Chronic myeloid leukemia stages of the disease. Chronic myeloid leukemia: pathogenesis and treatment

Diagnosis(CML) in most cases, it is easy to establish or, in any case, suspect by characteristic changes in the blood picture. These changes are expressed in 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 up 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 up to 5-10%, often with a simultaneous increase in the level of eosinophils up to 5-8% ("eosinophilic-basophilic association", not found in other diseases) and a decrease in the number of lymphocytes up to 10-5%.

Sometimes the number of basophils reaches significant numbers - 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 is described, in which 20-40% of eosinophils are constantly in the blood. Currently, these variants are not isolated, and an increase in the number of basophils or eosinophils is considered as a sign of an advanced stage of the disease.

Most patients have increased 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 erythrocytes can remain normal for a long time, decreasing only with very high leukocytosis. In some patients, at the beginning of the disease, even a slight erythrocytosis is observed - 5.0-5.5 10 12 liters.

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 a high content of these cells in the blood. As a rule, a large number of mitotic figures are noted.

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

At morphological study there are no changes in the structure of granulocytic cells in CML compared with normal ones, however, electron microscopy reveals asynchronism in the maturation of the nucleus and cytoplasm: at each stage of granulocyte maturation, the nucleus lags behind in its development from the cytoplasm.

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

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

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

Some patients have permanent increased uric acid levels leads to the formation of urate urinary stones and gouty arthritis, the deposition of uric acid crystals in the tissues of the auricles with the formation of visible nodules. The vast majority of patients have a high level of serum lactate dehydrogenase.

Start diseases in most cases almost or completely asymptomatic. Usually, when blood changes have already appeared, the spleen is not enlarged. As the disease progresses, it progressively increases, sometimes reaching enormous proportions. Leukocytosis and the size of the spleen 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 of 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. The large size of the spleen is especially characteristic of CML with high basophilia.

When expressed splenomegaly the liver is also usually enlarged, but always to a much lesser extent than the spleen. Enlargement of lymph nodes is not typical for CML, it sometimes occurs in the terminal stage of the disease and is due to infiltration of the lymph node by blast cells.

Complaints weakness, a feeling of heaviness, sometimes pain in the left hypochondrium, sweating, subfebrile temperature appear only with a developed clinical and hematological picture of the disease.

At 20-25% of CML patients is detected by chance, when there are still no clinical signs of the disease, but there are only mild hematological changes (leukocytosis and a small percentage of immature granulocytes in the blood), which are found in 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 blood changes, unfortunately, do not attract the attention of a doctor, 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 the cells of the blood and bone marrow of a characteristic cytogenetic marker - the Ph-chromosome. This marker is present in all patients with CML and does not occur in other diseases.

Chronic myeloid leukemia- the first oncological disease 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, USA, P. Nowell and D. Hungerford found shortening of the long arm of one of the chromosomes of the 21st pair, as they mistakenly believed, in all the patients with CML they examined. By 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. 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, the most important 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 the small terminal part of the long arm of chromosome 9 is transferred to chromosome 22. As a result, a characteristic cytogenetic anomaly occurs - the lengthening of the long arm of one of the chromosomes of the 9th pair and the chromosome 22 pair. It is this chromosome from the 22nd pair with a shortened long arm that is designated as the Ph chromosome.

By now, it has been established that Ph chromosome- t(9;22)(q34;q11) is found in 95-100% of metaphases in 90-95% of patients with CML. In about 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 additionally 2 or 3 chromosomes. With complex translocations, there are always the same molecular changes as with standard t(9;22)(q34;q11). Standard and variant translocations can be simultaneously detected in the same patient in different metaphases.

Sometimes the so-called masked translocation with the same molecular changes as in typical, but not determined by conventional cytogenetic methods. This is due to the transfer of smaller sections of chromosomes than in standard translocation. Cases are also described when t (9; 22) is not detected during a conventional cytogenetic study, however, 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 standard for CML - the formation chimeric gene BCR-ABL. Studies of such cases have shown that sometimes there is a transfer of a section of chromosome 9 to chromosome 22, but there is no translocation of a section of chromosome 22 to chromosome 9.

In the initial period cytogenetic study of chronic myeloid leukemia two variants were distinguished - 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 the previously described observations in most cases referred to BCR-ABL-positive CML, but with a type of chromosomal rearrangement that could not be detected by known at that time by cytogenetic methods.

Thus, received to present time, the 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 that are similar to CML in clinical manifestations (splenomegaly) and blood picture (hyperleukocytosis, neutrophilia). The most common is chronic myelomonocytic leukemia (CMML), which in the 2001 WHO classification refers to diseases that have both myeloproliferative and myelodysplastic features. With CMML, the number of monocytes in the blood and bone marrow is always increased.

In chronic myeloid leukemia, many patients have translocations with the participation of chromosome 5: t (5; 7), t (5; 10), t (5; 12), in which fusion genes are formed that involve the PDGFbR gene located on chromosome 5 (the 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 sprouts of myelopoiesis, 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 with acute leukemia. No characteristic cytogenetic changes were found.

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

Chronic myeloid leukemia equally affects the body of a man or woman. It is difficult to recognize the course of the disease, because. The process is initially asymptomatic. Often, myeloid leukemia is detected in the later stages, and then the survival rate is reduced.

According to ICD-10, the disease has a classification: C 92.1 - Chronic myelocytic leukemia.

Causes of Chronic Myeloid Leukemia

The pathogenesis of myeloid leukemia originates in myelosis. In the course of certain factors, a tumorigenic clone of the cell appears, which is able to differentiate into white blood cells responsible for maintaining immunity. This clone actively reproduces in the bone marrow, excluding useful hematopoietic sprouts. The blood is saturated with neutrophils in equal amounts with erythrocytes. Hence the name - 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. There is acute leukemia. There is damage to the liver tissues, heart, kidneys and lungs. Anemia intensifies, 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.
• Reception of cytostatics.

Stages of development of pathology

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

1. Initial - due to a slight overgrowth of the spleen, as well as an increase in leukocytes in the blood. At this stage, patients are monitored, without prescribing a specific treatment.
2. Expanded - clinical signs dominate. The patient is prescribed specialized drugs. Myeloid tissue, located in myelosis and in the spleen, increases. Rarely, the lesion affects the lymphatic system. There is a proliferation of connective tissue in the bone marrow. Severe liver infiltration. The spleen thickens. When touched, intense pain occurs. After an infarction of the spleen, noises of friction 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 tract.
3. Terminal - there is a decrease in the level of platelets, anemia develops. There are complications 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 pink spots appear on the skin. This is what a tumor infiltrate looks like. Lymph nodes increase due to the formation of tumors in them like sarcomas. Sarcoid-type tumors can appear and develop in any organ or even bones of a person. There are signs of subcutaneous hemorrhage. A high content of leukocytes provokes the development of hyperleukocytosis syndrome, in which the central nervous system is damaged. There are also mental disorders and visual impairment due to swelling of the optic nerve.

A blast crisis is an acute worsening of myelogenous leukemia. The condition of the patients is grave. Most of the time is spent in bed, unable to even roll over. Patients are severely malnourished and may suffer from severe bone pain. The skin becomes bluish in color. Lymph nodes are stony, enlarged. The organs of the abdominal cavity, the liver and spleen, reach their maximum size. The strongest infiltration affects all organs, causing failure, leading to death.

Symptoms of the disease

The chronic period lasts on average up to 3 years, isolated cases - 10 years. During this time, the patient may not be aware of the presence of the disease. Unobtrusive symptoms, such as fatigue, decreased ability to work, a feeling of a full stomach, are rarely given importance. On examination, the spleen is enlarged and granulocytes are elevated.

In the early stages of CML, there may be a decrease in hemoglobin in the blood. Normochromic anemia appears. The liver in chronic myeloid leukemia is enlarged, as is the spleen. There is an enlargement of erythrocytes. In the absence of medical control, the disease accelerates its development. The transition to the deterioration phase can be indicated either by tests or by the general condition of the patient. Patients quickly get tired, suffer from frequent dizziness, bleeding becomes more frequent, which is difficult to stop.

The ongoing treatment in the later stages does not reduce the level of leukocytes. The appearance of blast cells is observed, there is a change in their functions (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 writes down the 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 taken and histological studies are carried out.

The final point in the diagnosis is the study of the polymerase chain reaction with reverse transcription 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, for 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.
• Removal of leukocytes from the blood.

Chemotherapy is carried out with such drugs as: Sprysel, Mielosana, Gleevec, etc. The most effective method is bone marrow transplantation. After the transplant procedure, the patient must be in the hospital under the supervision of doctors, because. such an operation destroys the entire immunity of a person. After a while, 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 the operation, the overall development of the pathology slows down, and treatment with medicines enhances the effectiveness.

The leukapheresis procedure is carried out with the highest level of leukocytes. The procedure is similar to plasmapheresis. With the help of a special apparatus, all leukocytes are removed from the blood.

Life expectancy in chronic myeloid leukemia

The majority of patients die in the second or third stage of the disease. Approximately 8-12% die after chronic myeloid leukemia is diagnosed in the first year. After the final stage, survival is 5-7 months. In the case of a positive outcome after the terminal stage, the patient can last 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 the treatment prolongs life up to 4-6 years. Bone marrow transplantation prolongs life much more than other treatments.

Until recently, it was generally accepted that chronic myeloid leukemia is a disease that occurs more often 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?

The essence of the disease

In the human body, the bone marrow is responsible for the processes of hematopoiesis. Blood cells are produced there - erythrocytes, platelets and leukocytes. Most of all in the hemolymph of leukocytes. They are responsible for immunity. Chronic myeloid leukemia leads to the failure of these processes.

In a person suffering from this type of leukemia, the bone marrow produces leukocytes with pathology - oncologists call them blasts. They begin to multiply uncontrollably and leave the bone marrow without having time to mature. In fact, these are “immature” leukocytes that cannot perform protective functions.

Gradually, they are carried 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. The human immune system, due to the lack of leukocytes, ceases to fight 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 that fuses with chromosome 9. A fragment of chromosome 9 attaches to chromosome 22. This is how the genes fail, and then the immune system.

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

• exposure to radiation. After the nuclear attacks on Hiroshima and Nagasaki, the incidence of CML among residents of Japanese cities increased significantly;
• exposure to certain chemicals - alkenes, alcohols, aldehydes. Smoking affects the condition of patients negatively;
• taking certain medications - cytostatics, if cancer patients take them along with undergoing radiation therapy;
• radiotherapy;
• hereditary genetic diseases - Klinefelter's syndrome, Down's syndrome;
• viral diseases.

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

There are, 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 is the disease progressing?

Doctors distinguish three stages in the development of chronic myelogenous leukemia:

• chronic stage;
• accelerating 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 general malaise. The disease is diagnosed by chance, for example, when a person comes to take 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. On palpation, the doctor will find an enlarged spleen due to a tumor, and a blood test will reveal an excess of granulocytes and platelets. Men often experience long, painful erections.

The spleen enlarges, a person experiences problems with appetite, quickly becomes satiated, feels pains radiating to the back in the left side of the abdominal cavity.

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

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

A person loses weight, becomes weak, dizzy 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 profusely, especially at night.

The duration of the accelerative 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 is already progressing.

The third, terminal phase occurs when the disease passes into an acute stage.

A blast crisis occurs in chronic myeloid 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 lose weight rapidly;
• the patient feels joint pain;
• hypohidrosis;
• hemorrhage and bleeding.

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

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

Chronic myeloid leukemia in the third stage is incurable, and only palliative therapy will prolong the patient's life for several months.

How to diagnose a disease?

Since at first the disease has non-specific signs, it is often discovered almost by accident when a person comes, for example, to take a complete blood count.

A hematologist, if oncology is suspected, should not only conduct a survey and examine his lymph nodes, but also palpate the abdomen in order to understand if the spleen is enlarged and if there is a tumor in it. To confirm or refute the suspicions, the subject is sent for an ultrasound scan of the spleen and liver, as well as for a genetic study.

Methods for diagnosing chronic myeloid leukemia:

• common and ;
• bone marrow biopsy;
• cytogenetic and cytochemical study;
• 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 allow you to determine the level of "normal" and "immature" white blood cells, granulocytes and platelets.

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

If the proportion of blasts exceeds 20 percent, and the number of platelets decreases, then the third stage of the disease has begun.

Biochemical analysis will help to establish the presence in the blood of substances that are characteristic of this disease. We are talking about uric acid, vitamin B12, transcobalamin and others. Biochemistry determines whether there are malfunctions in the work of the 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 needed to determine the presence of abnormal cells. The doctor uses a special needle to take the brain tissue (a suitable place for puncture is the femur).

Cytochemical examination distinguishes 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 bodies 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 for chronic myeloid leukemia has two main goals: to shrink the spleen and to stop the bone marrow from making abnormal cells.

Oncologists-hematologists use four main methods of treatment:

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

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

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

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

In the late phases, doctors use traditional drugs: Cytosar, Myelosan, Dazanitib, or modern drugs like Glivec and Sprycel. These drugs act on 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 not allowed to do this on his own.

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

If the disease is in an advanced phase, hematologists prescribe several drugs at the same time. The duration of the course of intensive chemotherapy depends on how soon the laboratory parameters return to normal. Usually, a cancer patient should undergo three to four courses of chemotherapy per year.

If cytostatics and chemotherapy do not give results, and the disease continues to progress, the hematologist sends his ward to radiation therapy.

The indications for it are:

• an increase in a tumor in the bone marrow;
• enlargement of the spleen and liver;
• if the blasts hit the tubular bones.

The oncologist must determine the mode 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 applied at the accelerating stage of the disease.

Bone marrow transplantation is one of the most effective treatments. It guarantees long-term remission in 70 percent of patients.

Bone marrow transplantation is a rather expensive method of treatment. 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. It is quite difficult to do this, since the chances that foreign elements will take root in the patient's body are less than if a member of his family became the donor. Sometimes it is the patient himself. Doctors can transplant peripheral cells into his bone marrow. The only risk is associated with a high probability that blasts will get there along with healthy leukocytes.
2. Patient preparation. Before the operation, the patient must undergo a course of 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. First, they move through the vascular system, then they 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. After transplantation, two to four weeks should pass. Since the person's immunity is at zero, he is ordered to be in the hospital. He receives antibiotics, he is protected from contact with infectious agents. At this stage, the patient's body temperature rises, chronic diseases may worsen.
5. post-transplantation period. When it is clear that the foreign leukocytes are accepted by the bone marrow, the patient's condition improves. Full recovery takes months or even years. All this time, a person must be observed by an oncologist and vaccinated, since his 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 carried out at the first stage.

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

• a spleen infarction has occurred, or there is a threat of its rupture;
• if the organ has increased so much that it interferes with the functioning of neighboring organs of the abdominal cavity.

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

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

Survival Predictions

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

The likelihood of recovery depends on what stage of chronic myelogenous 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.

A negative sign is leukocytosis, thrombocytopenia, as well as an increase in the content of blast cells.

The more manifestations and the 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.

The lethal outcome most often occurs in the accelerative 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 a blast crisis prolongs the life of the patient, at most, by half a year. The life expectancy of a cancer patient is calculated in a year if remission occurs after a blast crisis.

RCHD (Republican Center for Health Development of the Ministry of Health of the Republic of Kazakhstan)
Version: Clinical Protocols of the Ministry of Health of the Republic of Kazakhstan - 2015

Chronic myeloid leukemia (C92.1)

Oncohematology

general information

Short description

Recommended
Expert Council
RSE on REM "Republican Center
health development"
Ministry of Health
and social development
Republic of Kazakhstan
dated July 9, 2015
Protocol #6

Protocol name: Chronic myeloid leukemia

Chronic myeloid leukemia (CML)- clonal myeloproliferative process that develops as a result of malignant transformation in early hematopoietic precursors. The cytogenetic marker of CML is the acquired chromosomal translocation t(9;22), which is called the Philadelphia chromosome (Ph+). The emergence of the Ph`-chromosome occurs as a result of the exchange of genetic material between chromosomes 9 and 22 t (9;22). As a result of the transfer of genetic material from chromosome 9 to chromosome 22, the BCR-ABL fusion gene is formed on it.

Protocol code:

ICD code -10: C92.1 - chronic myeloid leukemia

Protocol development date: 2015

Abbreviations used in the protocol:
* - drugs purchased as part of a single import
HIV - human immunodeficiency virus
TKI - tyrosine kinase inhibitors
ELISA - enzyme immunoassay
OAM - general urinalysis
KLA - complete blood count
TCM - hematopoietic stem cell/bone marrow transplantation
CML - chronic myeloid leukemia
ECG - electrocardiogram
Ultrasound - ultrasonography
BCR - ABL - breakpoint cluster region-Abelson
CCA - Complex chromosomal aberrations
ELN - European Leukemia Net
FISH - Fluorescence in situ hybridization (Fluorescence in situ hybridization)
RT-Q-PCR - Real-Time Quantitative Reverse Transcription PCR
Nested PCR - Nested polymerase chain reaction
HLA - Human leukocyte antigen (human leukocyte antigen)
Ph - Philadelphia chromosome
WHO - World Health Organization.

Protocol Users: therapists, general practitioners, oncologists, hematologists.

Level of Evidence Scale

Level of Evidence	Characteristics of the studies that formed the basis of the recommendations
BUT	A high-quality meta-analysis, a systematic review of randomized clinical trials (RCTs), or a large RCT with a very low probability (++) of bias, the results of which can be generalized to an appropriate population.
AT	High-quality (++) systematic review of cohort or case-control studies or High-quality (++) cohort or case-control studies with a very low risk of bias or RCTs with a low (+) risk of bias, the results of which can be extended to the appropriate population.
FROM	Cohort or case-control or controlled trial without randomization with a low risk of bias (+), the results of which can be generalized to the appropriate population or RCTs with a very low or low risk of bias (++ or +), the results of which are not can be directly extended to the relevant population.
D	Description of a series of cases or
	uncontrolled study or
	Expert opinion

Classification

Clinical classification:
During CML, 3 phases are distinguished: chronic, transitional (acceleration phase) and terminal phase (blast transformation or blast crisis). The criteria for acceleration phases and blast crisis are presented in the table.

Criteria for acceleration phases and blast crisis according to WHO and ELN

Options	Acceleration phase		blast crisis phase
	WHO	ELN	WHO	ELN
Spleen	increase in size despite ongoing therapy	Not applicable	Not applicable	Not applicable
Leukocytes	an increase in the number of leukocytes (> 10x109 l) in the blood despite ongoing therapy	Not applicable	Not applicable	Not applicable
Blasts, %	10-19	15-29	≥20	≥30
Basophils, %	>20	>20	Not applicable	Not applicable
Platelets, x 109/l	>1000 uncontrolled by therapy <100 неконтролируемые терапией	Not applicable	Not applicable	Not applicable
CCA/Ph+1	Available	Available	Not applicable	Not applicable
Extramedullary lesions2	Not applicable	Not applicable	Available	Available

1 - clonal chromosomal abnormalities in Ph+ cells

2 - excluding the liver and spleen, including lymph nodes, skin, central nervous system, bones and lungs.

Clinical picture

Symptoms, course

Diagnostic criteria for diagnosis :
the presence of the Philadelphia chromosome (balanced translocation t(9;22) (q34; q11) according to the standard cytogenetic study of the bone marrow 1
The presence of the BCR-ABL gene in bone marrow or peripheral blood cells according to molecular genetic methods (FISH, real-time polymerase chain reaction);
myeloproliferative syndrome - neutrophilic leukocytosis with a shift to the left to blasts (up to 10%) with the presence of all transitional forms (there is no "leukemic failure"), basophilic-eosinophilic association, in some cases thrombocytosis, in the myelogram - hypercellular bone marrow, hyperplasia of the erythroid germ, splenomegaly (in 50% of patients in the early chronic phase).

Complaints:
· weakness;
· sweating;
· fatigue;
subfebrile condition;
· chilling;
pain in the bones or joints;
Decrease in body weight;
hemorrhagic rashes in the form of petechiae and ecchymosis on the skin;
epistaxis;
menorrhagia;
Increased bleeding
swollen lymph nodes;
pain and heaviness in the left upper abdomen (enlarged spleen);
heaviness in the right hypochondrium.

Anamnesis: attention should be paid to:
Long-lasting weakness
fast fatigue;
frequent infectious diseases;
increased bleeding;
the appearance of hemorrhagic rashes on the skin and mucous membranes;
enlargement of the liver, spleen.

Physical examination:
pallor of the skin;
hemorrhagic rashes - petechiae, ecchymosis;
shortness of breath
· tachycardia;
Enlargement of the liver
Enlargement of the spleen
Enlargement of lymph nodes.

1 - In approximately 5% of CML cases, the Philadelphia chromosome may be absent and the diagnosis is verified only on the basis of data from molecular genetic methods - FISH or polymerase chain reaction (detection of the chimeric BCR-ABL gene)

Diagnostics

The list of basic and additional diagnostic measures:

The main (mandatory) diagnostic examinations carried out at the outpatient level:
UAC;

myelogram;

biochemical blood test (uric acid);
X-ray of the chest organs.

Additional diagnostic examinations performed at the outpatient level:
bone marrow examination by FISH (t(9;22)/BCR/ABL);

ELISA for HIV markers;
ELISA for markers of herpes group viruses;
Reberg-Tareev test;
· OAM;
· coagulogram;

· HLA typing;
ECG;
Echo - cardiography;
CT scan of the thoracic and abdominal segments with contrast.

The minimum list of examinations that must be carried out when referring to planned hospitalization:
UAC;
blood type and Rh factor;
biochemical blood test (total protein, albumin, globulins, level, uric acid, creatinine, urea, LDH, ALT, AST, total and direct bilirubin);
Ultrasound of the abdominal organs and spleen, peripheral lymph nodes;
X-ray of the chest organs.

The main (mandatory) diagnostic examinations carried out at the hospital level:
KLA with counting platelets and reticulocytes;
biochemical blood test (total protein, albumin, globulins, IgA, IgM, IgG, uric acid, creatinine, urea, LDH, ALT, AST, total and direct bilirubin);
Ultrasound of peripheral lymph nodes, abdominal organs, incl. spleen;
X-ray of the chest organs;
myelogram;
cytogenetic study of the bone marrow;
bone marrow examination by FISH (t (9; 22)/BCR/ABL);
ELISA and PCR for markers of viral hepatitis;
ELISA for HIV markers;
ECG;
Echocardiography;
Reberg-Tareev test;
· OAM;
· coagulogram;
blood type and Rh factor;
· HLA typing.

Additional diagnostic examinations carried out at the hospital level:
pro-BNP (atrial natriuretic peptide) in blood serum;
bacteriological examination of biological material;
cytological examination of biological material;
Immunophenotyping of peripheral blood/bone marrow on a flow cytofluorimeter (acute leukemia panel);
Histological examination of the biopsy specimen (lymph node, iliac crest);
PCR for viral infections (viral hepatitis, cytomegalovirus, herpes simplex virus, Epstein-Barr virus, Varicella / Zoster virus);
radiography of the paranasal sinuses;
radiography of bones and joints;
FGDS;
· Ultrasound of blood vessels;
bronchoscopy;
colonoscopy;
daily monitoring of blood pressure;
daily ECG monitoring;
spirography.

Diagnostic measures taken at the stage of emergency medical care:
collection of complaints and anamnesis of the disease;
physical examination.

Instrumental Research:
· Ultrasound of the abdominal organs, lymph nodes: an increase in the size of the liver, spleen, peripheral lymphadenopathy.
· CT scan of the thoracic segment: to exclude infiltration of the lung tissue.
· ECG: violation of the conduction of impulses in the heart muscle.
· EchoCG: to exclude heart defects, arrhythmias and other diseases in patients, accompanied by damage to the heart.
· FGDS: leukemic infiltration of the mucous membrane of the gastrointestinal tract, which can cause ulcerative lesions of the stomach, duodenum 12, gastrointestinal bleeding.
· Bronchoscopy: detection of the source of bleeding.

Indications for consultation of narrow specialists:
Doctor for X-ray endovascular diagnostics and treatment - installation of a central venous catheter from a peripheral access (PICC);
hepatologist - for the diagnosis and treatment of viral hepatitis;
· gynecologist - pregnancy, metrorrhagia, menorrhagia, consultation when prescribing combined oral contraceptives;
dermatovenereologist - skin syndrome
infectious disease specialist - suspicion of viral infections;
cardiologist - uncontrolled hypertension, chronic heart failure, cardiac arrhythmia and conduction disturbances;
· neuropathologist acute cerebrovascular accident, meningitis, encephalitis, neuroleukemia;
neurosurgeon - acute cerebrovascular accident, dislocation syndrome;
nephrologist (efferentologist) - renal failure;
oncologist - suspicion of solid tumors;
otorhinolaryngologist - for the diagnosis and treatment of inflammatory diseases of the paranasal sinuses and middle ear;
Ophthalmologist - visual impairment, inflammatory diseases of the eye and appendages;
proctologist - anal fissure, paraproctitis;
psychiatrist - psychoses;
psychologist - depression, anorexia, etc.;
· resuscitator - treatment of severe sepsis, septic shock, acute lung injury syndrome in differentiation syndrome and terminal states, installation of central venous catheters.
rheumatologist - Sweet's syndrome;
Thoracic surgeon - exudative pleurisy, pneumothorax, pulmonary zygomycosis;
· transfusiologist - for the selection of transfusion media in case of a positive indirect mantiglobulin test, transfusion failure, acute massive blood loss;
Urologist - infectious and inflammatory diseases of the urinary system;
phthisiatrician - suspicion of tuberculosis;
surgeon - surgical complications (infectious, hemorrhagic);
· maxillofacial surgeon - infectious and inflammatory diseases of the dento-jaw system.

Laboratory diagnostics

Laboratory research:
· General blood analysis: leukocytes, erythrocytes and platelets are counted. Absolute neutrophilic leukocytosis with a shift of the nuclear formula to the left (up to promyelocytes or blasts), the absence of a leukemic dip, and a basophilic-eosinophilic association are characteristic. At the onset of the disease, the hemoglobin level may be within the normal range or elevated, and moderate thrombocytosis may be observed. In the phase of acceleration and blast crisis, thrombocytopenia and anemia may develop.
· Blood chemistry: there is an increase in LDH activity, hyperuricemia.
· Morphological study: in a bone marrow aspirate hypercellular bone marrow, an increase in the number of blasts, basophils and eosinophils.
· Immunophenotyping: is carried out to determine the immunophenotype of blasts in their excess (more than 20-30%).

Differential Diagnosis

differential diagnosis.
The diagnosis of chronic myeloid leukemia in classical cases is not difficult. Difficulties usually arise in the initial period of the disease, when there are still no clear leukemic changes in the blood and pronounced signs of systemic metaplasia in the organs.
The main pathognomonic sign of the disease is the detection of the Philadelphia chromosome (t(9;22)) and the chimeric BCR/ABL gene during cytogenetic examination.
Differential diagnosis can be carried out with a myeloid-type leukemoid reaction that occurs with various infections (sepsis, tuberculosis) and some tumors (Hodgkin's lymphoma, solid tumors), as well as other chronic myeloproliferative diseases. The main diagnostic criteria for chronic myelogenous leukemia are:

• the presence of anemia, not characteristic of a leukemoid reaction;
• an increase in the number of basophils and eosinophils in the leukogram;
• sometimes hyperthrombocytosis;
• myelogram data, which in myeloid leukemia is characterized by an increase in the number of myelokaryocytes and a sharp shift to the left, while with a leukemoid reaction, the myelogram is little changed;
• dynamics of the blood picture (the leukemoid reaction usually disappears with the elimination of the cause that caused it, while changes in the blood with myeloid leukemia are steadily progressing).

In the phase of the blast crisis, differential diagnosis should be carried out with acute leukemia. The duration of the course of the process, as well as the degree of metaplasia in the organs in these cases, are not a decisive criterion, given, on the one hand, the possibility of an early exacerbation of chronic leukemia, when certain difficulties arise in determining the time of onset and duration of the course of the disease, and on the other hand, the presence acute leukemia with a protracted course, in which the liver and spleen are significantly enlarged. In such cases, the strong points of differential diagnosis are some differences in the blood picture:

• the presence in chronic myelosis of intermediate forms between "powerful" elements and mature granulocytes, while "leukemic gaping" is characteristic of acute leukemia;
• the presence of an eosinophilic-basophilic association, which is absent in acute leukemia;
• sometimes observed in chronic myelosis hyperthrombocytosis, while in acute leukemia already from the very beginning there is thrombocytopenia.

For differential diagnosis with chronic myeloproliferative diseases (idiopathic myelofibrosis, erythremia), cytogenetic and molecular genetic studies play a decisive role.

Treatment

Treatment goals:
Obtaining hematological remission, cytogenetic and molecular response.

Treatment tactics:

Non-drug treatment.
Mode: general protection.
Diet: neutropenic patients are advised not to follow a specific diet ( level of evidence B).

Transfusion support
Prophylactic transfusions of apheresis virus-inactivated, preferably irradiated platelets are performed when thrombocytopenia is less than 10x109/l or at a level of less than 20x10 9 /l in case of fever or planned invasive procedures. (level of evidence D)
In patients resistant to platelet transfusions, screening for HLA antibodies and individual selection of platelets is necessary.
Transfusions of leukofiltered, preferably irradiated red blood cells are performed in the presence of poor tolerance of anemia (weakness, dizziness, tachycardia), especially in the presence of symptoms at rest. (level of evidence D)
Indications for transfusion therapy are determined primarily by clinical manifestations individually for each patient, taking into account age, comorbidities, chemotherapy tolerance and the development of complications at previous stages of treatment.
Laboratory indicators for determining indications are of secondary importance, mainly for assessing the need for prophylactic transfusions of platelet concentrate.
Indications for transfusions also depend on the time after the course of chemotherapy - the predicted decrease in indicators in the next few days is taken into account.
Erythrocyte mass/suspension (level of evidenceD):
· Hemoglobin levels do not need to be increased as long as normal reserves and compensation mechanisms are sufficient to meet tissue oxygen needs;
· There is only one indication for transfusion of red blood cells in chronic anemia - symptomatic anemia (manifested by tachycardia, dyspnea, angina pectoris, syncope, denovo depression or ST elevation);
· A hemoglobin level of less than 30 g/l is an absolute indication for erythrocyte transfusion;
In the absence of decompensated diseases of the cardiovascular system and lungs, hemoglobin levels may be indications for prophylactic transfusion of erythrocytes in chronic anemia:

Platelet concentrate (level of evidenceD):
· If the level of platelets is less than 10 x 10 9 /l, transfusion of apheresis platelets is performed to maintain their level at least 30-50 x 10 9 /l, especially in the first 10 days of the course.
· In the presence of a high risk of hemorrhagic complications (age over 60 years, increased creatinine more than 140 µmol/l), it is necessary to maintain a platelet level of more than 20 x10 9 /l.

Fresh frozen plasma (level of evidenceD):
· FFP transfusions are performed in patients with bleeding or before invasive interventions;
· Patients with an INR of ³2.0 (for neurosurgical interventions of ³1.5) are considered as candidates for FFP transfusion when planning invasive procedures.

Medical treatment:
During the examination, until the results of a cytogenetic study confirming the presence of the Ph + chromosome in the bone marrow cells, the patient is prescribed hydroxyurea. The dose of the drug is determined taking into account the number of leukocytes and the weight of the patient. With leukocytosis more than 100 x10 9 /l, hydrea is prescribed at a dose of 50 mcg / kg daily. Further, with a decrease in the number of leukocytes in the blood, the dose of hydrea is reduced: with leukocytosis 40-100 x10 9 / l, 40 mg / kg is prescribed, at 20-40 x 10 9 / l - 30 mg / kg, at 5 - 20 x 10 9 / l - 20 mg/kg daily.
Imatinib can be started at any WBC count. Imatinib is given (in the chronic phase) at a dose of 400 mg/day orally after meals.
To obtain stable results, taking imatinib should be constant, long-term. Doses of imatinib are adjusted according to the severity of complications. It is necessary to take into account the toxicity of therapy in this patient (table 2).

Table 2. Hematological Toxicity Scale

Index	DEGREE OF TOXICITY
	0	1	2	3	4
Leukocytes	≥4.0×10 9 /l	3,0-3,9	2,0-2,9	1,0-1,9	<1,0
Platelets	Norm	75.0-norm	50-74,9	25,0-49,0	Less than 25
Hemoglobin	Norm	100-norm	80-100	65-79	Less than 65
Granulocytes	≥2.0×10 9 /l	1,5-1,9	1,0-1,4	0,5-0,9	Less than 0.5

In the chronic phase of CML, the drug is taken continuously. Breaks in treatment should be done with the development of severe hematological toxicity grade ³3.
Treatment is resumed when clinical and hematological parameters are restored (neutrophils > 1.5 thousand / μl, platelets > 75 thousand / μl). After toxicity has resolved, imatinib 400 mg is resumed if treatment is interrupted for less than 2 weeks. With repeated episodes of the development of cytopenia or if they last more than 2 weeks, it is possible to reduce the dose of imatinib to 300 mg / day. Further reduction in the dose of imatinib is not advisable. it is not possible to achieve its therapeutic concentration in the blood. Therefore, with repeated episodes of cytopenia, breaks in treatment with imatinib are taken. With the stabilization of clinical and hematological parameters within 1-3 months, it is necessary to consider the issue of resuming the drug at a dose of 400 mg / day.
Patients who previously received long-term busulfan recommended to continue taking busulfan(switching to imatinib therapy is ineffective due to the possibility of myelosuppression).
The tactics of treating patients in case of intolerance to imatinib or insufficient response to therapy, as well as in the phase of acceleration and blast crisis are presented in table 2, response criteria in tables 4 and 5.

chronic phase
1st line	All patients	Imatinib4 400mg daily
2nd line (after imatinib)	Toxicity, intolerance	Dasatinib or Nilotinib
	Suboptimal response	Continue imatinib at previous or higher doses, dasatinib, or nilotinib
	No response	Dasatinib or nilotinib AlloHSCT with progression to acceleration or blast crisis and in the presence of the T315I mutation
3rd line	Suboptimal response to dasatinib or nilotinib	Continue Dasatinib or Nilotinib. In patients with prior resistance to imatinib, presence of mutations in patients with EBMT scores ≤2, consider allo-TKM
	No response to Dasatinib or Nilotinib	alloTKM
Phase of acceleration and blast crisis
1st line therapy	Patients who did not receive TKIs	Imatinib 600 mg or 800 mg or dasatinib 140 mg or nilotinib 400 mg twice daily followed by allo-BMT
2nd line therapy	Patients previously treated with imatinib	AlloTKM, nilotinib or dasatinib therapy

4 Patients at high risk in the chronic phase of CML can use nilotinib and dasatinib in the first line of therapy (with a total score of >1.2 by Socal et al, >1480 by EURO, >87 by EUTOS - score calculator http://www .leukemia-net.org/content/leukemias/cml/eutos_score/index_eng.html , or http://www.leukemia-net.org/content/leukemias/cml/cml_score/index_eng.html). The drug is selected according to the following scheme (level of evidenceD) .

Doses of drugs(level of evidence A):
· Imatinib 400 mg/day;
Nilotinib 300 mg/day;
Dasatinib 100 mg/day

Medical treatment provided on an outpatient basis:
− a list of essential medicines with an indication of the form of release (having a 100% probability of use):

Antineoplastic and immunosuppressive drugs
− imatinib 100 mg, capsules;
− nilotinib 200 mg capsules;
− dasatinib* 70mg tablets;
− hydroxycarbamide 500 mg, capsules;
- allopurinol 100 mg, tablets.

Drugs that reduce the toxic effect of anticancer drugs
· filgrastim, solution for injections 0.3 mg/ml, 1 ml;
Ondansetron, injection 8 mg/4 ml.

Antibacterial agents
azithromycin, tablet/capsule, 500 mg;
amoxicillin/clavulanic acid, film-coated tablet, 1000 mg;
levofloxacin, tablet, 500 mg;
moxifloxacin, tablet, 400 mg;
ofloxacin, tablet, 400 mg;
ciprofloxacin tablet, 500 mg;
metronidazole, tablet, 250 mg;
metronidazole, dental gel 20g;
erythromycin, 250mg tablet.

anidulafungin, lyophilized powder for solution for injection, 100 mg/vial;
voriconazole tablet, 50 mg;

Clotrimazole, solution for external use 1% 15ml;
fluconazole, capsule/tablet 150 mg.

acyclovir, tablet, 400 mg;



famciclovir tablets 500mg

sulfamethoxazole/trimethoprim 480 mg tablet.

Solutions used to correct violations of water, electrolyte and acid-base balance

· dextrose, solution for infusions 5% 250ml;
Sodium chloride, solution for infusion 0.9% 500 ml.

Heparin, injection 5000 IU/ml, 5 ml; (for flushing the catheter)


rivaroxaban tablet.
· tranexamic acid, capsule/tablet 250 mg;

Ambroxol, oral and inhalation solution, 15mg/2ml, 100ml;

atenolol, tablet 25 mg;
acetylsalicylic acid, 50 mg, 100 mg tablets



Drotaverine, tablet 40 mg;

· lactulose, syrup 667g/l, 500 ml;

Lisinopril 5mg tablet
methylprednisolone, tablet, 16 mg;

omeprazole 20 mg capsule;

prednisolone, tablet, 5 mg;


Torasemide, 10mg tablet;
fentanyl, transdermal therapeutic system 75 mcg/h; (for the treatment of chronic pain in cancer patients)

Chlorhexidine, solution 0.05% 100ml;

Medical treatment provided at the hospital level:
- a list of essential medicines with an indication of the form of release (having a 100% probability of use):
Imatinib 100mg capsules
nilotinib 200mg capsules
dasatinib* 70mg tablets;
Hydroxycarbamide 500mg capsules.

- a list of additional medicines with an indication of the form of release (less than 100% probability of use):

Drugs that weaken the toxic effect of anticancer drugs:
. filgrastim, injection 0.3 mg/ml, 1 ml;
. ondansetron, injection 8 mg/4 ml;
. allopurinol 100mg tablets.

Antibacterial agents:
azithromycin, tablet/capsule, 500 mg; lyophilized powder for solution for intravenous infusion, 500 mg;
Amikacin, powder for injection, 500 mg/2 ml or powder for solution for injection, 0.5 g;
amoxicillin/clavulanic acid, film-coated tablet, 1000 mg; powder for solution for intravenous and intramuscular administration 1000 mg + 500 mg;
Vancomycin, powder/lyophilisate for solution for infusion 1000 mg;
· gentamicin, solution for injections 80mg/2ml 2ml;
imipinem, cilastatin powder for solution for infusion, 500 mg/500 mg;
Sodium colistimethate*, lyophilisate for solution for infusion 1 million U/vial;
Levofloxacin, solution for infusion 500 mg/100 ml; tablet, 500 m;
linezolid, solution for infusion 2 mg/ml;
Meropenem, lyophilisate/powder for solution for injection 1.0 g;
metronidazole, tablet, 250 mg, solution for infusion 0.5% 100ml, dental gel 20g;
moxifloxacin, tablet, 400 mg, solution for infusion 400 mg/250 ml;
ofloxacin, tablet, 400 mg, solution for infusion 200 mg/100 ml;
piperacillin, tazobactam powder for solution for injection 4.5 g;
· tigecycline*, lyophilized powder for solution for injection 50 mg/vial;
Ticarcillin/clavulanic acid, lyophilized powder for solution for infusion 3000mg/200mg;
cefepime, powder for solution for injection 500 mg, 1000 mg;
cefoperazone, sulbactam powder for solution for injection 2 g;
· ciprofloxacin, solution for infusion 200 mg/100 ml, 100 ml, tablet 500 mg;
erythromycin, 250 mg tablet;
Ertapenem lyophilizate, for solution for intravenous and intramuscular injections 1 g.

Antifungal medicines
Amphotericin B*, lyophilized powder for solution for injection, 50 mg/vial;
anidulofungin, lyophilized powder for solution for injection, 100 mg/vial;
voriconazole, powder for solution for infusion 200 mg/vial, tablet 50 mg;
· itraconazole, oral solution 10 mg/ml 150.0;
Caspofungin, lyophilisate for solution for infusion 50 mg;
Clotrimazole, cream for external use 1% 30g, 15ml;
· micafungin, lyophilized powder for solution for injection 50 mg, 100 mg;
fluconazole, capsule/tablet 150 mg, solution for infusion 200 mg/100 ml, 100 ml.

Antiviral drugs
acyclovir, cream for external use, 5% - 5.0, tablet 400 mg;
aciclovir, powder for solution for infusion, 250 mg;
acyclovir, cream for external use, 5% - 5.0;
Valaciclovir, tablet, 500mg;
valganciclovir, tablet, 450 mg;
· ganciclovir*, lyophilisate for solution for infusion 500 mg;
famciclovir, tablets, 500 mg №14.

Drugs used for pneumocystosis
sulfamethoxazole/trimethoprim, concentrate for solution for infusion (80mg+16mg)/ml, 5ml, 480mg tablet.

Additional immunosuppressive drugs:
Dexamethasone, injection 4 mg/ml 1 ml;
· methylprednisolone, tablet, 16 mg, injection, 250 mg;
Prednisolone, injection 30 mg/ml 1 ml, tablet 5 mg.

Solutions used to correct violations of water, electrolyte and acid-base balance, parenteral nutrition
albumin, solution for infusion 10%, 100 ml, 20% 100 ml;
· water for injections, solution for injections 5 ml;
dextrose, solution for infusion 5% - 250 ml, 5% - 500 ml, 40% - 10 ml, 40% - 20 ml;
· potassium chloride, solution for intravenous administration 40 mg/ml, 10 ml;
· calcium gluconate, solution for injections 10%, 5 ml;
· calcium chloride, solution for injections 10% 5 ml;
Magnesium sulfate, injection 25% 5 ml;
Mannitol, injection 15% -200.0;
Sodium chloride, solution for infusion 0.9% 500ml, 250ml;
Sodium chloride, potassium chloride, sodium acetate solution for infusions in a 200ml, 400ml, 200ml vial;
· sodium chloride, potassium chloride, sodium acetate solution for infusions 400ml;
Sodium chloride, potassium chloride, sodium bicarbonate solution for infusions 400ml;
L-alanine, L-arginine, glycine, L-histidine, L-isoleucine, L-leucine, L-lysine hydrochloride, L-methionine, L-phenylalanine, L-proline, L-serine, L-threonine, L- tryptophan, L-tyrosine, L-valine, sodium acetate trihydrate, sodium glycerophosphate pentihydrate, potassium chloride, magnesium chloride hexahydrate, glucose, calcium chloride dihydrate, olive and soybean oil mixture emulsion for inf.: three-chamber containers 2 l;
hydroxyethyl starch (penta starch), solution for infusion 6% 500 ml;
Amino acid complex, infusion emulsion containing a mixture of olive and soybean oils in a ratio of 80:20, an amino acid solution with electrolytes, a dextrose solution, with a total calorie content of 1800 kcal 1 500 ml three-piece container.

Medicines used for intensive care (cardiotonic drugs for the treatment of septic shock, muscle relaxants, vasopressors and anesthetics):
Aminophylline, injection 2.4%, 5 ml;
· amiodarone, injection, 150 mg/3 ml;
atenolol, tablet 25 mg;
Atracurium besylate, solution for injection, 25 mg/2.5 ml;
atropine, solution for injections, 1 mg/ml;
diazepam, solution for intramuscular and intravenous use 5 mg/ml 2 ml;
dobutamine*, injection 250 mg/50.0 ml;
· dopamine, solution/concentrate for solution for injection 4%, 5 ml;
regular insulin;
· ketamine, solution for injections 500 mg/10 ml;
· morphine, solution for injections 1% 1ml;
norepinephrine*, injection 20 mg/ml 4.0;
pipecuronium bromide, lyophilized powder for injection 4 mg;
propofol, emulsion for intravenous administration 10 mg/ml 20 ml, 50 ml;
rocuronium bromide, solution for intravenous administration 10 mg/ml, 5 ml;
sodium thiopental, powder for solution for intravenous administration 500 mg;
· phenylephrine, solution for injections 1% 1ml;
phenobarbital, tablet 100 mg;
human normal immunoglobulin, solution for infusion;
Epinephrine, injection 0.18% 1 ml.

Drugs that affect the blood coagulation system
· aminocaproic acid, solution 5%-100 ml;
. anti-inhibitor coagulant complex, lyophilized powder for injection, 500 IU;
. acetylsalicylic acid, 50 mg, 100 mg, tablets
Heparin, injection 5000 IU/ml, 5 ml;
hemostatic sponge, size 7*5*1, 8*3;
Nadroparin, injection in pre-filled syringes, 2850 IU anti-Xa/0.3 ml, 5700 IU anti-Xa/0.6 ml;
Enoxaparin, injection solution in syringes 4000 anti-Xa IU/0.4 ml, 8000 anti-Xa IU/0.8 ml.

Other medicines
bupivacaine, injection 5 mg/ml, 4 ml;
Lidocaine, solution for injection, 2%, 2 ml;
Procaine, injection 0.5%, 10 ml;
human immunoglobulin normal solution for intravenous administration 50 mg/ml - 50 ml;
· omeprazole, capsule 20 mg, lyophilized powder for solution for injection 40 mg;
famotidine, lyophilized powder for solution for injection 20 mg;
Ambroxol, solution for injection - 15 mg / 2 ml, solution for oral administration and inhalation - 15 mg / 2 ml, 100 ml;
amlodipine 5 mg tablet/capsule;
acetylcysteine, powder for oral solution, 3 g;
Heparin, gel in a tube 100000ED 50g;
Dexamethasone, eye drops 0.1% 8 ml;
Diphenhydramine, injection 1% 1 ml;
Drotaverine, injection 2%, 2 ml;
captopril, tablet 50 mg;
· ketoprofen, solution for injections 100 mg/2 ml;
· lactulose, syrup 667 g/l, 500 ml;
Levomycetin, sulfadimethoxine, methyluracil, trimecaine ointment for external use 40g;
Lisinopril 5mg tablet
· methyluracil, ointment for local use in a tube 10% 25g;
naphazoline, nose drops 0.1% 10ml;
nicergoline, lyophilisate for the preparation of an injection solution 4 mg;
povidone-iodine, solution for external use 1 l;
salbutamol, solution for nebulizer 5mg/ml-20ml;
Dioctahedral smectite, powder for oral suspension 3.0 g;
spironolactone, 100 mg capsule;
Tobramycin, eye drops 0.3% 5 ml;
Torasemide, 10mg tablet;
· tramadol, solution for injections 100 mg/2 ml;
tramadol, capsule 50 mg, 100 mg;
fentanyl, transdermal therapeutic system 75 mcg/h (for the treatment of chronic pain in cancer patients);
folic acid, tablet, 5 mg;
furosemide, solution for injection 1% 2 ml;
chloramphenicol, sulfadimethoxine, methyluracil, trimecaine ointment for external use 40g;
Chlorhexidine, solution 0.05% 100ml
Chloropyramine, injection 20 mg/ml 1 ml.

Drug treatment provided at the stage of emergency emergency care: not carried out.

Other types of treatment:

Other types of treatment provided at the outpatient level: do not apply.

Other types of treatment provided at the inpatient level:

Hematopoietic stem cell transplantation.
Carrying out allogeneic transplantation of hematopoietic stem cells can lead to a cure in patients with CML. However, this type of treatment is applicable in few patients with CML, given the high risk of complications and mortality.
When making a diagnosis and in the process of treating patients with CML, it is necessary to take into account prognostic factors that determine the life expectancy and prognosis of patients.
The relative risk in patients with CML may need to be calculated prior to initiating therapy.

Prognostic scales for patients with CML:

	Socal et al.	EURO	EUTOS[21 ]
Age (years)	0.116 (age-43.4)	0.666 if older than 50	Not used
The size of the spleen (cm) palpation below the costal arch	0.345 x (spleen-7.51)	0.042 x dim. spleen	4 x size spleen
Platelets (x10 9 /l)	0.188 x [(platelets/700) 2 −0.563]	1.0956 if platelets ≥1500	Not used
Blasts in blood, %	0.887×(blasts-2.1)	0.0584 x blasts	Not used
Basophils in blood, %	Not used	0.20399 if basophils are more than 3	7 x basophils
Eosinophils in blood, %	Not used	0.0413 x eosinophils	Not used
Relative Risk	Exponent of the sum	Amount x 1000	Sum
Short	<0,8	≤780	≤87
Intermediate	0,8-1,2	781-1480	Not used
High	>1,2	>1480	>87

Hammersmith 2nd generation TKI response prognostic scale

Other types of treatment provided at the stage of emergency medical care: do not apply.

Surgical intervention:

Surgical intervention provided on an outpatient basis: not carried out.

Surgical intervention provided in a hospital:
With the development of infectious complications and life-threatening bleeding, patients may undergo surgical interventions for emergency indications.

Treatment effectiveness indicators

Criteria for response to treatment and monitoring.

Response Category	Definition	Monitoring
Hematological Full	Platelets<450х10 9 /л Leukocytes<10 х10 9 /л No immature granulocytes, basophils<5% The spleen is not palpable	At initial diagnosis, then every 15 days until a complete hematological response is achieved, then every 3 months
cytogenetic Full (CCgR) 5 Partial (PCgR) Small Minimum Not	No metaphases with Ph 1-35% Ph+ metaphases 36-65% Ph+ metaphases 66-95% Ph+ metaphases >95% Ph+ metaphases	At diagnosis, 3 months, 6 months, then every 6 months until CCgR is achieved, then every 12 months if regular molecular monitoring is not available. Investigation should always be performed in treatment failure (primary or secondary resistance) and in unexplained anemia, thrombocytopenia and leukopenia.
Molecular Full (CMR) Large (MMR)	No BCR-ABL mRNA transcript detected by quantitative RT-PCR and/or nested PCR in two blood samples with adequate quality (sensitivity > 104) The ratio of BCR-ABLto ABL≤0.1% according to the international scale	RT-Q-PCR: every 3 months until MMR is reached, then at least once every 6 months Mutation analysis: performed on suboptimal response or treatment failure, always before switching to another TKI

5 If the number of metaphases is insufficient, the degree of cytogenetic response can be assessed by FISH results (at least 200 nuclei). CCgR for BCR-ABL positive nuclei<1%.

Determination of optimal, suboptimal responses, treatment failure in primary patients with chronic phase CML receiving imatinib 400 mg/day.

Time	Optimal Answer	Suboptimal response	Treatment failure	Attention!
Primary diagnosis	-	-	-	high risk CSA/Ph+
3 months	CHR, not less than a small cytogenetic response	No cytogenetic response	Less than CHR	-
6 months	Not less than PCgR	Less PCgR	No CgR	-
12 months	CCgR	PCgR	Less PCgR	Less MMR
18 months	MMR	LessMMR	Less than CCgR	-
Anytime during therapy	Stable or increasing MMR	MMR loss, mutations	CHR loss, CCgR loss, mutations, CCA/Ph+	Transcript boost CCA/Ph+

Table 6 Determination of response to treatment with second-generation TKIs as second-line therapy in patients with resistance to imatinib.

Drugs (active substances) used in the treatment

Hemostatic sponge

Azithromycin (Azithromycin)

Allopurinol (Allopurinol)

Human albumin (Albumin human)

Ambroxol (Ambroxol)

Amikacin (Amikacin)

Aminocaproic acid (Aminocaproic acid)

Aminoacids for parenteral nutrition + Other medicines (Fat emulsions + Dextrose + Multimineral)

Aminophylline (Aminophylline)

Amiodarone (Amiodarone)

Amlodipine (Amlodipine)

Amoxicillin (Amoxicillin)

Amphotericin B (Amphotericin B)

Anidulafungin (Anidulafungin)

Antiinhibitory coagulant complex (Antiingibitorny coagulant complex)

Atenolol (Atenolol)

Atracurium besylate (Atracurium besylate)

Acetylsalicylic acid (Acetylsalicylic acid)

Acetylcysteine ​​(Acetylcysteine)

Acyclovir (Acyclovir)

Bupivacaine (Bupivacaine)

Valaciclovir (Valacyclovir)

Valganciclovir (Valganciclovir)

Vancomycin (Vancomycin)

Water for injection (Water for Injection)

Voriconazole (Voriconazole)

Ganciclovir (Ganciclovir)

Gentamicin (Gentamicin)

Heparin sodium (Heparin sodium)

Hydroxycarbamide (Hydroxycarbamide)

Hydroxyethyl starch (Hydroxyethyl starch)

Dasatinib (Dasatinib)

Dexamethasone (Dexamethasone)

Dextrose (Dextrose)

Diazepam (Diazepam)

Diphenhydramine (Diphenhydramine)

Dobutamine (Dobutamine)

Dopamine (Dopamine)

Drotaverine (Drotaverinum)

Imatinib (Imatinib)

Imipenem (Imipenem)

Immunoglobulin human normal (IgG + IgA + IgM) (Immunoglobulin human normal (IgG + IgA + IgM))

Human normal immunoglobulin (Human normal immunoglobulin)

Itraconazole (Itraconazole)

Potassium chloride (Potassium chloride)

Calcium gluconate (Calcium gluconate)

Captopril (Captopril)

Caspofungin (Caspofungin)

Ketamine (Ketamine)

Ketoprofen (Ketoprofen)

Clotrimazole (Clotrimazole)

Colistimethate sodium (Colistimethate sodium)

Complex of amino acids for parenteral nutrition

Platelet concentrate (CT)

Lactulose (Lactulose)

Levofloxacin (Levofloxacin)

Lidocaine (Lidocaine)

Lisinopril (Lisinopril)

Linezolid (Linezolid)

Magnesium sulfate (Magnesium sulfate)

Mannitol (Mannitol)

Meropenem (Meropenem)

Methylprednisolone (Methylprednisolone)

Methyluracil (Dioxomethyltetrahydropyrimidine) (Methyluracil (Dioxomethyltetrahydropyrimidine))

Metronidazole (Metronidazole)

Micafungin (Micafungin)

Moxifloxacin (Moxifloxacin)

Morphine (Morphine)

Nadroparin calcium (Nadroparin calcium)

Sodium acetate

Sodium bicarbonate (Sodium hydrocarbonate)

Sodium chloride (Sodium chloride)

Naphazoline (Naphazoline)

Nilotinib (Nilotinib)

Nicergoline (Nicergoline)

Norepinephrine (Norepinephrine)

Omeprazole (Omeprazole)

Ondansetron (Ondansetron)

Ofloxacin (Ofloxacin)

Pipecuronium bromide (Pipekuroniyu bromide)

Piperacillin (Piperacillin)

Plasma, fresh frozen

Povidone - iodine (Povidone - iodine)

Prednisolone (Prednisolone)

Procaine (Procaine)

Propofol (Propofol)

Rivaroxaban (Rivaroxaban)

Rocuronium bromide (Rocuronium)

Salbutamol (Salbutamol)

Smectite dioctahedral (Dioctahedral smectite)

Spironolactone (Spironolactone)

Sulfadimethoxine (Sulfadimethoxine)

Sulfamethoxazole (Sulphamethoxazole)

Tazobactam (Tazobactam)

Tigecycline (Tigecycline)

Ticarcillin (Ticarcillin)

Thiopental-sodium (Thiopental sodium)

Tobramycin (Tobramycin)

Torasemide (Torasemide)

Tramadol (Tramadol)

Tranexamic acid (Tranexamic acid)

Trimekain (Trimecaine)

Trimethoprim (Trimethoprim)

Famotidine (Famotidine)

Famciclovir (Famciclovir)

Phenylephrine (Phenylephrine)

Phenobarbital (Phenobarbital)

Fentanyl (Fentanyl)

Filgrastim (Filgrastim)

Fluconazole (Fluconazole)

Folic acid

Furosemide (Furosemide)

Chloramphenicol (Chloramphenicol)

Chlorhexidine (Chlorhexidine)

Chloropyramine (Chloropyramine)

Cefepime (Cefepime)

Cefoperazone (Cefoperazone)

Ciprofloxacin (Ciprofloxacin)

Enoxaparin sodium (Enoxaparin sodium)

Epinephrine (Epinephrine)

Erythromycin (Erythromycin)

erythrocyte mass

Erythrocyte suspension

Ertapenem (Ertapenem)

Groups of drugs according to ATC used in the treatment

Hospitalization

Indications for hospitalization:

Indications for emergency hospitalization:
infectious complications;
· blast crisis;
hemorrhagic syndrome.

Indications for planned hospitalization:
For verification of the diagnosis and selection of therapy;
administering chemotherapy.

Prevention

Preventive actions: no.

Further management:
Patients with an established diagnosis of CML are under the supervision of a hematologist and they are monitored for the effectiveness of treatment according to indicators (see paragraph 15).

Information

Sources and literature

1. Minutes of the meetings of the Expert Council of the RCHD MHSD RK, 2015
   1. References: 1) Scottish Intercollegiate Guidelines Network (SIGN). SIGN 50: a guideline developer's handbook. Edinburgh: SIGN; 2014. (SIGN publication no. 50). . Available from URL: http://www.sign.ac.uk. 2) Khoroshko N.D., Turkina A.G., Kuznetsov S.V. and others. Chronic myeloid leukemia: advances in modern treatment and prospects // Hematology and transfusiology. - 2001. - No. 4. - C. 3-8. 3) Baccarani M., Pileri S., Steegmann J.-L., Muller M., Soverini S., Dreyling M. Chronic myeloid leukemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology 23 (Supplement 7): vii72–vii77, 2012. 4) Baccarani M., Cortes J., Pane F. et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European Leukemia Net. J Clin Oncol 2009; 27:6041–6051. 5) Vardiman JW, Melo JV, Baccarani M, Thiele J. Chronic myelogenous leukemia, BCR-ABL1 positive. In Swerdlowsh .et al (eds), WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues. Lyon: IARC 2008; 32–37. 6) Turkina A.G., Khoroshko N.D., Druzhkova G.A., Zingerman B.V., Zakharova E.S., Chelysheva E.S., Vinogradova O.Yu., Domracheva E.V., Zakharova A.V., Kovaleva L.G., Koloseinova T.I., Kolosova L.Yu., Zhuravlev V.S., Tikhonova L.Yu. The effectiveness of therapy with matinib mesylate (Glivec) in the chronic phase of myeloid leukemia; 2003. 7) Rüdiger Hehlmann. How I treat CML blast crisis. July 26, 2012; Blood: 120(4). 8) Moody K, Finlay J, Mancuso C, Charlson M. Feasibility and safety of a pilot randomized trial of infection rate: neutropenic diet versus standard food safety guidelines. J Pediatr Hematol Oncol. 2006 Mar; 28(3):126-33. 9) Gardner A, Mattiuzzi G, Faderl S, Borthakur G, Garcia-Manero G, Pierce S, Brandt M, Estey E. Randomized comparison of cooked and noncooked diets in patients undergoing remission induction therapy for acute myeloid leukemia. J Clin Oncol. 2008 Dec 10; 26(35):5684-8. 10) Carr SE, Halliday V. Investigating the use of the neutropenic diet: a survey of UK dietitians. J Hum Nutr Diet. 2014 Aug 28. 11) Boeckh M. Neutropenic diet-good practice or myth? Biol Blood Marrow Transplant. 2012 Sep; 18(9):1318-9. 12) Trifilio, S., Helenowski, I., Giel, M. et al. Questioning the role of a neutropenic diet following hematopoetic stem cell transplantation. Biol Blood Marrow Transplant. 2012; 18:1387–1392. 13) DeMille, D., Deming, P., Lupinacci, P., and Jacobs, L.A. The effect of the neutropenic diet in the outpatient setting: a pilot study. Oncol Nurs Forum. 2006; 33:337–343. 14) Blood Transfusion Guideline, CB0, 2011 (www.sanquin.nl) 15) Programmed treatment of diseases of the blood system: Collection of diagnostic algorithms and protocols for the treatment of diseases of the blood system / ed. V. G. Savchenko. - M.: Practice, 2012. - 1056 p. 16) Szczepiorkowski ZM, Dunbar NM. Transfusion guidelines: when to transfuse. Hematology Am SocHematolEduc Program. 2013; 2013:638-44. 17) Timothy Hughes and Deborah White. Which TKI? An embarrassment of riches for chronic myeloid leukemia patients. ASH Education Book December 6, 2013vol. 2013 no. 1 168-175. 18) NCCN Clinical Practice Guidelines in Oncology, 2014 (http://www.nccn.org). 19) Sokal JE, Cox EB, Baccarani M et al. Prognostic discrimination in ‘good-risk’ chronic granulocytic leukemia. Blood 1984; 63:789–799. 20) Hasford J, Pfirrmann M, Hehlmann R et al. A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. J Natl Cancer Inst 1998; 90:850–858. 21) Hasford J, Baccarani M, Hoffmann V et al. Predicting complete cytogenetic response and subsequent progression-free survival in 2060 patients with CML on imatinib treatment: the EUTOS score. Blood 2011; 118:686–692.

Information

List of protocol developers with qualification data:
1) Kemaykin Vadim Matveyevich - Candidate of Medical Sciences, JSC "National Scientific Center of Oncology and Transplantation", Head of the Department of Oncohematology and Bone Marrow Transplantation.
2) Klodzinsky Anton Anatolyevich - Candidate of Medical Sciences, JSC "National Scientific Center of Oncology and Transplantology", Hematologist, Department of Oncohematology and Bone Marrow Transplantation.
3) Ramazanova Raigul Mukhambetovna - doctor of medical sciences, professor of JSC "Kazakh Medical University of Continuing Education", head of the course of hematology.
4) Gabbasova Saule Telembaevna - RSE on REM "Kazakh Research Institute of Oncology and Radiology", head of the department of hemoblastoses.
5) Karakulov Roman Karakulovich - Doctor of Medical Sciences, Professor, Academician of the MAI RSE on REM "Kazakh Research Institute of Oncology and Radiology", Chief Researcher of the Department of Hemoblastoses.
6) Tabarov Adlet Berikbolovich - Head of the Innovation Management Department of the RSE on the REM "Hospital of the Medical Center Administration of the President of the Republic of Kazakhstan", clinical pharmacologist, pediatrician.

Indication of no conflict of interest: missing.

Reviewers:
1) Afanasiev Boris Vladimirovich - Doctor of Medical Sciences, Director of the Research Institute of Pediatric Oncology, Hematology and Transplantation named after R.M. Gorbacheva, Head of the Department of Hematology, Transfusiology and Transplantology of the State Budgetary General Educational Institution of Higher Professional Education of the First St. Petersburg State Medical University. I.P. Pavlova.
2) Rakhimbekova Gulnara Aibekovna - Doctor of Medical Sciences, Professor, JSC "National Scientific Medical Center", Head of Department.
3) Pivovarova Irina Alekseevna - Medicinae Doctor, Master of Business Administration, Chief Freelance Hematologist of the Ministry of Health and Social Development of the Republic of Kazakhstan.

Indication of the conditions for revising the protocol: revision of the protocol after 3 years and / or when new methods of diagnosis and / or treatment with a higher level of evidence appear.

Attached files

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Malignant cells can affect any system, organ, tissue of the body, including blood. With the development of tumor processes of the myeloid blood germ, accompanied by intensive reproduction of altered white blood cells, a disease called myeloid leukemia (myeloid leukemia) is diagnosed.

What is myeloid leukemia

The disease is one of the subtypes of leukemia (blood cancer). The development of myeloid leukemia is accompanied by malignant degeneration of immature lymphocytes (blasts) in the red bone marrow. As a result of the spread of mutated lymphocytes throughout the body, the cardiovascular, lymphatic, urinary, and other systems are affected.

Classification (types)

Specialized medical specialists distinguish myeloid leukemia (ICD-10 code - C92), occurring in an atypical form, myeloid sarcoma, chronic, acute (promyelocytic, myelomonocytic, with 11q23 anomaly, with multilinear dysplasia), other myeloid leukemia, not specified pathological forms .

The acute and chronic stages of progressive myeloid leukemia (unlike many other ailments) do not transform into each other.

Acute myeloid leukemia

Acute myeloid leukemia is characterized by rapid development, active (excessive) growth of blast immature blood cells.

The following stages of acute myeloid leukemia are distinguished:

• Initial. In many cases, it is asymptomatic, being detected during blood biochemistry. Symptoms are manifested by exacerbation of chronic diseases.
• Expanded. It is characterized by severe symptoms, periods of remissions and exacerbations. With effectively organized treatment, a complete remission is observed. Running forms of myeloid leukemia pass into more severe stages.
• Terminal. Accompanied by destabilization of the hematopoietic process.

Chronic myeloid leukemia

Chronic myeloid leukemia (the abbreviation CML is used in the description) is accompanied by an intensive growth of leukocyte cells, the replacement of healthy bone marrow tissues with connective tissue. Myeloid leukemia is found predominantly in the elderly. During examinations, one of the stages is diagnosed:

• Benign. Accompanied by an increase in the concentration of leukocytes without deterioration of health.
• Accelerative. Signs of the disease are detected, the number of leukocytes continues to grow.
• Blistering crisis. It is manifested by a sharp deterioration in the state of health, low sensitivity to treatment.

If during the analysis of the clinical picture it is impossible to accurately determine the nature of the progressive pathology, the diagnosis is “not specified myeloid leukemia” or “other myeloid leukemia”.

Reasons for the development of the disease

Myeloid leukemia is one of the diseases characterized by not fully understood mechanisms of development. Medical professionals, studying the potential causes that provoked chronic or acute myeloid leukemia, use the term "risk factor".

An increase in the likelihood of developing myeloid leukemia is due to:

• Hereditary (genetic) features.
• Complicated course of Bloom and Down syndromes.
• Negative consequences of the influence of ionizing radiation.
• Passing courses of radiation therapy.
• Prolonged use of certain types of drugs.
• Postponed autoimmune, cancerous, infectious diseases.
• Severe forms of tuberculosis, HIV, thrombocytopenia.
• Contacts with aromatic organic solvents.
• Environmental pollution.

Among the factors provoking myeloid leukemia in children, there are genetic diseases (mutations), as well as features of the course of the pregnancy period. An oncological blood disease in a baby can develop due to the harmful effects of radiation and other types of radiation on women during pregnancy, poisoning, smoking, other bad habits, and serious illnesses of the mother.

Symptoms

The predominant symptoms that occur with myeloid leukemia are determined by the stage (severity) of the disease.

Manifestations at the initial stage

Benign myeloid leukemia at the initial stage is not accompanied by severe symptoms and is often detected by chance during concomitant diagnosis.

Symptoms of the accelerating stage

The accelerative stage manifests itself:

• Loss of appetite.
• Slimming.
• Elevated temperature.
• Loss of strength.
• Shortness of breath.
• Increased bleeding.
• Skin blanching.
• Hematomas.
• Exacerbations of inflammatory diseases of the nasopharynx.
• Suppuration of damage to the skin (scratches, wounds).
• Painful sensations in the legs, spine.
• Forced limitation of motor activity, changes in gait.
• Enlarged palatine tonsils.
• Swelling of the gums.
• An increase in the concentration of uric acid in the blood.

End stage symptoms

The terminal stage of myeloid leukemia is characterized by the rapid development of symptoms, deterioration of well-being, and the development of irreversible pathological processes.

Symptoms of myeloid leukemia are supplemented by:

• Numerous hemorrhages.
• Sweating intensification.
• Rapid weight loss.
• Aching bone, joint pains of varying intensity.
• An increase in temperature to 38-39 degrees.
• Chills.
• Enlargement of the spleen, liver.
• Frequent exacerbations of infectious diseases.
• Anemia, decrease, the appearance of myelocytes, myeloblasts in the blood.
• The formation of necrotic zones on the mucous membranes.
• Enlarged lymph nodes.
• Failures in the functioning of the visual system.
• Headaches.

The terminal stage of myeloid leukemia is accompanied by a blast crisis, an increased risk of death.

Features of the course of chronic myeloid leukemia

The chronic stage has the longest duration (on average, about 3-4 years) among all stages of the disease. The clinical picture of myeloid leukemia is predominantly blurred and does not cause concern for the patient. Over time, the symptoms of the disease worsen, coinciding with the manifestations of the acute form.

A key feature of chronic myeloid leukemia is the lower rate of symptoms and complications compared to the rapidly progressive acute form.

How is the diagnosis carried out

Primary diagnosis of myeloid leukemia includes examination, analysis of anamnesis, assessment of the size of the liver, spleen, lymph nodes using palpation. In order to study the clinical picture as carefully as possible and prescribe effective therapy, specialized medical institutions carry out:

• Detailed blood tests (myeloid leukemia in adults and children is accompanied by an increase in the concentration of leukocytes, the appearance of blasts in the blood, the indicators of erythrocytes and platelets are reduced).
• Bone marrow biopsy. During manipulation, a hollow needle is inserted through the skin into the bone marrow, biomaterial is taken, followed by microscopic examination.
• Spinal puncture.
• X-ray examination of the chest.
• Genetic studies of blood, bone marrow, lymph nodes.
• PCR test.
• Immunological examinations.
• Scintigraphy‎ of the bones of the skeleton.
• Tomography (computer, magnetic resonance).

If necessary, the list of diagnostic measures is expanded.

Treatment

Myeloid leukemia therapy, prescribed after confirmation of the diagnosis, is carried out in a hospital of a medical institution. Treatment methods may vary. The results of previous stages of treatment (if any) are taken into account.

Treatment for chronic myeloid leukemia includes:

• Induction, drug therapy.
• Stem cell transplant.
• anti-relapse measures.

Induction therapy

The procedures carried out contribute to the destruction (cessation of growth) of cancer cells. Cytotoxic, cytostatic agents are injected into the cerebrospinal fluid, foci, where the bulk of oncocells are concentrated. To enhance the effect, polychemotherapy is used (the introduction of a group of chemotherapy drugs).

Positive results of induction therapy for myeloid leukemia are observed after several treatment courses.

Additional methods of drug therapy

Specific treatment with arsenic trioxide, ATRA (trans-retinoic acid) is used in the detection of acute promyelocytic leukemia. Monoclonal antibodies are used to stop the growth and division of leukemic cells.

stem cell transplant

Transplantation of stem cells responsible for hematopoiesis is an effective method of treating myeloid leukemia, which helps to restore the normal functioning of the bone marrow and the immune system. The transplant is carried out:

• in an autologous way. Cell sampling is carried out from the patient during the remission period. Frozen, treated cells are injected after chemotherapy.
• allogeneic way. Cells are transplanted from donor relatives.

IMPORTANT! The issue of radiation therapy for myeloid leukemia is considered only if the spread of cancer cells to the spinal cord and brain is confirmed.

Anti-relapse measures

The purpose of anti-relapse measures is to consolidate the results of chemotherapy, eliminate residual symptoms of myeloid leukemia, and reduce the likelihood of repeated exacerbations (relapses).

As part of the anti-relapse course, drugs are used that improve blood circulation. Supportive chemotherapy courses with a reduced dosage of active substances are carried out. The duration of anti-relapse treatment of myeloid leukemia is determined individually: from several months to 1-2 years.

To assess the effectiveness of the applied treatment regimens, to control the dynamics, periodic examinations are carried out aimed at identifying cancer cells, determining the degree of tissue damage by myeloid leukemia.

Complications from therapy

Complications from chemotherapy

Patients diagnosed with acute myeloid leukemia are treated with drugs that damage healthy tissues and organs, so the risk of complications is inevitably high.

The list of commonly detected side effects of drug therapy for myeloid leukemia include:

• Destruction of healthy cells along with cancer cells.
• Weakened immunity.
• General malaise.
• Deterioration of the condition of hair, skin, baldness.
• Loss of appetite.
• Violation of the functioning of the digestive system.
• anemia.
• Increased risk of bleeding.
• Cardiovascular exacerbations.
• Inflammatory diseases of the oral cavity.
• Distortions of taste sensations.
• Destabilization of the functioning of the reproductive system (menstrual disorders in women, cessation of sperm production in men).

Most of the complications of myeloid leukemia treatment resolve themselves after completion of chemotherapy (or in between cycles). Some subtypes of potent drugs can cause infertility and other irreversible consequences.

Complications after bone marrow transplantation

After the transplant procedure, the risk increases:

• development of bleeding.
• Spread of infection throughout the body.
• Transplant rejection (may occur at any time, even several years after the transplant).

In order to avoid complications of myeloid leukemia, it is necessary to constantly monitor the condition of patients.

Nutrition Features

Despite the deterioration in appetite observed in chronic and acute myeloid leukemia, it is necessary to adhere to the diet prescribed by the specialist.

To restore strength, meet the needs of the body, oppressed by myeloid (myeloid) leukemia, to prevent the adverse effects of intensive therapy for leukemia, a balanced diet is necessary.

With myeloid leukemia and other forms of leukemia, it is recommended to supplement:

• Foods rich in vitamin C, trace elements.
• Greens, vegetables, berries.
• Rice, buckwheat, wheat porridge.
• Sea fish.
• Dairy products (low-fat pasteurized milk, cottage cheese).
• Rabbit meat, offal (kidneys, tongue, liver).
• Propolis, honey.
• Herbal, green tea (has an antioxidant effect).
• Olive oil.

To prevent overload of the digestive tract and other systems with myeloid leukemia, exclude from the menu:

• Alcohol.
• Products containing trans fats.
• Fast food.
• Smoked, fried, salty dishes.
• Coffee.
• Baking, confectionery.
• Products that help thin the blood (lemon, viburnum, cranberries, cocoa, garlic, oregano, ginger, paprika, curry).

With myeloid leukemia, it is necessary to control the amount of consumption of protein foods (no more than 2 g per day per 1 kg of body weight), maintain water balance (from 2-2.5 liters of fluid per day).

Life expectancy forecast

Myeloid leukemia is a disease with an increased risk of death. Life expectancy for acute or chronic myeloid leukemia is determined by:

• The stage at which myeloid leukemia was detected and treatment started.
• Age characteristics, health status.
• The level of leukocytes.
• Sensitivity to chemical therapy.
• The intensity of brain damage.
• The length of the remission period.

With timely treatment, the absence of symptoms of complications of AML, the prognosis of life in acute myeloid leukemia is favorable: the probability of five-year survival is about 70%. In case of complications, the rate is reduced to 15%. In childhood, the survival rate reaches 90%. If therapy for myeloid leukemia is not carried out, even the 1-year survival rate is at a low level.

The chronic stage of myeloid leukemia, in which systematic therapeutic measures are carried out, is characterized by a favorable prognosis. In most patients, life expectancy after timely identification of myeloid leukemia exceeds 20 years.

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