedAboutMe figured out what kind of disease this is and whether there are chances to get rid of it completely, for example, with the help of a new remedy created by our scientists.

CML: history of discovery

The history of the discovery of chronic myeloid leukemia (CML) and its treatment is closely connected with the history of science and medicine. Doctors' acquaintance with CML began in 1811, when Peter Kallen described a patient with acute inflammation spleen and “milk blood”. In 1845, when microscopes were already available and methods for staining cells had not yet been invented, Scottish pathologist John Bennett described in his articles tissues of an enlarged spleen and liver obtained from two patients who died “of blood poisoning.” In particular, Bennett presented images of leukocythemia - unusual blood cells. And literally 1.5 months later, a similar picture was published by another pathologist - the German Rudolf Virchow. And he was the first to suggest that the issue was not sepsis, but a previously unknown disease. Another 2 years later, Virchow discovered a similar case and for the first time announced the name of the alleged disease - “splenic leukemia.” So CML is the first disease called "leukemia".

It should be noted that the medical community reacted negatively to Virchow’s reports. One of his colleagues even said: “We already have enough diseases, we don’t need new ones!” But history took its course. In 1846, a detailed description of the disease was published, made not by a pathologist, but by a doctor who treated a still living person. And since 1880, with the advent of methods for staining cells for microscopic examination, scientists have been able not only to examine CML cells in detail, but also to identify different forms of “leukemia.”

In the 1950s, American researchers P. Nowell and D. Hungerford discovered that all patients with CML had one of their chromosomes shortened. Moreover, the data they obtained indicated the clonal nature of the disease, that is, it developed from a single cell that received additional growth advantages due to mutation. This ultimately led to an increase in the clone of diseased cells. After the name of the city in which this discovery was made, the shortened chromosome became known as the “Philadelphia” chromosome (Ph+). But later it turned out that it was not just a matter of a shortened chromosome...

What is chronic myeloid leukemia?

Today it is known that chronic myeloid leukemia develops as a result of translocation - the exchange of sections between the 9th and 22nd chromosomes. That is, the 9th chromosome loses a piece, and the 22nd attaches it to itself. The main problem is that during transfer this section of DNA is inserted into the area where the ABL oncogene is located. In humans, this gene encodes a protein necessary for hematopoiesis, and its separate domain plays the role of a tyrosine kinase enzyme and triggers the processes of cell proliferation (their active reproduction). Another domain is designed to stop tyrosine kinase activity. When a section is moved from the 9th chromosome, a new gene BCR-ABL is formed - this is a marker of chronic myeloid leukemia. The protein that is supposed to block tyrosine kinase function no longer works. Proliferation is launched “to the fullest” and, in addition, apoptosis (the programmed death of old and damaged cells) is canceled.

Stem cells with a translocation from chromosome 9 to 22 are called Ph-positive. Patients with CML have both Ph-positive and Ph-negative cells. And the former, due to their uncontrolled activity, are crowding out the latter.

How does CML manifest?

To describe chronic myeloid leukemia, they do not use a list of symptoms - it is too extensive, but a list of syndromes, that is, symptom complexes. Accordingly, they distinguish:

Tumor intoxication syndrome.

The patient is anemic, feels weak, sweating, pain in joints and bones, and constant itching. The person loses weight, his appetite worsens, and he has a low-grade fever.

Tumor proliferation syndrome (that is, uncontrolled proliferation of cells and their transformation into tumor cells).

An enlarged spleen leads to pain in the left side. The liver is often also enlarged.

Anemic syndrome.

Weakness, constant shortness of breath, tachycardia, decreased arterial pressure, exercise intolerance, pallor of the mucous membranes and skin. Against this background, existing cardiovascular diseases may become more active.

Hemorrhagic syndrome.

It develops against the background of platelet deficiency (thrombocytopenia) and manifests itself in the form of bleeding even with minor injuries, rashes in the form of petechiae (small pinpoint bruises) and bruises.

Thrombotic manifestations.

The risk of developing thromboembolism of organs and tissues and thrombosis increases significantly.

Three phases of the disease

There are three main phases during CML:

Chronic phase - it is diagnosed in 80% of patients; this is the initial phase of the disease. Acceleration phase - at this stage, 8-10% of patients are identified, the pathological process is in full swing. Blast crisis - only 1-2% see doctors for the first time at this stage. The disease in this phase is most aggressive.

The life span of patients in whom the disease was detected in the acceleration phase and at the blast crisis stage is short - 6-12 months.

Who has CML?

This is a rare disease. It occurs with a frequency of 1.4-1.6 cases per 100 thousand adults. It is mainly adults who suffer from chronic myeloid leukemia: this disease accounts for 20% of all leukemia among them and only 2% in children. More often, the disease first appears in patients aged 40-50 years.

Men get sick slightly more often than women, the ratio is 1.4:1.

In our country, there are 8 thousand people diagnosed with chronic myeloid leukemia. The incidence is 0.08 cases per 100 thousand Russians.

Treatment of CML: from arsenic to modern chemotherapy CML and arsenic

Since 1865, they began to try to treat the new disease. Arsenic was especially loved by doctors in the mid-to-late 19th century. It was used in the form of a “Fowler’s solution,” which was a 1% aqueous-alcohol solution of potassium arsenite. In order not to confuse the drug with water, it was flavored with lavender. This remedy was invented back in the 13th century by Thomas Fowler, and it was used to treat almost everything that could not be treated in other ways: asthma, syphilis, eczema, epilepsy, rheumatism... It is not surprising that it was decided to try the arsenic panacea against newly discovered leukemia.

And in general, a certain effect was achieved. The spleen became smaller, the patients felt better. True, not for long - the life of a person with CML after diagnosis, even with treatment, did not exceed 2-3 years.

Radiation therapy for CML In 1895, science discovered a powerful tool for diagnosis and therapy - x-rays. For this discovery, K. Roentgen received the Nobel Prize in Physics, but doctors quickly figured out how to use x-ray radiation for treating patients. The American N. Senn first used radiation therapy for the treatment of CML in 1903. The spleen treated with X-rays actually became smaller, the number of leukocytes decreased - it seemed that a solution had been found. But, alas, over time it turned out that the effect of radiation therapy lasts about six months, and with each subsequent time it becomes weaker and shorter.

And yet, in the absence of other means, X-ray therapy remained the only method for treating patients with CML almost until the middle of the 20th century. The disease was brought into remission, which lasted about six months, and on average such a patient lived 3-3.5 years. Only 15% of patients managed to survive 5 years.

Chemotherapy for CML The era of chemotherapy for CML was opened by the Englishman D. Galton. He was the first to use myelosan, synthesized in 1953 by his compatriots, to fight the disease. This drug has many names: Americans call it busulfan, the French call it mizulban, the British call it mileran, and myelosan is the common name in Russia.

The new medicine seemed like a miracle. It was well tolerated and showed high efficacy, even in people who did not respond to radiation therapy. The drug made it possible to keep the level of leukocytes under control and prevented the spleen from growing. Patients with CML stopped becoming disabled already in the first year of the disease - instead of hospitals, they were able to live at home and lead a full life. And its duration also increased and amounted to 3.5-4.5 years. 30-40% of patients survived to 5 years. The reason for this was the absence of severe side effects characteristic of x-ray therapy: anemia, cachexia (exhaustion), infections.

Myelosan extended life, patients began to live longer and, therefore, more patients began to survive to the blast crisis phase and the terminal stage of the disease. The death of such patients was not easy. Fluctuations in temperature, alternating with attacks of chills, cachexia, rapid enlargement of the spleen and liver, weakness and, most importantly, severe pain. A dispute even arose: should myelosan not be considered the cause of the development of blast crisis? After all, such a number of cases were not observed with radiotherapy. But in 1959, a study was conducted in which it was proven that after 3 years from its start, 62% of patients treated with myelosan remained alive, and only a third of the group treated with x-rays. Overall, life expectancy with myelosan was one year longer than with radiation therapy. This study was the final point in making the decision to almost completely abandon radiotherapy as the main method of treating CML.

Scientists continued to search for a cure. The effectiveness of the use of hydroxyurea, which blocked the enzyme ribonucleotidase involved in DNA synthesis, has been proven. And this substance extended the life of patients with CML by another 10 months.

And in 1957, medicine received interferons at its disposal - and a new stage began in the treatment of CML. With their help, in just a couple of months it was possible to put the patient into remission, and in some patients the number of Ph-positive cells decreased.

By combining interferons with other drugs, it was possible to achieve that from 27% to 53% of patients had every chance of living 10 years from the moment of diagnosis, and in groups where the disease was detected at very early stages, they could expect 10 years of life from 70 % to 89% of patients.

The main thing that did not suit doctors and scientists about interferons was that it was still not a method of treating CML. It was not possible to completely get rid of Ph-positive cells even with their help.

Stem cell transplant

At the end of the last century, the method of transplantation of geopoietic stem cells began to gain popularity. We were already talking about 10- and even 20-year survival rates - and these were quite realistic figures for a third of patients treated with this method. But, firstly, this method did not cure the patient completely. And secondly, only 20-25% of people with chronic myeloid leukemia have a chance of finding a compatible related donor. If we are talking about an unrelated donor, the likelihood of finding him is much lower. That is, initially not all patients can be treated with this method.

Tyrosine kinase inhibitors

Finally, scientists managed to find weakness in illness. A real victory over CML was imatinib (Gleevec) - this substance is built into the “pocket” of the ABL-tyrosine kinase protein and blocks its work. The effectiveness of the new drug was so high that the FDA quickly registered it and gave the go-ahead for use. The results of treatment with imatinib were significantly better than with any other treatment.

But there is no perfection in the world. It turned out that over time, many patients develop resistance to this medicine, and increasing the dose is too toxic for the body.

In the course of intensive pharmaceutical research, second generation tyrosine kinase inhibitors were created - nilotinib (Tasigna) and dasatinib (Sprycel). Today they are prescribed if there is a risk that imatinib therapy may stop working. Often such drugs are combined with interferons and other drugs that enhance the effect. And today it is the best working medicine that medicine has for patients with CML. Thanks to them, 80% of patients live for at least 10 years, and in a third of cases they die not from CML, but from other diseases.

In Russia, patients within the framework of the “7 nosologies” program receive imatinib free of charge (the cost of treatment per year ranges from 200 thousand to 1 million rubles). But those of them whose body has developed resistance to imatinib have a hard time. Second generation tyrosine kinase inhibitors in our country are not covered under the government guarantee program. That is, treatment must be carried out at the expense of the budget of the region where the person lives. This means endlessly delaying the allocation of money and, as a result, receiving the medicine too late.

At the beginning of the article, we mentioned the achievement of Russian researchers from the Fusion Pharma company, which is part of the biomedical technology cluster of the Skolkovo Foundation. Scientists have developed a selective third-generation tyrosine kinase inhibitor. It is assumed that the molecule they created, called PF-114, will be even more effective in suppressing the activity of the protein, which is encoded by the BCR-ABL gene. On this moment researchers have started phase 1 clinical trials. And the fact that the FDA assigned orphan status to the drug indicates the significance and importance of these trials not only for Russia, but also for the global medical community. Perhaps it is our scientists who will take another step towards a complete cure for chronic myeloid leukemia.

Conclusions Over the 200 years since the first description of the disease, medicine has extended the life of a patient with CML from several months to full life decades long. But the question of a complete cure still remains open. Studies show that some patients are completely cured during long-term use of tyrosine kinase inhibitors. But some do not; after stopping the medication, they develop a relapse of the disease. How to distinguish the first from the second is still unclear. Research continues.