Mieloproliferative Diseases: What is this forecast

What is myeloproliferative diseases

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Not every person has an idea of ​​what myeloproliferative disease is. However, those who have encountered this pathology know absolutely everything about it.

This is due to the fact that such people are forced throughout life from a specialist and maintain their health with drugs. After all, it is not so easy to independently fight against disorders in the bone marrow, which produces stem blood cells more than necessary.

Description of pathology

Chronic myeloproliferative blood disease belongs to the group of pathologies characterized by excessive production of platelets, erythrocytes, leukocytes.

In the normal state, stem immature cells are produced. Over time, their maturation occurs, they are transformed into full-fledged. Inchange, in turn, form three types:

Thrombocytes
  • platelets that contribute to preventing bleeding by forming blood clots;
  • Erythrocytes, which are involved in the transportation of oxygen and nutrients to all vital organs and tissues of the human body;
  • Leukocytes that are responsible for providing a protective response in the fight against infectious diseases or other pathologies.

Before their transformation occurs, stem cells are developing in several stages. In case of manifestation of myeloproliferative disease, their large amount is transformed into one type of shaped blood element. As a rule, the progression of pathology occurs at a slow pace.

In patients who have such a parable, significantly increases the risk of blood cloves and hemorrhagic complications.

Myeloproliferative diseases in most cases are observed in men over the age of 40. Women of such a state are significantly less . These forms of diseases are uncharacteristic for persons under the twentieth age, children have only isolated cases.

Types of pathologies

By type of illness, the following classification of myeloproliferative diseases is distinguished:

  • True polycythemia. It is characterized by an excess of erythrocytes, as a result of which blood thickening is observed. Being in large quantities, these cells begin to accumulate in the spleen, against the background of which it increases in size. In addition, the bleeding and formation of blood clots in vessels are possible. Such violations contribute to stroke or infarction. But despite even such a possible outcome, proceeds in a benign form and is of greater survival in comparison with the rest of the pathologies.
  • Essential thrombocytosis is a large amount of platelets.
  • Chronic form of myelolecosis. With this pathology in the bone marrow, excessive accumulation of leukocytes occurs.
  • Eosinophilic leukemia is characterized by an excessive content of eosinophils, which are one of the types of leukocytes. Fight with infectious diseases provoked by certain types of parasites and are responsible for allergic reactions of the body to stimuli.
  • Idiopathic myelofibrosis. There is a generation of pathological uniform elements, gradual replacement of the bone marrow fibrous fabric.
  • Chronic neutrophil leukemia. Stem cells form neutrophils responsible for the fight against infectious pathologies. Develops slowly.

All pathologies can go to the leukemia of acute form.

Development Stages

Myeloproliferative syndrome does not have a standard staging system, which is used in identifying the degree of development of tumor formations. The choice of treatment method is carried out depending on the type of pathology in the patient.

3 main paths are distinguished by which the tumor process applies to human body:

Blood cells
  1. Penetration of healthy tissue.
  2. Lymphogenic path. Pathogenic cell entering other systems and organs occurs through lymphatic vessels.
  3. Hematogenic. When penetrating into the circulatory system, malignant elements with blood flow fall into healthy fabrics.

When the third distribution path is noted, the likelihood of the formation of secondary type tumors increases. This process was called "Metastasation".

Characteristic signs

The clinical picture of each of the diseases will manifest itself in different ways. However, common common symptoms characteristic of all myeloproliferative pathologies are distinguished. These include:

Male tired
  • fatigue;
  • rapid loss in weight, up to anorexia;
  • tinnitus;
  • disturbed consciousness;
  • predisposition to bruises;
  • possible bleeding;
  • symptoms of thrombosis;
  • swelling;
  • pain in the joints;
  • Painful feelings in the abdomen and left forearm.

The patient may have such signs as:

  • hemorrhage;
  • pallor skin;
  • increase liver or spleen;
  • Shepherd;
  • Fever accompanied by the manifestation of the spots of a purple color on the limbs and face.

Only the inspection will allow us to evaluate the general state, as well as identify any pathological deviations that do not correspond to the norm of a healthy body.

Diagnostic events

To form a diagnosis of "myeloproliferative syndrome", a comprehensive examination is necessary, which should include various research methods and biopsy.

Laboratory diagnostics includes:

  • carrying out microscopy smear;
  • passing a general blood test;
  • cytogenetic analysis determining the level of changes in the PH-chromosomes;
  • Polymerase chain reaction.

Biopsy and aspiration are not possible in all cases . The procedure is to introduce the needle to the sternum area for taking a sample of blood and bone tissue. The study of the materials obtained allows you to determine the presence of pathological elements.

biopsy

With a confirmed diagnosis, patients should be observed in the hematologist throughout life.

How are myeloproliferative diseases treated

Currently, several therapeutic methods are used to treat such diseases. The choice of one or another variant depends on the general state of the patient and the severity of clinical manifestations. Treatment is possible in a standard way, repeatedly proven in practice, or experimental when a new means is applied.

Among the most commonly used methods are allocated as follows:

  1. Phlebotomy. With this method, blood is taken from the vein. After that, the material is sent to a biochemistry or overall analysis. In the treatment of myeloproliferative disease, the main task will be to decrease the level of erythrocytes.
  2. Apferes platelet. This method is similar to the previous one, the only difference is that actions are sent to reducing the number of platelets using the equipment intended for this. The essence of the method is as follows: the patient's blood is passed through the so-called separator. In purified form, it is re-influenced by the patient.
  3. Chemotherapy. It implies the use of drugs of the cytostatic group. They effectively affect tumor cells, to the result of which eliminate them and prevent the development of neoplasms. The use of them is possible orally, intramuscularly or intravenously. In any case, the active ingredients of the drug in the bloodstream occurs, which contributes to the suppression of pathological cells. This method is called systemic. At the regional drug is introduced into the channel of the spinal region or directly into the body where tumor changes occur.
  4. Radiation therapy. Based on the use of x-ray or other radiation having high frequencies. This method contributes to the complete removal of tumors and slows down the development of new formations. In medical practice, two types of such treatment are used:
    • Outside, the radiation comes from the drug, which is disposed of directly near the patient;
    • internal when tubes, needles and catheters fill the means containing radioactive substances; After that, they are inserted into the tumor itself or into the fabric located near it.

The choice of one way or another is based on what the degree of flow has a malignant process. In patients with a diagnosis of "myeloproliferative blood illness", the region of the spleen is exposed to radiation.

blood transfusion
  1. Transfusion - blood transfusion, characterized by the substitution of some elements to others. As a result, instead of destruction cells, a person receives transfusion consisting of platelets, erythrocytes and leukocytes.
  2. Chemotherapy with cell transplantation. Medication tools are prescribed in high doses, and the affected cells are replaced by healthy, which are obtained from the patient or at the donor. Such elements are subject to freezing. Upon completion of the course of chemotherapy, this material is placed in the body. There they are already ripening and form new cells.

Food

In each case, a special diet for the patient is developed individually. It is necessary in how few quantities can use fatty, salty and acute food. Power must be balanced.

Recovery period

After all therapeutic activities are carried out, the patient must be constantly under the supervision of a specialist, that is, to regularly come to accept.

To evaluate how effective the treatment was, those procedures that were used in the diagnosis of the disease can be appointed. Only after receiving repeated results, the doctor may stop, continue or change the therapy applied to this.

A number of surveys should be carried out constantly, even after the end of the entire course of therapeutic process. This will allow you to trace changes in the body and prevent or detect recurrence in time.

Forecasting

In the chronic form of the course of the disease using standard therapeutic methods, the life expectancy is about 5-7 years.

In case of transplantation, the forecast is the most favorable. The cure is about 60%. The effectiveness of this method will depend on the pathology phase.

We strongly recommend not to engage in self-medication, better contact your doctor. All materials on the site are familiarizing!

Methods, approaches and diagnostic procedures [9-12] Diagnostic criteria: Complaints, history, physical research data is important in diagnosis and differential diagnosis of chronic myeloproliferative diseases, but nonspecific in connection with which they are not related to the diagnostic criteria . Complaints for IP (nature of the occurrence and manifestation of pain syndrome) for dizziness, headaches, impairment of vision, skin itch, attacks of angina - Pletic syndrome most characteristic of true polycythemia. Clear itching, sweating, weakness, elevated body temperature, bone pain - Myeloprolifeattvic syndrome NB. !The pilor syndrome (from the word "Pletic" - full-range) - is characterized by an increase in the mass of circulating erythrocytes, which leads to the appearance of dizziness complaints, headaches, impaired vision, skin itching after washing, burning pain and paresthesia in the tips of the fingers, attacks of angina. When examining the skin and visible mucous membranes with a blue hint (positive symptom of Cooperman). Vascular complications - thrombosis of any localization, attacks of redness of the fingers and legs, which are accompanied by pain and burning (erythrolealgia). The increase in the volume of circulating erythrocytes leads to the appearance of arterial hypertension in patients, who, before the beginning of the disease, did not complain about this symptom, or the exacerbation of an existing hypertension, which is poorly treated with traditional hypotensive drugs. The symptoms of ischemic heart disease, cerebral atherosclerosis are becoming more pronounced. In the early stage of the disease, the erythrocytosis is marked, in the bone marrow - Päyelosis. Since the disease is developing gradually, from its beginning to formulate a diagnosis takes place from 2 to 4 years. The duration of this steel is up to 5 years. NB. !Myeloproliferative syndrome is due to the hyperplasia of three sprouts of blood formation. It is manifested in the form of a skin, sweating, weakness, elevated body temperature, bone pain. The increased decay of granulocytes is accompanied by a violation of the urate exchange, which is manifested in the form of a diatemic diatela, stone formation in the kidneys, gout, gout polyartralgia. Splenomegaly may be due to an increase in the sequest-end function of the spleen. Physical examination: · In case of inspection: the color of the skin is determined (the blue shade is a positive symptom of Cooperman). Redness of the skin. · When palpation: Splenomegaly. Laboratory research : · general blood analysis - with a differential count using an automatic analyzer (hematocrit, counting the number of reticulocyte, platelets, averages of erythrocyte indexes (MCV - average volume of erythrocyte, MCH - average hemoglobin content in red blood cell, RDW - the width of the distribution of erythrocytes in volume)); Study of morphology of red blood cells, platelets, neutrophils. · мOlocular-genetic study of peripheral blood - Determination of the allelic load of mutant JAK2 V617F and "wild" types of JAK2 genes in real-time PCR. · Cytological study of bone marrow aspirate - Three-stage hyperplasia (Päyelosis): an increase in the proliferation of elements of erythroid, granulocytic, megacariocytic sprouts of myelopopower. · Standard cytogenetic study of blood / bone marrow - For differential diagnosis with pH-positive MPZ. Instrumental research : · Abdominal ultrasound - With the determination of the volume of the spleen, to eliminate the development of the silence infarct, thrombosis in the portal vein system. · Tinpalobiopia bone marrow with histological assessment and histochemical studies To identify reticulin and collagen fibrosis; It is also necessary to assess the effect of therapy, progression and transformation of the disease. To compare with the histological picture in the debut of the disease (before treatment). Indications for consulting professionals : · Consultations of other narrow specialists - by testimony. Diagnostic algorithm [9-11]

© Author: Soldatenkov Ilya Vitalevich, doctor of the therapeutic department, especially for V. Visidofo.ru (about the authors)

Myeloproliferative disease (MPZ) is a rather rare hematoncological pathology at which Red bone marrow produces excessive blood cells . This dangerous disease carries a serious threat to human life. "Melo" means "bone marrow", and proliferation is "rapid division". The disease is more often developing in men 40-50 years. Among children and women there are isolated cases of disease. Persons who have bad heredity on the development of oncopathology of blood-forming organs make up a risk group.

Normally, unripe stem cells are produced in the spongy substance of the bone marrow in the cavity of large bones of the skeleton. Gradually, they ripen and transformed into full-fledged uniform elements:

  • Erythrocytes delivering oxygen to organs and tissues,
  • leukocytes protecting the body from infectious agents and other alien substances
  • Platelets forming blood clots and stopping bleeding.

Ripening of blood shaped blood elements

If a person has a myeloproliferative disease in the blood, cells are incapable of performing their functions. Stem cells in pathology are often converted only to one type of uniform elements. The pathological process is characterized by slow progression.

Myeloproliferative disease is a collective concept that includes a group of hemoblastosis, which are characterized by an abnormal growth of bone marginal structures responsible for the formation of blood cells. Several major forms of the MPZ are isolated, under which various cellular elements are affected:

  1. True polycythemia
  2. Essential thrombocytemy,
  3. Chronic myelolomicosis.

These forms have general signs and are called "classic". They are most often found. Persons who receive proper treatment do not impose no complaints. Clinical manifestations of the disease are minimal or completely absent for a long time. Persons with the MPZ are forced to observe the doctor with a doctor and take medication supporting health at the optimal level. It is impossible to independently cope with the bone marrow dysfunction. In the absence of adequate treatment, pathology leads to the development of thrombohemorgic complications.

Causes

Example JAK2 mutations for true polycythemia (excess of erythrocytes)

At the heart of the MPZ lies Acquired  Gene mutation due to the influence of negative external or internal factors. Mutation of MPL and JAK 2 genes leads to damage to the DNA of one hematopoietic cell, which gives the beginning to all types of cellular elements. An abnormally changed blast form acquires negative features - ceases to develop, does not ripen completely, it does not self-suite, but is continuously divided and generates numerous clones. That is why the MPZ is called clonal. Clones also remain at the initial level of development and have a fully undifferentiated structure. It can be damaged as one, so immediately several sprouts of blood formation.

As a result, the number of erythrocyte, platelet and leukocyte type cells increases in the bone marrow. As they accumulate in the bloodstream deteriorates the well-being of patients. The nature of the pathology, its symptoms and the forecast depends on which sprout. MPS forms are distinguished by slow development. If the disease was revealed at an early stage, the patient has every chance to achieve a resistant.

The reasons that caused mutational processes remain completely unexplored. Some scientists belong to them negative environmental factors, others - errors in cell division. MPZ is not hereditary . Gene mutations may arise throughout the human life. They are called acquired. The risk of developing pathology increases with age. Persons over 50 years old must be carefully related to health and when suspicious symptoms appear to handle hematologist. The probability of the development of illness increases under the influence of risk factors - irradiation and chemicals that have toxic influence on the body.

Classification

Myeloproliferative diseases have a code on the ICD 10 - D47.1. By the type of flow, they are divided into acute and chronic. The first group includes the most aggressive and rapidly progressive ailments, striking mostly young people. The group of chronic myeloproliferative diseases includes slowly developing pathologies with a relatively favorable forecast and emerging among the elderly.

Depending on the affected blood formation sprout, the following forms of the process are distinguished:

  • True polycythemia - hyperproduction of red blood cells and blood thickening. Erythrocytes are delayed in the spleen, splenomegaly develops. In patients there are signs of thrombohemorrhagic syndrome, the risk of strokes and heart attacks increases. In general, this form is distinguished by a benign flow. Compared to other types of MPZ, it is characterized by high survival.
  • Essential thrombocytosis - life-threatening condition at which the strengthened formation of platelet cells occurs.
  • Chronic myelolomicosis - malignant disease characterized by preferably damage to the granulocytic sprout and the appearance of undifferentiated leukocytes in the blood.
  • Eosinophilic leukemia - enhanced growth and damage to eosinophils, which relate to leukocyte cells. At the same time, their main functions are violated - the struggle against infection and the immune response to potential allergens.
  • Myelofibrosis - Education in the bone marrow of pathologically modified cells with the replacement of functional tissue with connective tissue fibers.
  • Chronic neutrophil leukemia - The formation of immature neutrophils that cease to protect the body from pathogens.

The classification of the MPZ is important for the diagnosis of oncological diseases of the blood formation organs. With its help, hematologists-oncologists can easily determine the type of formed pathology and choose a patient adequate therapy that can save life.

Video: Lecture by classification and pathogenesis HDPZ

Development and symptoms

There are three ways to disseminate the disease in the body:

  1. Lymphogenic - abnormal structures penetrate into the internal organs on lymphatic vessels.
  2. Hematogenic - penetration of modified cells into healthy tissues in the bloodstream.
  3. Implantation - germination of affected blast forms in neighboring organs and nearby fabrics.

The hematogen spread of malignant cells is considered the most dangerous. Such patients, together with therapeutic activities, conduct dynamic observation of the functioning of the internal organs. This type of pathology gives metastase into the most remote areas of the human body, which leads to the formation of secondary oncological foci.

The clinical picture of the MPZ depends on the specific form of the process, accompanied by the growth of blood-made bone marrow tissues and excessive admission to the bloodstream of atypical blood cells who stopped in their development. Each type of disease is characteristic of characteristic symptoms. But there are common common symptoms. These are signs of anemia or thrombosis:

  • not passing weakness, fast fatigue, decay of forces,
  • Lack of appetite and weight loss,
  • noise in ears and dizziness,
  • permanent consciousness
  • disorientation in time and space,
  • Hematomas on the body
  • frequent bleeding and hemorrhage,
  • Eyeflow of fabrics and arthralgia,
  • abdominal pain
  • skin pallor
  • hepatosplegaly
  • Pletics ("full-time"),
  • fever.

This is a general symptomative arising from any form of the MPZ. There are also specific manifestations characteristic of each of them.

  1. Signs typical of polycythemia : hepatomegaly and splenomegaly, skin hyperemia, hypertension, night sweat, headache, skin itching, diplopia, vision of vision, numbness and burning in steps, sawing and severity in the left hypochondrium.

    Manifestations of polycythemia

  2. Essential thrombocytemia It is manifested by fainting and pre-corrupt states, pain in the chest, pulsating pain in brushes or feet, cephalgia, numbness of half of the body, illegible and vague speech, nasal bleeding, hematuria, blood in feces.

    blood painting during thrombocytemia

  3. Signs of myelofibrosis : shortness of breath, weakness, skin pallor, abdominal pain, weight loss, hepatosplegegaly, belendment, hyperhydrosis, fever, pain in the bones and joints.
  4. Chronic myelolomicosis In the initial stages proceeds asymptomatic. After some time, the patients appear fast fatigue, sweating, heaviness in the hypochondrium on the left, shortness of breath, epigastric pain after meal, skin itching, heat, articular pain, sharp weakness, weight loss, signs of hemorrhagic syndrome, regional lymphhadenitis, parires, nerve infiltration.

    Total clinic leukemia

Diagnostics

The symptoms of the MPZ is the basis for the patient to the patient of diagnostic procedures that allow you to confirm or disprove the presence of the process, and also find out which the pathology of the blood formation organs proceeds.

The survey starts with a survey and collection of history. Doctors clarify what way of life is the patient, whether there are destructive addictions, which diseases suffered and what was treated. Inspection of the patient - determination of the overall condition and identification of signs that are usually absent in healthy people.

Laboratory diagnostics of the MPZ is to carry out a number of studies and tests:

  • The hemogram is calculated leukocyte formula, determining the number of erythrocytes, platelets, hemoglobin levels, hematocrit.
  • Microscopy of peripheral blood smear - detection of blastous forms.
  • The tank is determining the functional state of the liver and other internal organs.
  • The myelogram is the result of the microscopy of the bone marrow smear, reflecting the qualitative and quantitative composition of the nucleus-containing cells of myeloid tissue.

    PCTC for myelogram

  • The cytogenetic analysis of bone marginal structures and cellular elements allows you to determine the high content of atypical cells.
  • Molecular genetic study - identification of pathological changes in chromosomes. The presence of JAK 2 mutation is the main criterion for diagnosis, and PCR is a standard method for diagnosing pathology. The identification of a mutant gene undoubtedly confirms the presence of a clonal disease and eliminates the possibility of reactive erythrocytosis or thrombocytosis.

In addition to laboratory diagnostics, the results of instrumental research are needed for diagnosis. Patients conduct an abdominal ultrasound to determine the degree of hepatosplegegaly. In diagnostically complex cases, they are sent to a tomographic study.

If the patient is diagnosed with "Chronic myeloproliferative disease JAK 2 positive", he needs to be treated. He must be under the supervision of a hematologist. Re-diagnostic research is carried out after the course of treatment is completed. The results of laboratory analyzes allow you to reveal the recurrence of the disease and stop its development.

Treatment

Oncohematologists prescribe treatment with their patients according to the results of diagnostic research. There are standard therapeutic techniques that are used for various types of MPZ. If the patient has the initial stage of the process, when there are no clinical signs, there is a dynamic observation. When the first signs of pathology are transferred directly to treatment.

Each patient is selected an individual medical technique in accordance with its condition and the degree of severity of the existing disorders.

  1. Phlebotomy - Regular fence of venous blood in a patient, which allows to reduce the content of erythrocytes in the bloodstream. The selected material in a volume of 400-500 ml is sent to the laboratory for carrying out generally clinical and biochemical studies.
  2. Apferes of thrombocyte - The technique aimed at purifying blood from the excess of thrombocytarium elements. For this, special equipment is used - the separator through which the patient's blood is passed, and then after purification, it is introduced back.
  3. Hemotransphusion treatment - Ordinary blood transfusion, during which atypical cells are replaced with healthy, donor.
  4. Immunomodulatory therapy - Introduction of medicinal patients reinforcing the functional activity of immunocompetent cells and stimulating the immune system as a whole. These drugs are used to ensure that the body struggles on their own disease.
  5. Chemotherapy - The use of cytostatics, which are classic and generally accepted means to combat cancer cells. Antitumor drugs impede the growth and development of neoplasms. It is possible to apply them systemically and regional. In the first case, the medicine is administered parenterally, orally or intramuscularly. The active components of cytostatics penetrate the systemic bloodstream and destroy atypical cells. With regional use, the medicine affects directly on the lesion center. Injection is made in the spinal cord or pathologically modified organ.
  6. Persons with affected and enlarged spleen showing radiation therapy based on the use of high-frequency radiation, such as X-ray. This is a very effective technique that allows you to fully free the organ from tumor structures. External radiation therapy - ionizing radiation on the area of ​​the spleen from the drug, located next to the patient, internal - the introduction of a radioactive substance in the tissue surrounding the affected organ.
  7. There are also other, less effective methods of conservative treatment - the use of drugs "Lenalidomide", "Talidomide", which prevent the formation of new blood vessels in the bone marrow tumor.
  8. Surgical intervention - Splenectomy. The spleen is removed when it is significantly increased.
  9. Patients may optionally try new treatments on themselves, which are at the clinical trial stage. Often, such therapy gives good results and results in some cases to long-term remission.
  10. Bone marrow transplantation - The only method that can fully cure the patient. Cell transplantation is a replacement of atypical cells full, which are taken from the patient or donor. Cellular elements are frozen, and after chemotherapeutic treatment is introduced into the body. This procedure is very seriously transferred to patients, especially elderly people with a number of concomitant diseases. They are prescribed by the hematologists with complex antitumor therapy, which allows you to achieve a resistant remission.

KM pericatization is the most radical, but also a potentially effective technique with a successful outcome.

After the full treatment course comes the period of rehabilitation. The patient must be under the constant observation of the doctor and strictly fulfill all its prescriptions. allowing the body to restore the organism.

Patients are recommended:

  • proper, balanced nutrition with restriction of oily, salt, sharp dishes and the complete exception of alcohol, smoking;
  • Long walks in the fresh air, preferably near the water branch;
  • Exception of excessive physical overvoltage;
  • Compliance with the day of the day - full sleep, alternation of labor and recreation.

Myeloproliferative disease is a recurrent process capable of aggravating at any time. That is why all patients need to regularly visit the attending physician and undergo diagnostic studies with a prophylactic goal.

The prediction of the MPZ is considered favorable only in the case of successful bone marrow transplantation, which is not allowed to all patients. Chronic forms are transferred easier to sharp. The life expectancy of patients in this case is 5-7 years old, subject to comprehensive therapy. If metastases are found in patients, the forecast becomes disappointing - they die for 6 months.

Video: Lecture on the experience of HMPZ treatment

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Table of contents

Keywords

  • Chronic myelolomicosis
  • Ph chromosome
  • Tyrosine kinase inhibitors,
  • hematology response
  • cytogenetic response
  • molecular answer
  • gene BCR-ABL,
  • BCR-ABL transcript,
  • Mutations BCR-ABL. ,
  • optimal answer
  • therapy failure
  • Allogeneic transplantation of hematopoietic stem cells.

List of abbreviations

Allo-TGSK - allogeneic transplantation of hematopoietic stem cells;

Achn - the absolute number of neutrophils;

BK - Blastic Crisis;

BMO - a big molecular answer;

VGN - the upper limit of the norm;

WHO - World Health Organization;

Deep MO - deep molecular answer;

Mr. KSF is a granulocytic colonystimulating factor;

GSK - hematopoietic stem cells;

DHA - additional chromosomal aberrations;

ITC - Tyrosine kinase inhibitors;

ITQ1 - the inhibitors of the tyrosine kinases of the first generation;

ITQ2 - second-generation tyrosine kinase inhibitors;

IF? - Interferon Alpha;

MO - molecular answer;

MINCO - the minimum cytogenetic response;

MCO - small cytogenetic response;

NGN - the lower boundary of the norm;

From-PCR - polymerase chain reaction with reverse transcription;

PGO - a full hematological response;

FOS - a full cytogenetic response;

PCR - polymerase chain reaction;

PCR-RV - quantitative PCR in real time;

SCI - standard cytogenetic study;

CSD cardiovascular diseases

F - phase of acceleration;

HML - chronic myelolomicosis;

HF - chronic phase;

CO - cytogenetic response;

Czzo - partial cytogenetic response;

ARA-C - cytarabin;

BCR-ABL. - chimeric gene, translocation result between 9 and 22 chromosomes;

BCR-ABL - protein with increased tyrosine kinase activity, product gene BCR-ABL;

EBMT - European bone marrow transplantation society4

ELN - European organization for the treatment of leukemia;

ESMO - European Society of Medical Oncology;

FISH - fluorescent hybridization;

IS - International quantitative transcript level estimation scale BCR-ABL;

NCCN - US National Oncological Network;

NCI CTCAE - the toxicity scale of the National Institute of US Cancer (criteria for general terminology of unwanted phenomena);

PH - Philadelphia chromosome;

PH + - cells containing Philadelphia chromosome;

PHOTR / - - Cells that do not contain Philadelphia chromosome;

Terms and Definitions

Analysis of Mutation Gene BCR -ABL - Analysis of point mutations gene BCR-ABL. Sequencing using Singer.

Hematological resistance - Lack of hematological response (not achieved or lost).

Hematological toxicity - reduction of hemoglobin, neutropenia and thrombocytopenia.

Hematology response, cytogenetic response, molecular response - Types of answers that characterize the volume of tumor clone under the treatment of ITC and determined on the basis of the results of clinical analysis of blood, cytogenetic research, molecular genetic research.

Risk group - It is estimated only at the time of diagnosing the disease, prior to the start of therapy on the basis of prognostically significant characteristics in patients with chronic phase (HF) HML.

Additional chromosomal aberrations - Additional karyotype anomalies detected with a standard cytogenetic study.

Tyrosine kinase inhibitor - a drug with selectivity in relation to BCR-ABL. Tyrosine kinase used for the treatment of HMD.

Tyrosine kinase inhibitor The first generation is the Imatinib preparation, first developed for targeted therapy of HML.

Second-generation tyrosine kinase inhibitors - Preparations with more active, compared with imatinib, exposure to the tumor clone, designed for targeted therapy of HML.

Clinical (general) blood test - Analysis of peripheral blood with the determination of leukocyte levels, hemoglobin, platelets, blood formulas (hemograms).

First, second, next line therapy - Severity of therapeutic approaches

INTERNATIONAL SCALE - IS) - Standardization scale, which is used to represent the results of a molecular genetic study.

Molecular genetic study - Measurement of gene expression BCR-ABL. The method of quantitative PCR in real time.

Interence of therapy - The presence of undesirable phenomena of therapy, which impede its conduct in the recommended mode.

Failure of therapy - The combination of the characteristics of the response to the therapy of ITC (hematological, cytogenetic, molecular genetic), which involves the low probability of long-term uniodic survival and is an indication for changing therapy.

Optimal answer The combination of the characteristics of the response to the ITC therapy (hematological, cytogenetic, molecular genetic), which indicates a favorable forecast, which is expected to be highly dedicious survival and further expected to improve the response.

Warning - A combination of the characteristics of the response to the ITC therapy (hematological, cytogenetic, molecular genetic), which indicates the need for careful monitoring and readiness to change therapy, taking into account the biological signs of a more aggressive course of the disease.

Commitment of therapy - Compliance with the patient's recommendations of a specialist.

UTI's selectivity - Narrow orientation in relation to the tumor clone, a relatively small number of side targets of misuse.

Standard cytogenetic study (SCI) - cytogenetic study of the bone marrow with counting at least 20 metafaz.

Phase chronic myelolecosis - determines the stage of HML and the forecast; It is estimated in the debut of the disease, under progression, with a change in treatment.

Chronic myelolomicosis - a clonal myeloproliferative disease, developing as a result of malignant transformation in early hematopoietic stem cells, characterized by the occurrence of the acquired chromosomal anomaly - translocation T (9; 22), as a result of which chimeric oncogen is formed BCR-ABL. .

Cytogenetic study by the method of Fish - cytogenetic bone marrow study by fluorescent hybridization in situ (Fish).

Citogenetic resistance - The absence or loss of a cytogenetic response.

1. Brief information

1.1. Determination

Chronic myelolomicosis (hml) - This is a clonal tumor disease due to malignant rebirth of stem hematopoietic cells and characterized by enhancing the proliferation of the granulocyte sprout without losing the ability to differentiate, hyperplasia of myeloid tissue, myeloid metaplasia of blood-forming organs associated with chromosomal analog translocation T (9; 22) (Q34; Q11) As a result of which chimeric oncogen is formed BCR-ABL.

1.2 etiology and pathogenesis

The etiology of the disease is not installed. The role of various factors - ionizing radiation, infections, toxins is discussed, but not a clear relationship was detected. [24] [25] [26].

Pathogenetically hML is a clonal myeloproliferative process, developing as a result of malignant transformation in early hematopoietic stem cells. The occurrence of translocationT (9; 22) (Q34; Q11), the so-called "Philadelphia chromosome" (PH chromosome) and, accordingly, chimeric oncogene BCR-ABL. Lay the pathogenesis of the disease. Product Gena BCR-ABL. It is tyrosine kinase with abnormally increased activity, regulating signals responsible for cell growth, activation, differentiation, adhesion and apoptosis [1]. Depending on the gap point, over 16 different options for transcriptabr-ABL can be detected with different molecular weight. The most common (up to 95%) is transcriptp210, significantly more rare and less characteristic for HML are transcript190, P230. The increased tyrosine kinase activity of the anomalous BCR-ABL protein determines not only the increased multiplication of cells, but also their advantages for growth signals, blocking apoptosis as a mechanism of cell self-destruction, as a result of which tumor bleeding gets an advantage over normal and gradually displaces it. As the volume of the tumor mass is raised, clinical symptoms associated with hyperplasia of myeloid tissue appears; In the future, as genetic instability develops, new subclones appear, the progression of the disease is developing to the blast transformation phase - BC GML.

1.3 Epidemiology

Chronic myelolomicosis (HML) is a rare disease. According to a population study in 6 regions of the Russian Federation, the incidence is 0.7 per 100,000 adult population. The median age in adult patients is 50 years old (from 18 to 82), the peak of morbidity falls at the age of 50-59 years, but the proportion of young patients under the age of 40 is significant: up to 33%. The disease can be detected at any age. In 2012, in the All-Russian register of patients with hML, 5655 patients were numbered, of which 93.1% in HF, 6.4% in Fa and 0.4% - in BC [2].

1.4. CCTV 10

C92.1. - chronic myeloid leukemia, BCR-ABL. -positive

1.5 Classification

By phases of the disease

During the CML, 3 phases are distinguished, reflecting the degree of progression of the disease, the disease may be first revealed at any stage.

The level of evidence A, the level of reliability of evidence ++ [19].

  • Chronic phase (HF) It is the initial stage of HML and is diagnosed in the majority (up to 94%) for the first time identified patients [27]. The diagnosis of HF is established in the absence of features of the FA and BC.

  • Acceleration phase (FA) It is determined in 3-5% of primary patients with HML and is more advanced compared to the HF stage of the development of the pathological process with the HML. FA may also develop when progressing the disease.

  • Blastic Crisis (BC) It is the most aggressive stage of HML. The debit of diseases with the BC is an unfavorable prognostic sign and is observed in 1-2% of the HML patients. The median life expectancy of patients with BC HML is 6-12 months [25] [26] [5] [18].

The phase valuation is performed in the debut of the disease, when progressing the disease and when changing therapy. Differential diagnostic criteria of the PHML phases are shown in Table 1.

Table 1.

Phase HML according to ELN classifications [19]

Phase hml

ELN classification [19]

Chronic

Lack of signs of the FA or BC

Accelerations

15-29% of blast cells in peripheral blood and / or bone marrow;

  • Amount of blast and promoelocytes? 30% (at the same time blast <30%);
  • Number of basophils in the blood? 20%;
  • persistent thrombocytopenia <100 x 109 / l not related to therapy;
  • Some Dha * in pH-positive cells, For therapy

Blastic crisis

  • Availability in peripheral blood or in bone marrow? 30% of blast cells
  • The emergence of extrumedullary infiltrates of blast cells

* Frequently found anomalies ("Major root") - trisomy of 8 chromosome, trisomy by pH (der (22) t (9; 22) (Q34; Q11)) chromosome, isochromosome 17 (I (17) (Q10)), trisomy of 19, and IDER (22) (Q10) T (9; 22) (Q34; Q11) [19],

Also -7 / del7q and perestroika 3 (Q26.2)) are prognostically unfavorable, comprehensive aberrations, including 2 DHA and more [105]

Fa or BC establish in the presence of at least one criterion

By risk group for HF HML

Group of risk of hml It is calculated on the basis of prognostically significant clinical hematological characteristics and is estimated in patients with HF at the time of diagnosis of the disease, prior to the start of therapy ( Level of evidence АThe level of reliability of evidence is 1+). ) [30] [31];

Sokal Risk Group

  • low risk;

  • intermediate risk;

  • high risk;

Group of risk of eutos.

  • Low risk

  • high risk;

A combination of criteria characterizing risk groups on J.E. Sokal, and EUTOS is presented in Table 2.

Table 2. Definition of Sokal Risk Groups, EUTOS

Sign

Sokal criteria

Eutos criteria

Age years old

0,0116 * (age - 43.4)

Selezenka (see from under the rib arc)

0,0345 * (the size of the spleen, see from under the rib arc - 7,51)

4 * (the size of the spleen, see from under the rib arc)

Platelets (x109 / l)

0.188 * [(platelets / 700) 2-0,563]

Blast (bone marrow)

0,0887 * (% of blasts - 2.10)

Eosinophils (periphe. Krov

Basophiles (periphetic)

7 x basophiles

Relative Risk Index

Exhibitor amount *

Sum

At-risk groups

Low

<0.8.

87.

intermediate

0.8-1,2

Tall

> 1,2

> 87.

* 2.72 to degree (0.0116 * (age - 43.4) + 0.0345 * (the size of the spleen, cm from under the rib arc - 7.51) + 0.188 * [(platelets / 700) 2-0,563 ] + 0.0887 * (% of blasts - 2,10))

2. Diagnostics

2.1 Complaints and history

The clinical picture at hML in most cases can be characterized by asymptomatic flow, the initial period of the disease in most patients can flow over a number of years.

  1. syndrome of tumor intoxication (weakness, decrease in appetite, weight loss, sweating, subfebrile temperature);

  2. tumor proliferation syndrome (pain and feeling of gravity in the left side with splenomegaly);

  3. anemic syndrome (general weakness, shortness of breath, reduction of tolerance to physical exertion, skin pallor and mucous membranes, tachycardia);

  4. Thrombotic complications for hypertroscopytosis and

  5. Hemorrhagic syndrome due to thrombocytopenia

Level of evidence А The level of reliability of evidence is 1 ++).  

Comment: Clinical symptoms at hML is not specific, the appearance of these syndromes is most characteristic of advanced phases of the disease (FA and BC). In most patients in the HF complaints and clinical symptoms, there are no signs of the disease at the time of diagnosis, only changes in the general blood test (leukocytosis, myelocitantic shift, basophilic-eosinophilic association) when performing a prophylactic examination or when accessing a doctor about the other pathology.

  1. accompanying illnesses;

  2. concomitant therapy;

  3. The presence of Siblingov.

The level of evidence is the level of reliability of evidence 1+).  

Comment: Taking into account the fact that the drug therapy for the hML is appointed for a long time, when choosing the spectrum of accompanying pathology, as well as the possibility of inter-road interactions is taken into account. Sibling information is necessary to assess the possibilities for the implementation of ALLOTGSK

2.2 Physical examination

  • Recommended In a physical examination, it is carried out [24] [25] [26] [27]:
  1. inspection of skin and visible mucous membranes;

  2. palpation of peripheral lymph nodes;

  3. Determination of the size of the liver and spleen (palpatorial, in centimeters from the edge of the rib arc);

The level of evidence A, the level of reliability of evidence 1+.  

2.3 Lab Diagnostics

Recommended Conduct laboratory studies when establishing the diagnosis of CML [2] [3] [28] [29]:

          Required research:

  1. Clinical analysis of blood with counting leukocyte formula and determination of platelet levels;
  2. Standard cytogenetic study (SCI) of the bone marrow: confirmation of the presence of translocation T (9; 22) (Q34; Q11) (PH chromosome). With the non-informativeness of SCI (no mitosis, unsatisfactory material quality) shows the study of the bone marrow by the FISH method: detection of chimeric gene BCR-ABL. ;
  3. Molecular genetic study of peripheral blood: determination of the expression of chimeric transcript BCR-ABL. P210 by high-quality and quantitative PCR;
  4. In the absence of PH-chromosome and clinical hematological signs of HML, the bone marrow study is shown by the FISH method to identify "cryptic" (hidden) or variable translocations (chimeric gene BCR-ABL. ), which cannot be detected during SCI;
  5. In the absence of a typical transcript BCR-ABL. P210 shows the definition of rare transcripts BCR-ABL. (P190, P230) and other method of high-quality or quantitative PCR;
  6. Morphological study of the bone marrow puncture (myelogram);
  7. Blood Biochemical Indicators: General Bilirubin, AST, Alt, LDH, Urine Acid, Urea, Creatine, Common Protein, Albumin, Alkaline Phosphatase, Electrolytes (Potassium, Sodium, Calcium, Phosphorus, Magnesium), Amilasa, Lipase, Glucose, General Cholesterol, high and low density lipids;

    Additional studies on indications  

  1. HLA-typing in the presence of Siblingov or the search for a HLA-compatible non-relevant donor in the absence of cibbles for patients with the debut in the FA or BC; patients with unfavorable prognostic factors (high risk);

  2. Cytochemical study of blood cells and bone marrow: myeloperoxidase, lipids, PAS reaction, alpha naphthylterase with blastosis more than 30%;

  3. Immunophenotyping of blast cells with blastosis more than 30%;

  4. Histological study of the bone marrow (trepalobiopsy) with the determination of the cellularity and degree of fibrosis during cytopenia;

    The level of evidence is the level of reliability of evidence 1 ++  .

    Comments : The diagnosis of HML is established with the mandatory discovery of PH chromosome and / or chimeric gene to estimate the HML phase and risk group, it is necessary to appreciate the results of a general blood test, myelograms. In the FA and BC, the HML, in patients with adverse factories of the forecast, it is necessary to immediately decide on the search for the HLA compatible donor and the implementation of Allo TGSC.

2.4 Instrumental diagnostics

  1. Ultrasound examination of the abdominal organs: liver, spleen, dimensions of peripheral lymph nodes;

  2. ECG standard in 12 leads (with definition QTCB, QTCF);

  3. X-ray of the organs of the chest cavity;

  4. Ultrasound of the pancreas; kidneys, thyroid gland, small pelvis organs;

    Proof level B, level of reliability of evidence 1+

Comments : These studies are recommended if there are indications. When choosing therapy, special attention should be paid to the assessment of cardiovascular risks. According to the testimony, an intersection of an ankle-brachic index can be assigned, vascular ultrasound to determine atherosclerotic changes.

2.5 other diagnostics

Recommended Consider the concomitant pathology when choosing therapy in patients with HML [24] [25] [26] [27].

The level of evidence B, the level of reliability of evidence 1+.  

Comment: For this purpose, consultations of specialists can be consulted: cardiologist, endocrinologist, gynecologist, other specialists, if there are indications. Special attention should be paid to the assessment of cardiovascular risks.

3. Treatment

3.1 Conservative Treatment

ЦThe fir of modern HML therapy is the maximum suppression of a PH-positive tumor clone, preventing the development of resistance and providing long-term survival in good quality of life. The main means of therapy and the treatment standard is currently the treatment of ITC. These drugs have a mechanism of targeted (targeted) impact on BCR-ABL-positive tumor cells and should be assigned to all patients after confirming the diagnosis of HML. The mechanism of operation of the ITC is due to the blockade of ATP-binding pocket of the BCR-ABL molecule, which deprives the BCR-ABL protein of tyrosinekinase activity, which gives tumor cells a proliferative advantage.

Compliance with the principle of continuous and continuous impact on the tumor clone is the basis of the effectiveness of treatment. Breaks in the reception can help reduce the effectiveness of therapy and progression of the disease. Regular control of the results of therapy with cytogenetic and molecular genetic methods, timely evaluation of the response and switching to the next line of therapy are fundamental to prevent the development of resistance at CML [13] [14] [15] [16]. Allogenic transplantation of hematopoietic stem cells (Alllo-TGSC) is considered for patients with HF HF with a high risk group of progression, in patients with the failure of therapy of the first line, as well as in advanced GML phases.

  • Recommended ITC therapy in continuous mode - daily, long, constantly. The initial dose of it is not depends on the floor, body weight, growth, patient race. Reception of ITC can be started at any number of leukocytes [2] [28] [29] [34] [35] [36] [37].

Level of evidence A, level of reliability of evidence 1 ++ .

Comment: Clear testimony to the safe cessation of ITC's therapy in clinical practice has not yet been developed, observation without therapy is performed only within the framework of clinical studies in patients with stable deep MO. Reducing the dose and breaks are permissible only with the development of toxicity phenomena 3-4 degrees. With the constant effects of the ITC, the reduction of the tumor clone and the restoration of normal hematopois, the risk of the progression of the disease is reduced, the survival rate of patients is increasing. Achieving a complete cytogenetic response (FOS) and a large molecular response (BMO) is a favorable prognostic signs of long-term survival without progression subject to constant therapy.

The definitions of a hematological cytogenetic, molecular response for the treatment of ITC in patients with HML are presented in Table 3.

Table 3. Types of response to the therapy of ITC with hML

View of the answer

Definition

Hematological (clinical hematology)

Full (PGO)

Leukocytes less than 10x109 / l

Basophiles less than 5%

In the hemogram there are no myelocytes, promoelocytes, myeloblasts

Platelets less than 450x109 / l

The spleen is not palpable

Cytogenetic 1

Full (FOS)

Ph chromosome in metafases is not determined (pH + 0%)

Partial (CZCO) 2

Ph chromosome 1-35% metafaz (pH + 1-35%)

Small (MCO)

Ph chromosome in 36-65% metafaz (pH + 36-65%)

Minimum (Mixo)

Ph chromosome in 66-95% metafaz (pH + 66-95%)

Lack (no central)

Ph chromosome in more than 95% metafaz (pH +> 95%)

Molecular 3

BMO (MO3.0)

BCR-ABL / ABL ratio? 0.1% and> 0.01% on the international scale (IS)

Deep Mo

MO4.0

Ratio BCR-ABL / ABL? 0.01 and> 0.0032% on the international scale (IS) or an indefinable BCR-ABL level with ABL? 1000

MO4.5

Relationship BCR-ABL / ABL? 0.0032% and> 0.001% on the international scale (IS) or an indefinable BCR-ABL level with ABL? 32000

MO5.0

Relationship BCR-ABL / ABL? 0.001% on the international scale (IS) or an indefinable BCR-ABL level with ABL? 10000

1. If the SCI is non-informative, the definition of a complete cytogenetic response can be based on the results of Fish (an analysis of at least 200 nuclei) The number of cells carrying chimeric gene should not exceed 1%.

2. Partial cytogenetic response and a complete cytogenetic response is included in the concept of a large cytogenetic response (BCC - pH + 0-35%).

3. To standardize the results, the recalculation of each result in the International Scale (IS) is required. In order to exclude intraboratory variability, changing the BCR-ABL level is less than 1 log (less than 10 times from the previous value) needs confirmation when re-analysis.

Preparations for HML Therapy and Dosing Mode

In the Russian Federation for the treatment of HMLs currently registered with ITC of the first generation IMATINIB ** and ITC2 Nilotinib **, Dazatinib **, Bostutinib. The first three drugs are used in the first, second line of treatment and after the failure of two therapy lines, Bosutinib - in the second treatment line and after the failure of two therapy lines. The choice of ITC is carried out taking into account the concomitant pathology, mutational status, the Phase of the HML.

Level of evidence A, level of reliability of evidence 1 ++ .

Comments: Imatinib - ITC of the first generation, with selectivity for BCR-ABL tyrosine kinase, is also capable of inhibiting C-Kit, PDGFr-kinase activity. When applying imatinib, the total survival rate by 8 years is 85%, the survival rate without progression to the FA and BC is 92%, the frequency of disease progression at 5-8 years of therapy does not exceed 0.5%. The big molecular answer (BMO) can be obtained from 86% of patients. Most patients retain a good quality of life and ability to work

The immatureba dose is 400 mg per day for the CF and 600 mg per day for the FA and BC [38]. The drug is recommended to take during meals, picking up a full glass of water. Doses of the drug depending on the HML phase are shown in Table 5.

Reduced dose must be carried out in the development of toxicity phenomena.

In part of patients, the clinically significant effect of therapy therapy Imatinib is not achieved or happens, that is, resistance to treatment [8] [3] [9] [5] develops [7]. In patients with immature resistance and intolerance, it is effective to use ITK2 in the second line of therapy [10] [11] [12]. Improving the Imatinib dose with the ineffectiveness of the standard dose of the drug can be effective in part of patients with cytogenetic resistance; The effectiveness of increasing the imatinib dose in the absence of the PGO is extremely low [112,113,114]. Considering that the advantage of changing therapy on ITC2 is uniquely proved before an increase in the Imatinib dose [115], an increase in the Imatinib dose should be considered as a temporary measure before the appointment of ITQ2 or the conduct of ALLOTGSK.

Table 4. Dose levels Imatiniba

Dose

HML HF

HML FA and BK

Starting dose

400 mg / day

600 mg / day

Raising dose (+1)

600 mg / day

800 mg / day

Raise dose (+2)

800 mg / day

Dose reduction (-1)

300 mg / day

400 mg / day

Level of evidence A, level of reliability of evidence 1 ++ [39] [40] [41] [42].

Comments: Nilotinib is a powerful, high-selective BCR-ABL-tyrosine kinase inhibitor. It has greater affinity for BCR-ABL-Tyrrosinkinase compared to imatinib, active in relation to mutant forms BCR-is produced in the form of capsules at 150 and 200 mg. In the first line of therapy is shown patients with HF HML in the initial dose of 600 mg / day and at a dose of 800 mg / day in the Fa. In the second line of therapy, nilotinib is prescribed at a dose of 800 mg / day in HF and Fa [41]. Regardless of the HML phase, the reception is carried out 2 times a day in equal doses (300 mg or 400mg) with an interval of about 12 hours. The drug is recommended strictly on an empty stomach, since food significantly increases the bioavailability of the drug (up to 80%), which leads to an increase in the concentration of nilotinib in plasma. Take the drug no earlier than 2 hours after meals, after taking Nilotinib food to accept no earlier than after 1 hour. Capsules should be squeezed with enough water.

With the development of toxic phenomena, the dose of nilotinib can be reduced to 300 mg 2 times a day or 400 mg 1 time per day (Table 6). The increase in the dose from 600 to 800 mg can lead to an improvement in cytogenetic or MO, however, these results are obtained on a small number of patients, with a small duration of observation, therefore there is sufficient grounds to recommend an increase in the dose of nilotinib in the resistance to the standard dose of the drug.

Level of evidence A, level of reliability of evidence 1 ++ .

Comments : Dasatinib is a multipurpose drug that interacts with many tyrosine kinase and non-sinosis proteins. Dazatinib inhibits the following tyrosine kinases: BCR-ABL and SRC families (SRC, LCK, YES, FYN), C-Kit, Epha2, PDGFR?, PDGFR? In vitro is active in In vitro mutant forms inhibit the growth of cell lines with BCR-ABL hyper expression, activation of alternative oncogenic paths, including kinases of the SRC family (Lyn, HCK) [43]. The possibility of dasatinib is shown to penetrate the blood hematorephaliac barrier [44].

Dasatinib is produced in the form of tablets of 20, 50, 70 and 100 mg. The recommended dose of dasatinib for HF is 100 mg / day, and for FA and BC 140 mg / day. When the toxicity phenomena of dose dose of dasatinib patients in the HF can be reduced to 80 mg 1 time per day, patients in the FA and BC up to 100mg x 1 time per day, with re-episodes of toxicity up to 80 mg / day (Table 6). Data on the efficiency of increasing dose of dosatinib to 140mg / d with resistance to the standard dose is not. In this regard, in clinical practice, an increase in the dose of the drug is inappropriate.

The level of evidence is the level of reliability of evidence 1 ++ .

Comments: Bozutinib-inhibitor BCR-ABL kinase, as well as kinases of the SRC family, including SRC, LYN and HCK. The drug has a minimal inhibitory activity for PDGFR receptors and a release form - a pill for oral administration of 100 and 500 mg. Standard dose - 500 mg per day.

In the case of undesirable phenomena that impede the continuation of therapy in a standard dose, the dose can be reduced to 400 and 300 mg 1 time per day (Table 5). There is no data on the effectiveness of increasing the dose of Bostutinib with the ineffectiveness of the standard dose of the drug, so the increase in doses is inappropriate.

Table 5. Doses of Nilotinib, Dazatinib and Bozutinib

Dose

Nilotinib

Dazatinib

Bostutinib

1st line therapy HF

2nd line of therapy HF and Fa

1st line and 2nd HF therapy line

1st line and 2nd line therapy FA and BC

2nd and subsequent lines of therapy HML HF, FA and BC

Starting dose

600 mg per day - (300mg x 2 times in day)

800 mg per day (400 mg x 2 times in day)

100 mg x 1 time per day

140 mg x 1 time per day

500mg x1raz in court

Dose reduction (-1)

400 mg x 1 time per day

600 mg per day (300mg x 2 times in day)

80 mg x 1 time per day

100 mg x 1 time per day

400mg x1raz in court

Dose reduction (-2)

400 mg x 1 time per day

50 mg x 1 time per day

80 mg x 1 time per day

300mg x1 times in day

The first line of therapy of ITC patients HML

Level of evidence A, level of reliability of evidence 1 ++

Comments : The use of ITQ2 (Nilotinib, Dazatinib) in the first line of treatment is reliably more efficiently compared to Imatinib to reduce the likelihood of HML progression and a higher frequency of achieving in-depth MO in earlier time. . Replacing the nilotinib in the first line at a dose of 600 mg / day allowed after 2 years of therapy to achieve BMO in 71% of patients compared with the achievement of BMOs in 44% of patients receiving imatinib 400 mg / day. By 5 years of therapy, deep MO4.5 was achieved in 54% of patients in the nilotinib group of 600 mg / day in comparison with 31% of patients in the Imatinib group [45] [18]. A comparison of Dazatinib in a dose of 100 mg / day with imatinib at a dose of 400 mg / day in the first line also showed an advantage in achieving the BMO to 2 years of treatment: in 64% of patients receiving dasatinib and in 46% of patients with imatinib therapy [17].

Nilotinib and Dazatinib provide a higher frequency of achievement MO; and MO4.5 compared to Imatinib [67], which can increase the number of patients ready in perspective to controlled observation without therapy. By 5 years of therapy, deep MO4.5 was achieved in 42% of patients in the dasatinib group in comparison with 33% of patients in the Imatinib group [49, 111].

At the same time, the possibility of developing adverse events (for example, occlusion of peripheral vessels with the use of nilotinib, the development of pleural effusion during long-term therapy by dazatinib) requires estimation of relevant risk factors in patients [55] [12] [56] [68]. Imatinibe toxicity profile is safe, experience in the first line of treatment is the longest. It is also the most affordable drug today. However, the likelihood of the rapid achievement of BMOs and deep MO compared to the ITQ2 is lower, their receipt is possible to expect only with a long period of treatment [66] [67]. Imatinib may be optimal therapy for patients with low risk group, patients over 60 years old, and / or patients with related diseases that limit the assignment of ITQ2.

The second and the following lines of therapy of ITC of patients with HML.

Level of evidence A, level of reliability of evidence 1 ++ .

Comments : The use of ITC2 in the second line of the treatment of HML is effective both in intolerance and immature resistance. In 59% of patients in the HML HML, when using nilotinib in the second treatment line, BCC was achieved in patients with resistance or intolerance to immatureba, while 44% of patients were observed in [46] [18]. The use of dasatinib in the second line of therapy in patients in HF HML during intolerance or resistance to IMATINBY made it possible to achieve BCC in 59% of patients, in 49% - to obtain a PCT [47] [12]. The use of dazatinib in the FA allowed to achieve a BCC in 33% and a PC in 24% of patients [48]. Dasatinib variation in BC made it possible to obtain a BCC in 30% of patients with myeloid BC and 50% of patients with lymphoid BC for 6 months, but these answers are not were durable [49].

Bostutinib also turned out to be effective in patients with resistance (n = 200) or intolerance (N = 88) of prior therapy Imatinab. With median of observation? 24 months The cumulative frequency of achievement of the PGO, BCC and PC was 77%, 57% and 46%, respectively, BMO and deep MO were obtained from 35% and 28%. Bozutinib also showed effectiveness in patients, with failure of therapy not only imatinib, but also new ITC (Dazatinib, Nilotinib). PGO, PCO and BMO reached 62/86 (72%), 16/72 (22%) and 20/78 (25%) patients after immature and dasatinib therapy. These same indicators were achieved in 20/26 (77%), 5/24 (21%) and 1/19 (5%) of patients who previously received imatinib and nilotinib. Thus, patients with the previous failure of therapy with two ITC on the background of reception of Bosutinib could reach not only the PGO, but also deeper (cytogenetic and molecular) responses [50] [51] [52].

Principles of the choice of ITC when changing therapy

Proof level B, level of reliability of evidence 1+

Comment: Some diseases and states are the risk factors for the development of undesirable phenomena when applying individual ITC. Taking into account the toxicity profile, the ITC is used with caution in some of the diseases listed below and states.

        Nilotinib **:

  1. Pancreatitis in history - In rare cases, the exacerbation of pancreatitis is noted; There may be an increase in the level of amylase, lipase;

  2. Diabetes - Against the background of therapy, Nilotinib may appear hyperglycemia;

  3. Atherosclerotic damage to vessels, cardiovascular ischemic events, occlusive peripheral arterial disease - the increased probability of their development in patients with already existing risk factors for the development of cardiovascular diseases compared to existing in the overall population [54] is shown.

     Dazatinib **:

    1. Chronic cardiovascular diseases, chronic obstructive lung diseases, bronchial asthma, pneumonia, chest injury, autoimmune disorders - factors affecting the frequency of development of pleural effluents [55] [56];

2. Chronic diseases of the gastrointestinal tract with high risk of bleeding, constant reception of antiagregants - dazatinib has an antiagregant effect [57].

Bostutinib: Heavy violation of liver and kidney function [58].

All ITC should be used with caution in patients with an elongated Qt interval, as well as with clinically pronounced heart failure, left ventricular dysfunction, arrhythmias. The simultaneous use of ITC with inductors and inhibitors of the CYP3A isoenzyme, as well as with drugs lengthening the Qt interval, should be avoided.

Level of evidence A, level of reliability of evidence 1 ++ .

Comment : BCR-ABL mutations determine the sensitivity of leukemic cells to the effects of a certain ITC. At the time of diagnosis, mutational status is advisable to determine when debuting HML in the FA and BC. Also, the presence of mutations of the Tyrosine kinase domain BCR-ABL is recommended to be explored with the failure of therapy and before changing the ITC.

Mutations that define low sensitivity to ITC:

  1. Dazatinib - F317V / L / I / C, T315A, V299L, Q252H. When identifying these mutations, therapy is preferable Nilotinib ;

  2. Nilotinib - Y253H, E255K / V, F359V / C / I. When identifying these mutations, preferably therapy Dasatinib ;

  3. To Bostutinib - E255K / V (preferably therapy of dazatinib), V299L (preferably therapy nilotinib), G250EV299L (possibly appointment of nilotinib and dasatinib).

Therapy by all ITC listed (immatinib, nilotinib, dazatinib, bostutinib) is ineffective if there is a Mutation T315i [62] [63]. When identifying this mutation, it is recommended to search for a HLA-identical donor, the implementation of Allo-TGSK or the inclusion of such a patient into clinical studies. With the impossibility of Allo-TGSK, hydroxymeuric, small doses of cytoosar, polyhemotherapy courses, interferonotherapy are prescribed as an alternative treatment. The drug of choice in patients with HMLs with T315i mutation is recently approved by Ponatinib (IClusig®, Ariad, United States), but at present the drug is not registered in the Russian Federation [64] [65].

Monitoring the results of ITQ's therapy in patients with HML

Level of evidence A, level of reliability of evidence 1 ++ .

Comment: For timely evaluation of the results of therapy and possible unwanted phenomena of therapy, it is necessary to regularly monitor clinical laboratory indicators (Table 6, 7). Taking into account the need for long-term reception of drugs, it is advisable to regular conversation with the patient in order to control the commitment of therapy.

Table 6. The frequency of the dynamic survey of hml patients receiving ITC

Study

Monitoring frequency

Clinical blood test

Every 15 days before the achievement and confirmation of the PGO, hereinafter, at least every 3 months or as needed

Standard cytogenetic study of bone marrow (STIs less than 20 metafaz) (if it is impossible - Fish)

On the 3rd 6th month of therapy;

On the 12th month of therapy (when the PC is reached on the 3rd month and confirmation on the 6th month - may not be performed);

With the failure of treatment (primary or secondary resistance), when an inexplicable cytopenia occurs;

If there is a DHA (in debut or during therapy), more frequent cytogenetic monitoring is appropriate in pH-positive and PH-negative cells;

At level BCR-ABL. less than 1% by the method of quantitative PCR cytogenetic research is inappropriate

Quantitative PCR real-time (level measurement BCR-ABL. indicating the number of copies of the control gene ABL )

Every 3 months before reaching and confirming the BMO, then every 6 months *

The laboratory must have a conversion factor for presentation of results on the international scale IS (%). In the absence of a conversion factor, it is advisable to study in the same laboratory.

Mutational analysis BCR-ABL.

For Failure first line therapy, when switching to other ITC or other types of therapy

Blood chemistry

Every 15 days during the 1st month of therapy;

1 time per month during the first 3 months of therapy,

Next, 1 time every 3 months to 12 months of therapy;

After 12 months - 1 time in 6 months.

If necessary, the toxicity estimate is shown more frequent control

ECG

In patients with risk factors, cardiovascular diseases recommended monitoring for clinical indications;

When moving to other ITC: Before starting a new ITC and in a week of receiving a new ITC

Radiography / Fluorography of the Breastfish Organs

1 time per year or clinical indications

* Frequent control is possible to assess the stability of a deep molecular response before inclusion in observation research without therapy

The tactics of keeping depending on therapy results

Level of evidence A, level of reliability of evidence 1 ++

Comment : The effect of first line therapy may be regarded as optimal, therapy failure, warning (Table 7).

With an optimal response, treatment is continued by the same TTC drug.

In the absence of an optimal response, it is recommended to check the patient's commitment to therapy and possible drug interaction, perform analysis on BCR- mutations

When setting warning on therapy Imatinib and ITC 2 Opening, continue the reception of the drug in the same dose, perform more frequent monitoring, to ensure the readiness to change therapy in the event of a failure.

If therapy fails, imatinib in the first line shows the transition to ITQ2, taking into account portability and mutational status. In conditions of limited access to ITQ2, with the failure of therapy, imatinib in the first line, it is necessary to immediately increase the immatureba dose to 600-800 mg, taking into account portability, as a temporary measure to the translation of the ITQ2.U Patients with a high Sokal risk group, DHA in pH-positive cells (which are prognostically unfavorable factors) preferably change of ITC than an increase in the Imatinib dose.

With the failure of the ITQ's therapy, the first line of treatment shows the change of the drug to another TQ2; In the interests of the patient, consider the options for experimental treatment within the framework of clinical research, it is shown to perform HLA typing cibbles if available. The effectiveness of an increase in ITQ2 in the first line is not sufficiently proved and therefore it is inexpedient.

Table 7. Recommendations for the treatment of patients in the chronic phase of the CML depending on the duration and nature of the response to the ITC therapy in the first line of treatment

Term of therapy

Optimal answer

Warning

Failure of therapy

At the time of diagnosis

High risk "Meaningful" anomalies in pH + cells

3 months

Full hematological response (PGO)

Ph +. <35% (CZCO)

BCR-ABL <10%

PH + 36% -65% (MCO)

No PGO

Ph +. >95%

Risk factors failure:

PH +> 65% (less MCO) and BCR-ABL? ten%*

6 months

PH + 0% (FOS)

BCR-ABL <1%

PH + 1-5% (CZCO)

BCR-ABL 1% -10%

PH +> 35% (less CZCO)

BCR-ABL? ten%

12 months

PH + 0% (FOS)

BCR-ABL. <0.1% (BMO)

PH + 0% (FOS)

BCR-ABL 0.1-1%

PH +> 0% (less than FOS)

BCR-ABL? one%

In the future and at any time

BCR-ABL. <0.1% (BMO) or less

DHA in PHOTP cells (-7 or 7q-)

Loss of the PGO,

PSO loss,

Loss BMO **

BCR-ABL mutations

DHA in pH + cells

* If only molecular analysis is performed, it is recommended to re-study for 1-3 months to confirm the result.

** Confirmed Loss of BMO: BCR-ABL> 0.1% in two or more consecutive analyzes, in one of which BCR-ABL> 1%.

Tactics of reference when setting failure for 3 months. Therapia

The level of evidence d, the level of reliability of evidence 4 .

Comment : One of the controversial and ambiguous positions is the question of early change in therapy at the BCR-ABL> 10% level to 3 months of ITC therapy. BCR-ABL> 10% is prognostically unfavorable to predict overall survival, survivalability without progression, to obtain a deep MO when applying any of the indicated ITC (the risk factor of therapy failure). Obviously, the continuation of treatment that is not effective, increases the risk of the progression of the disease. However, in different years, international experts have developed different concepts of change of therapy for a period of 3 months (recommendations of professional communities ESMO2012, ELN 2013, NCCN 2013-2016). This is due to the lack of randomized studies comparing the changes in the treatment regimen on this period at the BCR

The discussion of the Working Group reached a consensus that the early change in therapy is possible to carry out, starting from the 3rd month of treatment when identifying the BCR-ABL level> 10%. To confirm the failure on this treatment, it is shown to assess the results and cytogenetic, and molecular The genetic method at the same time - to consolidate the significant volume of the tumor mass (pH> 65% and BCR-ABL> 10% as the risk factors of the ITC therapy failure) are also justified by repeated laboratory tests (cytogenetic, molecular genetic) to confirm the changes identified.

Therapy with the failure of the second and subsequent treatment line

The level of evidence is the level of reliability of evidence 1 ++

Comment: According to domestic recommendations, the European Recommendations for the Application of ITK2 therapy in the second line, in the absence of the PGO by 3 months and, at least MCO to 6 months of therapy ITQ2 Software resistance to the treatment (Table 12) Therapy capabilities with the failure of the second and more ITC's therapy lines are limited. The absence of a reserve of normal blood formation, long cytopenia makes it difficult to fulfill the long-term use of ITC in constant mode and in full doses, which reduces the effectiveness of treatment. As therapeutic options, the translation to another ITQ2, Allo-TGSC. When obtaining clinical and hematological remission, as well as in the case of the reduction of the leukemic clone (clinical and hematological response, cytogenetic response) at the third line of therapy, the issue of the implementation of Allo-TGSC should be addressed immediately. In the absence of the effect and progression of the disease with a deterrent purpose, the use of cytostatic agents, hydroxymeurica is shown.

Table 8. Criteria for response to ITC as a second and more therapy

The duration of treatment of ITQ2, months

Characteristic answer

Target response level

Warning

Failure

Before treatment

Hematology resistance to imatinib

cytogenetic resistance to the first line

High risk

3 months

BCR-ABL? ten%

and / or pH + <65% (MCO)

BCR-ABL> 10%

and / or pH + 65% -95% (Mixo)

Lack of PGO

or pH +> 95%

Or new BCR-ABL mutations

6 months

BCR-ABL? ten%

and / or pH + <35% (CZCO)

PH + 36-65% (MCO)

BCR-ABL> 10%

and / or pH +> 65%

and / or new BCR-ABL mutations

12 months

BCR-ABL <1%

and / or pH + 0% (FOS)

BCR-ABL 1-10%

and / or pH + 1% -35% (CZCO)

BCR-ABL> 10%

and / or pH +> 35%

and / or new BCR-ABL mutations

At any subsequent time

BCR-ABL? 0.1% (BMO)

DHA in pharmaceutical cells: -7 or 7Q-

or BCR-ABL> 0.1%

Loss of PGO or a loss of a PC or CZCO

Confirmed loss of BMO1

The appearance of BCR-ABL mutations

DHA in pH + cells

Indications for Allogeneic TGSK with hml

The level of evidence A, the level of reliability of evidence 1+

Comments: Tactics of patients in cases of resistance or intolerance of the treatment of ITC 1-3 lines should be discussed individually taking into account the risk factors for the progression of HML, the tolerance of ITC and the risk factors of Allo-TSGK.

In patients in HF HML to the treatment with ITC, the discussion of HLA-typing is appropriate in patients from a prevention group with a high risk group of HML progression (identification of clinically significant DHA in pH-positive cells) subject to low risk of transplant complications and related donor (Table 12) . The testimony for allogenic bone marrow transplantation or hematopoietic stem cells of peripheral blood (Allo-TGSC) in patients in HF HML is the failure of the ITC of the second generation, the identification of the T315i mutation [28] [19]. In the case of HLA compatible sibling, the young (under 40 years of age) patients with HML HF and low transplant risk are advisable to consult patients in specialized centers performed by ALLOTGSK, for conclusion about the possibility of ALLOTGSK.

Patients in the BC GML recommended Hero-TGSK from a related or unrelated donor immediately after reaching the second HF on the background of ITC and / or a combination of ITC with chemotherapy [73]. Table 9 presents recommendations for the conduct of allogenic transplantation with HMD.

Table 9. Tactics for choosing therapy in patients with HF HML with the failure of therapy inhibitors of tyrosine kinases and the decision of the decision on allogeneic bone marrow transplantation / hematopoietic stem cells with HML

The first line of therapy:

Imatinib or Nilotinib or Dazatinib

HLA-typing patient and related donor only in patients from a warning group with a high risk group and identifying clinically significant DHA in pH + cells

Second line, intolerance to the first line

Any other of the registered ITC (Imatinib or Nilotinib or Dazatinib or Bozutinib)

The second line, the failure of the first line Imatinib

Nilotinib or Dazatinib or Bozutinib or Clinical Studies

HLA-typing patient and related donor

Second line, Nilotinib failure in the first line

Dasatinib, or Bozutinib or Clinical Studies (Ponatinib, Other Preparations),

HLA-typing of a patient and related donor, search for an unrelated donor, solving the issue of Allo-TGSK

The second line, the failure of dasatinib in the first line

Nilotinib or Bozutinib or Clinical Studies (Ponatinib, Other Preparations)

HLA-typing patient and related donor, search for an unrelated donor, solving the issue of Allo-TGSK

Third line, failure and / or intolerance 2 ITC

Any of the available ITC

participation in clinical studies,

Allo TGSC for patients having a donor

T315i mutation at any time

Ponatinib or clinical studies

HLA-typing of a patient and related donor, search for an unrelated donor, solving the issue of Allo-TGSK

Risk factors for all-TKM EBMT Society [36]:

- ironic phase 0 points, acceleration phase 1 point, prostrate crisis 2 points;

-Repers less than 20 years 0 points, 20-40 years 1 point, more than 40 years 2 points;

-time from diagnosis to Allo TCM less than 1 year 0 points, more than 1 year 1 point;

-Hla-identical sibling 0 points, other donors 1 score;

- Paul donor-Woman recipient-man 1 point, 0 points for other combinations of the recipient donor.

Citergrain and cytostatic therapy

  • Recommended Citergrain to reduce the tumor mass in the debut of the disease, cytioneducleizing and cytostatic therapy with resistance to several lines of ITC therapy, the impossibility of other therapy, with a palliative purpose [36]

The level of evidence d, the level of reliability of evidence 4

Comments : In HF HML, the use of chemotherapy products is carried out in monochimotherapy mode, which is assigned in the following cases: 1) to reduce the mass of the tumor for the period of the examination until the results of a cytogenetic study or a molecular genetic study and to maintain a hematological response; 2) When the holding of another therapy is impossible: resistance and / or intolerance to ITC.

The following drugs are most often used: hydroxycarbamide ** at a dose of 10-50 mg / kg / day, depending on blood test indicators (Table 10), Mercptopurin ** Citarabin **. For the prevention of complications associated with the syndrome of the tumor lysis during the CITT system, the introduction of an adequate volume of fluid (up to 2-2.5 l / m2 of the body surface in the absence of heart failure), allopurinol at a dose of 300-600 mg / day. In case of signs of leukostasis (microcirculation disorders: encephalopathy, reduction of vision, renal failure), leucafferes is shown with symptomatic purposes. Patients in the FA and BC can be carried out polychimotherapy according to the treatment of sharp leukemia, depending on the phenotype of blasts, with the inclusion of ITC.

Table 10. Scheme of the use of hydroxymeuruine

Number of blood leukocytes

Dose Hydroxycarbamide

> 100x10 ^ 9 / l

40-100x10 ^ 9 / l

50 mg / kg daily

40 mg / kg daily

20-40x10 ^ 9 / l

30 mg / kg daily

10-20x10 ^ 9 / l

20 mg / kg daily

10-5x10 ^ 9 / l

10 mg / kg daily

<3x10 ^ 9 / l

* Temporarily canceled

* The reception of hydroxymes must be regular, since when the drug is canceled, the leukocyte levels increase again. Monitoring the number of leukocytes and other hemogram indicators (hemoglobin + platelets + blood formula) must be carried out weekly.

Therapy Interferon Alpha

The level of evidence d, the level of reliability of evidence 4

Comments: Therapy drugs IF-? It is carried out in special cases when the ITC therapy is not shown. Application of IF-? Perhaps during the period of pregnancy, when the T315I mutation is detected and the impossibility of the implementation of Allo-TGSC. The greatest effectiveness of the drugs IF-? It is observed when prescribing in HML HML, with FA and BC, the effectiveness of the treatment of IF-? Not proven.

4. Rehabilitation

An important point in the treatment of patients is their psychological and social rehabilitation. Events aimed at restoring psychological and social functioning should be carried out on several levels:

  1. Individual - the work of a hematologist with patients with clarification of the features of the course of the disease, the prospects for full recovery in everyday life, to preserve the life expectancy comparable to the population, the possibility of preserving the reproductive function; If necessary, the advisory assistance of a psychotherapist and / or a psychiatrist, the appointment of the necessary drug therapy and non-drug impact methods;

  2. Family - provision with the permission of patient with relatives and close people of information on the state of health, explaining the need for moral support for the patient in order to increase the adherence to the treatment and acceleration of health restoration;

  3. Group / population - education and training of patients within "School of Patients of HML" with the provision of the latest information on development mechanisms, achievements in the diagnosis and treatment of HML, methods for the correction of undesirable therapy phenomena, exchange of experience and mutual assistance between patients with professional and social rehabilitation, communication with Health and social protection authorities.

  4. The undoubted achievement in the psychological and social rehabilitation of HML patients in the Russian Federation is broad cooperation between hematologists and a public organization of HML patients. The result of this cooperation is to organize and regularly carry out "Schools of Patients of HML" in almost all regions of the country with the involvement of leading hematologists.

Spa treatment

Traditional ideas about the presence of contraindications to any type of physiotherapeutic and sanatorium-resort treatment of HML patients in the era before the introduction of ITC is currently being revised. The generally accepted recommendations currently do not exist, however, if patients with deep response levels (FOS, BMO), the treatment of such patients in local sanatoriums should be admitted using physiotherapeutic local exposure methods. Possible provoking factors of deterioration of the disease may be ultraviolet irradiation (insolation), methods of electromagnetic effects. Additional contraindications may be manifestations of side effects of ITC therapy.

5. Prevention and dispensary observation

5 Primary prevention

Due to the inability to currently distinguish the etiological factors of the disease. Developing specific recommendations on the primary prevention of the CML is currently impossible.

  • Recommended Prevention of background prematubological diseases and states, commitment to healthy lifestyle, elimination of chronic intoxication, restriction of contact with harmful production factors, participation in dispensary events [28] [29].

The level of evidence d, the level of persuasiveness of evidence 4.

5.1 Secondary prophylaxis

After identifying the disease, the most important factors for the preservation of life and health of the patient are as quickly as possible the beginning of the treatment of ITC and strict commitment to the patient to fulfill the recommendations on the treatment and monitoring of the response to therapy. [28] [29].

Modern drug treatment of HML patients is highly efficient from the overwhelming majority of patients. Recommendations for the control of unwanted ITC phenomena and the possibility of alternative selection of drugs makes it possible to almost completely preserve the physical condition and the daily level of activity before the occurrence of the disease [28] [29].

6. Additional information affecting the course and outcome of the disease

Tactics of keeping with the development of unwanted phenomena of ITC therapy.

The anti-temium effect is the unconditional priority of HML therapy. However, to preserve the principle of maximum and constant influence on the tumor clone, it is important to minimize the undesirable effects of therapy, given the need for long-term reception of drugs [28] [2] [29].

Most of the unwanted effects of ITC therapy are well-controlled, low toxicity. The long-term results of the use of IMATINIB for more than 15 years have not revealed additional or vitreous phenomena of toxicity. The use of ITQ2 has a smaller observation period, the data on new undesirable phenomena continue to accumulate the current time.

Toxicity of therapy Against the background of the use of ITC can be divided into hematological and non-hematological. The degree of severity of undesirable phenomena is estimated in accordance with the criteria for toxicity NCI CTCAVER4.0 [74]. Some types of toxicity ITC are presented in the G1 Appendix.

Hematological toxicity

The hematological toxicity refers to a decrease in the level of hemoglobin, neutropenia and thrombocytopenia.

Anemia Any extent in all Phases of HML is not an indication for the interruption of ITC therapy. An additional examination of the patient was shown to eliminate other causes of anemia, taking into account the clinical situation. In case of clinically significant manifestations of anemic syndrome, replacement transfusion of the erythrocyte mass [28] [2] [29] are shown [28]. The appropriateness of the appointment of erythropoietin preparations is controversial. With neutropenia and thrombocytopenia 1-2 degrees, in any phase, the dose of the dose of ITC and interruptions in treatment is not required [28] [2] [29]. In HF HML at 3-4 degrees of neutropenia and / or thrombocytopenia, the temporary cancellation of the ITC with the control of clinical analysis of blood once a week [28] [2] was shown [29].

After the restoration of the absolute number of neutrophils (ACH) to the level of more than 1.0x109 / l, platelets more than 50x109 / l renew the therapy of ITC )[28] [2] [29]:

  • If the break in the treatment is less than 2 weeks, the treatment is resumed in the same dose, during a break for more than 2 weeks - in a double dose level (see Table 6 and Table 7 - Dose of ITC);

  • If the dose of ITC was previously reduced, with stable hemogram indicators after 1 month it is advisable to return to the standard dosage;

  • With prolonged neutropenia, a short-term use of a granulocyte colony positive factor (M-KSF) is possible: Filgrastim in a dose of 5 μg / kg / day subcutaneously, in the absence of an effect from the introduction of Mr. KSF, a dose reduction is required or a change in ITC, taking into account the results of the assessment of the leukemic clone - level BCR-ABL;

  • With long-lasting repeated cytops, it is necessary to conduct a survey (myelogram, histological examination of the bone marrow) in order to exclude the progression of the disease, the development of bone marrow fibrosis.

In the FA and BC, the CML even in the presence of neutropenia and thrombocytopenia 3-4 degrees for the purpose of induction of remission during the first 4 weeks therapy of the ITC should not be interrupted. With thrombocytopenia 3-4 degrees, hemorrhagic syndrome shows transfusion of platelet concentrate [28] [2] [29]. If myelosuppression persists after 1 month of therapy, it is shown to perform sternal puncture with a sielogram counting to eliminate the progression of the disease [28] [2] [29]:

The number of blasts is less than 5% and reducing the bone marrow cells should continue a break in therapy. Monitoring clinical analysis of blood is carried out at least once a week. Resume therapy after the restoration of the absolute number of neutrophils (ACH) to the level of more than 0.5x10 ^ 9 / l and platelets more than 50x10 ^ 9 / l. With a re-emergence of myelosuppression, the dose of itek should be reduced. With prolonged and / or repeated episodes of neutropenia and the absence of blastose in the peripheral blood and bone marrow, the use of M-KSF is possible;

If there are more than 5% of blasts and hyperclell bone marrow, the issue of changing therapy tactics should be discussed. When switching from one TQ to another, there is a possibility of developing cross hematological toxicity, since the development of trapid cytops in patients with HML, apparently, is more connected not so much with the features of the specific ITC, as with a decrease in normal blood reserves. This is especially clearly manifested in patients with advanced HML phases, as well as patients with resistance to 1-2 lines of ITC therapy. With repeated cytops of 3-4 degrees, which make it difficult to carry out the treatment of ITC in continuous mode and, accordingly, contribute to the reduction of treatment efficiency, the discussion of the implementation of Allo-TGSC is shown.

Negiatological toxicity

In addition to hematological toxicity, ITC Therapy may be complicated by other side effects associated only with the relative selectivity of ITC and the possibility of influencing a wide range of tyrosine kinases governing various processes of the organism. The most frequent side effects of treatment with ITC are nausea, vomiting, diarrhea, fluid delay with the development of edema, skin rash, itching, weakness, sleep disorders, muscle pain and joints. Special importance is particularly involved in connection with the need for constant reception of ITC drugs. Even a small severity of constantly existing side effects can lead to a decrease in adherence to treatment (compliance) - passing the reception or reduce the dose of the drug by patients, which leads to a decrease in therapy efficiency. Profiles of the non-hematological toxicity of immatureba, nilotinib, dasatinib and bostutinib are different.

In the occurrence of negteatological toxicity, the side effects of the treatment of ITC should be differentiated from possible clinical manifestations of concomitant diseases. Advanced additional examination of the patient to eliminate other pathology. To minimize toxicity phenomena, adequate symptomatic therapy is required.

The total tactics of patients under various manifestations of non-mahematological toxicity on the background of ITC is presented in Table 11. It should be emphasized that breaks in the treatment and reduction of the dose are permissible with long and / or repeated episodes of toxicity 2 degrees and with one-time toxicity of 3-4 degrees. The intolerance to the ITC's therapy is possible to state with a long (more than 2-3 months) to preserve the toxicity phenomena of 2 tbsp. Under the condition of adequate accompanying therapy, as well as with repeated phenomena of the toxicity of 3-4 degrees. The intolerance to therapy is an indication for translation to another ITC, since the profile of negiatological toxicity in drugs is different, and the cross-incubuse is minimal [28] [2] [29].

Table 11. Total tactics of therapy in the hiathematological toxicity of ITC

Degree of toxicity

Tactics therapy

Degree 1.

No dose breaks in the treatment and reduced dose

Degree 2:

- Delivacy <7days

- Duration> 7 days

or when re-emergence of toxicity

No dose breaks in the treatment and reduced dose

Preferably cancel treatment; After resolving toxicity, less than 2 degrees resume treatment.

During a break for less than 28 days, resume treatment in the same dose, more than 28 days is a reduction in the dose for one level.

If there is no increase in toxicity against the background of a reduced dose for 1 month, it is advisable to return to a standard dose.

Degree 3 or 4

Cancel treatment; After decreasing toxicity <2 degrees to resume treatment in a double dose level.

With the duration of toxicity more than 28 days, repeated episodes of the same type of toxicity shows the translation to another therapy.

It should be noted that the excess of some parameters (such as cholesterol levels) formally defined within the I-II degree according to CTCAE criteria, under therapy, nilotinib requires special attention and correction, taking into account the increased probability of the development of ischemic vascular events in the use of this drug [53]. Pleural traffic with Dazatinib therapy, despite the low degree of toxicity defined by CTCAE, does not always allow to continue therapy in constant mode due to a recurrent nature [75]. Diarrhea 1-2 tbsp. CTCAE under therapy Bozutinib can significantly worsen the quality of life of patients, but it is well amenable to correction with a decrease in the degree of severity and frequency of development during treatment.

Tactics of therapy in certain types of negiatral toxicity requires separate consideration.

The most frequent phenomena of negiatological toxicity.

Hyperholesterolemia and risk of ischemic vascular events

Violation of lipid metabolism and hypercholesterolemia were marked in 22% of patients with nilotinib, while at the use of immatureba only in 3%, this undesirable phenomenon can already be registered after 3 months of reception of nilotinyba- and was associated with the occurrence of ischemic vascular events, in particular peripheral occlusion Arteries [76] [77] [78] [79]. The cholesterol level is more than 240 mg / dL (6.2 mmol / l), recognized as high risk, in accordance with the management of the American Association of Clinical Endocrinologists (AACE), hypercholesterolemia is also one of the factors included in the risk scale from the vascular events Score [80 ].

Hyperholesterolemia can be reduced with the complex use of non-drug methods: a diet, physical activity, and also successfully suggests drug correction when applying various hypolypidemic drugs, for example, statins. Consequently, actions aimed at reducing cholesterol levels are appropriate to reduce the risk of vascular ischemic events in patients with HML. Target levels of cholesterol and its atherogenic factions (LDL) are covered in detail in Russian recommendations for the diagnosis and correction of lipid metabolism disorders in order to prevent and treat atherosclerosis [80]. The decision to conduct hypolipidemic therapy should be carried out after consulting the cardiologist.

Risk assessment of ischemic vascular events

Collecting anamnesis and physical assessment help identify modifiable (amenable to correction) and unmodifiable (permanent) risk factors for the development of cardiovascular complications in each particular patient. It is important to collect information on the following parameters: age, height, weight, smoking, body weight index, level of systolic blood pressure, general cholesterol, LDL, HDL, the presence of diabetes mellitus with targeted organs, presence in the family history of family dlypidemia.

The object of particular attention is the patients with already consisting of vascular events: coronary heart disease (IBS), atherosclerosis of brain, peripheral arteries and aorts, as well as patients with diabetes and targeting organs. All of them are related to the category of very high risk of death from cardiovascular events, and it is from this category of patients it is necessary to achieve the target levels of cholesterol, as well as as much as possible on modifiable risk factors Cardiovascular events that are: arterial hypertension, diabetes, smoking, low physical activity, obesity. Unmodifable factors for the development of ischemic events are male floor, age, burdened family history on cardiovascular diseases (CVD)

In patients who do not have clinical manifestations of IBS, an assessment of the risk of the development of CVD and Atherosclerosis in order to prevent their development is shown. The first stage is an assessment of a 10-year-old death from CVD on the Score scale Patients older than 40 years , in accordance with the approved recommendations [80]. The score includes the following indicators: age, gender, smoking, systolic blood pressure, cholesterol levels. Depending on the result obtained, the patient refers to the category of appropriate risk: low, moderate, high, very high.

To calculate the risk of the development of the CVD obtained when evaluating the SCore parameter (the probability of development in%) is multiplied by the corresponding coefficient (x 4 for women, x 3 for men); And in the presence of diabetes, the coefficient X 5 in women, x3 in men.

To calculate the relative risk of the development of CVD in young patients at the age of less than 40 years, a separate Score scale is provided, in which systolic pressure, smoking, cholesterol levels are taken into account.

Additionally, it is currently recommended to take into account the level of HDL, which is a favorable factor that protects atherosclerosis.

Depending on the established category of risk, individual therapeutic tactics, including a complex of measures acting by modifiable risk factors, including with the help of hypolipidemic drugs. For patients related to each category of risk, their target cholesterol level is established, in accordance with recommendations [80].

When conducting therapy, the nilotinib for life indications should be ensured by the corresponding correction of adverse risk factors. If necessary, it is shown to monitor the specialists (cardiologist, endocrinologist), which establish the final scope of the survey and additional assessment methods in each specific case: the definition of an ankle-shoulder index, detecting atherosclerotic plaques in duplex angiosication, performing multispiral computed tomography.

In the event of a high risk of the development of CVD, it is preferable to imatinib therapy, dazatinib, bostutinib.

Poormural effusion and accumulation of liquid in serous cavities (most often - pleural cavity, less often - pericardial, abdominal)

This undesirable phenomenon is specifically for therapy with dazatinib, more often occurs when applying a dose of 140 mg per day compared to lower dosages. The probability of development ranges from 14% to 25% according to various studies [111]. Patients should be warned that if they appear the symptoms of pleural effusion (shortness of breath, cough, tachycardia), urgent examination of the doctor and additional diagnostics: the percussion definition of the lungs, auscultation of the lungs, the x-ray study of the chest organs, ultrasound of pleural cavities with The purpose of estimating the volume of pleural effusion. This undesirable phenomenon can develop in various long-term terms of therapy (after 2.5-5.5 years of treatment), including patients with previously impossible tolerance of dasatinib [55] [56]. The amount of effusion can be estimated by radiological criteria and according to ultrasound diagnostics, depending on the volume of the pleural cavity occupied (Table 12).

Table 12. Classification of pleural effluent

Degree

Clinical symptoms and applied therapy

The volume of fluid in the pleural cavity

0

Absent

-

1

Asymptomatic and not requiring treatment

<10% of the amount of pleural cavity

2

Clinically pronounced, requiring diuretic or no more than two pleural punctures

11-25% of the amount of pleural cavity

3

Clinically pronounced, requiring oxygen inhalation, more than two pleural punctures and / or the establishment of pleural drainage, Plegrodez

26-50% of the amount of pleural cavity

4

Threatening life accompanied by hemodynamic disorders or requires artificial ventilation of the lungs

51-75% of the amount of pleural cavity

The presence of symptoms and the volume of the accumulated fluid may often not coincide. To determine therapeutic tactics, the presence of clinical symptoms and the degree of sensitivity of respiratory failure is greater importance.

Tactics of therapy of pleural effusion caused by the use of dasatinib, as follows:

  • A break in therapy, in the future it is possible to resume the preparation of the drug in a reduced dose;

  • Purpose of diuretics (furosemide 10-20 mg / day, ToramSemid 5-10 mg / day) with controlling level of blood electrolytes and / or short steroids (prednisone 0.5-1.0 mg / kg for 5-7 days) ;

  • if necessary - inhalation of oxygen;

  • With severe forms of pleural effusion (3-4 degrees observed in 4% of patients) with respiratory failure of II-III degrees - thoraccentsis with liquid removal.

Conducting pleural puncture is shown in the life-threatening states (the movement of the mediastinum, pronounced shortness of breath at rest) or with a diagnostic target when the cause of pleural effusion is unclear.

By itself, the fact of the appearance of pleural effusion does not worsen the forecast. With an optimal response to therapy, it is possible to reduce the dose of the drug. If the answer to the treatment is disadvantaged, the translation of the patient to an alternative IT complex is shown that pleural effusion is often a recurrent nature, in such cases a translation to another ITC is advisable.

Pulmonary arterial hypertension (lag)

Extremely rare (0.45% of cases), but at the same time a severe complication that occurs when using dasatinib, at the time of establishing this diagnosis in most patients, significant hemodynamic disorders were noted, as well as heart failure, which demanded observations in the intensive care unit. The median of the development date of Lag is 34 months (8-48 months) therapy by dazatinib [82] [83] [84]. It can be detected as in patients with pleural effusion (68% of cases) and without it. Dyspnea and fainting are leading in the clinical picture, weakness, fatigue, pain in the heart pain, not allowed by receiving nitrates can also be present. Signs of hypertrophy and overload of the right heads of heart diagnostic methods for confirmation of lag can be detected on the ECG to confirm the lag: transtorical echocardiography, catheterization of the right heart departments.

It has been established that this phenomenon can be reversible when canceling dasatinib. In the development of the lag shows the termination of therapy by dazatinib and the appointment of other ITC.

Pneumonite

It is extremely rare complication requiring a differential diagnosis. In most cases, it is described in the use of Imatinib, as well as in Asian countries; It may be reversible or irreversible [85] [86] [87] [88] [89] [90] [91].

When using dasatinib in the second line at a dose of 70 mg twice a day, 17% of patients describe the changes of the pulmonary parenchyma, according to the type of "matte glass" or thickening of septal partitions [91]. It is advisable to transfer to other ITC.

Nausea

The development of nausea is most characteristic of the use of imatinib or bostutinib. Nilotinib and Dazatinib cause nausea rarely. With nausea, an on-line immaturity should be eliminated, to recommend to take a drug with a meal, drink with plenty of water. The latter intake of IMATUNIB should be no later than 2 hours before sleep, especially in patients with esophagitis as anamnesis. If toxicity, despite all the activities taken, is 2 degrees, it is advisable to appoint anti-metician drugs: Cerukal, Ondansetron, others. However, it should be borne in mind that anti-anemic drugs can extend the Qt interval. Antacid drugs reduce the effectiveness of ITC.

Liquid delay with edema development

It is necessary to limit salt intake in the diet, reduce the volume of the used liquid. In more severe cases, diuretics are prescribed, preparations are selected individually.

Muscle spasms

Symptom characteristic of treatment with imatinib. It is more common at the beginning of therapy, but maybe very long. Spasms (more often thanky muscles, foot muscles) arise, as a rule, at night, after exercise. To eliminate them, it is necessary to replenish the deficit of minerals (potassium, calcium, magnesium, phosphorus). With pronounced manifestations of toxicity (3-4 degrees), a break of receiving ITC (3-5 days), which often reduces clinical manifestations, a temporary decrease in the dose of the drug by 1 level.

Pains in the bones and joints

Usually arise at the beginning of treatment, the frequency of them decreases after 1-2 months of therapy. Brief (for 3-5 days) Break in the reception of the drug and a short course of non-steroidal anti-inflammatory drugs can stop these phenomena.

Skin rashes

It is usually stopped at the purpose of antihistamine preparations, calcium chloride and / or with local treatment with corticosteroidal ointments. With a more pronounced dermatitis, it becomes necessary to interrupt the reception of the ITC and assign systemic corticosteroids at a dose of 1 mg / kg per os with a gradual dose reduction to 20 mg / day. In patients with a large number of basophils (> 30%) in the blood, the cause of the appearance of urctural rashes can be the release of histamic-like substances from basophil granules, as the amount of basophils decreases the intensity of the rash.

Moderate skin rashes under therapy Nilotinib - a frequent undesirable phenomenon that is not accompanied by itching, discomfort and rarely requires dose correction of the drug.

Bleeding and hemorrhage

The most often observed bleeding - from the gastrointestinal tract (in 4% of patients), less often - hemorrhages in the brain (severe - less than 1% of patients). Observed mainly in the treatment of dasatinib. As a rule, they arise with severe thrombocytopenia. In most cases, with bleeding, it is possible to cope with the suspension of the preparation of the drug and the use of transfusions of blood components, primarily the thromboconcentrate.

Under therapy with imatinib in 11% of cases, hemorrhages can be marked in the scler, as a rule, passing after a short break in the treatment or reduction of doses; In some cases, the successful use of steroids [84, 86], [53] was described [92].

Diarrhea

It is stopped with a diet with the exception of products that enhance the intestinal motorcycle, the appointment of symptomatic anti-stage funds (absorbents, loperamide). For therapy, Bozutinib is effectively focused on the use of loperamide.

Hepatotoxicity

Increasing the level of hepatic transaminase may occur at various times for the treatment of ITC. In some cases, heavier liver damage was described when using imatinib and acetaminophen (paracetamol), as well as with viral hepatitis V. Therefore, it is shown to eliminate the presence of viral hepatitis, cancel potential hepatotoxins (alcohol, canned food, medicinal preparations with hepatotoxic effect). Hepatoprotectors (heptral, URSofalc) are also used inward, in severe cases - intravenously in combination with disinfective measures. With continuous hepatotoxicity of 2 degrees after its permission, the dose of the drug is advisable to temporarily reduce. When re-developing hepatic toxicity, it is necessary to carry out a more careful study of the liver function; The discussion of the issue of transition to therapy by other ITC is shown, taking into account the absence of cross-hepatotoxicity.

Increase body weight

A small increase in weight may be due to a fluid retention, in part - an improvement in overall well-being against the background of the regression of symptoms of intoxication and the normalization of appetite. With overweight patients, it is necessary to warn about the possibility of its increase when taking the ITC and recommend restricting salt intake, low-calorie diet and increasing physical exertion.

QTCF interval elongation

All ITC are drugs capable of lengthening the duration of the Qt interval. With a significant elongation of Qt (more than 480 ms), there is a risk of developing life-degraded arrhythmias - pyruette tachycardia. When estimating the Qt interval, it is necessary to use the adjusted (taking into account the heart rate), for example, QTCF (QT, proorigued by the Fridericia method). Cases of the elongation of QTCF are extremely rare - less than 1% of patients. Patients with initial elongation of QTCF, as well as with concomitant cardiac pathology, should remain in the zone of attention from the point of view of monitoring changes to the ECG. Before the start of treatment, ITC should, if possible, eliminate factors that also affect the elongations of this interval. In particular, potassium and magnesium levels should be normalized; When taking drugs, also lengthening Qt about the accompanying diseases, the possibility of replacing the latter should be considered. It should be remembered for the existence of a congenital elongation of Qt, which requires special attention to such patients in the treatment of ITC. The algorithm for conducting patients with the elongation of QTCF is given in Table. 13.

Table 13. Tactics of conducting patients when lengthening the QTCF interval on the background of ITC therapy

QTCF extension

Tactics therapy

> 480 ms.

- Temporarily stop receiving

- Determine the content of K + and Mg ++ in the blood serum. With a deficit, fill their level to normal.

- Analyze the concomitant drugs taken by the patient and eliminate funds extending Qt

- If QTCF remains> 480 ms, repeat the ECG on clinical indications, at least 1 time per day, until Qtcf is <480 ms

- ITQ's therapy can be resumed in the same dose if the reason for increasing Qt is installed and eliminated, and QTCF has returned to the value of <450 ms and is within 20 ms from the value at the initial level.

- If when re-defined the value of QTCF goes beyond 20 ms from the value at the initial level or is between 450 and? 480 ms, the dose of UTC should be reduced by 1 level

- when renewing the treatment of ITC in the same or reduced dose after temporary cessation of treatment due to the increase in QTCF to> 480 ms, it is necessary to hold an ECG to the 2nd, 3rd and on the 8th day after the resumption of treatment

- in the case of a repeated increase in QTCF to> 480 ms to stop receiving the drug, the treatment is required.

Hyperbilirubiney

The most frequent laboratory deviation occurred in the treatment of nilotinib (69% - either degree, 7% - 3-4 degrees). This phenomenon is associated with disrupting the conjugation of indirect bilirubin, so the increase occurs mainly due to this fraction. It is more common in patients with polymorphism of the promoter region of the UGT1A1 gene (phenotype (TA) 7 / (TA) 7; (TA) 7 / (TA) 6, etc.)), characteristic of benign hyperbilirubinea (Zhilbera, Rotor, Dabinde Johnson) . If hemolysis is excluded, the activity of amylase and lipase is not increased, and the degree of bilirubinemia is 1-2, the treatment of nilotinib should be continued in the same dose. According to the majority of researchers, even the toxicity of the 3 degree is not a reason for the termination of therapy and a decrease in the dose. With a long hyperbilirubinemia, it is advisable to appoint choleretics (URSOFALK, ISOSAN).

Asymptomatic increase in amylase and / or lipase

May often be observed in the treatment of nilotinib. Pancreatitis phenomena (abdominal symptoms in combination with laboratory changes) were observed in less than 1% of patients in 2 phase of clinical studies. At 1-2 degrees of severity of these phenomena, observation is needed in dynamics (repeated biochemical tests, assessment of the clinical picture). When developing 3-4 degrees of toxicity, cease therapy, to carry out the CT abdominal cavity with contrasting to exclude pancreatic pathology; When identifying signs of pancreatitis - its treatment. With a normal CT-picture after decreasing symptoms to? 1 degree should be resumed treatment for nilotinib in a reduced dose (400 mg / day). With repeated asymptomatic increase in amylase and lipase up to 3-4 degrees, the treatment of nilotinib can be canceled or continued by a doctor's decision.

Hyperglycemia

Also occurs only when treating nilotinib. With any degree of this side effect, the correction should begin immediately when it is detected: a hypoglycemic diet. In the absence of normalization of the level of glucose on the background of the diet, the consultation of the endocrinologist is shown to eliminate diabetes.

Hipophosphamia

It is found under therapy by all ITC, as a rule, clinically insignificant (low degree, fast normalization). Recommended diet with an increase in the diet of rich in phosphorus of dairy and fish products, reduction of glucose; Purpose inside preparations containing phosphates (vitamins, nutritional supplements).

Hypocalcemia

Recommended diet with the inclusion of products with increased calcium content (dairy products), reduce carbohydrate consumption. If necessary, the purpose of calcium preparations inside.

Hypolomannia, hypokalemia

Considering the risk of elongation of the Qt interval with a shortage of these electrolytes, correction is required in the form of the appointment of combined potassium and magnesium preparations (Panangin, Asparkov) inside; With an isolated hypomantee - magnesium preparations - magnesot inside.

Medicinal interactions for ITC therapy

The metabolism of all OTC is carried out mainly in the liver with the participation of enzymes relating to the cytochrome system P450; Basically through CYP3A4, to a lesser extent - by its other isoforms, such as CYP1A2, CYP2D6, CYP2C9.

The simultaneous reception of drugs that activate or overwhelming the activity of cytochrome P450 can lead to a change in the concentration of both the ITC and the acute medication taken together, which should be taken into account in clinical practice. In case the HML patient takes at the same time several drugs as a concomitant therapy, and at the same time there is an ineffectiveness of treatment or severe toxicity of therapy, it is possible to suspect the presence of drug interactions affecting the level of the ITC in the blood. Therefore, in order to maximize the effectiveness of therapy in the occurrence or weighing of toxicity, it is important to eliminate or minimize the simultaneous reception of drugs activating or overwhelming the activity of cytochrome P450, give preference to analogues with other methods of metabolism.

With simultaneous reception of drugs that increase the activity of CYP3A4 P450, a decrease in the concentration of ITC in the blood plasma may be observed, which reduces the effectiveness of the ITC. Accordingly, the Inhibitors of the CYP3A4 P450 enzyme inhibitors lead to an increase in the concentration of the ITC in the plasma, which is expressed clinically in strengthening the manifestations of the toxicity of therapy.

In the presence of pronounced toxicity or insufficient response to the treatment in order to eliminate possible interprehensive interactions in the reception of drugs about the concomitant diseases, it is advisable to determine the concentration of ITC in plasma (serum).

Grapefruit juice is also a powerful inhibitor of this enzyme, so patients should be prevented about the need to avoid its use.

In addition, as noted above, the ITC can potentially lengthen the Qt interval. In this regard, they are not recommended to use simultaneously with other drugs that affect the elongation of the Qt interval. A brief list of drugs capable of indonging the Qt interval is presented in the application G1.

Tactics of pregnancy

According to the instructions for the use of ITC, pregnancy is a contraindication to therapy.

Women accepting ITC shows effective contraception [28] [19] [29]. Patients need to be informed about the potential teratogenic effect of Imatinib and Dazatinib; Little studied impact of ITQ2 on the fruit and the described embryotoxic action in preclinical experiments; The possibilities of recurrence of HML when canceling therapy for a period of pregnancy; A small number of observations of cases of pregnancy at CML [81] [93] [94].

Recommendations for planning and maintaining pregnancy at hML are based on a small observation experience and require individual use in each specific case [95]. Installing pregnancy It is possible to discuss in patients with a stable deep MO4, under the strict control of the level of minimum residual disease. In case of unplanned pregnancy and categorical failure of the patient from its interrupt, the tactics of CML therapy is determined individually. Considering the rarity of cases, it is advisable to accumulate and analyze the data obtained in the register of cases of pregnancy at HML.

During the lactation of the ITQ's therapy, the cessation of breastfeeding is shown, since drugs penetrate breast milk [96].

For men receiving ITC, there are no contraindications to conception. According to data available in the literature, cases of successful completion of pregnancy have a partner of patients with HML who received ITC, and the birth of healthy children [94] [95]. In some cases, a decrease in spermatogenesis is described against the background of receiving ITC [97].

Criteria for assessing the quality of medical care

Quality criteria

Estimation

The level of reliability of evidence

Level of persuasive recommendations

Confirmation of the diagnosis of standard cytogenetic study of bone marrow and / or bone marrow studies by FISH to detect chimeric gene BCR-ABL.

Well no

1 ++.

А

Confirmation of the diagnosis of molecular genetic data data with the type of transcript type determination BCR-ABL.

Well no

1 ++.

А

Targeted therapy has been performed by tyrosine kinase inhibitors

Well no

1 ++.

А

Cytochemical study of blast cells at their level> 30%

Well no

1 ++.

А

Therapy is performed by tyrosine kinase inhibitors for 1 month after cytogenetic and / or molecular genetic confirmation of the diagnosis

Well no

1 ++.

А

An assessment of clinical hematological indicators in the process of therapy is at least 2 times a month before the achievement of a complete hematological response.

Well no

1 ++.

А

A standard cytogenetic study of the bone marrow is performed: a study of at least 20 metafaz to 3 months of therapy

Well no

1 ++.

А

Molecular genetic study of peripheral blood is performed: determination of the expression of chimeric transcript BCR-ABL. P210 by quantitative PCR by 3 months of therapy

Well no

1 ++.

А

A standard cytogenetic study of the bone marrow is performed: a study of at least 20 metafaz to 6 months of therapy

Well no

1 ++.

А

Molecular genetic study of peripheral blood is performed: the definition of chimeric transcript BCR-ABL. P210 by the method of quantitative PCR to 6 months of therapy

Well no

1 ++.

А

Molecular genetic study of peripheral blood is performed: determination of the expression of chimeric transcript BCR-ABL. P210 by the method of quantitative PCR or high-quality PCR in the presence of atypical transcripts BCR-ABL. By 12 months of therapy

Well no

1 ++.

А

Molecular genetic study of peripheral blood is performed: determination of the expression of chimeric transcript BCR-ABL. P210 by the method of quantitative PCR in the absence of a large molecular response every 3 months of therapy or with a large molecular answer every 6 months of therapy

Well no

1 ++.

А

The determination of the mutational status of the chimeric transcript BCR-ABL. In accordance with the following indications: the phase of acceleration or the phase of a blast chip or quantitative level BCR-ABL. more than 10% by 3 months of therapy or more than 1% in subsequent terms of therapy; or no indications for determining mutational status BCR-ABL.

Well no

1 ++.

А

Therapy has been completed in the absence of signs of the failure of therapy * or a change in the drug inhibitor tyrosinekinases, taking into account the mutation status and the concomitant pathology, with the failure of therapy * and / or continuous / recurrent toxicity of 2 degrees and more

Well no

1 ++.

А

* The failure of therapy is the absence of a complete hematological or any cytogenetic response to 3 months of therapy; or lack of partial cytogenetic response or level BCR-ABL. more than 10% by 6 months of therapy; Or the absence of a complete cytogenetic response or loss of a complete hematological response or a complete cytogenetic response or a confirmed loss of a large molecular response in any time of therapy above 6 months

Therapy is continued in the absence of signs of failure of therapy * or with the failure of therapy * made a conclusion about the feasibility and possibility of performing Allo TCM.

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Appendix A1. Composition of the Working Group

Afanasyev B.V., Honored Doctor of Russia, D.N., Prof., Director of Children's Oncology, Hematology and Transplantology. R.M. Gorbacheva GBOU VPO. There is no conflict of interest.

Abdulkadyrov K.M., Honored Doctor of the Russian Federation, prof., Ph.D., Head of the Clinical Department of Chemotherapy Gemoblastozes, Bloodmatian Depression and Bone Mody Transplantation "Russian Research Institute of Hematology and Transfusiology of the Federal Medical and Biological Agency". There is no conflict of interest.

Abdullayev A.O., Ph.D., Art. n. from. Laboratory of Molecular Hematology FGBU Hematology Research Center of the Ministry of Health of the Russian Federation, Member of MPN & MPNR-EURONET. There is no conflict of interest.

Vinogradova O.Yu., d. M., Prof. Departments of hematology, oncology and radiation therapy GOBOs "Russian Research Medical University". N.I. Pyrogovamz Russia, head. Moscow City Hematology Center GBUZ GKB them. S.P. Kotkin, ch. n. Sot. FGBU "Federal Scientific and Clinical Center for Children's Hematology, Oncology and Immunology. D. Rogachev "Ministry of Health of Russia, a member of the Russian Professional Society of Oncohematologists, National Hematology Society (NGO). He was awarded the diploma of the Ministry of Health of the Russian Federation "For merit in the field of health care". There is no conflict of interest.

Golenkov A.K., Honored Doctor of the Russian Federation, d. N., Prof., Head. Department of Clinical Hematology and Immunotherapy GBUZ MO Monica. M.F. Vladimirsky, the main hematologist of the Moscow region, an expert of the territorial Fund of the OMS of the Moscow Region, Roszdravnadzor in Moscow and the Moscow Region, Academician of Raen, Member of the Dissertation Council of the Hematology Scientific Center, Member of the Monica Council. M.F. Vladimirsky, member of the editorial board of journals "Hematology and Transfusiology", "Russian Biotherapeutic Journal", "Oncohematology", Member of the Expert Council of the Russian Federation for Chronic Mielolomicosis, Invited Member of the European Council of Experts on Multiple Melty. He was awarded the medal of the Order "For Merit to Fatherland" Sirephen from 21Apprel 2012. There is no conflict of interest.

Gusarova G.A., Ph.D., St.N. Scientific and Advisory Department of Chemotherapy Meloproliferative Diseases of the FGBU of the GSC of the Ministry of Health of Russia. There is no conflict of interest.

Zarutsky A.Yu., D.M., prof. Department of Faculty's Therapy with a course of endocrinology, cardiology and functional diagnostics with a clinic of FGBOU in "First St. Petersburg State Medical University ACAD. IP Pavlova" Ministry of Health of the Russian Federation, Director of the Institute of Hematology of the Federal State Unitary Enterprise "Szfmitz them Va Almazov" Ministry of Health of the Russian Federation, Representative of Russia in the International Fund chronic myelolecosis ( International Chronic Myeloid Leukemia Foundation ). 2011 EUROPEANLEUKEMIANETMERITEWARD (Honorary Motion from ELN). There is no conflict of interest.

Kuzmina L.A., Ph.D., head. The scientific and clinical department of highly visible chemotherapy and bone marrow transplantation of the FGBU of the SSC Ministry of Health of the Russian Federation, expert wounds, a member of a national hematological society, was awarded the badge of the "Excellence of Health". There is no conflict of interest.

Kutsev S.I., D.M., Director of the Fano of Russia, Head of the Fano of Russia, head of the Russian-Genetic Scientific Center. The Department of Molecular and Cellular Genetics GBOU in RNIMA NAM. Ipirogov of the Ministry of Health of Russia, the chief freelance specialist in the medical genetics of the Ministry of Health of Russia, Chairman of the Board of Medical Genetic Council, a member of the Presidium of the Management Board of the Russian Society of Medical Genetics. There is no conflict of interest.

Lomai E.G., Ph.D., c. n. from. Neil oncoMatology Institute of Hematology of the FSBI "Szfmitz them V.A. Almozov". Honorary diploma of the Ministry of Health of the Russian Federation for the merits in the field of health care for many years of conscientious work from 2013. Conflict of Interests: Novartis, BMS, Pfeiser - lectures. NOVARTIS, BMS-GRANTS support.

Martynkevich I.S., D.B., Head of the Laboratory of Molecular Genetics of the FSBI "Russian Research Institute of Hematology and Transfusion of the Federal Medical and Biological Agency", Member of the Academic Council of the FSBI "Russian Research Institute of Hematology and Transfusiology of the Federal Medical Biological agency. " There is no conflict of interest.

Morozova E.V., Ph.D., Associate Professor of the Department of Hematology, Transfusion and Transplantology of PSPBGMU. Academician I.P. Pavlova, EUROPEAN LEUKEMIA NET (ELN) member. There is no conflict of interest.

Obukhova T.N., Ph.D., doctor-laboratory genetic, the head of the scientific and clinical laboratory of the Kariology of the Federal State Unitary Enterprise of the Ministry of Health of the Ministry of Health of Russia, a mendic hematology society, the Russian society of oncohematologists, the European Society of Citogenetics, was awarded the Honorary Diploma of the Ministry of Health of the Russian Federation. There is no conflict of interest.

Pospelova T.I., d. M., Prof., Honored Doctor of Russia, Vice-Rector for the scientific work of the Federal State Budgetary Educational Institution of Higher Education "Novosibirsk State Medical University" Ministry of Health of the Russian Federation, head. Department of Therapy, Hematology and Transfusion FPK and PPV FSBEA in the NGMU of the Ministry of Health of Russia, the head of the city hematology center of Novosibirsk, the chief hematologist of the Siberian Federal Structure and the Novosibirsk Region, Chairman of the MOO "Association of Hematologists Association". There is no conflict of interest.

Sudarikov AB, D.BN, Head. The Laboratory of Molecular Oncology of the FSBI of the UGTS Ministry of Health of Russia, an expert of the RFB, RNF, FSVK. There is no conflict of interest.

Turkina A.G., d. M., Prof., Head. Scientific and Advisory Department of Chemotherapy of Myeloproliferative Diseases of the SSC GNS Ministry of Health of the Russian Federation, Chairman of the Working Research Group on Chronic Mielolic Society of the National Hematology Society (NGO), Head of the Russian Group and Member of the EUROPEANLEUKEMIANET Expert Council (ELN), European Hematology Society for the study of leukemias, Member of Russia in Russia The international committee for the study of leukemia and associated diseases, IACrlrd World Committee, a member of the European Research Group on Chronic Mielolecosis (EICML), the American ASH Hematology Association (American Society of Hematology), Siberian Society of Hematologists. Awarded a diploma of the Ministry of Health of the Russian Federation in 2012. There is no conflict of interest.

Tsace G.A., d. M. N., Head. Laboratory of Molecular Biology, Immunophenotyping and Patomorphology GBUZ CO "Regional Children's Clinical Hospital No. 1", Baterinburg, doctor of clinical laboratory diagnostics GAUZ with "Institute of Medical Cellular Technologies", Bratisrugburg, a member of the National Society for Children's Hematologists and Oncologists. There is no conflict of interest.

Fomins M.S., scientific Sot. FGBU "Russian Research Institute of Hematology and Transfusiology of the Federal Medical Biological Agency", Member of EHA, ASH, ELN. There is no conflict of interest.

Chelyrava E.Yu., Ph.D., St.N. Scientific and Advisory Department of Chemotherapy Meloproliferative Diseases of the FGBU of the GSC of the Ministry of Health of Russia. Member of the National Hematology Society, ELN. Conflict of interests: grants for participation in scientific events, reading lectures - Novartis Pharma, "Bristol Myers Skwibb".

Shuvayev V.A., Ph.D., St.N. FSBI "Russian Research Institute of Hematology and Transfusiology of the Federal Medical and Biological Agency", a member of the National Hematology Society. Conflict of interests: grants for participation in scientific events, lectures - "Novartis Pharma", "Bristol Myers Skwibb", "Pfeiser".

Shukhov O.A., Ph.D., scientists. Scientific and Advisory Department of Chemotherapy Myeloproliferative Diseases of the FGBU of the SSC Ministry of Health of Russia, a member of the National Hematology Society, a member of EHA, ELN. Conflict of interests: grants for participation in scientific events, reading lectures - Novartis Pharma, "Bristol Myers Skwibb".

Appendix A2. Clinical Recommendation Development Methodology

Target audience of clinical recommendations:

  1. Specialists hematologists;

  2. Specialists oncologists;

  3. Specialists therapists;

  4. Specialists obstetric gynecologists;

  5. Students of medical universities.

Methodology for collecting evidence

Methods used to collect / selection of evidence:

Search for publications in specialized periodic prints with impact factor> 0.3;

Search in electronic databases.

Databases used to collect / selection of evidence:

The evidence base for recommendations are publications included in the Kohrinovskaya library, PubMed and Medline databases. The depth of search was 30 years.

Methods used to analyze evidence:

Methods used for quality and force of evidence:

Table P1. Rating scheme for assessing the level of reliability of evidence

Levels of reliability of evidence

Description

1 ++.

Meta-analyzes of high quality, systematic reviews of randomized controlled studies (RKK), or RCCs with a very low risk of systematic errors

1+

Qualitatively conducted meta-analyzes, systematic reviews or RKK

one-

Meta tests, systematic reviews or RCKs with high risk of systematic errors

2 ++.

High-quality systematic research reviews Case control or cohort studies with the lack of or very low risk of mixing effects or systematic errors and the high probability of causal interconnection

2+

Well conducted research case-control or cohort studies with the average risk of mixing effects or systematic errors and the average probability of causal relationship

2-

Research case-control or cohort studies with high risk of mixing effects or systematic errors and the average probability of causal interconnection

3

Not analytical research (descriptions of cases, series of cases)

4

Opinion experts

Description of the methodology for analyzing evidence and developing recommendations

When selecting publications, as potential sources of evidence, a methodology used in each study was studied in order to ensure its compliance with the principles of evidence-based medicine. The result of the study influenced the level of evidence assigned to publication, which in turn affects the strength of the recommendations arising from it.

Methodological studies focused on the design features of the study, which had a significant impact on the quality of the results and conclusions.

In order to eliminate the influence of subjective factors, each study was estimated independently at least two independent members of the author's team. Differences in the assessment were discussed at the meetings of the working group of the author's group of recommendations.

Based on the analysis of evidence, sections of clinical guidelines were developed consistently developed in accordance with the rating scheme of recommendations (Table P2).

Methods used to formulate recommendations:

Table p2. - Rating scheme for assessing persuasive recommendations

Levels of persuasive recommendations

Description

A

Recommendations are based:

at least on one meta analysis, systematic overview or RCK, estimated as 1 ++, directly applicable to the target population and demonstrating the sustainability of the results

or a group of evidence that includes research results estimated as 1+, directly applicable to the target population and demonstrating the overall sustainability of the results

B

Recommendations are based:

On the evidence group, including the results of studies, evaluated as 2 ++, directly applicable to the target population and demonstrating the overall sustainability of the results

or extrapolated evidence from studies rated as 1 ++ or 1+

C

Recommendations are based:

In a group of evidence, including research results, estimated as 2+, directly applicable to the target population and demonstrating the overall sustainability of the results

or extrapolated evidence from studies rated as 2 ++

D

Recommendations are based on the evidence of level 3 or 4

or extrapolated evidence from studies rated as 2+

Indicators of benign clinical practice (GoodPracticePoints - GPPS):

Benign practice of recommendations is based on the qualifications and clinical experience of the author's team.

Validation methodology Recommendations

Recommendations Validation Methods:

Appendix A3. Related documents

Types, forms, the conditions for the provision of medical care at CML are determined in accordance with the procedure for providing medical care, the order of the Ministry of Health of the Russian Federation No. 930 N. from 29.12.2014 "On approval of the procedure for organizing the provision of high-tech medical care using a specialized information system", as well as taking into account the standards developed by experts on the diagnosis and therapy of HML.

Appendix B. Patient Leading Algorithms

 

Appendix B. Information for patients

Deep-devaable ...........!

You have identified a disease chronic myelolomicosis (HML). In the development of this disease, a clone of leukemia cells occurs, which displaces the cells of normal blood formation in the bone marrow. Leukemian cells contain a marker of this disease - Philadelphia chromosome (pH +) and / or transcriptBCR-ABL. These markers are detected under cytogenetic study of bone marrow or molecular genetic study of peripheral blood. The CML is often detected with random blood test, and the clinical symptoms of the disease at the time of its diagnostics may be absent. However, in the absence of specific treatment, the gradual progression of the disease is inevitably happened.

For the treatment of patients with hML, modern targeted therapy is used - preparations of tyrosine kinase inhibitors (ITC), which makes it possible to achieve a significant decrease in the number of leukemic cells and determines the favorable long-term forecast of the disease. Currently, inhibitors of tyrosine kinases 1 and 2 generations are available in the Russian Federation. The choice of the drug for your treatment of therapy is carried out taking into account the phase of the disease, concomitant pathology and side effects of each ITC, in accordance with modern recommendations on HML therapy. In most cases, HML is detected in the chronic phase (HF), and the treatment is carried out outpatient. However, in the presence of testimony, hospitalization can be carried out.

The main principle of HML therapy is the induction of the response to the treatment and suppression of a clone of leukemic pH + cells in order to reduce the risk of disease progression. The results of only a general blood test after achieving full hematological remission are not informative enough to assess the response to therapy. The main methods of estimating the volume of leukemic clone and parameters characterizing the effectiveness of therapy with HML are cytogenetic and molecular genetic research methods

The key to more efficient drugs in the failure of the first line therapy fails and timely resolving the question of the implementation of allogeneic transplantation of blood-made bone marrow cells. In order to determine the indications for the continuation of treatment or to change therapy, the response to treatment with hML is determined as optimal, failure or warning. On each observation period, there are criteria for these definitions.

Optimal answer For treatment with hML, consider: reducing the level of the transcript BCR-ABL. ? 10% after 3 months, <1% after 6 months? 0.1% after 12 months of treatment, as well as a partial cytogenetic response (pH +? 35%) after 3 months of therapy and a full cytogenetic response (FOS) to 6 months of therapy. The optimal response with good tolerance of treatment, indicates a favorable forecast and long survival without progression. With optimal response and long survival without progression, therapy will continue in the same mode.

Failure of therapy It assumes an increased risk of progression of the disease and is the basis for discussing the issue of the feasibility of changing therapy. If therapy fails, it is primarily necessary to assess the patient's commitment to treatment, that is, the regularity of the drug intake. The criteria for the failure of therapy are: BCR-ABL level> 10%, pH +> 95% and lack of hematological response after 3 months; BCR-ABL. ? 10%, pH +> 35% after 6 months; BCR-ABL. ? 1%, pH +> 0% after 12 months. The risk factors for 3 months of therapy are the BCR-ABL> 10% level, pH +> 65%. If an insufficient answer is not related to the disorder of the drug, the mutations of the BCR gene will be carried out - Therapy Imatinib will be switched to ITC2 or increase the immature dose. The choice of ITC with a change in treatment will be carried out taking into account the concomitant pathology, side effects and analysis of mutations BCR-ABL. .

To category Warnings These intermediate values ​​of the answers. If there are adverse factors and a high risk group, for this category of patients consider a dose increase or replacement of ITC.

Thus, the effectiveness of therapy is planned to be estimated after 3, 6 and 12 months from the beginning of treatment of ITC. In this period, the execution of the bone marrow puncture, cytogenetic and molecular genetic study is scheduled. After reaching the PCO according to the results of a cytogenetic study (in the absence of PH-positive cells), the response to treatment will be evaluated only by the molecular genetic method, as it has a greater sensitivity. Peripheral blood and the definition of the relative expression of the BCR-ABL will be regularly carried out, and the bone marrow puncture will be carried out only in special clinical situations by solving your doctor.

At each visit to the doctor, it is planned to evaluate the portability of ITC therapy, according to the results of a conversation with a patient, physical inspection and evaluation of clinical and laboratory parameters: general blood analysis, biochemical analysis of blood. In case of toxicity, additional recommendations will be given, taking into account the degrees of toxicity and its duration.

Currently, the HML refers to those diseases that are well controlled by the ITC therapy. Obtaining a deep remission of the disease - the so-called deep molecular response, in which the level of expression of BCR-ABL is not determined, can be stated after several years of therapy. However, even with a deep molecular answer, according to modern recommendations, it is shown to continue the treatment of ITC in constant mode, since even the minimum volume of the tumor clone can become a source of recurrence when canceling treatment.

It is important to note that the success of treatment will largely depend on your commitment to therapy -T.E. Connecting the recommendations of a specialist and permanent reception of drugs, taking into account the treatment will be carried out override years. Given the optimistic results of the long-term survival of patients (12 year old overall survival rate up to 85%), there is a real perspective of a total life expectancy comparable to such in the usual population.

In the event of the development of disease resistance, insensitivity to the treatment, intolerance to treatment, all measures will be taken to choose the further optimal tactics of your management. Doctors who observe you are always ready to provide you with advisory and medical and diagnostic support.

Appendix G.

Appendix G1.

List of drugs that are possible intercompositional interaction with ITC

The most significant intercomposition interactions are possible between ITC and drugs extending the Qt interval (Table 14), as well as drugs that are substrates of cytochrome P450 (Table 16)

Table 14. The list of drugs lengthening the Qt interval

Group of drugs

Titles of drugs

Antiarrhythmic

Adenosine, amiodar, freakinide, quinidine, sotalol;

Anticomponian

Felbamat, Phenitoin

Antidepressants

Amitriptyline, cytitalopram, desipramine, doxypin, imipramine, paroxetine, sertraline;

Antihistamine

Asthemisol, Diphenhydramine, Loratadine, Terfenadine;

Antihypertensive

Indapamide, Mibifradil, hydrochlorostiazide, nifedipine;

Antimicrobials

Macrolids, fluoroquinolones;

Antitumor

Arsenic trioxide, tamoxifen;

Antipsychotic

Chlorpromazine, clozapine, Droperidol, Haloperidol, Risperidone;

Gastrointestinal tract

Cisaprid, dollanetron, octreotide

Table 15. List to the most important inhibitors or inductors of cytochrome P450

CYP3A4 / 5 stimulants-products that reduce the concentration of ITC plasma

CYP3A4 / 5 inhibitors are preparations that increase the concentration of ITC in plasma

Glucocorticoids

Griefullvin

Dexametanone

Diphenin

Carbamazepine

Oxarbazepine

Progesterone

Rifabutin

Rifampicin

Sulfadymisin

Sulfapirazon

Troglitazon

Phenylbutazon

Phenobarbital

Etosuximide

Amiodar

Anastrosol

Azithromycin

Cimetidine

Clarithromycin

Clotrimazole

Cyclosporin

Danazol.

Dexametanone

Diltiazem

Diritromycin

Disoulphyram.

Erythromycin

Ethinyl estradiol)

Fluochetine

Fluuofsamin

Guestful

Grapefruit juice

Isoniazid

Iratenazole.

Ketokonazolmetronidazole

Mibeffradil

Mikonazole (medium)

Norfloxacin

Norfluoksetin.

Omeprazole (weak)

Oxyconazole.

Paroxetine (weak)

Hinidin

Quinine

Serindol.

Seraralin

Verapamil

Zafirlukast

Appendix G2.

Criteria toxicity NCI CTCAE V4.0 *

The criteria for toxicity NCI CTCAE help determine the degree of toxicity of an undesirable phenomenon in order to determine the tactics of reference. Table 17 presents the criteria for hematological and non-hematological toxicity, which may be observed with ITC therapy.

Table 16. Criteria for toxicity NCI CTCAE V4.0 * (Favorites)

Unwanted phenomenon

Degree of toxicity

1

2

3

4

Hematologic

Hemoglobin

NGN * -100 g / l

100 - 80 g / l

80 - 65 g / l

Life-degrading complications need urgent therapy

Leukocytes

NGN-3.0X 10 ^ 9 / l

3.0 - 2.0 x 10 ^ 9 / l

2.0 - 1.0 x 10 ^ 9 / l

<1.0 x 10 ^ 9 / l

Neutrophila

NGN - 1.5 x 10 ^ 9 / l

1.5 - 1.0 x 10 ^ 9 / l

1.0 - 0.5 x 10 ^ 9 / l

<0.5 x 10 ^ 9 / l

Thrombocytes

NGN - 75.0 x 10 ^ 9 / l

75.0 - 50.0 x 10 ^ 9 / l

50.0 - 25.0 x10 ^ 9 / l

<25.0 x 10 ^ 9 / l

NGN - Lower Border

Laboratory deviations

Alkaline phosphatase

VGN * - 2.5 x VGN

2.5- 5.0 x VGN

5.0 - 20.0 x VGN

> 20.0 x VGN

Bilirubin

VGN - 1.5 x VGN

1.5 - 3.0 x VGN

3.0 - 10.0 x VGN

> 10.0 x VGN

AST

VGN - 3.0 x VGN

3.0 - 5.0 x VGN

5.0 - 20.0 x VGN

> 20.0 x VGN

Alt.

VGN - 3.0 x VGN

3.0 - 5.0 x VGN

5.0 - 20.0 x VGN

> 20.0 x VGN

Lipasa

VGN - 1.5 x VGN

1.5 - 2.0 x VGN

2.0 - 5.0 x VGN

> 5.0 x VGN

Hyperglycemia

Glucose level VGN empty stomach - 8.9 mmol / l

Glucose level on an empty stomach 8.9 - 13.9 mmol / l

13.9 - 27.8 mmol / l, hospitalization is necessary

> 27.8 mmol / l, life-degrading complications

* VGN - Upper limit

Edema (peripheral)

Entrance females

Localized swelling of the face

Moderate edema faces restricting everyday activity

Heavy swelling, limiting everyday activity and self-service ability

-

Edemales Torch

Eveny or smoothing anatomical formations at local inspection

Noticeable smoothing of anatomical formations, filling of skin folds, noticeable distortion of anatomical contours, restriction of everyday activity

Heavy swelling, limiting everyday activity and self-service ability

-

Edema extremities

5-10% difference in limb circumference, swelling or smoothing anatomical formations during local inspection

10-30% difference in limb circumference, noticeable smoothing of anatomical formations, filling of skin folds, noticeable distortion of anatomical circuits, restriction of everyday activity

> 30% difference in limb circumference Heavy swelling, limiting everyday activity and self-service ability

-

Toxicity from the gastrointestinal tract

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