Myeloid leukemia is a malignant degeneration of stem cells in the bone marrow, which is responsible for the production of blood cells - red and white blood cells and platelets. With myeloid leukemia (leukemia,) the bone marrow produces blast, immature cells, which, gradually, displace normal shaped elements from the bloodstream.

The disease is predominantly chronic and affects mainly adults. A blood test for myeloid leukemia is required to make a diagnosis. Since significant changes occur at different stages of the disease, it is required to conduct analyzes several times. If myeloid leukemia is suspected, doctors recommend regular examinations.

Causes

Myeloid leukemia is the result of a mutation in the bone marrow. The abnormal cell loses its ability to function normally and begins to spontaneously divide. Cancer cells, multiplying, gradually crowd out healthy ones. As a result, anemia occurs and the body loses its defense against infections. Leukemia cells penetrate the lymph nodes, cooperate in tumors and provoke pathological processes.

The cause of multiple myeloma can be radioactive radiation or exposure to carcinogens, among which are drugs, paint thinners, rodent and insect control agents.

Hereditary factors in leukemia, as in other diseases, take place. In families where relatives fall ill with multiple myeloma, the probability of diseases among descendants is high. It is not the disease itself that is transmitted to children, but the predisposition to it.

There is a hypothesis about the infectious etiology of the disease. In this case, the race and place of residence of a person matters.

Diagnostics

A preliminary diagnosis of myelogenous leukemia is made on the basis of the results, a standard diagnostic procedure for any disease. The doctor should be alerted by an increase in the number of leukocytes.

For multiple myeloma, first of all, it should take into account the number of leukocytes and their ratio with the calculation of the leukocyte formula. When calculating the leukocyte formula, there is a shift to the left, the appearance of promyelocytes. The percentage of basophils and eosinophils is growing,. The number of platelets is normal, or slightly increased. Mild anemia symptoms are observed.

If myeloid leukemia progresses, change. Therefore, it is necessary to repeat the blood test for myeloid leukemia after a while. The results of the studies reveal severe anemia, the formed elements change size and deform (anisocytosis and poikilocytosis); the number of leukocytes increases many times in comparison with previous results. The number of blast cells reaches 15%. and erzinophils exceeds the norm. The action of alkaline phosphatase in neutrophils is blocked.

Symptoms associated with myeloid leukemia are liver problems, confirmed by an increase in the activity of serum enzymes - alanine aminotransferase and alkaline phosphatase.

Symptoms

The symptoms of myeloid leukemia are:

• Pain in the bones. The femurs, spine, pelvis, ribs hurt;

• Pathological fractures;
• Hypercalcemia. Manifested by vomiting, nausea, constipation, polyuria. There may be brain disorders, the person falls into lethargy or coma;
• Kidney diseases. Nephropathy manifests itself in the form of an increase in the content of calcium and uric acid in the blood, the appearance of protein in the urine;
• Anemia is normochromic. normally, ESR rises sharply;
• Osteoporosis;
• Compression of the spinal cord by tumors of the spine. It manifests itself in the form of back pain, aggravated by coughing, sneezing. The work of the bladder and intestines is disturbed .;
• Vulnerability to bacterial infections. Associated with a weakened immune system;
• Hemorrhages. , uterus, gums, subcutaneous hemorrhages.

Preparation for analysis

The rules for donating blood for a general analysis do not provide for specific rules for preparation. How to take a blood test for chronic myeloid leukemia is known. , in the morning, to avoid "interference" that distorts the results. On the day before blood donation, heavy physical exertion is not recommended. It is highly undesirable, within three days before the procedure, the use of fatty and fried foods. If these conditions are met, then a diagnostic blood test for myeloid leukemia will be extremely informative.

Make or finger. Venous blood is more concentrated than capillary blood, which is why some physicians require just such sampling for analysis.

Deciphering the results of myeloid leukemia takes two days from the moment the results are accepted for processing. If the laboratory is overloaded with work, then the result can be obtained later.

Provide for the taking of bone marrow samples for cytogenetic analysis from the femur. Samples are taken by biopsy or aspiration. Studying chromosomes. Affected cells contain an abnormal chromosome 22. In order to detect an abnormal chromosome, a polymerase chain reaction is used.

Treatment

The quality of the analysis is the key to successful therapy. The choice of treatment method and the intensity of the recommended procedures depend on the phase of the disease. In some patients with multiple myeloma, an increasing progression of the process is observed over many years, and does not require antitumor treatment.

In patients with metastases, local radiation therapy is used. With the slow development of myeloid leukemia, expectant tactics are used.

If the pain increases, which indicates the growth of the tumor, cytostatics are prescribed. The terms of treatment, subject to the presence of positive results, last up to two years.

Provide treatment to prevent complications. To stop hypercalcemia, corticosteroids are used against the background of heavy drinking. Medicines are used to treat kidney disease and osteoporosis.

Forecast

Myeloma in the indolent phase is not an indication for immediate treatment. The need to start therapy is the appearance of a paraprotein in the blood, or a decrease in viscosity, the presence of bleeding, bone pain, fractures, hypercalcemia, kidney damage, spinal cord compression, infectious complications.

Compression of the spinal cord requires surgical treatment, as well as local radiation. Bone fractures require orthopedic fixation.

In some cases, if radiation therapy is not indicated, cytotoxic treatment is used. In this case, it must be borne in mind that secondary myeloid leukemia can become a side effect.

If left untreated, multiple myeloma patients live up to two years. A complete cure for myeloma is the future.

Modern methods of treatment can slow down the destructive effect of the disease on the body and fight its specific symptoms.

Chronic myeloid leukemia- a tumor disease of the blood. It is characterized by uncontrolled growth and reproduction of all blood germ cells, while young malignant cells are able to mature to mature forms.

Chronic myeloid leukemia (synonymous with chronic myeloid leukemia) - a tumor disease of the blood. Its development is associated with changes in one of the chromosomes and the appearance chimeric (“cross-linked” from different fragments) of a gene that disrupts hematopoiesis in the red bone marrow.

During chronic myeloid leukemia, the content of a special type of leukocytes increases in the blood - granulocytes . They are formed in the red bone marrow in large quantities and enter the blood without having time to fully mature. At the same time, the content of all other types of leukocytes decreases.

Some facts about the prevalence of chronic myelogenous leukemia:

• Every fifth tumor disease of the blood is chronic myelogenous leukemia.
• Among all blood tumors, chronic myeloid leukemia occupies the 3rd place in North America and Europe, and the 2nd place in Japan.
• Globally, chronic myelogenous leukemia occurs in 1 in 100,000 people every year.
• Over the past 50 years, the prevalence of the disease has not changed.
• Most often, the disease is detected in people aged 30-40 years.
• Men and women get sick with about the same frequency.

Causes of Chronic Myeloid Leukemia

The causes of chromosomal abnormalities leading to chronic myeloid leukemia are still not well understood.

The following factors are believed to be relevant:

As a result of breakdowns in chromosomes, a DNA molecule with a new structure appears in the cells of the red bone marrow. A clone of malignant cells is formed, which gradually crowd out all the others and occupy the main part of the red bone marrow. The vicious gene provides three main effects:

• Cells multiply uncontrollably, like cancer cells.
• For these cells, the natural mechanisms of death cease to work.

They very quickly leave the red bone marrow into the blood, so they do not have the opportunity to mature and turn into normal leukocytes. There are many immature leukocytes in the blood, unable to cope with their usual functions.

Phases of chronic myeloid leukemia

• chronic phase. The majority of patients who visit a doctor (about 85%) are in this phase. The average duration is 3-4 years (depending on how timely and correctly the treatment is started). This is the stage of relative stability. The patient is concerned about minimal symptoms to which he may not pay attention. Sometimes doctors discover chronic phase myelogenous leukemia by accident during a complete blood count.
• Acceleration phase. During this phase, the pathological process is activated. The number of immature white blood cells in the blood begins to increase rapidly. The acceleration phase is, as it were, a transitional phase from chronic to the last, third.
• Terminal phase. final stage of the disease. Occurs with an increase in changes in chromosomes. The red bone marrow is almost completely replaced by malignant cells. During the terminal stage, the patient dies.

Manifestations of chronic myelogenous leukemia

Chronic phase symptoms:

More rare symptoms of chronic phase myelogenous leukemia :

• Signs associated with dysfunction of platelets and white blood cells : various bleeding or, conversely, the formation of blood clots.
• Signs associated with an increase in the number of platelets and, as a result, an increase in blood clotting : circulatory disorders in the brain (headaches, dizziness, memory loss, attention, etc.), myocardial infarction, visual impairment, shortness of breath.

Symptoms of the acceleration phase

In the acceleration phase, the signs of the chronic stage increase. Sometimes it is at this time that the first signs of the disease appear, which make the patient visit the doctor for the first time.

Symptoms of end-stage chronic myelogenous leukemia:

• Sharp weakness , a significant deterioration in general well-being.
• Prolonged aching pain in the joints and bones . Sometimes they can be very strong. This is due to the growth of malignant tissue in the red bone marrow.
• pouring sweats .
• Periodic unreasonable rise in temperature up to 38 - 39⁰C, during which there is a strong chill.
• Weight loss .
• Increased bleeding , the appearance of hemorrhages under the skin. These symptoms result from a decrease in the number of platelets and a decrease in blood clotting.
• Rapid enlargement of the spleen : the stomach increases in size, there is a feeling of heaviness, pain. This is due to the growth of tumor tissue in the spleen.

Diagnosis of the disease

Which doctor should I contact if I have symptoms of chronic myelogenous leukemia?

A hematologist is engaged in the treatment of blood diseases of a tumor nature. Many patients initially turn to a general practitioner, who then sends them for a consultation with a hematologist.

Examination at the doctor's office

Admission to the hematologist's office is carried out as follows:

• Questioning the patient . The doctor finds out the patient's complaints, specifies the time of their occurrence, asks other necessary questions.
• Feeling the lymph nodes : submandibular, cervical, axillary, supraclavicular and subclavian, ulnar, inguinal, popliteal.
• Feeling the abdomen to determine the enlargement of the liver and spleen. The liver is felt under the right rib in the supine position. The spleen is on the left side of the abdomen.

When can a doctor suspect chronic myelogenous leukemia in a patient?

Symptoms of chronic myelogenous leukemia, especially in the initial stages, are non-specific - they can occur in many other diseases. Therefore, the doctor cannot assume a diagnosis only on the basis of the examination and complaints of the patient. Suspicion usually arises from one of two studies:

• General blood analysis . An increased number of leukocytes and a large number of their immature forms are found in it.
• abdominal ultrasound . An increase in the size of the spleen is revealed.

How is a complete examination for suspected chronic myeloid leukemia performed??

Study title	Description	What reveals?
General blood analysis	Routine clinical examination, performed when any disease is suspected. A general blood test helps to determine the total content of leukocytes, their individual varieties, immature forms. Blood for analysis is taken from a finger or a vein in the morning.	The result depends on the phase of the disease. chronic phase: a gradual increase in the content of leukocytes in the blood due to granulocytes; the appearance of immature forms of leukocytes; an increase in the number of platelets. Acceleration phase: the content of leukocytes in the blood continues to increase; the proportion of immature white blood cells increases to 10 - 19%; the content of platelets can be increased or decreased. Terminal phase: the number of immature leukocytes in the blood increases by more than 20%; decrease in the number of platelets;
Puncture and biopsy of red bone marrow	Red bone marrow is the main hematopoietic organ of a person, which is located in the bones. During the study, a small fragment is obtained using a special needle and sent to the laboratory for examination under a microscope. Carrying out the procedure: The puncture of the red bone marrow is carried out in a special room in compliance with the rules of asepsis and antisepsis. The doctor performs local anesthesia - punctures the puncture site with an anesthetic. A special needle with a limiter is inserted into the bone so that it penetrates to the desired depth. The puncture needle is hollow inside, like a syringe needle. It collects a small amount of red bone marrow tissue, which is sent to a laboratory for examination under a microscope. For puncture choose bones that are shallow under the skin: sternum; wings of the pelvic bones; calcaneus; tibial head; vertebrae (rare).	In the red bone marrow, approximately the same picture is found as in the general blood test: a sharp increase in the number of precursor cells that give rise to leukocytes.
Cytochemical study	When special dyes are added to blood and red bone marrow samples, certain substances may react with them. This is the basis of the cytochemical study. It helps to establish the activity of certain enzymes and serves to confirm the diagnosis of chronic myeloid leukemia, helps to distinguish it from other types of leukemia.	In chronic myeloid leukemia, a cytochemical study reveals a decrease in the activity of a special enzyme in granulocytes - alkaline phosphatase .
Blood chemistry	In chronic myeloid leukemia, the content of certain substances in the blood changes, which is an indirect diagnostic sign. Blood sampling for analysis is carried out from a vein on an empty stomach, usually in the morning.	Substances, the content of which in the blood is increased in chronic myeloid leukemia: vitamin B 12 ; lactate dehydrogenase enzymes; transcobalamin; uric acid.
Cytogenetic study	During a cytogenetic study, the entire genome (a set of chromosomes and genes) of a person is studied. For research, blood is used, which is taken from a vein into a test tube and sent to the laboratory. The result is usually ready in 20-30 days. The laboratory uses special modern tests, during which various parts of the DNA molecule are detected.	In chronic myeloid leukemia, a cytogenetic study reveals a chromosomal disorder, which was called Philadelphia chromosome . In the cells of patients, chromosome number 22 is shortened. The missing piece is attached to chromosome 9. In turn, a fragment of chromosome #9 is attached to chromosome #22. There is a kind of exchange, as a result of which the genes begin to work incorrectly. The result is myelogenous leukemia. Other pathological changes on the part of chromosome No. 22 are also detected. By their nature, one can partially judge the prognosis of the disease.
Ultrasound of the abdominal organs.	Ultrasonography is used in patients with myelogenous leukemia to detect enlargement of the liver and spleen. Ultrasound helps to distinguish leukemia from other diseases.

Laboratory indicators

General blood analysis

• Leukocytes: significantly increased from 30.0 10 9 /l to 300.0-500.0 10 9 /l
• Shift of the leukocyte formula to the left: young forms of leukocytes predominate (promyelocytes, myelocytes, metamyelocytes, blast cells)
• Basophils: increased amount of 1% or more
• Eosinophils: increased level, more than 5%

• Platelets: normal or elevated

Blood chemistry

• Alkaline phosphatase of leukocytes is reduced or absent.

genetic research

• A genetic blood test reveals an abnormal chromosome (Philadelphia chromosome).

Symptoms

The manifestation of symptoms depends on the phase of the disease.
I phase (chronic)

• Long time without symptoms (3 months to 2 years)
• Heaviness in the left hypochondrium (due to an increase in the spleen, the higher the level of leukocytes, the larger its size).
• Weakness
• Decreased performance
• sweating
• weight loss

It is possible to develop complications (spleen infarction, retinal edema, priapism).

• spleen infarction - acute pain in the left hypochondrium, temperature 37.5 -38.5 ° C, sometimes nausea and vomiting, touching the spleen is painful.

• Priapism is a painful, excessively long erection.

II phase (acceleration)
These symptoms are harbingers of a serious condition (blast crisis), appear 6-12 months before its onset.

• Decreased effectiveness of drugs (cytostatics)
• Anemia develops
• Increases the percentage of blast cells in the blood
• General condition worsens
• Enlarged spleen

III phase (acute or blast crisis)

• Symptoms correspond to the clinical picture in acute leukemia ( see Acute lymphocytic leukemia).

How is myeloid leukemia treated?

Purpose of treatment reduce the growth of tumor cells and reduce the size of the spleen.

Treatment of the disease should be started immediately after the diagnosis is established. The prognosis largely depends on the quality and timeliness of therapy.

Treatment includes various methods: chemotherapy, radiation therapy, removal of the spleen, bone marrow transplant.

Drug treatment

Chemotherapy

• Classic drugs: Mielosan (Mileran, Busulfan), Hydroxyurea (Gidrea, Litalir), Cytosar, 6-mercaptopurni, alpha-interferon.
• New drugs: Glivec, Sprycell.

Drugs used for chronic myelogenous leukemia

Name	Description
Hydroxyurea preparations: hydroxyurea; hydroxyurea; hydrea.	How the drug works: Hydroxyurea is a chemical compound capable of inhibiting the synthesis of DNA molecules in tumor cells. When can they appoint: With chronic myeloid leukemia, accompanied by a significant increase in the number of leukocytes in the blood. How to appoint: The drug is released in the form of capsules. The doctor prescribes the patient to receive them in accordance with the selected dosing regimen. Possible side effects: digestive disorders; allergic reactions on the skin (spots, itching); inflammation of the oral mucosa (rare); anemia and decreased blood clotting; disorders of the kidneys and liver (rarely). Usually, after stopping the drug, all side effects disappear.
Glivec (imatinib mesylate)	How the drug works: The drug inhibits the growth of tumor cells and enhances the process of their natural death. When can they appoint: in the acceleration phase; in the terminal phase; during the chronic phase if treatment interferon (see below) has no effect. How to appoint: The drug is available in the form of tablets. The scheme of application and dosage is chosen by the attending physician. Possible side effects: The side effects of the drug are difficult to assess, since patients who take it usually already have severe disorders on the part of various organs. According to statistics, the drug has to be canceled due to complications quite rarely: nausea and vomiting; liquid stool; muscle pain and muscle cramps. Most often, doctors manage to cope with these manifestations quite easily.
Interferon-alpha	How the drug works: Interferon-alpha increases the body's immune forces and inhibits the growth of cancer cells. When appointed: Typically, interferon-alpha is used for long-term maintenance therapy after the number of leukocytes in the blood has returned to normal. How to appoint: The drug is used in the form of solutions for injection, administered intramuscularly. Possible side effects: Interferon has a fairly large number of side effects, and this is associated with certain difficulties in its use. With the correct prescription of the drug and constant monitoring of the patient's condition, the risk of unwanted effects can be minimized: flu-like symptoms; changes in the blood test: the drug has some toxicity in relation to the blood; weight loss; depression; neuroses; development of autoimmune pathologies.

Bone marrow transplantation

Bone marrow transplantation makes it possible to fully recover patients with chronic myeloid leukemia. The efficiency of transplantation is higher in the chronic phase of the disease, in other phases it is much lower.

Red bone marrow transplantation is the most effective treatment for chronic myeloid leukemia. More than half of transplanted patients experience sustained improvement over 5 years or longer.

Most often, recovery occurs when red bone marrow is transplanted to a patient younger than 50 years in the chronic phase of the disease.

Stages of red bone marrow transplantation:

• Finding and preparing a donor. The best donor of red bone marrow stem cells is a close relative of the patient: twin, brother, sister. If there are no close relatives, or they are not suitable, a donor is sought. A series of tests are carried out to make sure that the donor material will take root in the patient's body. Today, large donor banks have been established in developed countries, which contain tens of thousands of donor samples. This gives a chance to find suitable stem cells faster.
• Patient preparation. Usually this stage lasts from a week to 10 days. Radiation therapy and chemotherapy are carried out to destroy as many tumor cells as possible, to prevent rejection of donor cells.
• The actual red bone marrow transplant. The procedure is similar to a blood transfusion. A catheter is inserted into the patient's vein, through which stem cells are injected into the bloodstream. They circulate in the bloodstream for some time, and then settle in the bone marrow, take root there and begin to work. To prevent rejection of the donor material, the doctor prescribes anti-inflammatory and anti-allergic drugs.
• Decreased immunity. Donor cells of the red bone marrow cannot take root and begin to function immediately. This takes time, usually 2-4 weeks. During this period, the patient's immunity is greatly reduced. He is placed in a hospital, completely protected from contact with infections, antibiotics and antifungal agents are prescribed. This period is one of the most difficult. The body temperature rises sharply, chronic infections can be activated in the body.
• Engraftment of donor stem cells. The patient's condition begins to improve.
• Recovery. Within months or years, red bone marrow function continues to recover. Gradually, the patient recovers, his working capacity is restored. But he still needs to be under medical supervision. Sometimes the new immunity cannot cope with some infections, in this case, vaccinations are given about a year after the bone marrow transplant.

Radiation therapy

It is carried out in cases of no effect of chemotherapy and with an enlarged spleen after taking medications (cytostatics). The method of choice in the development of a local tumor (granulocytic sarcoma).

In what phase of the disease is radiation therapy used?

Radiation therapy is used in the advanced stage of chronic myeloid leukemia, which is characterized by signs:

• Significant proliferation of tumor tissue in the red bone marrow.
• The growth of tumor cells in tubular bones 2 .
• Great enlargement of the liver and spleen.

How is radiation therapy performed in chronic myelogenous leukemia?

Gamma therapy is used - irradiation of the spleen area with gamma rays. The main task is to destroy or stop the growth of malignant tumor cells. The radiation dose and radiation regimen is determined by the attending physician.

Removal of the spleen (splenectomy)

Removal of the spleen is rarely used for limited indications (splenic infarction, thrombocytopenia, severe abdominal discomfort).

The operation is usually performed in the terminal phase of the disease. Together with the spleen, a large number of tumor cells are removed from the body, thereby facilitating the course of the disease. After surgery, the effectiveness of drug therapy usually increases.

What are the main indications for surgery?

• Rupture of the spleen.
• The threat of rupture of the spleen.
• A significant increase in the size of the organ, which leads to severe discomfort.

Cleansing the blood of excess white blood cells (leukapheresis)

At high levels of leukocytes (500.0 10 9 /l and above), leukapheresis can be used to prevent complications (retinal edema, priapism, microthrombosis).

With the development of a blast crisis, the treatment will be the same as for acute leukemia (see acute lymphocytic leukemia).

Leukocytepheresis - a treatment procedure plasmapheresis (purification of the blood). A certain amount of blood is taken from the patient and passed through a centrifuge, in which it is cleaned of tumor cells.

In what phase of the disease is leukocytapheresis performed?
As well as radiation therapy, leukocytapheresis is performed during the advanced stage of myeloid leukemia. Often it is used in cases where there is no effect from the use of drugs. Sometimes leukocytapheresis complements drug therapy.

Definition. Chronic myeloid leukemia is a myeloproliferative disease with the formation of a tumor bone marrow clone of progenitor cells capable of differentiating to mature granulocytes of a predominantly neutrophilic series.

ICD10: C92.1 - Chronic myeloid leukemia.

Etiology. The etiological factor of the disease may be infection with a latent virus. Ionizing radiation, toxic effects can be a triggering factor that reveals the antigens of a latent virus. A chromosomal aberration appears - the so-called Philadelphia chromosome. It is the result of a reciprocal translocation of part of the long arm of chromosome 22 to chromosome 9. Chromosome 9 contains the abl proto-oncogene, and chromosome 22 contains the c-sis proto-oncogene, which is a cellular homologue of the monkey sarcoma virus (virus-transforming gene), as well as the bcr gene. The Philadelphia chromosome appears in all blood cells with the exception of macrophages and T-lymphocytes.

Pathogenesis. As a result of exposure to etiological and triggering factors, a tumor clone from a progenitor cell appears in the bone marrow, capable of differentiating to mature neutrophils. The tumor clone spreads in the bone marrow, displacing normal hematopoietic sprouts.

A huge number of neutrophils appears in the blood, comparable to the number of red blood cells - leukemia. One of the causes of hyperleukocytosis is the exclusion of the bcr and abl genes belonging to the Philadelphia chromosome, which causes a delay in the final completion of the development of neutrophils with the expression of apoptosis antigens (natural death) on their membrane. Fixed spleen macrophages must recognize these antigens and remove old, obsolete cells from the blood.

The spleen cannot cope with the rate of destruction of neutrophils from the tumor clone, as a result of which compensatory splenomegaly is formed at first.

In connection with metastasis, there are foci of tumor hematopoiesis in the skin, other tissues and organs. Leukemic infiltration of the spleen contributes to its even greater increase. In the huge spleen, normal erythrocytes, leukocytes, and platelets are also intensively destroyed. This is one of the leading causes of hemolytic anemia and thrombocytopenic purpura.

Myeloproliferative tumor in the course of its development and metastasis undergoes mutations and turns from monoclonal to multiclonal. This is evidenced by the appearance in the blood of cells with other than the Philadelphia chromosome aberrations in the karyotype. As a result, an uncontrolled tumor clone of blast cells is formed. There is acute leukemia. Leukemic infiltration of the heart, lungs, liver, kidneys, progressive anemia, thrombocytopenia are incompatible with life, and the patient dies.

clinical picture. Chronic myeloid leukemia goes through 3 stages in its clinical development: initial, advanced benign (monoclonic) and terminal malignant (polyclonal).

initial stage corresponds to myeloid hyperplasia of the bone marrow in combination with small changes in peripheral blood without signs of intoxication. The disease at this stage does not show any clinical symptoms and often goes unnoticed. Only in isolated cases, patients can feel dull, aching pain in the bones, and sometimes in the left hypochondrium. Chronic myeloid leukemia at the initial stage can be recognized by the accidental detection of "asymptomatic" leukocytosis, followed by a sternal puncture.

An objective examination at the initial stage may reveal a slight enlargement of the spleen.

Expanded stage corresponds to the period of monoclonal tumor proliferation with moderate metastasis (leukemic infiltration) outside the bone marrow. It is characterized by complaints of patients on progressive general weakness, sweating. Loss of body weight. There is a tendency to protracted colds. Disturbed by pain in the bones, in the left side in the region of the spleen, the increase in which the patients notice themselves. In some cases, protracted subfebrile condition is possible.

An objective examination revealed severe splenomegaly. The organ can occupy up to half the volume of the abdominal cavity. The spleen is dense, painless, and with extremely pronounced splenomegaly - sensitive. With a spleen infarction, intense pain suddenly appears in the left half of the abdomen, the noise of peritoneal friction over the infarction zone, body temperature rises.

When pressing a hand on the sternum, the patient may experience a sharp pain.

In most cases, moderate hepatomegaly is detected due to leukemic infiltration of the organ.

Symptoms of damage to other organs may appear: peptic ulcer of the stomach and duodenum, myocardial dystrophy, pleurisy, pneumonia, leukemic infiltration and / or retinal hemorrhages, menstrual disorders in women.

Excessive production of uric acid during the breakdown of neutrophil nuclei often leads to the formation of uric acid stones in the urinary tract.

terminal stage corresponds to the period of polyclonal bone marrow hyperplasia with multiple metastasis of various tumor clones to other organs and tissues. It is subdivided into the phase of myeloproliferative acceleration and blast crisis.

phase myeloproliferative acceleration can be characterized as a pronounced exacerbation of chronic myeloid leukemia. All subjective and objective symptoms of the disease are aggravated. Constantly worried about severe pain in the bones, joints, in the spine.

In connection with leukemoid infiltration, severe lesions of the heart, lungs, liver, and kidneys occur.

An enlarged spleen can occupy up to 2/3 of the volume of the abdominal cavity. Leukemids appear on the skin - pink or brown spots, slightly raised above the surface of the skin, dense, painless. These are tumor infiltrates consisting of blast cells and mature granulocytes.

Enlarged lymph nodes are revealed, in which solid tumors such as sarcomas develop. Foci of sarcomatous growth can occur not only in the lymph nodes but also in any other organ, bones, which is accompanied by appropriate clinical symptoms.

There is a tendency to subcutaneous hemorrhages - thrombocytopenic purpura. There are signs of hemolytic anemia.

Due to a sharp increase in the content of leukocytes in the blood, often exceeding the level of 1000 * 10 9 / l (true "leukemia"), a clinical syndrome of hyperleukocytosis with shortness of breath, cyanosis, damage to the central nervous system, manifested by mental disorders, visual impairment due to edema optic nerve.

Blast Crisis is the sharpest exacerbation of chronic myeloid leukemia and, according to clinical and laboratory data, is an acute leukemia.

Patients are in serious condition, emaciated, with difficulty turning in bed. They are disturbed by severe pains in the bones, spine, debilitating fever, heavy sweats. The skin is pale cyanotic with multi-colored bruising (thrombocytopenic purpura), pink or brown foci of leukemids. There is noticeable icterus of the sclera. Sweet's syndrome may form: acute neutrophilic dermatosis with high fever. Dermatosis is characterized by painful seals, sometimes large nodes on the skin of the face, arms, torso.

Peripheral lymph nodes are enlarged, stony density. The spleen and liver were enlarged to the maximum possible size.

As a result of leukemic infiltration, severe lesions of the heart, kidneys, and lungs occur with symptoms of cardiac, renal, and pulmonary insufficiency, which leads the patient to death.

Diagnostics.

In the initial stage of the disease:

Complete blood count: the number of erythrocytes and hemoglobin is normal or slightly reduced. Leukocytosis up to 15-30*10 9 /l with a shift of the leukocyte formula to the left to myelocytes and promyelocytes. Basophilia, eosinophilia, moderate thrombocytosis are noted.

Biochemical blood test: elevated level of uric acid.

Sternal punctate: increased content of cells of the granulocytic line with a predominance of young forms. The number of blasts does not exceed the upper limit of normal. The number of megakaryocytes is increased.

In the advanced stage of the disease:

General blood test: the content of erythrocytes, hemoglobin is moderately reduced, the color index is about one. Reticulocytes, single erythrokaryocytes are detected. Leukocytosis from 30 to 300*10 9 /l and above. A sharp shift of the leukocyte formula to the left to myelocytes and myeloblasts. The number of eosinophils and basophils is increased (eosinophilic-basophilic association). The absolute content of lymphocytes is reduced. Thrombocytosis, reaching 600-1000 * 10 9 /l.

Histochemical examination of leukocytes: in neutrophils, the content of alkaline phosphatase is sharply reduced.

Biochemical blood test: elevated levels of uric acid, calcium, reduced cholesterol, increased LDH activity. The level of bilirubin may increase due to hemolysis of red blood cells in the spleen.

Sternal punctate: brain with a high content of cells. The number of cells of granulocytic lines was significantly increased. Blasts no more than 10%. Many megakaryocytes. The number of erythrokaryocytes is moderately reduced.

Cytogenetic analysis: in the myeloid cells of the blood, bone marrow, spleen, the Philadelphia chromosome is detected. This marker is absent in T-lymphocytes and macrophages.

In the terminal stage of the disease in the phase of myeloproliferative acceleration:

Complete blood count: a significant decrease in hemoglobin and erythrocytes in combination with anisochromia, anisocytosis, poikilocytosis. Single reticulocytes may be seen. Neutrophilic leukocytosis, reaching 500-1000 * 10 9 /l. A sharp shift of the leukocyte formula to the left to blasts. The number of blasts can reach 15%, but there is no leukemic dip. The content of basophils (up to 20%) and eosinophils is sharply increased. Decreased platelet count. Functionally defective megaplatelets, fragments of nuclei of megakaryocytes are revealed.

Sternal punctate: erythrocyte germ is suppressed more significantly than in the advanced stage, the content of myeloblast cells, eosinophils and basophils is increased. Reduced number of megakaryocytes.

Cytogenetic analysis: in myeloid cells, a specific marker of chronic myeloid leukemia, the Philadelphia chromosome, is detected. Other chromosomal aberrations appear, which indicates the emergence of new clones of tumor cells.

The results of histochemical examination of granulocytes, the biochemical parameters of the blood are the same as in the advanced stage of the disease.

In the terminal stage of the disease in the phase of the blast crisis:

Complete blood count: a deep drop in the content of erythrocytes and hemoglobin with a complete absence of reticulocytes. Slight leukocytosis or leukopenia. Neutropenia. Sometimes basophilia. Many blasts (over 30%). Leukemic failure: there are mature neutrophils and blasts in the smear, and there are no intermediate maturing forms. thrombocytopenia.

Sternal punctate: reduced number of mature granulocytes, cells of erythrocyte and megakaryocytic lines. The number of blast cells is increased, including abnormal ones with enlarged, deformed nuclei.

In histological preparations of skin leukemid, blast cells are detected.

Generalized criteria for clinical and laboratory diagnosis of chronic myelogenous leukemia:

Neutrophilic leukocytosis in peripheral blood over 20*10 9 /l.

The presence in the leukocyte formula of proliferating (myelocytes, promyelocytes) and maturing (myelocytes, metamyelocytes) granulocytes.

Eosinophilic-basophilic association.

Myeloid hyperplasia of the bone marrow.

Decreased activity of neutrophil alkaline phosphatase.

Detection of the Philadelphia chromosome in blood cells.

Splenomegaly.

Clinical and laboratory criteria for assessing risk groups necessary for choosing the optimal tactics for the treatment of an advanced stage of chronic myelogenous leukemia.

In peripheral blood: leukocytosis over 200*10 9 /l, blasts less than 3%, the sum of blasts and promyelocytes more than 20%, basophils more than 10%.

Thrombocytosis more than 500*10 9 /l or thrombocytopenia less than 100*10 9 /l.

Hemoglobin is less than 90 g/l.

Splenomegaly - the lower pole of the spleen 10 cm below the left costal arch.

Hepatomegaly - the anterior edge of the liver below the right costal arch by 5 cm or more.

Low risk - the presence of one of the signs. Intermediate risk - 2-3 signs. High risk - 4-5 signs.

differential diagnosis. It is carried out with leukemoid reactions, acute leukemia. The fundamental difference between chronic myelogenous leukemia and diseases similar to it is the detection of the Philadelphia chromosome in blood cells, a reduced content of alkaline phosphatase in neutrophils, and an eosinophilic-basophilic association.

Survey plan.

General blood analysis.

Histochemical study of the content of alkaline phosphatase in neutrophils.

Cytogenetic analysis of the karyotype of blood cells.

Biochemical blood test: uric acid, cholesterol, calcium, LDH, bilirubin.

Sternal puncture and/or trepanobiopsy of the iliac wing.

Treatment. In the treatment of patients with chronic myeloid leukemia, the following methods are used:

Therapy with cytostatics.

Introduction of alpha-2-interferon.

Cytopheresis.

Radiation therapy.

Splenectomy.

Bone marrow transplantation.

Therapy with cytostatics begins in the advanced stage of the disease. At low and medium risk, monotherapy with a single cytostatic agent is used. At high risk and in the terminal stage of the disease, polychemotherapy with several cytostatics is prescribed.

The drug of first choice in the treatment of chronic myeloid leukemia is hydroxyurea, which has the ability to suppress mitosis in leukemic cells. Start with 20-30 mg/kg/day per os at one time. The dose is adjusted weekly depending on changes in the blood picture.

In the absence of effect, myelosan is used at 2-4 mg per day. If the level of leukocytes in the peripheral blood is reduced by half, the dose of the drug is also halved. When leukocytosis drops to 20*10^9/l, myelosan is temporarily cancelled. Then they switch to a maintenance dose - 2 mg 1-2 times a week.

In addition to myelosan, myelobromol can be used at 0.125-0.25 once a day for 3 weeks, then maintenance treatment at 0.125-0.25 once every 5-7-10 days.

Polychemotherapy can be carried out according to the AVAMP program, which includes the administration of cytosar, methotrexate, vincristine, 6-mercaptopurine, prednisolone. There are other schemes of multicomponent therapy with cytostatics.

The use of alpha-interferon (reaferon, intron A) is justified by its ability to stimulate antitumor and antiviral immunity. Although the drug does not have a cytostatic effect, it still contributes to leukopenia and thrombocytopenia. Alfa-interferon is prescribed as subcutaneous injections of 3-4 million U/m 2 2 times a week for six months.

Cytopheresis reduces the content of leukocytes in the peripheral blood. A direct indication for the use of this method is resistance to chemotherapy. Patients with the syndrome of hyperleukocytosis and hyperthrombocytosis with a primary lesion of the brain and retina need urgent cytopheresis. Sessions of cytopheresis are carried out from 4-5 times a week to 4-5 times a month.

The indication for local radiation therapy is giant splenomegaly with perisplenitis, tumor-like leukemids. The dose of gamma-ray exposure to the spleen is about 1 Gy.

Splenectomy is used for threatening rupture of the spleen, deep thrombocytopenia, severe hemolysis of erythrocytes.

Bone marrow transplantation gives good results. In 60% of patients undergoing this procedure, a complete remission is achieved.

Forecast. The average life expectancy of patients with chronic myeloid leukemia with a natural course without treatment is 2-3.5 years. The use of cytostatics increases life expectancy up to 3.8-4.5 years. A more significant lengthening of the life expectancy of patients is possible after bone marrow transplantation.

Myeloid leukemia or myeloid leukemia severe malignant disease, which affects the human bone marrow and is characterized by the destruction of certain blood cells. Over time, they cease to perform their functions, which has an extremely negative impact on the health of internal organs and can lead to death.

myeloid leukemia popularly referred to as leukemia, since the malignant process in this disease affects the stem cells of the bone marrow.

They produce several blood elements at once (leukocytes, platelets, erythrocytes), and with the development of a pathological process in the body, pathologically altered cells begin to grow and multiply.

They interfere with the growth of normal cells, and after the growth of the bone marrow stops, abnormal elements are transferred through the bloodstream to all organs.

Acute and chronic myeloid leukemia

The disease is divided into acute and chronic forms, which differ from each other in the features of the clinical course. Chronic myeloid leukemia progresses rather slowly and is characterized by uncontrolled maturation of mature leukocytes, and in the acute form, which is characterized by a rapid course, immature cells multiply in the body. Unlike other diseases, acute myeloid leukemia never becomes chronic, and the latter, in turn, never worsens.

Diagnostics

To make a diagnosis of myeloid leukemia, a patient needs to take blood tests and undergo instrumental diagnostic methods.

1. Complete blood count. In acute or chronic myeloid leukemia, the blood picture in the general analysis will look like this: ESR and the number of leukocytes increase to 40 and 20-500 * 109 / l, respectively, and the level of erythrocytes and hemoglobin decreases, which indicates the development of anemia, and in the blood formula the concentration basophils rises to 1%, eosinophils - up to 5%, and there is also a shift to the left.
2. Blood chemistry. In a biochemical blood test for myeloid leukemia, the focus is on liver tests (AST and ALT), alkaline phosphatase, bilirubin, which allow you to evaluate the functioning of the kidneys and liver, as well as albumin and glucose indicators involved in metabolic processes. Liver tests, bilirubin in patients usually increase (especially in the later stages of the disease), and the concentration of glucose and albumin decreases.
3. Biopsy and aspiration of the bone marrow. Methods for taking a bone marrow sample for further study, which allow you to evaluate the shape, number and size of blood elements. With myeloid leukemia, there is an increase in the granulocytic germ, the presence of leukocytes of all stages of development, and not just mature ones, as in healthy people. In the analysis, an increased number of platelet precursor cells (megakaryocytes) is often present, basophils and eosinophils increase, as well as the number of immature cell forms (blasts), which depends on the stage of the disease. They speak of acute leukemia when their number is increased by 20%, and the diagnosis of chronic leukemia is made when the level of leukocytes rises to 17 units and above.
4. cytogenetic study. The basis of this technique is the study of the gene and chromosome set of the patient. Myeloid chronic myeloid leukemia is characterized by the presence of the so-called Philadelphia chromosome (Ph-chromosome), which is considered the main cause of the malignant process.
5. Hybridization in situ (FISH). Allows you to detect cells with BCR-ABL translocation in the body, which are responsible for the production of an excess amount of tyrosine kinase (a special protein) - under its influence, the mechanism of uncontrolled cell division starts.
6. PCR. Like the hybridization method, diagnostics using the polymerase chain reaction is aimed at determining the BCR-ABL1 gene, which causes blood cancers. The analysis requires the patient's bone marrow or venous blood, and if the gene is detected even in minimal amounts, the diagnosis of chronic myelogenous leukemia is confirmed.
7. Instrumental diagnostic methods (CT, ultrasound, MRI) are prescribed to patients in order to assess the condition of the internal organs, brain and bones.

If we talk about the geographical features of the spread of pathology, then most of the patients live in Europe, North America and Oceania, least of all in Asia and Latin America.

Watch a video about chronic myeloid leukemia

The risk group includes older men, as well as people who have previously been exposed to radioactive irradiation.

Causes

Exact etiology of chronic myelogenous leukemia not clarified, but scientists have found that the following factors influence the development of the disease:

• burdened family history (the presence of genetic chromosomal mutations - for example, Down syndrome, or cases of blood cancer in the family);
• exposure to ionizing radiation, harmful chemicals, as well as long-term use of anticancer drugs;
• diseases of the hematopoietic system, especially oncological;
• some viral infections.

Moreover, negative impact on the state of the hematopoietic system has alcohol abuse and nicotine addiction.

Symptoms and stages

In the initial stages of myeloid leukemia, the symptoms may not be noticeable to the patient, but as the tumor process develops, they become more pronounced, and laboratory parameters change. The classification of chronic myeloid leukemia distinguishes three stages of the clinical course of the disease: chronic, accelerated and terminal.

1. chronic stage. It is asymptomatic, and the only manifestations of the disease may be mild weakness and weakness, which are perceived by patients as a manifestation of overwork. After some time, the patient begins to lose weight, suffer from lack of appetite and pain in the left side of the abdomen, in the region of the spleen. Visual impairment, shortness of breath, bleeding of unknown etiology may be added to the list of symptoms.
2. Acceleration stage, or advanced stage of chronic myeloid leukemia. This stage is characterized by an increase in symptoms, severe fever, chills, weight loss and intense pain in the left hypochondrium. The spleen enlarges so much that it can be felt during palpation, the work of the cardiovascular system worsens, which causes attacks of arrhythmia and tachycardia.

After the extended stage, the most dangerous stage of the disease comes - the terminal stage, or blast crisis.

Blast crisis in chronic myelogenous leukemia

Blast crisis in patients with chronic myelogenous leukemia occurs immediately after the advanced stage, and its main feature is a significant increase in the number of blasts in the bone marrow (above 30%). Accompanied by severe pain in the bones, body weight continues to decline, and fever and discomfort in the spleen region persist. The patient is prone to all kinds of infectious diseases due to a decrease in immunity, bruises and bruises appear on his body, which indicates a decrease in the number of platelets.

The blast crisis in chronic myeloid leukemia is divided into several types: lymphoblastic (lymphoid) and myeloid, which occur respectively in 65 and 25% of cases. Another 10% falls on the rarest variety - erythroblast crisis.

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Chronic myeloid leukemia (CML) is a neoplastic clonal disease of a multipotent hematopoietic stem cell predominantly involving the granulocytic cell line.

The disease was first described by R. Virchow in the middle of the 19th century under the name "splenic leukemia". CML accounts for approximately 20% of all leukemias in Europe.

It is more common in middle-aged and older adults with a median age of about 50 years, although CML can develop at any age.

There is no dependence in incidence on gender and ethnicity.

The etiology of CML is unknown. Among survivors of the atomic bombings in Japan, an increase in the incidence of CML was observed after a three-year latency period, peaking at 7 years. In a group of patients in the UK who received radiation therapy for ankylosing spondylitis, there was an increase in the incidence of chronic myeloid leukemia after a latency period of 13 years.

In general, exposure to ionizing radiation was noted in the anamnesis in less than 5% of patients with CML. Contact with myelotoxic agents was detected in isolated cases. Although an increase in the frequency of expression of the HLA-Cw3 ​​and HLA-Cw4 antigens has been noted in CML, there are no reports of cases of familial CML. The incidence of CML is 1.5 per 100,000 population.

In 1960, G. Nowell and D. Hungerford found in patients with CML a shortening of the long arm of one chromosome (Xp), as they believed, the 21st pair. They called this chromosome the Philadelphia or Ph chromosome.

However, in 1970 T.Caspersson et al. found that in chronic myeloid leukemia there is a deletion of one of the Xp 22 pairs. In 1973, J. Rowley showed that the formation of the Ph chromosome is due to reciprocal translocation (mutual transfer of part of the genetic material) between Xp9 and Xp22. This altered chromosome is from the 22nd pair with a shortened long arm and is designated as the Ph chromosome.

In the initial period of the cytogenetic study of CML, two variants, Ph+ and Ph-, were described. However, it must now be recognized that Ph-CML does not exist, and the reported cases probably belonged to myelodysplastic conditions. Ph-chromosome, t (9; 22) (q34; q11) is found in 95-100% of patients with CML.

In other cases, the following translocation options are possible:

Complex translocations involving Xp9, 22 and some third chromosome
- masked translocations with the same molecular changes, but not detected by conventional cytogenetic methods,
- the presence of t (9; 22) without transferring the Xp22 site to Xp9.

Thus, in all cases of CML, there are changes in Xp9 and Xp22 with the same gene rearrangement in a certain region of Xp22 (2).

The proto-oncogene ABL (Abelson) is located on the long arm of Xp9 (q34), which encodes, through the synthesis of a specific mRNA, the formation of the p145 protein belonging to the family tyrosine kinase (TK)- enzymes that catalyze the processes of phosphorylation of amino acids in the cell cycle. The M-BCR region (Major breakpoint cluster region) is located on the long arm of Xp22 (q 11).

The gene located in this region is referred to as the BCR gene. It encodes the formation of the p160BCR protein, which is involved in the regulation of several functions of neutrophils. As a result of translocation t(9;22)(q34;q11), the c-acr proto-oncogene is transferred to the bcr Xp22 region.

Typically, the breakage of the BCR gene occurs between exons b2 and b3 or exons b3 and b4, and exon 2 of the ABL gene fuses with the remaining part of the BCR gene on Xp22 (with exon b2 or b3). As a result, a chimeric BCR-ABL gene is formed, encoding an abnormal 8.5 kb ribonucleic acid (mRNA), which produces the p210BCR-ABL fusion protein with tyrosine kinase activity.

Sometimes the breakpoint of the BCR gene is located in the m-BCR (minor breakpoint cluster region), while the production of the chimeric gene is 7.5 kb of mRNA encoding the p190BCR-ABL protein. This type of translocation is associated with the involvement of lymphoid cells in the process and often causes the development of Ph+ acute lymphoblastic leukemia (ALL).

Due to the activation of the ABL gene resulting from its fusion with the BCR gene, the p210BCR-ABL protein has a significantly more pronounced tyrosine kinase activity than its normal prototype p145ABL. MCs phosphorylate tyrosine in proteins that regulate the growth and differentiation of cells, including hematopoietic ones.

Mutations of tyrosine kinases with an increase in their activity lead to unregulated phosphorylation of tyrosine and, accordingly, to disruption of the processes of cell growth and differentiation. However, this is not the only and not the main mechanism in the pathogenesis of CML symptoms.

The biological effect of the chimeric BCR-ABL gene is reduced to the following main disturbances in the life of the cell:

An increase in mitogenic activity due to increased proliferation signal transmission by activating hematopoietic cell receptors due to increased phosphorylation. This not only enhances proliferation, regardless of the regulatory influence of growth factors, but also disrupts the differentiation of progenitor cells;

Violation of cell adhesion to the stroma, which leads to a decrease in the interaction time of the stroma/hematopoietic cells. The consequence of this is that the normal proliferation/maturation sequence is disrupted, so progenitor cells stay longer in the late progenitor proliferative phase before differentiation. This leads to an increase in the proliferation and circulation time of progenitor cells and the appearance of foci of extramedullary hematopoiesis;

Inhibition of apoptosis due to the protective effect of the p210 protein and activation of the MYC gene, which is an inhibitor of apoptosis, as well as due to overexpression of the BCL-2 gene. As a result, leukocytes in CML live longer than normal cells. A characteristic feature of the p210BCR-ABL protein is the ability to autophosphorylate, leading to autonomous cell activity and its almost complete independence from external regulatory mechanisms;

The emergence of an unstable cell genome due to a decrease in the function of the ABL gene, since its role as a tumor growth suppressor decreases with its deletion. As a result, cell proliferation does not stop. In addition, other cellular oncogenes are activated during proliferation, which leads to a further increase in cell proliferation.

Thus, an increase in proliferative activity, a decrease in sensitivity to apoptosis, a violation of differentiation processes, an increased ability of immature hematopoietic progenitor cells to exit the bone marrow into peripheral blood are the main characteristics of leukemic cells in chronic myeloid leukemia.

Chronic myeloid leukemia: phases of development, criteria for risk groups

CML goes through three phases in its development: chronic phase (CP), acceleration phase (FA) and phase blast crisis (BC).

The chronic phase (CP) of the disease in most cases is almost or completely asymptomatic. Complaints of fatigue, weakness, sometimes heaviness in the epigastrium. Examination can reveal an enlarged spleen and, very rarely, the liver.

The clinical and hematological picture may be asymptomatic, the number of leukocytes and platelets may be normal or slightly increased; in the leukocyte formula, a moderate left shift can be observed - single metamyelocytes and myelocytes, sometimes a slight increase in the number of basophils. Cytological examination reveals only the Ph chromosome without additional changes from other chromosomes.

In the acceleration phase, patients note increased fatigue when performing their usual work, discomfort in the left hypochondrium; weight loss, periodic “unmotivated” increases in body temperature reflect the presence of hypercatabolism. As a rule, an enlarged spleen is determined, and in 20-40% of cases, an enlarged liver.

The main sign of the transition of the disease to FA are changes in blood tests: leukocytosis uncontrolled by cytostatic drugs increases with a quantitative predominance of immature forms of leukocytes, the number of basophils increases, less often the number of eosinophils or monocytes increases.

The number of platelets may increase with the development of thrombotic complications at the beginning of FA, followed by the development of thrombocytopenia with manifestations of hemorrhagic syndrome in the petechial-spotted type. In the bone marrow, FA shows a slight increase in the number of blast cells (usually less than 20%) and an increase in the content of promyelocytes and myelocytes. A cytogenetic study of FA, in addition to the presence of the Ph chromosome, can reveal additional changes in other chromosomes, which indicates the emergence of a more malignant cell clone.

In the phase of the blast crisis, there is a sharp general weakness, pronounced ossalgia due to subperiosteal infiltration by blast cells, periodic fever, sweating, and a pronounced decrease in body weight. Growing hepatosplenomegaly. As a rule, there is a pronounced hemorrhagic diathesis. Hematological manifestations are characterized by an increase in the number of blast cells in the peripheral blood and / or bone marrow above 20% with a variable number of leukocytes.

The predominant variant of CD is the myeloid variant - approximately 50% of all cases; lymphoblastic and undifferentiated variants - about 25% of cases each. Lymphoblastic CD has an extremely malignant nature, which is associated with changes in blast clones and, therefore, with resistance to ongoing therapy.

Sometimes CD is characterized by a sharp increase in the number of basophils of varying degrees of maturity in the peripheral blood and bone marrow without a large number of blast cells. In some cases, basophilia is replaced by monocytosis.

Usually, there is normochromic anemia and thrombocytopenia of varying severity, normoblastosis, and fragments of megakaryocytes in a blood smear. Approximately 10-15% of patients in the CD phase develop extramedullary blast infiltrates.

Less commonly, lesions of the central nervous system with symptoms of neuroleukemia or damage to peripheral nerves are observed. Some patients with CD have cutaneous leukemids or priapism as a result of leukostasis and leukemic infiltration of the cavernous bodies. It should be noted that in some cases, in the presence of extramedullary foci of blast infiltration, the picture of peripheral blood and bone marrow may not show signs of CML transition to the CD phase.

According to the WHO classification (2002), the following criteria have been identified for FA and CD.

The acceleration phase in the presence of one or more signs:

Blasts 10-19% in peripheral blood or bone marrow,
- basophils less than 20% in peripheral blood,
- persistent thrombocytopenia (less than 100.0x10 9 /l) or persistent thrombocytosis more than 1000.0x10 9 /l, despite ongoing therapy,
- an increase in the size of the spleen and an increase in the level of leukocytes, despite ongoing therapy,
- cytogenetic evidence in favor of clonal evolution (in addition to cytogenetic abnormalities identified at the time of diagnosis of HF CML),
- megakaryocytic proliferation in the form of clusters in combination with significant reticulin and collagen fibrosis and / or severe granulocytic dysplasia.

Power crisis phase in the presence of one or more of the following:

Blasts 20% or more in peripheral blood or bone marrow,
- extramedullary proliferation of blasts,
- large accumulations or clusters of blasts in the bone marrow during trephine biopsy.

The chronic phase of CML is established in the absence of FA criteria and the CD phase.

Splenomegaly and hepatomegaly of any size are not signs of FA and CCMLD.

It is important to determine not only the phase of CML, but also the risk group for disease progression at the onset of the disease, taking into account the data of the initial examination of the patient. J.E.Sokal et al. in 1987, they proposed a prognostic model taking into account four features: the age of the patient at the time of diagnosis, the size of the spleen, the number of platelets and the number of blasts in the blood. This model is the most widely used and is used in most studies.

The calculation of the prognostic index is carried out according to the formula:

Sokal index = exp(0.0116(age - 43.4) + 0.0345(spleen size - 7.51) + 0.188[(platelet count: 700)2 - 0.563] + 0.0887(blood blast count - 2.10)).

Exp (exponent) -2.718 is raised to the power of the number that appears in curly brackets.

If the index is less than 0.8 - low-risk group; with an index of 0.8-1.2 - a group of medium risk; with an index of more than 1.2 - a high-risk group.

Methods for diagnosing chronic myeloid leukemia

Differential diagnosis of CML should be carried out with leukemoid reactions of the myeloid type and with diseases representing chronic myeloproliferative neoplasms.

The mandatory methods of examination of patients to establish the diagnosis of CML include:

Morphological examination of peripheral blood with the calculation of the leukocyte formula and the number of platelets,
- morphological study of bone marrow punctate,

Since the only reliable criterion for the diagnosis of chronic myeloid leukemia is the presence of the Ph chromosome, a cytogenetic study of the bone marrow with an analysis of at least 20 metaphase plates is necessary; with a negative answer - the absence of t (9; 22) (q34; q11) - with a high possibility of diagnosing CML, it is necessary to use molecular genetic techniques - FISH (fluorescence in situ hybridization) or polymerase chain reaction (PCR),
- palpation and ultrasound-determination of the size of the spleen, liver, lymph nodes. Since splenomegaly or hepatomegaly of any size are not criteria for FA or a phase of CD, a specific lesion of any other organs and tissues should be considered as a sign of the transformation of the disease into CD,

HLA typing for potential candidates for allogeneic hematopoietic stem cell transplantation (allo-HSCT) indicated for patients with CML in FA and CD who have no contraindications to the use of this treatment method,
- patients in the CD phase of CML are shown to determine the type of blasts by cytochemical examination and immunophenotyping.

Optional examination methods include:

Trepanobiopsy to assess the presence and extent of fibrosis in the bone marrow,
- instrumental methods of examination - ultrasound examination (ultrasound), magnetic resonance imaging (MRI), lumbar puncture to determine the presence of extramedullary foci of hematopoiesis,
- before starting therapy tyrosine kinase inhibitors (TKIs) it is advisable to perform PCR to determine the initial level of expression of the BCR-ABL gene.

Therapy for chronic myelogenous leukemia

For several decades, CML therapy remained palliative. Treatment hydroxyurea (HU), busulfan (myelosan, mileran) improved the quality of life of patients, but did not increase overall survival.

The standard therapy for Ph+ CML, recommended by the experts of the American Hematological Society in 1998, included HU, recombinant interferon a (rINF) without or in combination with low-dose cytosar (LDAC), TKIs (tyrosine kinase inhibitors) - imatinib mesilate and allo-HSCT. The combination of rINF + LDAC was found to be superior to HU; advantage of using IM at a dose of 400 mg/day in comparison with rINF+LDAC.

Standard allo-HSCT caused long-term molecular remission or recovery in 50% of patients with a significant difference when taking into account risk groups. In countries where TKI therapy is available and allo-HSCT is being implemented, the two strategies are not mutually exclusive, although since the introduction of TKI into clinical practice, there has been a noticeable decrease in the annual number of allo-HSCT over the past 7 years.

The effectiveness of the therapy is determined by the following criteria:

1. The presence of hematological remission: data from blood tests:

- complete clinical and hematological remission (CHR):
- platelets below 450.0x10%,
- white blood cells below 10.0x10%,
- in the leukogram, blasts are less than 5%, there are no immature granulocytes.

2. The presence of cytogenetic remission: the presence of Ph chromosomes:

Full - 0%,
- partial - 1-35%,
- small - 36-65%,
- minimum - 66-95%.

3. Presence of molecular remission: presence of BCR-ABL transcript:

Complete - the transcript is not determined,
- large - 0.1%.

Complete cytogenetic (CCyR) and partial cytogenetic remission (PCyR) in combination can be considered as major cytogenetic remission (MCyR). Major molecular remission (MMolR) is the equivalent of a 1000-fold reduction from the baseline of 100%.

Complete molecular remission (CMolR) it is stated if the BCR-ABL transcript is not determined by the RQ-PCR (real-time quantitative polymerase chain reaction) method.

Treatment options for chronic myeloid leukemia

Currently, the use of hydroxyurea (HU) can be recommended:

In order to achieve cytoreduction,
- during pregnancy to maintain a hematological response,
- in cases of resistance and / or intolerance to interferon or TKI preparations,
- if it is impossible to perform allo-HSCT,
- when it is impossible to provide patients with CML with a sufficient amount of TKI.

The usual therapy for HU is to prescribe this drug at a dose of 2-3.0 grams per day in combination with allopurinol at a daily dose of 600-800 mg with sufficient hydration. The dose is corrected depending on the degree of decrease in the level of leukocytes, when they decrease below 10.0x10 9 /l, they switch to a maintenance dose of 0.5 g / day with or without allopurinol. It is desirable to maintain the number of leukocytes at a level not higher than 6-8.0x10 9 /l.

In the event of a decrease in the number of leukocytes below 3.0x10 9 /l, the drug is temporarily stopped. Tolerability of the drug is quite good, but with prolonged use, the formation of stomach ulcers is possible.

The introduction of rINF preparations into practice made it possible to obtain in some CML patients not only long-term clinical and hematological, but also cytogenetic remission, although the frequency complete cytogenetic response (CCyR) was low - 1015%. The combination of rINF+LDAC drugs slightly increased the frequency of CCyR (25-30%), but sooner or later the disease progressed in almost all patients of this group.

Method of treatment with rINF drugs

Initially, patients are prescribed HU to reduce the number of leukocytes to 10.0x10 9 /l, after which rINF is prescribed in the following dosage:

1st week: 3 million U / m2 subcutaneously daily,
- 2nd and 3rd weeks: 5 million U/m subcutaneously daily,
- in the future, the drug is prescribed at 5 million U / m subcutaneously daily or 3 times a week.

The drug can cause allergic reactions, fever, skin itching, muscle pain (usually at the beginning of use). Therapy usually continues for 2 years, then there is a withdrawal from the control of the drug.

With the combination of rINF+LDAC (cytosar 20 g/m2 s.c. twice daily for 10 days monthly), the cytogenetic response was higher than with rINF alone, but there was no difference in overall survival.

A comparison of the results of using rINF at a dose of 3 million U/m 3 times a week and at a dose of 5 million U/m daily showed that low doses were as effective as high doses, but better tolerated. However, in all patients on such therapy, the presence of minimal residual disease was determined, which suggests the inevitability of relapse.

In routine clinical practice, sequential or combined use of IM or new TKIs with rINF preparations is not yet recommended, since the results of ongoing clinical trials are unknown. Currently, the use of rINF can be recommended in the same cases in which hydroxyurea therapy is recommended.

Conducting allo-HSCT as first-line therapy in the presence of an HLA-compatible donor, as well as the age of the patient below 50-55 years, has become a standard recommendation for patients with initially diagnosed CML since the early 1990s. Allo-HSCT is considered the only method that can completely eliminate the leukemic clone of cells from the body.

However, there are several problems that limit its widespread use in patients with CML:

The predominance in the population of patients with CML in the age group of 50-60 years,
- the impossibility for most patients to find an HLA-compatible related or unrelated donor,
- mortality up to 20% in the early post-transplantation period from complications polychemotherapy (PCT) or graft-versus-host disease (GVHD).

In FA, the decision to conduct allo-HSCT should be made taking into account the following data:

Assessment of the risk of progression of chronic myeloid leukemia (according to the Sokal index),
- determination of the effectiveness of TKI taking into account cytogenetics and PCR data,
- risk assessment of transplant and post-transplant complications,
- availability of an available donor.

According to the recommendations of the EBMT, in CML, allo-HSCT in HF, in FA or in late CP is indicated from a related or unrelated compatible donor, not from an unrelated incompatible donor; the problem of performing auto-HSCT is under development. In the CD phase, allo- or auto-HSCT is not indicated.

If a decision is made to perform allo-HSCT, the question arises of which conditioning regimen to offer the patient: myeloablative or non-myeloablative. One of the myeloablative regimens for allo-HSCT in CML patients is BuCy: busulfan at a dose of 4 mg/kg of body weight per day and cyclophosphamide 30 mg/kg of body weight per day for 4 days before allo-HSCT.

The non-myeloablative (reduced) regimen of Bu-Flu-ATG consists of a single dose of a combination of busulfan at a dose of 8 mg/kg of body weight, fludarabine 150 mg/m and rabbit antithymocyte globulin at a dose of 40 mg. However, due to the lack of randomized trials, this option is not recommended as a standard of care.

Role Awareness tyrosine kinase activity (TKA) BCR-ABL protein during myeloproliferation led to the synthesis of a new series of drugs targeting BCR-ABL encoded proteins. Inhibition of TKA leads to the interruption of signals that control the leukemic phenotype. The first of the TKA inhibitors, imatinib mesylate (IM), has a high and relatively specific biochemical activity in CML, which has led to its rapid introduction into clinical practice.

With the advent of TKI, indications for allo-HSCT have changed dramatically. In early CP CML, allo-HSCT is indicated in the development of resistance or intolerance to TKI, so its implementation in adult patients as a first-line therapy is not currently recommended.

However, there are two exceptions to this rule:

In pediatric practice, it is preferable to use allo-HSCT as primary therapy in the presence of an HLA-compatible related donor,
- if the cost of the proposed TKI treatment significantly exceeds the cost of allo-HSCT.

In general, the majority of patients with CML in HF should be treated with initial MI if possible.

Imatinib mesylate (IM)- glivec, which is a tyrosine kinase inhibitor, was used in the clinic in 1995. IM (2-phenylaminopyrimidine) effectively blocks the kinase activity of the BCR-ABL protein and can block other proteins with protein kinase activity necessary for normal cell survival.

Studies have shown that IM selectively inhibits cell proliferation in chronic myeloid leukemia. The drug is mainly eliminated by the liver, a 50% decrease in its plasma concentration is about 18 hours. The recommended starting dose of the drug is 400 mg / day, which allows you to achieve Pcomplete clinical and hematological remission (CHR) in 95% and CCyR in 76% of cases. In the group of patients with CCyR major molecular remission (MMolR) was determined only in 57% of cases.

The use of MI in "late" CP at the same dosage allows to achieve CCyR in 41-64% with progression-free survival in 69% of patients. With the use of MI in FA at a dose of 600 mg/day, CHR was achieved in 37%, CCyR in 19% of cases and three-year PFS in 40% of patients. With the use of MI at the same dose in CD CML, CHR was achieved in 25%, PFS was less than 10 months, overall survival over 3 years was in 7% of cases.

Since the frequency of CCyR is very high in patients treated for MI, it is necessary to measure the level of the BCR-ABL transcript to determine the presence minimal residual disease (MRD). The frequency of the absence of this transcript is considered as CMolR, is very variable and ranges from 4-34%. It has been shown that Ph+ stem cells are less sensitive to MI than late Ph+ progenitors.

In the case of a suboptimal effect from the use of MI in CP at a dose of 400 mg/day, it is proposed to escalate the dose of the drug to 600-800 mg/day, provided that resistance to MI is not associated with additional BCR-ABL mutations. Taking MI at a dose of 600 mg per day is significantly more effective in FA and BC. In CP patients with hematological and cytogenetic resistance to MI at a dose of 400 mg/day, increasing the MI dose to 800 mg per day caused CHR in 65% and CCyR in 18% of patients.

When using MI, some complications can be observed:

Anemia and/or pancytopenia
- infraorbital edema, rarely - generalized edema,
- pain in the bones and joints,

- decrease in the level of calcium and phosphorus in the blood,
- skin itching.

To date, there are two drugs of the TKI group registered for use as 2nd-line drugs in CML therapy in cases of development of resistance to MI: dasatinib and nilotinib.

Dasatinib (Sprycel) is an inhibitor of ABL kinases (it inhibits about 50 kinases in total) and differs from IM in that it can bind both active and inactive (open and closed) conformations of the ABL kinase domain, and also inhibits the Src family of kinases, including Srk and Lyn.

It can be considered as a dual inhibitor. Dasatinib is 300-fold more potent than IM and is also active against most IM-resistant mutant subclones, with the exception of clone T315I and probably the mutant clone F317L. The drug is used to treat CML patients with resistance or intolerance to MI. Remission was observed to the same extent in patients with and without kinase mutations, except for T315I mutations.

The drug can cause complications in the form of neutropenia, thrombocytopenia, vomiting, diarrhea, gastrointestinal bleeding, generalized edema, skin rashes, hypertension, COPD. In single patients, pleural and pericardial effusion may be observed. To correct complications, you should take a break in taking the drug, prescribe diuretics, corticosteroids, and, if necessary, thoracocentesis.

The 100 mg dose once daily is comparable in efficacy to 70 mg twice daily but is better tolerated.

Nilotinib (Tasigna) is an aminopyrimidine derivative, ie. modified derivative of IM, which explains their similar spectrum of inhibition (inhibits four TCs). The drug has an increased ability to bind the ATP region of the BCR-ABL oncoprotein. It is 20-50 times more effective than IM against IM-sensitive leukemic cells, and is also active against all IM-resistant cell lines with mutations in the ABL kinase domain, with the exception of the T315I mutation and, probably, the Y253H mutant clone.

In the group of patients in CP CML resistant to MI, CHR was achieved in 71% and CCyR in 48% of patients. Overall 2-year survival in this group was 95%. There were no differences in the number of remissions in patients with or without a mutation in the ABL kinase domain. When using the drug in FA, one month after the start of therapy, CHR was registered in 55% of cases, overall survival after 12 months was 82%. In the CD phase, with 12 months of therapy, overall survival was 47%.

skin itch,
- constipation,
- increased levels of liver enzymes,
- increase in the level of indirect bilirubin,
- rashes on the skin.

For dasatinib, a 50% reduction in plasma levels is 3-5 hours, for nilotinib and MI, 15-18 hours. For dasatinib, long-term inhibition of the BCR-ABL protein does not necessarily mean the elimination of leukemic cells in chronic myeloid leukemia. Therefore, the postulate about the prevalence of the effectiveness of long-term inhibition of kinases in the treatment of CML is not applicable to dasatinib.

In general, dasatinib and nilotinib have approximately equal potency in patients with no response to MI therapy. However, none of them is recommended for use in patients with the N315I mutant clone.

Bosutinib, which inhibits both ABL and Srk kinases and is therefore a dual kinase inhibitor, is in clinical trials. It is active against cell lines carrying mutations in three of the four kinase domains. However, it should be borne in mind that the use of the above drugs does not provide a complete cure.

After the use of imatinib, in case of development of resistance to the drug, with its intolerance or severe complications, patients should be offered TKI therapy of the 2nd line of therapy;
- the choice of drug should be determined by the degree of its toxicity.

Allo-HSCT is offered for:

The presence of T315I mutations and other mutations
- no effect in the treatment of TKI in FA and BC,
- no effect in the treatment of TKI of the 2nd line of therapy.