Chronic myeloid leukemia stage 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 a gradually increasing leukocytosis, small at the beginning of the disease (10-15 10 9 / l) and reaching, as the disease progresses, without treatment, huge numbers - 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 figures - 15-20% or more.

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

In most patients, the number of platelets up to 400-600 10 9 / l, and sometimes more - up to 800-1000 10 9 / l, rarely even higher. The content of hemoglobin and 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 observed.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Chronic myeloid leukemia affects men and women equally. It is difficult to recognize the course of the disease, because the process is initially asymptomatic. Often, myeloid leukemia is detected at later stages and then survival rate is reduced.

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

Causes of chronic myeloid leukemia

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

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

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

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

Stages of pathology development

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

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

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

Symptoms of the disease

The chronic period lasts on average up to 3 years, in isolated cases – 10 years. During this time, the patient may not be aware of the presence of the disease. Rarely do they attach importance to unobtrusive symptoms, such as fatigue, decreased ability to work, and a feeling of a full stomach. On examination, an increase in the size of the spleen and an increased level of granulocytes are revealed.

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

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

Diagnostic measures

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

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

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

How is myeloid leukemia treated?

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

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

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

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

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

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

Life expectancy with chronic myeloid leukemia

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

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

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

Essence of the disease

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

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

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

Causes of the disease

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

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

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

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

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

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

How is the disease progressing?

Doctors distinguish three stages of development of chronic myeloid leukemia:

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

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

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

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

Sometimes in the initial phase the function of platelets is disrupted - their level increases, blood clotting increases. A person develops thrombosis, which is associated with headaches and dizziness. Sometimes the patient 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 heavily, especially at night.

The duration of the acceleration phase is from one to one and a half years. Sometimes a person begins to feel unwell only in the second stage and goes to the doctor when the disease 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 rapidly lose weight;
• the patient feels joint pain;
• hypohidrosis;
• hemorrhages and bleeding.

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

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

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

How to diagnose the disease?

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

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

Methods for diagnosing chronic myeloid leukemia:

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

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

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

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

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

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

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

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

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

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

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

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

Treatment of the disease

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

Hematologic oncologists use four main treatment methods:

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

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

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

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

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

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

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

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

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

Indications for it are:

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

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

Irradiation is used at the accelerated stage of the disease.

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

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

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

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

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

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

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

Survival Projections

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

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

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

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

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

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

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

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

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 advice
RSE at the RVC "Republican Center"
healthcare development"
Ministry of Health
and social development
Republic of Kazakhstan
dated July 9, 2015
Protocol No. 6

Protocol name: Chronic myeloid leukemia

Chronic myeloid leukemia (CML)- a 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 22, the BCR-ABL fusion gene is formed on it.

Protocol code:

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

Protocol development date: 2015

Abbreviations used in the protocol:
* - drugs purchased as part of a one-time import
HIV - human immunodeficiency virus
TKIs - tyrosine kinase inhibitors
ELISA - enzyme immunoassay
OAM - general urine analysis
CBC - complete blood count
BMT - hematopoietic stem cell/bone marrow transplantation
CML - chronic myeloid leukemia
ECG - electrocardiogram
Ultrasound - ultrasound examination
BCR - ABL - breakpoint cluster region-Abelson
CCA - Complex chromosomal aberrations
ELN - European Leukemia Net
FISH - 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 for the recommendations
A	A high-quality meta-analysis, 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.
IN	High-quality (++) systematic review of cohort or case-control studies or High-quality (++) cohort or case-control studies with very low risk of bias or RCTs with low (+) risk of bias, the results of which can be generalized to an appropriate population.
WITH	A cohort or case-control study or a controlled trial without randomization with a low risk of bias (+), the results of which can be generalized to an appropriate population, or an RCT with a very low or low risk of bias (++ or +), the results of which are not can be directly generalized to the relevant population.
D	Case series description or
	Uncontrolled study or
	Expert opinion

Classification

Clinical classification:
During CML, there are 3 phases: chronic, transitional (acceleration phase) and terminal phase (blast transformation or blast crisis). The criteria for the acceleration and blast crisis phases 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 therapy	Not applicable	Not applicable	Not applicable
Leukocytes	an increase in the number of leukocytes (>10x109l) in the blood despite 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 liver and spleen, including lymph nodes, skin, central nervous system, bones and lungs.

Clinical picture

Symptoms, course

Diagnostic criteria for making a diagnosis :
· presence of the Philadelphia chromosome (balanced translocation t(9;22) (q34; q11) according to a standard cytogenetic study of bone marrow 1
· 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;
· low-grade fever;
· chilling;
pain in bones or joints;
· weight loss;
· hemorrhagic rashes in the form of petechiae and ecchymoses on the skin;
· epistaxis;
· menorrhagia;
· increased bleeding;
· enlarged lymph nodes;
· pain and heaviness in the left upper abdomen (enlarged spleen);
· heaviness in the right hypochondrium.

Anamnesis: you should pay attention to:
· long-term weakness;
· rapid fatigue;
· frequent infectious diseases;
· increased bleeding;
· appearance of hemorrhagic rashes on the skin and mucous membranes;
· enlarged liver, spleen.

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

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

Diagnostics

The list of basic and additional diagnostic measures:

Basic (mandatory) diagnostic examinations performed on an outpatient basis:
· UAC;

· myelogram;

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

Additional diagnostic examinations performed on an outpatient basis:
· bone marrow examination using FISH method (t(9;22)/BCR/ABL);

· ELISA for HIV markers;
· ELISA for markers of herpes group viruses;
· Rehberg-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 for 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.

Basic (mandatory) diagnostic examinations carried out at the hospital level:
· CBC with platelet and reticulocyte counting;
· biochemical blood test (total protein, albumin, globulins, IgA, IgM, IgG levels, 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 examination of bone marrow;
· bone marrow examination using FISH method (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 using a flow cytofluorimeter (acute leukemia panel);
· histological examination of biopsy material (lymph node, iliac crest);
· PCR for viral infections (viral hepatitis, cytomegalovirus, herpes simplex virus, Epstein-Barr virus, Varicella/Zoster virus);
X-ray of the paranasal sinuses;
· radiography of bones and joints;
· FGDS;
· Doppler ultrasound of vessels;
· bronchoscopy;
· colonoscopy;
daily blood pressure monitoring;
· 24-hour ECG monitoring;
· spirography.

Diagnostic measures carried out at the stage of emergency medical care:
· collection of complaints and medical history;
· physical examination.

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

Indications for consultation with 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;
Dermatovenerologist - skin syndrome
· infectious disease specialist - suspicion of viral infections;
· cardiologist - uncontrolled hypertension, chronic heart failure, heart rhythm and conduction disorders;
· neurologist 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 - psychosis;
· psychologist - depression, anorexia, etc.;
· resuscitator - treatment of severe sepsis, septic shock, acute pulmonary injury syndrome with differentiation syndrome and terminal conditions, 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 antiglobulin test, ineffective transfusions, 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 dentofacial system.

Laboratory diagnostics

Laboratory research:
· General blood analysis: leukocytes, erythrocytes and platelets are counted. Characterized by absolute neutrophilic leukocytosis with a shift of the nuclear formula to the left (to promyelocytes or blasts), absence of leukemic failure, basophilic-eosinophilic association. At the onset of the disease, the hemoglobin level may be within normal limits or elevated, and moderate thrombocytosis may be observed. In the acceleration phase and blast crisis, thrombocytopenia and anemia may develop.
· Blood chemistry: there is an increase in LDH activity, hyperuricemia.
· Morphological study: bone marrow aspirate shows hypercellular bone marrow, increased number of blasts, basophils and eosinophils.
· Immunophenotyping: is carried out to determine the immunophenotype of blasts when they are in 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 in a cytogenetic study.
Differential diagnosis can be carried out with leukemoid reaction of the myeloid type, which occurs in various infections (sepsis, tuberculosis) and some tumors (Hodgkin lymphoma, solid tumors), as well as other chronic myeloproliferative diseases. The main diagnostic criteria for chronic myeloid leukemia are:

• the presence of anemia that is not characteristic of the 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 in the case of 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 steadily progress).

In the blast crisis phase, differential diagnosis must be made with acute leukemia. The duration of the process, as well as the degree of metaplasia in the organs in these cases, are not the decisive criterion, if we take into account, on the one hand, the possibility of an early exacerbation of chronic leukemia, when known difficulties arise in determining the time of onset and duration 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 reference points for differential diagnosis are some differences in the blood picture:

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

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 security.
Diet: neutropenic patients are not recommended to follow a certain diet ( level of evidence B).

Transfusion support
Prophylactic transfusions of apheresis virus-inactivated, preferably irradiated platelets are carried out when thrombocytopenia is less than 10x109 / L or at a level less than 20x109 / L in the presence 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.
Transfusion of leukofiltered, preferably irradiated, red blood cells is carried out in the presence of poor tolerability 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, concomitant diseases, tolerability of chemotherapy and the development of complications in the previous stages of treatment.
Laboratory indicators for determining indications are of auxiliary value, mainly for assessing the need for prophylactic transfusions of platelet concentrate.
Indications for transfusions also depend on the time after a course of chemotherapy - the predicted decrease in indicators in the next few days is taken into account.
Red blood cell mass/suspension (level of evidence)D):
· Hemoglobin levels do not need to be increased as long as normal reserves and compensatory mechanisms are sufficient to meet tissue oxygen needs;
· There is only one indication for transfusion of red blood cell-containing media for chronic anemia - symptomatic anemia (manifested by tachycardia, shortness of breath, angina pectoris, syncope, denovo depression or ST elevation);
· A hemoglobin level of less than 30 g/l is an absolute indication for red blood cell transfusion;
· In the absence of decompensated diseases of the cardiovascular system and lungs, hemoglobin levels may be indications for prophylactic red blood cell transfusion in chronic anemia:

Platelet concentrate (level of evidence)D):
· If the platelet level decreases to less than 10 x 10 9 / l, apheresis platelet transfusion is performed in order to maintain their level not lower than 30-50 x 10 9 / l, especially in the first 10 days of the course.
· If there is a high risk of hemorrhagic complications (age over 60 years, increase in creatinine level 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 evidence)D):
· FFP transfusions are performed in patients with bleeding or before invasive interventions;
· Patients with an INR of ³2.0 (for neurosurgical interventions ³1.5) are considered candidates for FFP transfusion when planning invasive procedures.

Drug treatment:
During the examination, until the results of a cytogenetic study are received 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 patient’s weight. For leukocytosis of more than 100 x10 9 /l, hydrea is prescribed at a dose of 50 mcg/kg daily. Subsequently, when the number of leukocytes in the blood decreases, the dose of hydrea is reduced: for leukocytosis 40-100 x 10 9 /l, 40 mg/kg is prescribed, for 20-40 x 10 9 /l - 30 mg/kg, for 5 - 20 x 10 9 / l - 20 mg/kg daily.
Imatinib can be started at any white blood cell count. Imatinib is prescribed (in the chronic phase) at a dose of 400 mg/day orally after meals.
To obtain stable results, taking imatinib must be constant and long-term. Doses of imatinib are adjusted depending on 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	TOXICITY DEGREE
	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 is normal	50-74,9	25,0-49,0	Less than 25
Hemoglobin	Norm	100 is normal	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. Treatment breaks should be taken if severe grade 3 hematological toxicity develops.
Treatment is resumed when clinical and hematological parameters are restored (neutrophils >1.5 thousand/μl, platelets >75 thousand/μl). After relief of toxicity, imatinib is resumed at a dose of 400 mg if the break in treatment is less than 2 weeks. With repeated episodes of cytopenia or their duration lasting more than 2 weeks, the dose of imatinib may be reduced to 300 mg/day. Further reduction in the dose of imatinib is not advisable because it is not possible to achieve its therapeutic concentration in the blood. Therefore, with repeated episodes of cytopenia, breaks in imatinib treatment are taken. When clinical and hematological parameters stabilize within 1-3 months, it is necessary to consider resuming the drug at a dose of 400 mg/day.
Patients who have previously received long-term busulfan, it is recommended to continue taking busulfan(switching to imatinib therapy is ineffective due to the possibility of developing myelosuppression).
Treatment tactics for patients in case of intolerance to imatinib or insufficient response to therapy, as well as in the acceleration phase and blast crisis are presented in Table 2, response criteria in Tables 4 and 5.

Chronic phase
1st line	All patients	Imatinib4 400 mg daily
2nd line (after imatinib)	Toxicity, intolerance	Dasatinib or Nilotinib
	Suboptimal response	Continue imatinib at same or higher doses, dasatinib, or nilotinib
	No response	Dasatinib or nilotinib Allo-HSCT when progressing to accelerated or blast crisis and in the presence of the T315I mutation
3rd line	Suboptimal response to dasatinib or nilotinib	Continue Dasatinib or Nilotinib. In case of previous resistance to imatinib, the presence of mutations in patients with EBMT scores≤2, consider the possibility of alloBMT
	Failure to respond to Dasatinib or Nilotinib	alloBMT
Acceleration and blast crisis phase
1st line of therapy	Patients who did not receive TKIs	Imatinib 600 mg or 800 mg or dasatinib 140 mg or nilotinib 400 mg x 2 times a day followed by alloBMT
2nd line of therapy	Patients who have previously received imatinib	AlloBMT, nilotinib or dasatinib therapy

4 For high-risk patients in the chronic phase of CML, it is possible to use nilotinib and dasatinib in the first line of therapy (with a score of >1.2 according to Socal et al, >1480 according to EURO, >87 according to EUTOS - calculator for calculating points 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.

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

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

Medicines that weaken the toxic effect of anticancer drugs
· filgrastim, solution for injection 0.3 mg/ml, 1 ml;
· ondansetron, solution for injection 8 mg/4ml.

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, tablet 250 mg.

· 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, 500 mg.

· sulfamethoxazole/trimethoprim, tablet 480 mg.

Solutions used to correct disturbances in water, electrolyte and acid-base balance

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

· heparin, solution for injection 5000 IU/ml, 5 ml; (for flushing the catheter)


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

· ambroxol, solution for oral administration and inhalation, 15 mg/2 ml, 100 ml;

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



· drotaverine, tablet 40 mg;

lactulose, syrup 667 g/l, 500 ml;

Lisinopril, 5 mg tablet;
· methylprednisolone, tablet, 16 mg;

· omeprazole, capsule 20 mg;

Prednisolone, tablet, 5 mg;


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

· chlorhexidine, solution 0.05% 100ml;

Drug treatment provided at the inpatient level:
− list of essential medicines indicating the release form (having a 100% probability of use):
· imatinib 100 mg, capsules;
· nilotinib 200 mg, capsules;
· dasatinib* 70 mg, tablets;
· Hydroxyurea 500 mg, capsules.

− list of additional medicines indicating the release form (less than 100% probability of use):

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

Antibacterial agents:
Azithromycin, tablet/capsule, 500 mg; lyophilized powder for the preparation of 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 preparing a solution for intravenous and intramuscular administration 1000 mg+500 mg;
· vancomycin, powder/lyophilisate for solution for infusion 1000 mg;
· gentamicin, solution for injection 80 mg/2 ml 2 ml;
· imipinem, cilastatin powder for solution for infusion, 500 mg/500 mg;
· sodium colistimethate*, lyophilisate for the preparation of solution for infusion, 1 million units/bottle;
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% 100 ml, dental gel 20 g;
· 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/bottle;
Ticarcillin/clavulanic acid, lyophilized powder for the preparation of solution for infusion 3000 mg/200 mg;
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, 500 mg tablet;
· erythromycin, tablet 250 mg;
Ertapenem lyophilisate, for the preparation of a solution for intravenous and intramuscular injections 1 g.

Antifungal drugs
· 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/bottle, tablet 50 mg;
· itraconazole, oral solution 10 mg/ml 150.0;
· caspofungin, lyophilisate for the preparation of solution for infusion 50 mg;
· clotrimazole, cream for external use 1% 30g, 15ml;
· micafungin, lyophilized powder for the preparation of 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;
· acyclovir, powder for solution for infusion, 250 mg;
· acyclovir, cream for external use, 5% - 5.0;
· valacyclovir, tablet, 500 mg;
· valganciclovir, tablet, 450 mg;
· ganciclovir*, lyophilisate for solution for infusion 500 mg;
Famciclovir, tablets, 500 mg No. 14.

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

Additional immunosuppressive drugs:
· dexamethasone, solution for injection 4 mg/ml 1 ml;
· methylprednisolone, tablet, 16 mg, solution for injection, 250 mg;
· prednisolone, solution for injection 30 mg/ml 1 ml, tablet 5 mg.

Solutions used to correct disturbances of water, electrolyte and acid-base balance, parenteral nutrition
· albumin, solution for infusion 10%, 100 ml, 20% 100 ml;
· water for injection, solution for injection 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 injection 10%, 5 ml;
· calcium chloride, solution for injection 10% 5ml;
· magnesium sulfate, solution for injection 25% 5 ml;
· mannitol, solution for injection 15% -200.0;
· sodium chloride, solution for infusion 0.9% 500ml, 250ml;
· sodium chloride, potassium chloride, sodium acetate solution for infusion in a bottle of 200 ml, 400 ml, 200 ml;
· sodium chloride, potassium chloride, sodium acetate solution for infusion 400ml;
· sodium chloride, potassium chloride, sodium bicarbonate solution for infusion 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 emulsion mixture for inf.: three-chamber containers 2 l;
· hydroxyethyl starch (pentastarch), solution for infusion 6% 500 ml;
· amino acid complex, emulsion for infusion containing a mixture of olive and soybean oils in a ratio of 80:20, a solution of amino acids with electrolytes, a dextrose solution, with a total calorie content of 1800 kcal 1,500 ml three-section container.

Medicines used for intensive care (cardiotonic drugs for the treatment of septic shock, muscle relaxants, vasopressors and anesthetics):
· aminophylline, solution for injection 2.4%, 5 ml;
· amiodarone, solution for injection, 150 mg/3 ml;
· atenolol, tablet 25 mg;
· atracurium besylate, solution for injection, 25 mg/2.5 ml;
· atropine, solution for injection, 1 mg/ml;
· diazepam, solution for intramuscular and intravenous use 5 mg/ml 2 ml;
· dobutamine*, solution for injection 250 mg/50.0 ml;
· dopamine, solution/concentrate for the preparation of solution for injection 4%, 5 ml;
· simple insulin;
· ketamine, solution for injection 500 mg/10 ml;
· morphine, solution for injection 1% 1 ml;
· norepinephrine*, solution for 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 the preparation of solution for intravenous administration 500 mg;
· phenylephrine, solution for injection 1% 1ml;
· phenobarbital, tablet 100 mg;
human normal immunoglobulin, solution for infusion;
· epinephrine, solution for injection 0.18% 1 ml.

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

Other medicines
· bupivacaine, solution for injection 5 mg/ml, 4 ml;
· lidocaine, solution for injection, 2%, 2 ml;
· procaine, solution for injection 0.5%, 10 ml;
· human immunoglobulin normal solution for intravenous administration 50 mg/ml - 50 ml;
· omeprazole, capsule 20 mg, lyophilized powder for the preparation of solution for injection 40 mg;
· famotidine, lyophilized powder for the preparation of 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, tablet/capsule 5 mg;
· acetylcysteine, powder for solution for oral administration, 3 g;
· heparin, gel in tube 100,000 units 50 g;
· dexamethasone, eye drops 0.1% 8 ml;
Diphenhydramine, solution for injection 1% 1 ml;
· drotaverine, solution for injection 2%, 2 ml;
· captopril, tablet 50 mg;
· ketoprofen, solution for injection 100 mg/2ml;
lactulose, syrup 667 g/l, 500 ml;
· chloramphenicol, sulfadimethoxin, methyluracil, trimecaine ointment for external use 40g;
Lisinopril, 5 mg tablet;
· methyluracil, ointment for topical use in a tube 10% 25g;
· naphazoline, nasal drops 0.1% 10ml;
· nicergoline, lyophilisate for the preparation of injection solution 4 mg;
· povidone-iodine, solution for external use 1 l;
· salbutamol, solution for nebulizer 5 mg/ml-20 ml;
· dioctahedral smectite, powder for preparation of suspension for oral administration 3.0 g;
· spironolactone, capsule 100 mg;
· tobramycin, eye drops 0.3% 5ml;
· torasemide, tablet 10 mg;
· tramadol, solution for injection 100 mg/2ml;
tramadol, capsule 50 mg, 100 mg;
· fentanyl, therapeutic transdermal 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, solution for injection 20 mg/ml 1 ml.

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

Other types of treatment:

Other types of treatment provided on an outpatient basis: do not apply.

Other types of treatment provided at the inpatient level:

Hematopoietic stem cell transplantation.
Allogeneic hematopoietic stem cell transplantation can lead to a cure for patients with CML. However, this type of treatment is applicable to few patients with CML, given the high risk of complications and mortality.
When making a diagnosis and during the treatment of 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 should be calculated before initiating therapy.

Prognostic scores for patients with CML:

	Socal et al.	EURO	EUTOS [21 ]
Age (years)	0.116 (age-43.4)	0.666 if over 50	Not used
Dimensions of the spleen (cm) by palpation below the costal arch	0.345 x (spleen-7.51)	0.042 x size spleen	4 x size spleen
Platelets (x10 9 /l)	0.188 x [(platelet/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

Prognostic scale for the probability of response to 2nd generation TKI drugs according to Hammersmith

Other types of treatment provided during emergency medical care: do not apply.

Surgical intervention:

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

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

Indicators of treatment effectiveness

Treatment response criteria 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 No	No metaphases with Ph 1-35% Ph+ metaphases 36-65% Ph+ metaphases 66-95% Ph+ metaphases >95% Ph+ metaphases	At diagnosis, after 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 cases of treatment failure (primary or secondary resistance) and in cases of unexplained anemia, thrombocytopenia and leukopenia.
Molecular Full (CMR) Large (MMR)	BCR-ABL mRNA transcript is not detected by quantitative RT-PCR and/or nested PCR in two blood samples with adequate quality (sensitivity > 104) BCR-ABL to ABL ratio≤0.1% on the international scale	RT-Q-PCR: every 3 months until MMR is reached, then at least once every 6 months Mutation analysis: performed in case of suboptimal response or treatment failure, always before changing to another TKI

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

Determination of optimal, suboptimal responses, and 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 CCA/Ph+
3 months	CHR, at least minor 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 than MMR
18 months	MMR	Less than MMR	Less CCgR	-
Any time during therapy	Stable or increasing MMR	Loss of MMR, mutations	Loss of CHR, loss of CCgR, mutations, CCA/Ph+	Increased transcript levels CCA/Ph+

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

Drugs (active ingredients) used in treatment

Hemostatic sponge

Azithromycin (Azithromycin)

Allopurinol

Albumin human

Ambroxol

Amikacin

Aminocaproic acid

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

Aminophylline

Amiodarone

Amlodipine

Amoxicillin

Amphotericin B

Anidulafungin

Antiinhibitory coagulant complex

Atenolol

Atracurium besylate

Acetylsalicylic acid

Acetylcysteine

Acyclovir

Bupivacaine

Valacyclovir

Valganciclovir

Vancomycin

Water for Injection

Voriconazole (Voriconazole)

Ganciclovir (Ganciclovir)

Gentamicin (Gentamicin)

Heparin sodium (Heparin sodium)

Hydroxycarbamide

Hydroxyethyl starch

Dasatinib (Dasatinib)

Dexamethasone (Dexamethasone)

Dextrose (Dextrose)

Diazepam (Diazepam)

Diphenhydramine (Diphenhydramine)

Dobutamine (Dobutamine)

Dopamine (Dopamine)

Drotaverine (Drotaverinum)

Imatinib (Imatinib)

Imipenem (Imipenem)

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

Human normal immunoglobulin

Itraconazole (Itraconazole)

Potassium chloride (Potassium chloride)

Calcium gluconate

Captopril

Caspofungin

Ketamine

Ketoprofen

Clotrimazole

Colistimethate sodium

Complex of amino acids for parenteral nutrition

Platelet concentrate (CT)

Lactulose

Levofloxacin

Lidocaine

Lisinopril

Linezolid

Magnesium sulfate

Mannitol

Meropenem

Methylprednisolone

Methyluracil (Dioxomethyltetrahydropyrimidine)

Metronidazole

Micafungin

Moxifloxacin

Morphine

Nadroparin calcium

Sodium acetate

Sodium hydrocarbonate

Sodium chloride

Naphazoline

Nilotinib

Nicergoline

Norepinephrine

Omeprazole

Ondansetron

Ofloxacin

Pipecuronium bromide

Piperacillin

Fresh frozen plasma

Povidone - iodine

Prednisolone

Procaine

Propofol

Rivaroxaban

Rocuronium bromide

Salbutamol

Dioctahedral smectite

Spironolactone

Sulfadimethoxine

Sulfamethoxazole

Tazobactam

Tigecycline

Ticarcillin

Thiopental sodium

Tobramycin

Torasemide

Tramadol

Tranexamic acid

Trimecaine

Trimethoprim

Famotidine

Famciclovir

Phenylephrine

Phenobarbital

Fentanyl

Filgrastim

Fluconazole

Folic acid

Furosemide

Chloramphenicol

Chlorhexidine

Chloropyramine

Cefepime

Cefoperazone

Ciprofloxacin

Enoxaparin sodium

Epinephrine

Erythromycin

Red blood cell mass

Erythrocyte suspension

Ertapenem

Groups of drugs according to ATC used in treatment

Hospitalization

Indications for hospitalization:

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

Indications for planned hospitalization:
· to verify the diagnosis and select therapy;
· Carrying out chemotherapy.

Prevention

Preventive actions: No.

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

Information

Sources and literature

1. Minutes of meetings of the Expert Council of the RCHR of the Ministry of Health of the Republic of Kazakhstan, 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: successes of modern treatment and prospects // Hematology and transfusiology. - 2001. - No. 4. - pp. 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., Kolosheinova T.I., Kolosova L.Yu., Zhuravlev V.S., Tikhonova L.Yu. The effectiveness of therapy with matinib mesylate (Gleevec) 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. Mar 2006; 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, СВ0, 2011 (www.sanquin.nl) 15) Program 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.: Praktika, 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 details:
1) Kemaykin Vadim Matveevich - Candidate of Medical Sciences, JSC National Scientific Center of Oncology and Transplantology, Head of the Department of Oncohematology and Bone Marrow Transplantation.
2) Anton Anatolyevich Klodzinsky - Candidate of Medical Sciences, JSC National Scientific Center of Oncology and Transplantology, hematologist at the 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 hematology course.
4) Gabbasova Saule Telembaevna - RSE at the RSE "Kazakh Research Institute of Oncology and Radiology", head of the department of hemoblastosis.
5) Karakulov Roman Karakulovich - Doctor of Medical Sciences, Professor, Academician of the MAI RSE at the Kazakh Research Institute of Oncology and Radiology, chief researcher of the department of hemoblastosis.
6) Tabarov Adlet Berikbolovich - Head of the Department of Innovative Management of the RSE at the RSE "Hospital of the Medical Center Administration of the President of the Republic of Kazakhstan", clinical pharmacologist, pediatrician.

Disclosure of no conflict of interest: absent.

Reviewers:
1) Afanasyev Boris Vladimirovich - Doctor of Medical Sciences, Director of the Research Institute of Children's Oncology, Hematology and Transplantology named after R.M. Gorbacheva, Head of the Department of Hematology, Transfusiology and Transplantology, State Budgetary Institution of Higher Professional Education, First St. Petersburg State Medical University named after. I.P. Pavlova.
2) Rakhimbekova Gulnara Aibekovna - Doctor of Medical Sciences, Professor, JSC National Scientific Medical Center, head of the 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 reviewing the protocol: revision of the protocol after 3 years and/or when new diagnostic and/or treatment methods with a higher level of evidence become available.

Attached files

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Malignant cells can affect any system, organ, or tissue of the body, including the blood. With the development of tumor processes in the myeloid blood lineage, accompanied by intensive proliferation 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 multilineage dysplasia), other myeloid leukemia, unspecified 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 and active (excessive) growth of blast immature blood cells.

The following stages of acute myeloid leukemia are distinguished:

• Initial. In many cases, it is asymptomatic and is detected during blood biochemistry. Symptoms manifest as exacerbation of chronic diseases.
• Expanded. It is characterized by severe symptoms, periods of remissions and exacerbations. With effectively organized treatment, complete remission is observed. Advanced forms of myeloid leukemia progress to 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 intensive growth of leukocyte cells, replacement of healthy bone marrow tissue with connective tissue. Myeloid leukemia is detected mainly in old age. During examinations, one of the stages is diagnosed:

• Benign. Accompanied by an increase in the concentration of leukocytes without deterioration in well-being.
• Accelerative. Signs of the disease are detected, the number of leukocytes continues to increase.
• Blast crisis. It manifests itself as a sharp deterioration in 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, a diagnosis of “unspecified myeloid leukemia” or “other myeloid leukemia” is made.

Reasons for the development of the disease

Myeloid leukemia is one of the diseases characterized by incompletely studied development mechanisms. Medical professionals use the term “risk factor” when studying potential causes of chronic or acute myeloid leukemia.

An increased likelihood of developing myeloid leukemia is caused by:

• Hereditary (genetic) characteristics.
• Complicated course of Bloom's and Down's syndromes.
• Negative consequences of ionizing radiation.
• Taking courses of radiation therapy.
• Long-term use of certain types of medications.
• Past autoimmune, cancer, infectious diseases.
• Severe forms of tuberculosis, HIV, thrombocytopenia.
• Contacts with aromatic organic solvents.
• Environmental pollution.

Among the factors that provoke myeloid leukemia in children are genetic diseases (mutations), as well as features of the course of pregnancy. 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 appear in 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 discovered by chance during concomitant diagnosis.

Symptoms of the accelerated stage

The acceleration stage manifests itself:

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

End stage symptoms

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

Symptoms of myeloid leukemia are supplemented by:

• Numerous hemorrhages.
• Intensification of sweating.
• Rapid weight loss.
• Aching bone and joint pain of varying intensity.
• An increase in temperature to 38-39 degrees.
• Chills.
• Enlarged spleen and liver.
• Frequent exacerbations of infectious diseases.
• Anemia, decrease, appearance of myelocytes, myeloblasts in the blood.
• Formation of necrotic zones on mucous membranes.
• Enlarged lymph nodes.
• Malfunctions 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 mostly 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.

The key feature of chronic myeloid leukemia is the lower rate of development of symptoms and complications compared to the rapidly progressing acute form.

How is diagnostics carried out?

Primary diagnosis of myeloid leukemia includes examination, history analysis, assessment of the size of the liver, spleen, and lymph nodes using palpation. In order to study the clinical picture as thoroughly 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 decrease).
• Bone marrow biopsy. During the manipulation, a hollow needle is inserted through the skin into the bone marrow, biomaterial is collected, followed by microscopic examination.
• Spinal tap.
• X-ray examination of the chest.
• Genetic studies of blood, bone marrow, lymph nodes.
• PCR test.
• Immunological examinations.
• Scintigraphy of skeletal bones.
• Tomography (computer, magnetic resonance).

If necessary, the list of diagnostic measures is expanded.

Treatment

Therapy for myeloid leukemia, prescribed after confirmation of the diagnosis, is carried out in the 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 transplantation.
• Anti-relapse measures.

Induction therapy

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

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

Additional drug therapy methods

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, helping to restore the normal functioning of the bone marrow and immune system. The transplant is carried out:

• In an autologous way. Cell collection is carried out from the patient during the remission period. Frozen, processed cells are injected after chemotherapy.
• Allogeneic method. Cells are transplanted from relative donors.

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 goal 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 to improve blood circulation. Maintenance chemotherapy courses are carried out with a reduced dosage of active substances. The duration of anti-relapse treatment for myeloid leukemia is determined individually: from several months to 1-2 years.

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

Complications from therapy

Complications from chemotherapy

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

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

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

The vast majority of complications of treatment for myeloid leukemia resolve on their own after completion of chemotherapy (or in the intervals between courses). Some subtypes of potent medications 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 (can occur at any time, even several years after transplantation).

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 a specialist.

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

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

• Products rich in vitamin C and microelements.
• 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 in case of myeloid leukemia, the following are excluded from the menu:

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

In case of myeloid leukemia, it is necessary to control the volume of protein food consumption (no more than 2 g per day per 1 kg of body weight), maintain water balance (from 2-2.5 liters of liquid per day).

Life expectancy forecast

Myeloid leukemia is a disease accompanied by 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.
• Leukocyte level.
• Sensitivity to chemical therapy.
• The intensity of brain damage.
• The duration of the remission period.

With timely treatment and the absence of symptoms of AML complications, the life prognosis for 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 low.

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

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