How acute promelocytic leukemia is treated. Acute Promoelocytar Lakes: Forecast

Acute myeloblastic leukemia (IML) is a term that combines a number of acute myelolekosis, characterized by the development of failures in the mechanism of maturation of myeloblasts.

In the early stages of development, the disease is evident asymptomatic and is diagnosed too late.

To identify leukemia in a timely manner, you need to know what kind of symptoms talk about the start of the development of the disease and what factors affect its occurrence.

ICB-10 code

Code of the disease - C92.0 (acute myeloblastic leukemia refers to the group of myeloid leukemia)

What it is?

OML is a malignant transformation that encompasses the myeloid sprout of blood cells.

The affected blood taurins gradually replace healthy, and blood stops fully fulfilling its work.

This disease, like other types of leukemia, is called blood cancer in everyday communication.

The words of which this definition consists, make it possible to understand it better.

When leukemia, the altered bone marrow begins to actively produce leukocytes - blood elements that are responsible for maintaining the immune system - with a pathological, malignant structure.

They replace healthy leukocytes, penetrate into different parts of the body and form lesions, similar to malignant neoplasms there.

Differences of healthy blood from patient leukemia

Myeloblastic. In the IML, the oversight of the affected myeloblasts begins - elements that should turn into one of the varieties of leukocytes.

They displacing healthy predecessor elements, leading to a shortage of other blood cells: platelets, red blood cells and normal leukocytes.

Acute.This definition suggests that it is immature elements that are produced. If the affected cells are in a mature state, leukemia is called chronic.

Acute myeloblastosis is characterized by rapid progression: myeloblasts in the blood are spread over the body and cause tissue infiltration.

Symptoms

Usually an IML develops in adults and the elderly. The early stages of myeloblaste leukemia are characterized by the lack of pronounced symptoms, but when the disease covered the body, serious violations of many functions arise.

Hyperplastic syndrome

Developed due to tissue infiltration under the action of leukemia. Peripheral lymph nodes grow, the spleen, chicken almonds, liver is increasing.

Limph nodes of the mediastum region are affected: if they grow significantly, then it is transmitted by the upper hollow vein.

Bloodstock in it is brokenThat is accompanied by the occurrence of swelling in the neck area, rapid respiration, skin sinusiness, swelling of the vessels on the neck.

Sums are also affected: Stomatitis of Wensena appears, which is characterized by the development of heavy symptoms: the gums swell, bleed and hurt much, there is and care for the oral cavity is difficult.

Hemorrhagic syndrome

More than half of the patients have certain manifestations, develops due to an acute platelet lack, in which the walls of the vessels are thinned, the blood coagulation is disturbed: multiple bleeding is observed - nasal, internal, subcutaneous, which for a long time cannot be stopped.

Increases the risk of hemorrhagic stroke - Hemorrhage into the brain, in which mortality is 70-80%.

In the early stages of acute myeloblastic leukemia, the disorder of coagulation is manifested in the form of frequent nasal bleeding, bleeding of gums, bruises at different parts of the body that appear from minor influences.

Anemia

Characterized by the appearance:

• Severe weakness;
• Fast fatigue;
• Deterioration of working capacity;
• Irritability;
• Apathy;
• Frequent pains in the head;
• Dizziness;
• Fainting;
• The desires are chalk;
• Drowsiness;
• Pain in the heart;
• Skin palls.

Even minor physical activity is difficult (severe weakness, rapid breathing is observed). Anemia hair often falls out, fragile nails.

Intoxication

The body temperature is raised, the weight falls, the appetite disappears, weakness and excessive sweating are observed.

The initial manifestations of intoxication are observed at the initial stages of the development of the disease.

Neuroleikosis

If infiltration affected brain tissues, it worsens the forecast.

The following symptoms are observed:

• Multiple vomiting;
• Acute pain in the head;
• Epiprigances;
• Fainting;
• Intracranial hypertension;
• Failures in the perception of reality;
• Hearing, speech and vision.

Leukostasi

Develop in the later stages of the disease, when the number of affected myeloblasts in the blood becomes higher than 100,000 1 / μl.

Blood GusteetThe blood flow becomes slow, blood circulation is disturbed in many organs.

Brain leukostasis is characterized by the occurrence of intracerebral bleeding. Violations violated, comporant state occurs, coma, a fatal outcome is possible.

With pulucostase, there is a rapid breathing (The occurrence of tachipne is possible), chills, temperature increase. The amount of oxygen in the blood is reduced.

With acute myeloblastic leukemia, the immune system is extremely vulnerable and is not able to protect the body, so highness is highly susceptible to infections that occur hard and with a mass of hazardous complications.

Causes

The exact causes of the development of the IML are unknown, but there are a number of factors that increase the likelihood of disease development:

• Radiation irradiation.In the risk group, people who interact with radioactive materials and devices, liquidators of the consequences of the Chernobyl, patients passing radiation therapy in a friend of oncological disease.
• Genetic diseases.For anemia of fairy, Bloom syndromes and Down, the risk of leukemia is increasing.
• Impact of chemicals. Chemotherapy in the treatment of malignant diseases negatively affects the bone marrow. Also, the probability increases in chronic poisoning to poisonous substances (mercury, lead, benzene and others).
• Heredity.People close to whose relatives suffered by leukozes, can also get sick.
• MyelOflastic and myeloproliferative syndromes.If the treatment of one of these syndromes will be absent, the disease can be transformed into leukemia.

In children, this type of leukemia is extremely rare, in the risk group - people over 50-60 years old.

Oml form

Myeloblast leukemia has a number of varieties, on which the prognosis and tactics of treatment depends.

Name and classification by Fab	Description
OML with minor differentiation (M0).	Low susceptibility to chemotherapeutic treatment, easily acquires resistance to it. The forecast is unfavorable.
Oml without ripening (M1).	It is characterized by rapid progression, blast cells are contained in large quantities and constitute about 90%.
Oml with ripening (m2).	The level of monocytes with this variety is less than 20%. Not less than 10% of myeloblast elements are developing to the stage of speakelyocytes.
Promoelocitary leukemia (m3).	Promoelocytes accumulate in the bone marrow. Refers to the most favorable by the flow and forecast of leikozam - within 10-12 years they live at least 70%. Symptomatics is similar to the remaining varieties of the IML. It is treated with the use of arsenic and tertinine oxide. The average age of sick - 30-45 years.
Myllomocytic leukemia (M4).	Diagnosed in children more often than other varieties of the disease (but in general, an AML in the percentage, compared with other types of leukemia, is rarely detected in children). It is treated with the use of intensive chemotherapy and transplanting stem cells (TGC). The prognosis is unfavorable - survival rates for five years - 30-50%.
Monoblastic leukemia (M5).	With this species, the bone marrow contains at least 20-25% of blast elements. Current chemotherapy and TGC.
Erythitoid leukemia (M6).	Rarely found species. It is treated with the use of chemotherapy and stem cell transplants. The forecast is unfavorable.
Megakaryoblastic leukemia (M7).	This variety of Oml is subject to people with Down syndrome. It is characterized by a rapid flow and low susceptibility to chemotherapy. Children's forms of the disease are more often favorable.
Basophilic leukemia (M8).	It is more common in children's and youthful age, the forecast of the life of M8 is unfavorable. In addition to malignant elements, abnormal elements are detected in the blood, which is difficult to identify without special equipment.

Also, in addition to the species mentioned, there are other rare species not contributed to the general classification.

Diagnostics

Acute leukemia is detected using a number of diagnostic measures.

Diagnosis includes:

• Deployed blood test. With it, it is detected in the blood content of blast elements and the level of the remaining blood cells. When leukemia, an excess amount of blasts and a reduced platelet content of ripe leukocytes, red blood cells are found.
• Taking biomaterial from bone marrow.It is used to confirm the diagnosis and is carried out after conducting blood surveys. This method is applied not only in the diagnostic process, but also throughout the treatment.
• Biochemical analysis. Gives information about the state of organs and tissues, the content of various enzymes. This analysis is assigned to obtain a deployed pattern of lesion.
• Other types of diagnostics: Cytochemical study, genetic, ultrasound spleen, abdominal cavity and liver, chest zone x-ray, diagnostic measures to identify the degree of brain damage.

Other diagnostic methods can be assigned, depending on the patient's condition.

Treatment

OML treatment includes the use of the following methods:

Immunotherapy can also be applied - direction using immunological preparations.

Apply:

• Medicines based on monoclonal antibodies;
• Adaptive cell therapy;
• Inhibitors of control points.

With this diagnosis, like acute myelolomicosis, the duration of treatment is 6-8 months, but can be increased.

Forecast of Life

The forecast depends on the following factors:

• OML type;
• Sensitivity to chemotherapy;
• Age, gender and patient health;
• Leukocyte levels;
• The degree of brain involvement in the pathological process;
• Duration of remission;
• Indicators of genetic analysis.

If the disease is sensitive to chemotherapy, the concentration of leukocytes is moderate, and the neuroleycosis has not developed, the forecast is positive.

With a favorable forecast and the absence of complications, survival for 5 years is more than 70%, the frequency of relapses is less than 35%. If the patient's condition is complicated, the survival rate is 15%, while recurrenting the state may be in 78% of cases.

In order to reveal an OML in a timely manner, it is necessary to regularly undergo planned medical examinations and listen to the body: frequent bleeding, fast fatigue, the occurrence of bruises from a small effect, a long undue temperature rise can talk about the development of leukemia.

Video: acute myeloleikosis

Acute promoelocytar leukemia occurs quite rarely, more often in childhood up to 1 year or in an adult population of 40-45 years per-background after hemorrhagic DVS syndrome, when the leukocyte granular substrate accumulation is accumulated in the form of large grainy cells located in beams.

If you do not take urgent measures, death threatens death. The incidence came to us from Latin America and even the conduct of chemotherapy cannot be warned by the risk of recurrence. There is a certain transformation of white stem cells into promoelocytes, the amount of blood taurus - platelets is sharply reduced.

Acute promoelocytar leukemia - a patient is detected by thrombocytopenia, anemia, the production of platelets in the bone marrow is reduced, and they are no longer able to produce healthy red blood cells in the desired volume. During the diagnosis, the level of leukocytes is increased and the level of white Taurus is underestimated. Lakes developing.

As the disease flows

The course of the disease in the propellable leukemia is rapid. The patient has:

• weakness;
• anemia;
• fatigue;
• labored breathing;
• fever;
• bleeding from gums, nose;
• strengthening menstrual bleeding in women
• reduced blood coagulation;
• temperature increase;
• fevering condition;
• termination of the production of normal and white blood tauros;
• an increase in the spleen in size;
• hemorrhage;
• toxicosis in the presence of cytoplasmic granules in cells;
• overabundance of thromboplastin in the blood;
• disseminated blood coagulation;
• surability in the abdomen, although lymph nodes and the liver remain normal.

It is the low level of platelets that can lead to hemorrhage and strong bleeding even with minor skin damage. Against the background of weakened immunity, patients are not resistant before on the onslaught of infection.

How diagnostics is carried out

Analysis is subject to blood test. In promoelocytic leukemia, explicitly pronounced anemia, thrombocytopenia, atypical blass cells in the bone marrow or blood per periphery are detected. Promoelocytes glycemic and blastomas begin to quickly accumulate in the blood.

To set an accurate diagnosis:

• myelogram in order to evaluate platelet content in%;
• chemical study in order to identify myeloperoxidase /
• general blood test for calculating the formula for the content of blast cells in the percentage ratio;
• coagulogram;
• biochemical blood test as the main indicator for the giving assessment of the condition of the liver, kidney, electrolytes;
• the study of blood for the liquor to prevent the development of hemorrhagic syndrome in the future and appropriate treatment for the purpose of monitoring the toxicity of injected drugs;
• radiography of the chest and the abdominal region
• MRI brain.

In addition, patients are examined by a neuropathologist, a otolaryngologist, an oculist to confirm (refutation) of the diagnosis, the appointment of subsequent integrated treatment.

As a disease is treated

When a diagnosis is detected, the OPL measures must be taken in the complex. Coagulopathy is urgently carried out to maintain fibrinogen and platelet levels normally.

Therapy is aimed at stopping bleeding, elimination of hemorrhagic complications, in particular thrombocytopenia. Effective antifibrinolities are immediately prescribed, in particular dexamethasone (20mg per day) even without confirmation of an accurate diagnosis. The patients are constant monitoring in identifying cytogenetic molecular genetic signs. The state is monitored on the monitor to avoid the appearance of a strong feverish state.

It is recommended to urgently carry out cytostatic therapy together with a sharp deterioration in the state of the patient, when there is a threat to life when developing a rigid syndrome, inevitably leading to the death of cytostatics.

In this case, heparin is prescribed, cryoprecipitate, frozen plasma to increase blood coagulation. It is possible to achieve remission, but when you joining the life-threatening life of the retinoid and the engine of the syndrome, there is a massive release into the blood of progagulants and leukemic blast cells. The patient's condition becomes critical, the blood picture is not as terrible - shortness of breath appears, signs of pericarditis, arterial hypotension, fever. Urgently appointed:

• cytostatics to avoid the development of leukocytosis and its consequences;
• teratinoin to reduce the fatal outcome and development of retinoid syndrome.

What is the forecast

Considered weeks remains to live a patient with speakelyocytic leukemia, unless to take urgent treatment measures. The forecast is bad. Only when using modern protocols in therapy, doctors can achieve some improvements and sustainable remission in 90% of cases.

Today effective preparations are available in treatment, but this form of leukemia is the hardest. In the failure of measures to carry out rooted therapy, death may occur during the day, and the outcome is obvious.

The main thing is that at the right moment in the presence of retinic acid or a retinoid, an effective drug, which allows to reduce the risk of sudden death. This is one of the heavy forms of leukemia, and the forecast disappointing.

Informative video

It is characterized by an abnormal increase in the number of promoelocytes, among which 98% have a T (15; 17) transclocation and the PML / RARα fusion gene.

Acute Promioleomicosis - EmergencyHis diagnosis and treatment must be carried out immediately.

Prevalence

Acute promoelocytar leukemia is found in both children and adults, accounted for 3-9% and 10-15% of the total number of acute myelolecosis. Age maximum of 35-50 years. Residents and people from Spain and some provinces of China are more often sick.

Causes of acute promelocytic leukemia

Accurate cause of appearance malignant clone Promelocyte Not known. No connection is detected with the influence of the external environment. Does not develop against the background of other bone marrow diseases (myelodsplastic syndrome, myeloproliferative diseases).

The frequency of acute promoelocytic leukemia after chemotherapy and / or radiotherapy (for example, after breast cancer or lymphoma) - 1.7-5.8%.

Pathophysiology of acute promelocytic leukemia

Transfer retinic acid receptor gene type α (rarα) from the 17th on 15-yukhromosoma and the union of it with the genome PML - the genome of the Promelocytic Leukoza, lead to a violation of the ripening of blood cells and their active division.

Retinoic acid - This is one of the forms of vitamin A in the body.

Gene Rarα. (Retinoic Acid Receptor Alfa) regulates the reading of DNA sections responsible for the differentiation of blood cells. Rarα is blocked by SMRT and N-COR molecules, forms a complex with MSIN3-histoneeacetalase (HDAC). Under normal conditions, the minimum doses of retinic acid disconnect the blocking complex, which leads to reading information from DNA, and the normal ripening of blood cells.

PML Gen. He is responsible for the elongation of the lifetime of the Promelocyte and their division.

The combined (fusion) PML-RARα gene no longer responds to retinuous acid, cell differentiation stops at the Promelocyte level and the division of the same promoelocytes is launched.

Other mutations in acute promelocytic leukemia:

• Numa1 / Rarα.
• PLZF / RARα.
• STAT5B / RARα.
• NPM1 / RARα.
• PRKAR1A / RARα.
• FIP1L1 / RARα.
• Nabp1 / Rarα.

STAT5B / RARα and PLZF / RARα - do not react to the treatment with retinoic acid.

As in the remaining subspecies of acute myelolecosis, other genetic changes (except those described above) are detected, but they do not affect the forecast or treatment.

Blood coagulation disorder with acute proposal leukemia

Azurophilic granules of promoelocytes contain a fabric factor and other enzymes activating cascade of coagulation and fibrinolysis, so running syndrome dismedicated intravascular coagulation, Hyperfibrinolysis, nonspecific proteolysis.

10-20% of deaths in acute promelocytic leukemia are caused by bleeding.

Causes of bleeding in acute promelocytic leukemia:

1. Blood coagulation factors

• activation of the external blood coagulation path through an elevated tissue factor
• number of receptors on Promelocytes to Factor V (ProAKEKOMINA)
• isolation of the tumor pro-amateur factor and cysteine \u200b\u200bproteases that are capable of directly activating the X (Stewart Puera) factor

2. activation of fibrinolysis - the process of dissolving blood

• anomalous Promoelocytes with acute promoelocytic leukemia contain fabric and urock plasminogen activators (UPA, TPA) and a very high amount of annexin II, regulating the production of plasminogen fabric activator
• granulocyte proteases (elastases) directly split fibrinogen

3. secretion of pro-inflammatory cytokines (Interleukin I and tumor necrosis factor α) at \u200b\u200bthe endothelium level

• increased expression of fabric factor on endothelium
• reduced expression of Trombomodulin
• increased synthesis of plasminogen activator inhibitor PAI-1

All these changes lead to typical finds in the analysis of blood clotting in acute speech leukelosis (read below)

Classification of acute promelocytic leukemia

• classical acute promoelocitary leukemia
• microgranular - variant acute promelocytic leukemia, atypical propelocytes with small granules, characteristic of the nucleus

The most characteristic symptom of acute promoelocytic leukemia - bleeding (hemorrhagic syndrome):

• fast formation of bruises, even after minimal injury or in its absence
• small point hemorrhage on the skin (Petechia)
• long bleeding after small wounds
• hemorrhage under the mucous membrane of the eye (conjunctival)
• frequent repetitive bleeding from the nose
• blood when cleaning teeth
• hemorrhages in the gastrointestinal tract and urinary organs, less often in the brain and lungs

Consequence of bleeding will be anemia - Reducing the level of hemoglobin in the blood and red blood cells. Symptoms of anemia - fatigue, fast fatigue, shortness of breath.

Infectious complications are joined - heavy inflammation (sinusitis, pharyngitis, pneumonia), which are poorly or not reacting at all to antibiotic treatment.

Symptoms of acute promelocytic leukemia There are quickly (several weeks-months) and quickly progress.

Diagnosis of acute promoelocytic leukemia

General blood analysis

• in 80% of cases, the number of leukocytes below the norm (less than 4 * 10 9
• 9 / l) - observed with microgranular form or in launched cases of acute promelocytic leukemia, which indicates an unfavorable forecast
• levels of hemoglobin and red blood cells are reduced as a result of a bloodwater
• plateles are often below 50 * 10 9 / L.
• characteristic pancitopenia - reduction of all types of blood cells
• in the smear of blood find abnormal Promelocytes

Blood coagulation with acute promelocytic leukemia

• D-dimers
• fibrin degradation products

Red bone marrow with acute promelocytic leukemia

In suspected, the presence of a patient of acute promelocytic leukemia is necessarily a study of a red bone marrow, the material is obtained by sternal puncture or trepalobiopsy.

• histological study of the bone marrow in acute promoelocytic leukemia: increased cellularity with the predominance of anomalous transomelocytes - more than 20% of all cells

• hypergranulating form of acute promelocytic leukemia (90%) - Auer sticks in cytoplasm, some cells contain Auer sticks in bundles (Faggot Cells), the granules are sharply positive on myeloperoxidase
• microgranular shape (hypnotional, optional) - Promoelocyte cells do not contain granules visible in the light microscope, less often azurophilic grains and auer sticks, sometimes a positive reaction to Naftol-acetate Esterase, similar to monocytaria leukemia.
• the character of blast cells is similar to those at m1 and m2 of variants of acute myelolecosis

• immunophenotype - characteristic, but not sufficient for diagnosis: CD33 +, CD13 +, CD15-, CD34-; HLA-DR ±; Microgranular formCD34 +, CD2 +
• cytogenetic - analysis on PML / RARα PCR method - both to confirm the diagnosis and for the prediction of the success of the treatment with retinoic acid
• research T (15; 17) TRANSALLOBATION METHOD FISH

Unfavorable prognostic factors

• leukocytes 10 * 10 9 / l
• platelets ↓ 40 * 10 9 / l
• age 60 years

Treatment

The treatment of acute promelocytic leukemia is beginning immediately, with the first suspicion of the diagnosis, without waiting for the results of the PML / RARα study.

Induction therapy of acute promelocytic leukemia

Be sure to control the level of hemoglobin, platelet, fibrinogen, D-dimers, ABTV, fibrin degradation products with an interval of 8-12 hours. Induction therapy lasts up to 3 months.

ATRA 45 mg / m 2 per day divided by 2 doses until hematologic remission is achieved + yudarubitsin 12 mg / m 2 2, 4, 6, 8 days

Consolidation therapy

1. cytosinarabinoside 1 g / m 2 1 time per day 4 days + Idarubicin 5 mg / m 2 × 1 time per day 4 days
2. millomantron 10 mg / m 2 1 time per day + etoposide 100 mg / m 2 1 time per day 5 days
3. cytosinarabinoside 150 mg / m 2 Every 8 hours subcutaneously 5 days + Idarubicin 12 mg / m2 1 time per day 1 day + thioguanine 70 mg / m 2 3 times a day 5 days

After reaching consolidation therapy molecular remission - Two years of retaining treatment with periodic administration of retinic acid, sometimes in combination with chemotherapy.

retinoic acid 15 days every 3 months +/- methotrexate +/- 6 mercaptopurine

Supporting treatment for acute propellacic leukemia

• transfusion of thromboconcentrate with platelets is below 30 * 10 9 / l, at high risk - less than 50 * 10 9 / L.
• the introduction of fibrinogen with hypofibrinogenemia less than 2 g / l
• low molecular weight heparin (in a prophylactic dose) at a high level of D-dimers
• acid transition 100 mg / cell per day for fibrinolysis prophylaxis
• after the start of treatment, the blood coagulation parameters are normalized within 2-3 weeks

Retinoic acid syndrome

Retinoic acid syndrome(ATRA-syndrome, differentiation syndrome, RAS - Retinoic Acid Syndrome) is a specific complication of treatment with retinoic acid of acute speakelyocytic leukemia. Developed as a result of a massive yield of leukemic communications from bone marrow.

Symptoms: Increased body temperature, fluid delay with edema and weight increase, accumulation of fluid in pleural and pericardial cavities, shortness of breath, infiltrates in the lungs. Little, renal, hepatic, or multi-capital failure develops.

Treatment of retinoic acid syndrome Only in the separation of intensive therapy - dexamethasone 10 mg every 12 hours, sometimes with the time abolition of retinic acid.

Recurrent of Promelocytic Leukoza

Uspekhi in the treatment of propelocytic leukemia by retinoic acid unfortunately not absolutely, in 20% of patients develops relapse - the return of the disease. Hematological recurrence is always preceded by molecular, therefore it is so important to control the presence of PML-RARα gene.

The generally accepted protocol of the treatment of recurrence of acute promelocytic leukemia is not:

• retinoic acid + intensive chemotherapy
• bone marrow transplantation
• gematuzumab Ozogamicin (Mylotarg)
• arsenic trioxide (as 2 O 3, TRISENOX)

Forecast

After the consolidation therapy is completed, 90% of patients are in a state of molecular remission - i.e. There is no modified PML-RARα gene. The probability of recurrence is 7.6-20%, depending on the prognostic factors.

Complete recovery is observed in 75-85% acute promelocytic leukemia.

10% of hyperlauxcitar cases are found. Along with the classic OPP, the granular promoelocytic leukemia (M3V FAB) is released with leukemic cells of the monocyte-like species, the presence of a bean-shaped nucleus and a meager azurophilic, like dust, graininess. Attachts have a sharply positive reaction and often visualize the Auer sticks when painting on myeloproquidase. Myeloid cells - Promelocytes - abnormally accumulate. They precede granulocytes and occur when they are matured on one of the stages: myeloblast-promoelocyte-myelocyte-grangulocyte.

Important! The disease develops quickly and is manifested by pronounced skin-mucous hemorrhagic syndrome. It leads to dangerous complications: hemorrhage in the brain, renal and uterine unknown bleeding. With a rapid increase in leukocytosis in peripheral blood, thrombotic complications are manifested and symptoms develop.

Signs and symptoms

Acute Promoelocytic leukemia arises due to malignant transformation and disruption of differentiation of myeloid cells, which are precursors of hematopoietic cells.

Characteristic symptoms of leukemia:

• heat;
• thrombocytopenia (lack of platelets) with bleeding, bruises and bruises;
• hazardous bleeding in DVS syndrome (disseminated intravascular coagulation);
• infections due to lack of intact leukocytes;
• anemia with rapid fatigue, weakness and shortness of breath;
• increased liver and spleen;
• at the last stages - articular pain attacks, violation of the CNS, the manifestation of lymphadenopathy.

Diagnostics

Confirm the diagnosis of cytological and cytochemical studies of bone marrow puncture.

Important. Cytogenetic or molecular agenetic analysis should show a characteristic chromosomal translocation.

• physical examination;
• primary and general blood test to identify the hemoglobin and level of erythrocytes, leukocytes and blast cells (leukelocytes leukemic);
• on biochemical analysis of blood - evaluate the indicators of kidney functions, liver, electrolytes;
• determine the blood group and the rhesus factor, oncomarkers and the presence of viral hepatitis;
• conduct a coagulogram study;
• determine how reduced fibrinogen;
• coagulogram for detecting fibrinogen, APTU, Protromina;
• ECG and echo-kg, sternum radiography, ultrasound of the abnormal organs.

Earlier, we have already written about acute myeloblastic leukemia and recommended adding this article to bookmarks.

At-risk groups

Groups are determined in accordance with the number of leukocytes:

Treatment

Complete treatment conditions:

1. Install a high-quality central catheter.
2. Transfusion therapy is carried out with sufficient quantity and quality thromboconcentrate.
3. Organizational and drug measures are complied with the prevention of infectious diseases.

Primary events after confirming the diagnosis of OPL:

• Fresh-frozen plasma, cryoprecipitate and platelet concentrate - for the prevention of coagulopathy and maintain the amount of fibrinogen\u003e 150 mg / ml and platelets\u003e 50 × 10 9 / l. This is especially important for patients with the presence of active bleeding, high leukocytosis in the blood (more / μl) and thrombocytopenia<30×10 9 /л.
• ATRA therapy immediately begins after clinical monitoring. Reveal by retinic acid syndrome (SRK) on the basis of development: fever, dysnae, waste collection, peripheral edema, infiltrates in the lungs, effusion in the pleura and / or pericardium. When confirming the syndrome, the treatment is carried out by administering dexamethasone inside the veins of 20 mg / m 2 / day - 2-3 times.
• Patients prescribe Capsules Preparation Wearanoid Firm Hoffmann-La Rosh - 25 mg / m 2 / day together with meal (10 mg x 2-3 reception). The course is 1.5 months (no more).
• Conduct chemotherapy after 4 days of receiving ATRA: cytoosar and downhole.

Important. Immediately begin chemistry with leukocytosis of more than 5000 / μl. The hemogram is carried out daily to control leukocytes, platelets and hemoglobin. According to blood test, the level of albumin, total bilirubin and fraction, urea, creatinine, K, Na, Mg is determined.

After the recovery of the hemogram indicators, the 2nd course of chemotherapy is carried out (scheme 7 + 3) and 3rd year - after complete recovery of hemopoiesis.

Important. If there is a relapse at the expense of inefficient therapy and intolerance of ATRA, then the treatment is carried out by a texide of arsenic (trisenoxide, asadin). Side effect can be manifested by differentiating syndrome, impaired heart rhythm.

In severe cases, autologous or allogenic bone marrow transplantation is used.

Forecast

Life expectancy increases with remission. The forecast for 5 years in young patients is 90%, in the older generation - 70%. Without adequate treatment, patients with OPL live just a few weeks.

Acute PromoElocitarian leukemia (OPL) is a relatively rare variety of acute myeloid leukemia (IML), for which the abnormal accumulation of transomelocytes is characterized. Compared to the IML, it is quite "young" pathology (the average age of patients is about 30-40 years old), as well as one of the most favorable and treatable forms.

Development mechanism

The first sign of acute promelocytic leukemia is hemorrhages. Most often it is bleeding, developing in field injuries, it can also be uterine, nasal bleeding or bruising. The process is accompanied by moderate thrombocytopenia.

Signs of bleeding are gradually growing. Later they are joined by symptoms of tumor intoxication. The spleen and the liver increase rarely, and the lymph nodes are practically not involved in the pathological process. Because of these signs, acute promoelocyrtar leukemia is considered "slow" leukemia.

At the beginning of the acute Promoelocytic leukemia, the red blood indicators are normal or slightly reduced, in half cases the hemoglobin level is noted above 100 g / l. The number of platelets and leukocytes is reduced.

For laboratory blood indicators, the variety of blast cells is characterized, and the majority have cytoplasmic processes similar to false glasses. In 80% of cases, leukemic cells have a large grain, and then the ailments are classified as macrogranular. In 20% of cases, fine-grained cells prevail, and this form is called microgranular. With it, leukocytosis in the blood and the exit to it of leukemic cells is observed more often.

Symptoms

Acute corrosion leukemia proceeds quickly. The main feature is bleeding with minimal skin damage, after which bruises and hemorrhage are formed, and with a weakened immunite, an infection is joined. Patients often have bleeding gums, nasal bleeding, women are abundant menstrual selection.

In this regard, anemia is developing, fatigue, weakness, the difficulty of pulmonary respiration, fever. Leukopenia leads to a decrease in immunity. In the analysis, there is a reduced content of leukocytes, platelets, erythrocytes, anomalous blass cells appear (in 10-30% of cases). Blood coagulation disorders are developing, including DVS syndrome (disseminated intravascular coagulation).

With the beginning of cytostatic therapy, the OPL symptoms retreat, the temperature may decrease the next day, and also decreases bleeding. But this will not be a sign of blood recovery - only a cytostatic effect.

Diagnostics

To determine the disease and exclusion of other forms of acute myeloid leukemia, the bone marrow and blood tissues are being studied. At the same time, a significant sign of acute promoelocytic leukemia is a large percentage of atypical blasts in samples.

The overall blood test will show anemia and severe thrombocytopenia. The cytogenetic study will reveal the translocation of long shoulders chromosomes 17 and 15 or 17 and 11. Also, the method of polymerase chain reaction is tested for PML / RARA genes or PLZF / RARA. In addition, the disease indicates the excessive presence in the twist cells of peripheral blood Taurus Auer.

Treatment

Requires the participation of specialists of various profiles, as well as a high-quality laboratory and transfusiological service. If there is a suspicion of ops, the prevention of coagulopathy is first carried out (the introduction of freshly frozen plasma of cryoprecipitate and platelet concentrate), which is especially important in active bleeding or laboratory signs of coagulopathy. At the first symptoms of this form of leukemia, ATRA's therapy is carried out, even before confirming the diagnosis at the cytogenetic level. In addition, on the fourth day of receiving ATRA or immediately (depending on the indications) chemotherapy is carried out.

After the intensive phase, supporting therapy is assigned, which includes a combination of chemotherapy and ATRA. The course lasts 24 months. If ATRA therapy is ineffective, the patient is poorly tolerated or comes recurrence, arsenic trioxide is recommended.

Forecast

Currently, the life expectancy prognosis in this form of leukemia in 70% of cases is 12 years old without exacerbations. Previously, this form of leukose was considered one of the hardest and led to the death of the patient during the day. But after the invention of drugs effective at a given ailment, it has become one of the most curable malignant pathologies.

In 80% of cases, treatment causes improvement, increasingly resistant. Without treatment, the lifespan of a patient with acute speech-specific leukemia is several weeks or days.

This article is placed exclusively in cognitive purposes and is not a scientific material or professional medical council.

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Acute promoelocitary leukemia

• Treatment of acute promelocytic leukemia

What is acute promelocytic leukemia

Acute PromoELCitarian leukemia - OPL (MW on the Fab classification) is a rather rare variant of acute leukemia, its share accounts for no more than 10% among all acute non-lumfoblastic leukemia. A bright clinical picture and morphological features of the disease allowed Hillestad in 1957, long before the creation of the Fab classification, to highlight it as a separate form of acute leukemia.

What provokes acute promelocytar leukemia

The cause of acute promelocytic leukemia is the chromosomal translocation T (15; 17) leading to the compound of the retinic acid receptor gene (RAR-Alf) with the PML tumor suppressor genome, the product of which forms specific matrix-associated nuclear PML cores. Cytogenetic analysis reveals in the cells of patients with APL translocations, exciting chromosomes 15 and 17. This specific translocation q (15; 17) (Q22; Q11.2) was not depressed in any other type of myelocyte leukemia or other malignant disease. Translocation (15; 17) interrupts the Raralph gene and part of it merges with the PML locus chromosome 15, forming a chimeric fusion protein PML-RARA. The PML gene encodes a protein containing "zinc fingers", and may be an important transactional transcriptional factor in the process of differentiation of granulocytes.

It is assumed that chimeric PML / RAR-A protein is inactivated by the dominant-negative mechanism apoptogenic function of the normal PML protein, forming heterodimers with it. Apoptosis induction mechanisms with hyper-expression PML are not entirely clear. Expression of chimeric protein PML / RAR-A, causing inactivating the normal PML protein function, as well as the BCR / ABL restructuring, leads to changes in the regulation of the cell cycle, and to partial blocking of apoptosis induction (it should be noted that, unlike BCR / ABL, the restructuring PML / RAR-A also calls the differentiation unit). As a result of the multidirectional nature of the impact of hybrid molecules, cells appear with increased proliferative potential and simultaneously with resistance to negative regulatory signals and / or adverse environmental conditions. It is assumed that such changes may be sufficient for the development of at least some forms of hemoblastosis. And, indeed, the BCR / ABL or PML / RAR-A restructuring is often the only genetic changes detected by respectively with chronic myeloid and acute speech leukemia.

A plurality of leukemia-specific genes was identified, but as a result of the merger of retinoid acid receptor genes (RAR Alfa) and the leukemiasis gene, a new interesting example of such genes arose, leading to the occurrence of acute myelocyte leukemia (APL).

Three different chimeric PML-RARA hymers, long (L), medium (M) and short (S) are the result of a different type of splicing of the PML gene exon when splicing a translogenated RARA gene. Trans-retinoid acid (ATRA) leads to the recovery of the patients with APL, allowing to assume that a hormone-binding protein is formed during translocation. The chimeric PML-RARA protein seems to block the differentiation of myeloid cells, and the ATRA processing removes this effect.

The genes involved in the pathological process with APM apparently lead to structural changes in the normal gene (protoncogencogen), and its protein product, acting on the host cell, causes malignant rebirth. This protein is normally involved in proliferation and differentiation processes.

Molecular and clinical studies of APL patients detect that patient cells can begin differentiation under the influence of ATRA. Translocation detection 15; 17 gives a good forecast. With ATRA therapy, the RARA gene is 2-3 weeks, and then disappears; After recovery, the normal structure of the RARA gene is restored. The use of ATRA to restore the ripening of cells and their differentiation into granulocytes leads to a recovery of 85-90% of patients. This is the first example of the treatment of human cancer.

In some cases, patients with APL, RARA gene can be involved in other translocations and restructuring. Two patients were revealed, one with a perestroika 11; 17, and the other with translocation 15; 17, but without restructuring the PML gene. At both patients, ATRA's therapy did not affect. Observations about the need for sites in front of the PML gene to interact with ATRA increases the need for the Molecular Diagnostics of the APL before assigning or continuing atra therapy. Chimeric PML protein PML-RARA is clinically convenient for diagnosis and observation in the treatment of APL.

Pathogenesis (what is happening?) During acute promelocytic leukemia

Symptoms of acute promelocytic leukemia

Acute promelocytar leukemia notes a very rapid flow. It is inherent in pronounced intoxication, bleeding and hypoofibrinogenemia (decrease in blood coagulation) due to DVS syndrome (disseminated intravascular coagulation syndrome). Lymph nodes, liver and spleen are most often increasing. In the blood test: anemia, pronounced thrombocytopenia, in the bone marrow, and usually a large percentage of atypical blasts is detected in peripheral blood. The cores of these leukemian cells in the blood often have a two-grate form, even more often their form is difficult to distinguish between abundance of grainability in the cytoplasm. The immediate cause of the death of the patient most often has hemorrhage into the brain.

Acute proposal blood leukemia is characterized by an extraordinary malignancy of the process, the rapid increase in severe intoxication, severe hemorrhagic syndrome, leading to hemorrhage into the brain and to the death of the patient.

Acute myeloblastic leukemia is characterized by a progressive course, progressive intoxication and fever, severe anemia, moderate intensity of hemorrhagic manifestations (a tendency to bleeding), private ulcerative-necrotic lesions of mucous and skin.

Diagnosis of acute promoelocytic leukemia

Treatment of acute promelocytic leukemia

Treatment of acute promoelocytic leukemia may be complicated by two life-threatening states - DVS syndrome and retinoid syndrome.

The DVS syndrome is due to death under the action of cytostatics of leukemic cells and massive flow from them into the blood of probeagulant. In many cases, effectively treating heparin. The deficiency of coagulation factors compensate for cryoprecipitate and freshly frozen plasma.

Tertinoin, in contrast to cytostatics, contributes to the differentiation of leukemic cells. Treatment of acute speech-specific leukemia to them avoids bleeding, but causes leukocytosis.

The manifestations of retinoid syndrome include fever, shortness of breath, pleural effusion and pericardial effusion, arterial hypotension. And leukocytosis itself, and its consequences can be prevented by the appointment of cytostatics.

The mortality of the DVS-syndrome and the retinoid syndrome in the isolated assignment of cytostatics and tertinin reaches 15-20%. The simultaneous purpose of cytostatic and tertinine reduces mortality, preventing the development of both syndromes.

What doctors should contact if you have acute promelcytar leukemia

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Opportunities for modern therapy of acute Promoelocytic Leukoza

Acute PromoElyocytic leukemia - OPL (M3 according to the Fab classification) is a rather rare variant of acute leukemia, its share accounts for no more than 10% among all acute nonlimfoblastic leukemia. A bright clinical picture and morphological features of the disease allowed Hillestad in 1957, long before the creation of the Fab classification, to highlight it as a separate form of acute leukemia.

There are two main morphological options for OPL. In a typical M3, which accounts for 75-85% of all cases, leukemic cells have a characteristic morphology - a blade monocytoid nucleus, an abundant cherry-purple graininess in a cytoplasm, often superimposed on the core, a large amount of Auer sticks lying on beams. In 15-25% of cases, the so-called variant M3 (M3V - Variant) is found with an atypical morphology of leukemic cells, in which the graininess in the cytoplasm is represented by very small granules, distinguishable only for electron microscopy, a bean-like core or two-sighted, auer's sticks and they do not form Puchkov. Such morphology is often the cause of difficulties, and sometimes errors in the diagnosis.

For a typical OPP, a low number of leukocytes is characterized - less than 5 € 10 9 / l, and often less than 1 € 10 9 / l, while at variant M3, as a rule, a high leukocytosis is observed - 20.10 9 / L - 200 - 10 9 / l.

In 80%, with variant M3, expression of leukemic cells at the same time, CD34 and CD2 antigens and CD2 are found, with typical OPP pathological cells or do not express these antigens or express only one of them.

The bone marrow with ops can be hyper-, normo or hypoclececa. The percentage of pathological cells in the bone marrow is usually high, in the blood, their large number appears only with high leukocytosis.

Extramedullary foci for OPL is uncharacteristic, but recently the increase in cases of damage to the central nervous system is noted. In this regard, the question of the possible role of completely trans-retinic acid (ALL TRANS RETINOIC ACID - ATRA) in the development of this complication, since in the process of the resulting ATRA differentiation and ripening of leukemic cells, there is an increase in their migration properties and enhancing the expression of adhesion molecules on their surface.

The most striking clinical symptom of OPL is hemorrhagic diathesis, which is observed by the time of diagnosis in 90% of patients and without appropriate therapy is very often complicated by hemorrhages in the brain, which, according to various authors, is the cause of death 8-47% of patients.

In the pathogenesis of hemorrhagic syndrome, intravascular coagulation, elevated fibrinolysis and thrombocytopenia play the main role. In the breakdown of the Promelocytes in the blood, a large number of proteolytic enzymes are emitted - the process is figuratively called the "proteolytic explosion". Admission to the blood of elastase, plasminogen activators, lysosomal enzymes and stimulants of platelet aggregation causes coagulation and helps to increase the level of cytokines and tumor necrosis factor, which have a damaging effect on the endothelium of the vessels, which in turn contributes to the formation of microtrombov. The process of disseminated intravascular coagulation (DVS syndrome) is developing, the most terrible symptom of OPL.

The secondary fibrinolysis arising from the appearance of thrombinomes causes the consumption of fibrinogen and other coagulation factors, which simultaneously with thrombocytopenia, due to both the leukemous process, and the consumption of platelets in the formation of microtrombov, leads to the development of pronounced bleeding, often with gastrointestinal, profuse uterine, nasal bleeding and intracranial hemorrhages. Often, hemorrhagic diathesis is sharply enhanced with the beginning of cytostatic therapy causing the death of leukemic cells, therefore, before opening the therapeutic effect of fully trans-retinic acid, OPL treatment was recommended to begin with the introduction of heparin to prevent intravascular blood coagulation, transfusion of freshly frozen plasma and platelets before appointing cytostatic drugs.

Before the appearance in the medical arsenal of anthracycline antibiotics, the life of the patient of the OPP calculates days, at best, 2-3 weeks. The appearance in the therapy of the sharp leukemia of the Downorubicin, and soon after this and the cytosine-arababyida translated the OPL from the rjder of the most unfavorable to the group prognostically favorable both by the number of remission obtained and their duration: from 60 to 80% of full remissions with 5-year survival 35 -45% of patients.

The current stage of the OPL therapy is associated with deciphering molecular genetic changes in the retinoic acid receptor gene in the hematopoic cells of the myeloid series arising from the OPL and underlying the pathogenesis of the disease. In the 70s, as a result of J.ROWley's work, it was shown that with the OPL, the loss of part of the long shoulder of the chromosome 17 is always detected and that in most cases it is associated with the presence of reciprocal translocation between the long shoulders of chromosomes 15 and 17. To date, it is confirmed that changes in chromosome 17 are practically all patients with OPL. Translocation (15; 17) occurs about 90% of patients, in other cases the translocation (11; 17) is most often detected, less often - (5; 17). Approximately the third of the patients with op floor are found complex chromosomal aberrations with chromosomes 15, 17 and one more or more chromosomes. Sometimes a changed chromosome 17 is involved in translocations (15; 17), most often in the form of isochromosomes. In those rather rare observations, when ordinary cytogenetic methods cannot identify characteristic chromosomal rearrangements, they are detected using the FISH method or polymerase chain reaction with reverse transcriptase (RT-PCR), which allows to determine the presence of the appropriate transcript, for example, PML-RARA formed with T (15; 17).

In 1987 it was found that on the long shoulder of the chromosome 17 (17q21) there is a gene encoding one of the retinoic acid receptors - RARA. This receptor is a member of the family of receptors that bind retinoids with DNA cells. Retinoids - Vitamin A derivatives play a crucial role in human and animal organism: they participate in the regulation of the vision function, is necessary for the development of the embryo, regulate the proliferation and differentiation of the cells of myeloid series. The insufficient receipt of retinoids into the cell violates its ripening, the ability to perform its function and expose natural cell death (apoptosis), which leads to the accumulation of immature cells of myeloids in the bone marrow. Retinoides also suppress angiogenesis induced by tumor cells. When Vitamin A enters the body, it is subjected to metabolism in the liver, turning into a completely trans-retinue acid, which, with further metabolism, is converted into 9-cis-, 11-cis and 13-cis-retinic acids. These acids are associated with retinue receptors and are then carried out in the cell core, providing the regulation of differentiation and maturation signals. In the plasma of a healthy person, trans-retinic acid is in associated with proteins, its concentration is 10-9 mol / l.

With any of the translocations characteristic of OPL, a fusion gene is formed with the RARA retinuic acid receptor gene located on the long shoulder of chromosome 17, and the gene localized on the chromosome involved in the translocation occurred. The genes with which the RARA gene is associated with the relevant translocations, are regulators of the most important stages of growth, differentiation and proliferation of cells.

When translocations (15; 17), the part of the RARA gene is merged with a part of the PML chromosome located on the long shoulder 15, and the PML-RARA mens gene is formed. The PML gene (PROMYELOCYTIC LEUKEMIA GENE, named because, was first discovered in patients with OPL) expressed in all studied cell lines, it is an inducer of cell differentiation and cell growth suppressor. OPLs with translocation (15; 17) refers to either a typical M3 or M3V.

In cases of OPL with translocation (5; 17), the NPM-RARA mens gene is formed. NPM gene located on the long shoulder of chromosome 5 (Nucleophosmin Gene), - nuclear phosphoprotein, which is part of the cell transport system. It regulates the connection of nuclear chromatin with other nuclear substances. OPP with T (5; 17) Morphologically atypical - no abundance of Auer sticks, granules less, the kernel is often rounded, and not two-sighted. This option ops reminds m2. The unit observations of the OPL with the indicated translocation are still described.

Translocation (11; 17) is in two versions - T (11; 17) (Q13Q21) and T (11; 17) (Q23Q21). On the long shoulder of chromosome 11 in the Q13 area there is a NUMA gene - Nuclear Matrix Mitotic Apparatus Protein. This gene is involved in the final phase of mitosis and in the formation of the nucleus of subsidiaries. At t (11; 17) (Q13Q21), the NUMA-RARA mens gene is formed. OPL with such translocation is described in 1996 at a 6-year-old boy. Morphologically similar to the usual op.

On the long shoulder of chromosome 11 in the Q23 area there is a RLZF gene - ProMyelocytic Leukemia Zink Finger Gene. This gene is expressed in many tissues, especially in the central nervous system and hematopoietic precursors, suppresses cell growth, inhibits myeloid differentiation, contributes to the long life of cells, by increasing the expression of SDL-2. At T (11; 17) (Q23Q21), the PLZF-RARA mens gene is formed. Morphologically op floor with such a translocation of atypical - the granules are rare, the Auer sticks are not located beams, the core of the beanoid, and not two-sighted (morphologically - there is something mean between the M2 and M3 options). The diagnosis is based almost exclusively on cytogenetic research data. This option is characterized by expression on CD56 antigen pathological cells.

Another generator, STAT5B, localized in the Q21 region of chromosome 17, is described, which can also form a fusion gene with RARA genome in cases involving a changed chromosome 17 translocation.

In the natural state of RARA is due to its suppressors, released by contact with the retinoides entering the organism. In the formation of a junk gene, its connection with the suppressors is significantly more durable than the connection of unchanged RARA, and does not break under the influence of physiological doses of fully trans-retinic acid. As a result, there is a blocking of transcription signal from the cells sensitive to the retinoid elements to its kernel. When taking the retinol derivatives - cis-retinoic acids or completely trans-retinic acid - their blood concentration is created, as a result of which this unit is eliminated and the normal signal transmission is restored. 100 genes are already studied, which are activated, and 69, which are repressed under the influence of ATRA.

The use of completely trans-retinic acid, which marked a new era in op floor therapy, was not a random happy discovery. Since the late 70s, work was carried out to study the effect of retinoids on tumor cells and was shown the ability of 13-cis-retinoic and completely trans-retinic acids to suppress growth and cause cell differentiation in cell lines cultures from patients with OPL. Then several reports were published about the use of 13-cis-retinic acid for the treatment of OPLs with inconclusive results and, finally, in 1986, in China, a completely trans-retinic acid was successfully applied to the treatment of 6 patients with OPL. In 1988, the same authors published a message about the treatment of ATRA already 24 patients with op. All have been obtained full remission. After this message, the use of ATRA has become quickly distributed in all countries of the world.

To date, hundreds of patients with PPLs have been treated with completely trans-retinoic acid, the optimal daily dose and the necessary duration of therapy, efficiency in various OPL variants, side effects arising from ATRA, and their tools to eliminate themselves are determined. Laboratory studies have shown that in the cultivation of leukemic cells of patients with OPLs in the presence of a completely trans-retinic acid at a concentration-10 -7 mol / l, differentiation and maturation of these cells occurs. In the human body, this concentration of ATRA is achieved by a 45 mg / m 2 reception.

The clinical studies started after the first reports on the effectiveness of completely trans-retinic acid confirmed that the appointment of 45 mg / m2 ATRA per day for 45-90 days allows to obtain remission in 95% of patients. It was soon established that ATRA is highly effective in the treatment of patients with OPL with T (15; 17) and the formation of the chimeric gene PML-RARA, in cases of T (5; 17), at which the NPM-RARAA gene is formed and at t (11; 17 ) (Q13q21), which is the result of the NUMA - RARA mens gene. At the same time, it is not effective at the OPP with T (11; 17) (Q23Q21), the result of which is the formation of the PLZF-RARA gene. Patient cells with this option of OPLs in culture could be differentiated only at ATRA concentrations, highly toxic for humans.

As a result of clinical studies, it was found that the effectiveness of therapy affects the number of leukocytes before treatment. The number of leukocytes is more than 5 € 10 9 / l at the time of the diagnosis is considered a poor prognostic sign - the percentage of remissions in this form is the same as with an OPL with a low number of leukocytes, but the frequency of severe complications using completely trans-retinic acid (ATRA development -Sinter) and the frequency of relapses above.

The accumulated experience on the use of ATRA in OPL therapy showed that its use does not cause an increase in hemorrhagic diatic, which in previous years very often complicated the conduct of cytostatic therapy. The treatment of ATRA is not accompanied by a period of cytostatic aplasia of the bone marrow, since the mechanism of the resulting ATRA remission is the induction of differentiation and ripening of pathological cells. In favor of such a mechanism of action, the detection of patients with phenotypically unusual cells expressing antigens of mature and immature granulocytes, as well as the detection of the Auer and T (15; 17), and the detection of the auer and T (15; 17) in morphologically mature granulocytes at the same time. The use of ATRA, however, is accompanied by a number of side effects, some of them are heavy and dangerous, but in most cases eliminate fairly simple methods. In a number of patients, especially in cases with initial leukocytosis, a symptom complex is developing, called retinoic acid syndrome, or ATRA syndrome. The initial symptoms are the rapid increase in the number of leukocytes and the rise of body temperature to 37.5-38.5. Often, dry skin, mucous membranes, headache appear at the same time. If immediate treatment is not prescribed, respiratory failure (pulmonary distress syndrome) is developing, it may appear in pleural cavities and pericardial cavities, infiltrates from ripening neutrophils are formed in pulmonary tissue, renal failure, hypotension can be joined. The causes of the development of this syndrome, in all likelihood, are the release of vasoactive cytokines, strengthening the migration properties of ripening granulocytes and an increase in the expression of adhesion molecules on their surface. Without treatment, there may be a fatal outcome, at the same time, the purpose of dexamethasone is 10 mg intravenously 2 times a day at the first signs of this syndrome (an increase in body temperature and a rapid increase in the number of leukocytes) removes all the symptoms. Cytostatic therapy also suppresses the manifestation of ATRA-syndrome if it is assigned simultaneously or 3-4 days after the start of the treatment of ATRA, the development of retinic acid syndrome, as a rule, is not noted.

Shortly after the first success in the treatment of OPLs completely trans-retinoic acid, it turned out that the average duration of remission without the use of chemotherapy is 3-3.5 months, even with the continuation of ATRA. This led to the gradual development of modern combined therapy programs, including ATRA and cytostatic drugs, primarily anthracycline, to induce remission, a mandatory stage of consolidation of remission and maintaining therapy with cytostatic preparations and periodic courses ATRA.

In a large randomized study, undertaken by the European Group on the Study and Treatment of OPP and included 413 patients, it was shown that the frequency of remissions is the same when used to induce remission only ATRA and ATRA in combination with chemotherapy (95 and 94%, respectively), but recurrence frequency on For 2 years of observation, the surveillance was significantly higher in the group obtained by chemotherapy after ATRA (16% with a sequential use of drugs, 6% - while simultaneously). In addition, half of the patients who received for the induction of remission only ATRA developed a retiname syndrome of varying severity, demanding the appointments of chemotherapy and dexamethasone and the cause of death 5 patients, while in the group received chemotherapy from 3-4th day after ATRA therapy, severe manifestations of retinoid syndrome was not. Further randomization in the appointment of supportive treatment also showed the explicit advantages of the combination of ATRA with chemotherapy: for 2 years, recurrences have evolved in 25% of patients who received only chemotherapy, in 13.5% of the ATRA and in 7% of the combined treatment. These data was confirmed by the results of Italian and Spanish cooperative groups, in which, in addition, the lack of a fundamental difference in the results during consolidation only by anthracycline (in their studies it was an izadarbitsin and mitoxantrone) or anthracycline in combination with cytosine-arabinoside. Under the induction of remission with a combination of ATRA and Idarubicin, consolidation and then for 2 years of maintenance therapy with methotrexate and 6-mercaptopurine with a periodic addition of ATRA 3-year-old, non-periodic survival accounted for 90% in the group of patients receiving consolidation by anthracycline in combination with cytosin-arabinoside, and 86% in the group, where consolidation was carried out only by anthracycline.

Recently, the liposomal form of fully trans-retinoic acid was introduced into clinical practice, which is introduced intravenously. Treatment of a large group of patients showed good results: Full remissions were obtained in 91% of primary and in 69% of patients with recurrent OPL.

Since 1986, along with ATRA, for the first time, arsenic trioxide is used for the first time in China, AS2O3. Recently published treatment results of a large group of patients showed its high efficiency: 81% of complete remissions in the group of children, in the 2/3 of which was recurrence of OPL; 65% of patients lived without recurrence of 7 years, 5 of them gave birth to healthy children. ATRA and arsenic in adult patients with repeated recurrences of OPPs made it possible to obtain 65% of complete remissions and in 53% of patients - 7-year-old unidentified survival. In Europe, there are currently data on the treatment of AS2O3 only a small number of patients. Recently, there have been reports of cardiotoxicity of the drug and even a sudden heart stop in 3 patients during the treatment of AS2O3.

Attempts to treat arsenic trioxide patients with T (11; 17) (Q23q21) - genuine PLZF-RARA turned out to be equally unsuccessful as the treatment of this option of OPLs completely trans-retinoic acid. At the same time, the ATRA combination with chemotherapy and, as showed some observations, with a granulocytic-macrophageal colonistimulating factor can lead to the achievement of remission and at the same time op.

The successes of modern therapy of OPP - obtaining remissions, including molecular, and long-term survival, in 80-90% of patients make it possible to talk about the fundamental healing of this version of leukemia. Currently, allogenic bone marrow transplantation or peripheral stem cells for these patients is considered to be shown only in the second or subsequent remission.

The ability to achieve remission without a severe period of cytostatic myelosuppression and the associated danger of infectious and hemorrhagic complications made it possible to carry out full treatment of patients of any age. In published observations, patients are mentioned over 70 and even 80 years, which managed to be treated in full and obtain a long-term remission. We present our own observation.

Patient T., 77 years old, entered the department of chemotherapy hemoblastosis RONTS RAMN 10, 2000 with complaints of pronounced weakness, bleeding of gums and the education of "bruises" on the skin of the limbs. These complaints appeared, gradually enhanced, 2 weeks before entering the clinic. In the blood test made in the clinic, anemia and leukopenia were found. On the eve of hospitalization in the patient was fainting. During the inspection, the pallor of the skin, moderate shortness of breath, tachycardia is up to 100 strikes in 1 min, point and separate drain hemorrhages on the skin of the legs and arms. Peripheral lymph nodes, liver, spleen did not palpate. Blood test February 11: hemoglobin - 71 g / l, red blood cells - 2.5.1012 / l, leukocytes - 0.41 · 10 9 / l, platelets - 10 € 10 9 / l. Myelogram February 11: the bone marrow is moderately cellular, 90.2% are blast cells, mainly the meso and microform with incorrect outlines of the cytoplasm, twisted with bladed nuclei. In the cytoplasm, the coarse azurophilic graininess is determined, the Auer sticks are located singly and beams. Erythitoid and granulocyte sprouts are sharply oppressed, megakaryocytes are single in the drug. With a cytochemical study of the reaction to peroxidase and Sudan, black is sharply positive in 100% cells, the PAS substance is determined in a diffuse form in 100% cells, the reaction to nonspecific Esterase is negative. Acute Promoелоlocitarian leukemia - M3 was diagnosed.

On the same day, the patient began the treatment of ATRA (Preparation "Wearanoid" pharmaceutical company "F. Heffmann-la Roche Ltd.") at 45 mg / m2 (70mg) per day, transfusion of erythrocytic mass and platelets. The next day, the gums of bleeding stopped and skin hemorrhages quickly began to disappear. On the third day of treatment, on February 14, the number of leukocytes increased to 2.14 € 10 9 / l, platelets - up to 61 € 10 9 / l, February 15 - leukocytes 4,55 · 10 9 / l, platelets 116 · 9 / l.

With a standard cytogenetic study (Laboratory of Citogenetics of the RONTS) chromosomal aberrations, did not detect chromosomal aberration, but the characteristic picture of the blood, the morphological features of the blast cells typical for the m3 of the variant of acute leukemia, and the pronounced effect of weightside with a rapid increase in the number of leukocytes did not cause doubt about the correctness of the diagnosis. A cytogenetic study was taken by the FISH (Laboratory of Citogenetics Laboratory of the SSC RAMN), at which T (15; 17) was detected.

On the third day of treatment, Weshanoid in the patient appeared shortness of breath and fine-ventricular wheezing in the lungs without radiographic changes. Despite the lack of a temperature reaction, given the rapid increase in the number of leukocytes, the specified symptoms were regarded as the beginning of the retinoid syndrome, and the treatment with dexamethasone is 10 mg 2 times a day intravenously. Within 3 days, shortness of breath gradually stopped, and dexamethasone was canceled. From February 16 to February 22, at the same time with the reception of the Vesanoid patient, a course of treatment with a regulation of 50 mg / m2 (80 mg) per day 1-3 days and cytosine-arabinoside of 100 mg / m2 per day 1-7 days. Treatment suffered satisfactoryly, but on February 27, a productive fine-point reddish rash appeared on the limbs, forced to interrupt the reception of the weightside and resume treatment with dexamethasone, which led to the disappearance of rashes within 3 days. After a period of cytostatic barcitopenia in myelogram on March 6, 2.4% of blast cells were found at a moderately cell bone marrow.

Thus, as a result of the treatment of ATRA and the sole course of chemotherapy "3 + 7", a complete remission has been achieved in the patient.

Considering the short-term treatment of Weavanoid, the drug was appointed again during the consolidation course of remission.

Consolidation was carried out according to the "2 + 5" scheme with the same drugs in the same daily dosages as the induction course of therapy. After graduating from a consolidation rate in accordance with the European Protocol, providing for only one consolidation course for patients over 65 years old, the patient receives supportive treatment: 6 mercaptopurine of 90 mg / m2 per day, methotrexate at 15 mg / m2 1 time per week and every 3 Mes Wearanoid 45 mg / m2 per day for 2 weeks. During the period of receiving weights, the patient receives cytostatic drugs in full doses, during the rest of the time due to the doses of drugs developing in one degree or another, the dose of drugs is often reduced. Despite this, the remission remains to date throughout the year (in myelogram with a cellular bone 0.8-1.2% of blast cells), the patient is active, willingly move, performs homework, comes out of the house and even dances (in 78 years!).

This example convincingly demonstrates the possibilities of modern OPL therapy with its correct and timely conduct. Completely trans-retinic acid makes it possible to quickly eliminate the manifestations and danger of the development of the DVS-syndrome, cytostatic therapy is satisfactory, including the elderly patients, its use in the period of supportive treatment helps to maintain remission even with a forced reduction of doses of cytostatic preparations.

OPP is the first of the sharp leukemia, in which the decoding of the pathogenesis of the disease led to the creation of pathogenetic differentiating therapy, which radically changed the fate of patients. It may be possible to create precisely such therapy will be the next step in the treatment of other options for sharp leukemia.

2. Specchia G., Mestice A., Carluccio P. et al. Biological Features of CD34 + CD2 + Acute ProMyelocytic Leukemia. Blood 2000; 96: ABSTR 495.

3. Warrell R.P., DE THE H., WANG Z.-Y., DEGOS L. Acute ProMyelocytic Leukemia. N ENGL J MED 1993; 329: 177-89.

4. Kantarjan H.M., Keating M.J., Walters R.S. et al. Acute ProMyelocytic Leukemia: MD Anderson Hospital Experience. Am J Med 1986; 80: 789-97.

5. Cunningham I., GEE T.S., Reich L.M. et al. Acute ProMyelocytic Leukemia: Treatment Results During A Decade At Memorial Hospital. Blood 1989; 73: 1116-22.

6. RODEGHIERO F., AVVISATI G., CASTAMAN G. ET AL. Early Deaths and Anti-Hemorrhagic Treatment In Acute ProMyelacytic Leukemia: A Ginema Retrospective Study in 268 Consecutive Patients. Blood 1990; 75: 2112-27.

7. Gouault-Heilmann M., Chardon E., Sultan C. et al. The Procoagulant Factor of Leukemic ProMyelocytes. Br j hamat 1975; 30: 151-8.

8. Tallman M.S., Kwaan H.c. ReaSsessing The Hemostatic Disorder Associated with Acute ProMyelocytic Leukemia. Blood 1992; 79: 543-53.

9. MAYER R.J., Schiffer C.A., Peterson B.A. et al. Intensive PostRemission Therapy in Adults with Acute Nonlymphocytic Leukemia, a Progress Report from the Calgb. Semin oncol 1987; 14 (Suppl 1): 25-31.

10. Head D.R., Kopesky K., Hewlett J. et al. SURVIVAL WITH CYTOTOXIC THERAPY IN ACUTE PROMYELOCYTIC LEUKEMIA: A SWOG REPORT. Blood 1991; 78 (Suppl): ABSTR 268A.

11. GOLOMB H.M., ROWLEY J., VARDIMAN J. ET AL. Partial Deletion of Long Arm of Chromosome 17: a Specific Abnormality In Acute ProMyelocytic Leukemia? Arch Intern MED 1976; 136: 825-8.

12. ROWLEY J., GOLOMB H.M., DOUGHERTY C. 15/17 Translocation: A Consistent Chromosomal Change in Acute ProMyeloocytic Leukemia. Lancet 1977; 1: 549-50.

13. Grimwade D., Biondi A., Mozziconacci M.-J. et al. CHARACTERIZATION OF ACUTE PROMYELOCYTIC LEUKEMIA CASES LACKING THE CLASSIC T (15; 17): Results of The European Working Party. Blood 2000; 96: 1297-308.

14. Mattei M.G., Petkovich M., Mattei J.F. et al. Mapping of the Human Retinoic Acid Receptor to the Q21 Band of Chromosome 17. Hum Genet 1988; 80: 186-8.

15. Sainty D., Liso V., Head D. et al. A New Morphological Classification System for Acute ProMyeloCytic Leukemia Distinguishes Cases With Underlying Plzf / Rara Gene Rearrangements. Blood 2000; 96: 1287-96.

16. Wells R.A., Hummel J.L., DE KOVEN A .ET AL. A New Variant Translocation In Acute ProMyeloocytic Leukemia. Leukemia 1996; 10: 735-41.

17. ARNOULD C., Philippe C., Bourdon V. et al. The Signal Transducer and Activator of Transcription Stat5B Gene Is a New Partner of Retinoic Acid Receptor A in Acute ProMyeloCytic-like Leukemia. Hum Mol Genet 1999; 8: 1741-9.

18. Liu T., Zhang J., Tao J. et al. Gene Expression Networks Underlying Retinoic Acid-Induced Differentiation of Acute ProMyelocytic Leukemia Cells. Blood 2000; 96: 1496-504.

19. Breitman T.R., Selonick S.E., Collins S.J. INDUCTION OF DIFFERENTIATION OF THE HUMAN PROMYELCYTIIC LEUKEMIA CELL LINE BY RETINOIC ACID. PROC NATI ACAD SCI USA 1980; 77: 2936-40.

20. Huang M.E., Ye Y.c., Chen S.R. et al. All-TRANS-RETINOIC ACID WITH OR WITHOUT LOW DOSE CYTOSINE ARABINOSIDE IN ACUTE PROMYELOCYTIC LEUKEMIA: Report of 6 Cases. Chin Med J 1987; 100: 949-53.

21. Huang M.E., Ya Y.c., Chen S.R. et al. Use of All-TRANS-RETINOIC ACID IN THE TREATMENT OF ACUTE PROMYELCYTIIC LEUKEMIA. Blood 1988; 72: 567-72.

22. Elliott S., Taylor K., White S. et al. PROF OF DIFFERENTIATIVE MODE OF ACTION OF ALL-TRANS RETINOIC ACID IN ACUTE PROMYELCYTIC LEUKEMIA USING X-LINKED CLONAL ANALYSIS. Blood 1992; 79: 1916-9.

23. Frankel S.R., Eardley A., Lauwers G. et al. The "Retinoic Acid Syndrome" in Acute ProMyelocytic Leukemia. ANN INTERN MED 1992; 117: 292-6.

24. Warrel R.P., Frankel S.P., Millet W.H. et al. All-TRANS RETINOIC ACID FOR REMISSION INDUCTION OF ACUTE PROMYELCYTIC LEUKEMIA: Results of New York Study. Blood 1992; 80 (Suppl), ABSTR 360A.

25. Fenaux P., Chastang C., Chevret S. et al. A RANDOMIZED COMPARISON OF ALL TRANS-RETINOIC ACID FOLLOWED by Chemotherapy and Atra Plus Chemotherapy and Role of Maintenance Therapy In Newly Diagnosed Acute ProMyeloocytic Leukemia. Blood 1999; 94: 1192-200.

26. Sanz M., Lo Coco F., Martin G. et al. Definition of Relapse Risk and Rile of NonanthracyCline Drugs for Consolidation in Patients with Acute ProMyelocytic Leukemia. Blood 2000; 96: 1247-53.

27. Douer D., Santillana S., Adamson P. et al. Efficasy of Intravenous Liposomal All-Trans-Retinoic Acid In The Treatment of Acute ProMyelocytic Leukemia. Blood 2000; 96: 722a-3A.

28. Jun M., Guoqiang X., Guang Y. et al. Clinical Observation of AS2O3 Safety In The Treatment of Pediatric Patients with Acute ProMyelocytic Leukemia. Blood 2000; 96 (11): ABSTR 3119.

29. Jun M., Jiwei L. Clinical Study on ATRA Plus AS2O3 in The Treatment of Refractory Acute ProMyeloCytic Leukemia. IBID. ABSTR 3120.

30. Ohnishi K., Yoshida H., Takeshita A. et al. ARSENIC TRIOXIDE THERAPY INDUES PROLONGATION OF THE QT INTERVAL AND VENTRICULAR TACHYCARDIA IN ACUTE PROMYELCYTIC LEUKEMIA. IBID. ABSTR 3125.

31. WESTERVELT P., BROWN R., ADKINS D. ET AL. Sudden Death Among Acute ProMyelocytic Leukemia Patients Treated with Arsenic Trioxide. IBID. ABSTR 3127.

32. Jansen J.h., Ridder M.C., Geertsma W.M. et al. Complete Remission of T (11; 17) Positive Acute ProMyelocytic Leukemia Indied by All-Trans-Retinoic Acid and Granulocyte Colony-Stimulating Factor. Blood 1999; 94: 39-45.

RCRZ (Republican Center for Health Development MD RK)
Version: Clinical Protocols MOR RK - 2015

Acute Promoelocytar Lakes (C92.4)

Oncohematology

general information

Short description

Recommended
Expert Council
RGP on PFV "Republican Center
Health Development »
Ministry of Health
and social development
Republic of Kazakhstan
from July 9, 2015
Protocol No. 6.

Definition:
Acute promoelocytic leukemia - a variant of acute myeloid leukemia, which is characterized by an abnormal accumulation of one of the types of myeloid cells - promelocyte. In turn, Promoelocytes are the precursor cells of granulocytes arising at one of the stages of their maturation (myelocytes - melocytes - granulocytes).

Phenotypic characteristic of promelocytes, with op floor

Protocol name:Acute promoelocytar leukemia in adults

Protocol code:

ICB -10 code:
C92.4 - Promoelocitary leukemia

Protocol development date:2015 year.

Abbreviations used in the protocol:
* - Preparations purchased as part of one-time importation
AG - arterial hypertension
Hell - blood pressure
Alat - Alaninotransferase
Asat - Aspartataminotransferase
HIV - human immunodeficiency virus
GGTP - GammaglutamilTransPeptidase
ELISA - immunoformal analysis
CT - Computer Tomography
LDH - lactate dehydrogenase
MDS - myelodsplastic syndrome
MPO - myeloperoxidase
Na - Naphtillaza
OAK - Common Blood Analysis
Oml - acute myeloblastic leukemia
OPP - acute promelocytic leukemia
PCR - polymerase chain reaction
ESO - Erythrocyte settlement speed
UDG - Ultrasonic Doppler
Ultrasound - Ultrasonic Study
FV - Emission fraction
FGDS - Fibrogastroduodenoscopy
CH - Breathing Frequency
Heart rate - cardiac frequency
ECG - electrocardiography
EchoCG - Echocardiography
YMRR - Nuclear Magnetic Resonance Tomography
ARA-C - Citarabin
ATRA - TRATINOIN *
DNR - Downorubicin
Fab- Classification - Franco-American-British Classification System
Fish - Fluorescent in Situ Hybridization
HLA - human leukocyte antigens system
Ida-Darubicin *

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

Scale levels of proven

Level evidence Characteristics of studies that have formed the basis of recommendations AND High-quality meta-analysis, a systematic review of randomized clinical studies (RCI) or large RCCs with a very low probability (++) systematic error, the results of which can be distributed to the corresponding population. IN High-quality (++) systematic overview of cohort or studies Case-control or high-quality (++) cohort or studies Case control with a very low risk of systematic error or RCC with low (+) risk of systematic error, the results of which can be distributed to the appropriate Population. FROM Cohort or study case-control or controlled study without randomization with a low risk of systematic error (+), the results of which can be distributed to the appropriate population or rock with a very low or low risk of systematic error (++ or +), the results of which cannot Be directly distributed to the appropriate population. D. Description of a series of cases or Uncontrolled study or Opinion experts

Classification

Clinical classification

ClassificationWorld Health Organization, 2008.
Acute myeloid leukemia with consistently detected translocations:
OML with translocation T (15; 17) (Q22; Q12); PML-RARA;
OML with translocation T (11; 17) (Q23; Q12); ZBTB16-RARA;
OML with translocation T (11; 17) (Q13; Q12); Numa1-Rara;
OML with translocation T (5; 17) (Q35; Q12); NPM1-RARA;
OML with translocation Der (17); STAT5B-RARA;

Morphological characteristic op floorFab.-classification for acute nonlimfoblastic leukemia

Option	Frequency	Morphology	Citoochemistry			Features
			MGO	Sudanecher	NE.
M3 is not in acute promoelocitary	8-15%	Hypereloculated speakelyocytes with multiple Auer sticks. M3V option: granulation is poorly expressed	+	+	-	t (15; 17) or variations with the involvement of the RARα gene in 100% of cases

Risk groups OPL

Low risk group:

· Leukocytes ≤ 10x10 9 / l;
· Platelets ≥ 40x10 9 / l.

Intermediate risk group:

· Leukocytes ≤ 10x10 9 / l;
· Platelets less than 40x10 9 / l.

High risk group:

· Leukocytes more than 10 x10 9 / l.

Diagnostics

List of basic and additional diagnostic measures:
Main (mandatory) diagnostic surveys conducted on an outpatient level:

· Myelogram.

Additional diagnostic surveys conducted on an outpatient level:




· general urine analysis;
· Coagulogram;

· Biochemical blood test (total protein, albumin, common bilirubin, straight bilirubin, creatinine, urea, alote, asate, glucose, LDH, C-jet protein, alkaline phospotase);

· ELISA on HIV markers;
· ELISA on the markers of the virus chamber of the group;
· ECG;
· Abdominal ultrasound (liver, spleen, pancreas, gallbladder lymph nodes, kidneys), in women - small pelvis;
· The radiography of the organs of the breast cell.

The minimum list of the survey, which must be carried out in the direction of the planned hospitalization:
· General blood test (leukophoretum counting, platelets in a smear);
· Myelogram;
· Blood group and Rhus factor
· Biochemical blood test (general protein, albumin, common bilirubin, direct bilirubin, creatinine, urea, alote, asate, glucose, LDH, C-jet protein);

· Uzi small pelvis organs - for women.

Main (mandatory) diagnostic surveys conducted at the stationary level:
· General blood test (leukophoretum counting, platelets in a smear);
· Myelogram;
· Cytochemical study of blast cells (MPO, Glycogen, Alpha Na, Sudan black);
· Immunophenotyping "Panel for sharp leukemia" by flow cytofluorimetry;
· Standard cytogenetic study;
· Study using the FISH and molecular genetic study - chimeric transcriptPML / RARα;
· general urine analysis;
· Blood group and Resh factor;
· Coagulogram;
· Determination of antithrombin III in blood plasma;
· Quantitative determination of the level D - dimers in the blood plasma;
· Biochemical blood test (protein, albumin, allya, asat, bilirubin, alkaline phosphatase, GGTP, creatinine, urea, uric acid, electrolytes, glucose, glucose, C-jet protein, immunoglobulin G, a, m);
· Rebarga's test;
· IFA on virus hepatitis markers;
· IFA on HIV markers;

Additional diagnostic surveys conducted at the stationary level:
· Pro-BNP (atrial sodium peptide) in blood serum;

· Bacteriological study of biological material on mushrooms of the genus Candida (high culture selection)
· Bacteriological study of feces on intestinal dysbacteriosis
· Bacteriological study of feces on pathogenic and conditionally pathogenic microflora (discharge of pure culture)
· Bacteriological examination of blood on Neisseria Meningitis (secretion of pure culture)
· Bacteriological examination of sputum (discharge of pure culture)
· Bacteriological study of sputum, wasches from bronchi on mycobacterium tuberculosis (high culture)
· Bacteriological study of separated from ZEV, wounds, eyes, ears, urine, bile, etc. (discharge of pure culture)
· Bacteriological study of wasches from bronchi (discharge of pure culture)
· Bacteriological examination of the spinal fluid on Neisseria Meningitis (high culture)

· Vaginal smear microscopy manual method
· Determination of sensitivity to antimicrobial drugs of dedicated crops
· Bacteriological study of autopsy material
· Bacteriological research of biological material for anaeroba (discharge of pure culture)
· Bacteriological study of transudate, exudate for sterility (discharge of pure culture)
· Identification of selected pure culture by mass spectrometry
· Cytological study of biological material; specify
· Immunogram;
· Bioptate histological examination (lymph node, combustion comb);
· Investigation of the spinal fluid (with suspected neurolecosis, neuroinfection);
· PCR for viral infections (viral hepatitis, cytomegalovirus, east herpes virus, Epstein-Barr virus, VARICELLA / ZOSTER virus);
· HLA - typing;
· Echocardiography;
· Abdominal ultrasound (liver, spleen, pancreas, gallbladder), lymph nodes, kidneys, in women - small pelvis;
· Radiography of the apparent sinuses of the nose;
· Radiography of bones and joints;
· CT of the thoracic segment, abdominal segment, head, small pelvis (if suspected extmullular defeat, infectious complications);
· Yamrt chest segment, abdominal segment, head, small pelvis (with suspected extmullular defeat, infectious complications);
· FGDS;
· Weszov Weszov;
· Bronchoscopy (with pneumonia, invasive aspergillosis);
· Colonoscopy (pseudomambranous colitis, intestinal bleeding);
· Di-emmonition blood pressure;
· Daily monitoring of ECG;
· Spirography.

Diagnostic measures carried out at the stage of emergency medical assistance:
· Collection of complaints and anamnesis of the disease;
· Physical examination.

Diagnostic criteria for diagnosis:

Complaints and anamnesis:
· Weakness;
· Sweating;
· Tired;
· Subfebrile;
· Cameplate;
· Pains in the bones or joints;
· Reducing body weight;
· Hemorrhagic rash in the form of petechia and ekkimosis on the skin;
· Epistaxis;
· Menorragia;
· Increased bleeding.

Anamnesis: Attention should be paid to:
· Long-term weakness;
· Fast fatigue;
· Frequent infectious diseases;
· Increased bleeding;
· The appearance of hemorrhagic spindles on the skin and mucous membranes.

Physical examination[ 7-12 ] :
· Pallor of skin cover;
· Hemorrhagic rash - petechia, ekkimosis of various localities;
· Shortness of breath;
· Tachycardia;
· Increased liver;
· Increased spleen.

Laboratory research:
· The main criterion of OPP is the presence of ≥20% of atypical promoelocytes / blasts in the bone marrow in combination with chromosomal translocations affecting the alpha retinoic acid receptor gene (RARα) located on 17 chromosome.
· General blood analysis:For opl is characterized by pancytopenia. Anemia has a normal, normocitary nature. With OPP high risk, leukocytosis is possible more than 10x10 9 / l.
· Morphological study:OPP, characterized by the presence of atypical forms of transomelocytes in the bone marrow and peripheral blood.
· Immunophenotyping: The expression of CD13, CD33 is noted; Weakly express, and often there is no expression of CD34, HLA-DR and CD11B. Unlike normalpromelocytes there is no or weak expressed expression CD15 and CD117. Sometimes unbearable expression of CD2 CD56 is observed.
· Molecular genetic study: Acute PromoELCitarian leukemia - confirmed by the presence of translocation - T (15; 17) (Q22; Q12); The PML-RARA gene is formed as a result of reciprocal translucent between long shoulders 15 and 17 chromosomes.

Tools:
· Ultrasound of the abdominal organs: Increase the size of the liver, spleen.
· CT of the thoracic segment:infiltrative changes in lung fabric.
· ECG: Violation of the conductivity of pulses in the heart muscle.
· EchoCG:signs of heart failure (FV<60%), снижение сократимости, диастолическая дисфункция, легочная гипертензия, пороки и регургитации клапанов.
· FGDS: Signs of esophagitis, gastritis, bullbits, duodenitis (surface, catarrhal, erosive, ulcerative).
· bronchoscopy:detection of the bleeding source.

Indications for the consultation of narrow specialists:
· Physician diagnostics and treatment doctor - installation of the central venous catheter from peripheral access (PICC);
· Hepatologist - for the diagnosis and treatment of viral hepatitis;
· Gynecologist - pregnancy, metroragia, menorragia, consultation in the appointment of combined oral contraceptives;
· Dermatovenerologist - skin syndrome
· Infectiousist - suspicion of viral infections;
· Cardiologist - uncontrollable ag, chronic mining deficiency, heart rate disorders and conductivity;
· Neuropathologist acute violation of cerebral circulation, meningitis, encephalitis, neuroleycosis;
· Neurosurgeon - acute violation of cerebral circulation, dislocation syndrome;
· Nephrologist (Efferentologist) - renal failure;
· Oncologist - suspicion of solid tumors;
· Otorhinolaryngologist - for the diagnosis and treatment of inflammatory diseases of the apparent sinuses of the nose and the middle ear;
· Ophthalmologist - impairment of vision, inflammatory diseases of the eye and appendages;
· Proctologist - anal crack, paraproititis;
· Psychiatrist - psychosis;
· Psychologist - depression, anorexia, etc.;
· Resuscitator - treatment of severe sepsis, septic shock, acute pulmonary damage syndrome in differentiation syndrome and terminal states, installation of central venous catheters;
· Rheumatologist - Syndrome Sweet;
· Thoracic surgeon - exudative pleurisy, pneumothorax, lung zigomics;
· Transfusiologist - for the selection of transfusion media with a positive indirectantiglobulin test, inefficiency of transfusions, acute massive blood loss;
· Urologist - infectious inflammatory diseases of the urinary system;
· Phthisiatric - suspicion of tuberculosis;
· Surgeon - surgical complications (infectious, hemorrhagic);
· Maxillofacial surgeon infectious inflammatory diseases of the teubo-jaw system.

Differential diagnosis

Differential diagnosis.
The differential diagnosis of leukocytosis and / or pancytopenia includes sharp leukemia, congenital aplastic anemia, myelodysplastic syndromes, leukemia from large granulated lymphocytees Other lymphomas, myelofibrosis (primary and secondary), metastatic bone marrow damage, megaloblastic anemia, classical paroxysmal night hemoglobinuria.
· Congenital aplastic anemia, incl. Anemia Fanfoni.excluded on the basis of the lack of characteristic clinical signs (lowerness, on the skin of the color of the color of "coffee with milk", anomalies of a skeleton, kidneys) and negative chromosome fragility tests. In some cases, clinical manifestations may be absent. The disease is most often diagnosed at the age of 3-14 years, but in some cases revealed after 40 years.
· Myelodsplastic syndromes / sharp leukemia.Bone marrow infiltration by blasts (more than 20%) without detection of anomalous polylocytes eliminates OPL. For MDS are characterized by signs of dispensease, an excess of blasts in the bone marrow, chromosomal aberrations, incl. repeated (monosomy 7 chromosome, 5q-), no translocation (15; 17) (Q22; Q12); PML-RARA gene.
· Acute lymphoblastic leukemia. In the debut of acute lymphoblastoolecraft, shecontal and reticuline bone marrow fibrosis can be observed. Flow cytometry, histological and immunohistochemical study of the bone marrow allows you to verify the diagnosis.
· Leukemia from large granular lymphocytes, lymphomaportezhna, non-Hodgkinskiemphoma with myelofibrosisexcluded on the basis of these flow cytometry (especially important for leukemia from large granulated leukocytes and high-tech leukemia) and data from the bone marrow histological and immunohistochemicalism (the focal or diffuse proliferation of lymphocytes and / or signs of myelofibrosis is detected).
· Primary myelofibrosisit is excluded on the basis of the presence of signs of fibrosis according to histological research. Changes in the UAC in the terminal stage of the disease can correspond to the OPL, but they are distinguished by a special form of dierythropower - the dacryocytes are detected and high normocytosis is characterized, the absence of anomalous promoelocytes.
· Methattatic bone marrow damageit is excluded on the basis of histological studies. An indirect sign of bone damage can be osselagia and normocytosis in the UAC, a significant acceleration of the ESP.
· Megaloblastic anemia.The main method of diagnostics is the estimate of vitamin B12 vitamin and folic acid. Indirect signs characteristic of megaloblastic anemia are an increase in the average hemoglobin content in red blood cells, an increase in the average volume of erythrocytes, the megaloblastic type of blood formation according to myelograms. In contrast to the OPL in Megaloblasemiamia, despite thrombocytopenia, there is no hemorrhagic syndrome.

Treatment abroad

Treat treatment in Korea, Israel, Germany, USA

Get advice on medical examination

Treatment

Treats of treatment:
· Achievement and retention of remission.

Tactics of treatment:
Non-drug treatment:
Mode II:food.
Diet:Neutropenic patients are not recommended to comply with a certain diet ( the level of evidence B.) .

Algorithm for the treatment of acute promelocytic leukemia

Therapeutic tactics during the induction of remission
Calculation of doses of cytostatic drugs - cytosine-arababrideid, desorubicin - is carried out in accordance with the surface area of \u200b\u200bthe patient's body using calculators, for example http://www.calculator.net/body-surface-area-calculator.html. Doses of cytostatic drugs are recalculated after each induction course and consolidation, as many patients lose weight during treatment. Reducing doses of drugs during the course is unacceptable in any case, with the exception of the following testimony:
· In renal failure;
· With liver failure;
· With the development of specific complications (differentiation syndrome and pseudo-turn of the brain) associated with the admission of ATRA.
ATRA is prescribed inside from the first day of the course 45 mg / m 2 / day in 2 reception (the dose is rounded to 10 mg). The dose is reduced in patients younger than 20 years to 25 mg / m 2 / day. Therapy is temporarily terminated in the development of differentiation syndrome, pseudo-pumping of the brain and signs of severe hepatotoxicity (increasing transaminase activity more than 5 times).

Differentiation syndrome - inexplicable fever, dynake, pleural and / or pericardial effusion, pulmonary infiltrates, renal failure, hypotension and inexplicable weight gain of more than 5 kg:
· Heavy differentiation syndrome - manifestation of 4 or more described symptoms or syndromes;
· The average form of differentiation syndrome is a manifestation of 2 and 3 described symptoms or syndromes.
At the first described symptoms or syndromes, the Cancellation of ATRA is needed and the treatment of dexamethasone 10 mg x 2 times per day.

The pseudo-turn of the brain is a condition accompanied by a pronounced headache with nausea, vomiting, violations of vision. The temporary cancellation of ATRA and treatment using opiates is necessary.

Therapy continues until remission, but not more than 90 days. In case, by 28-30 days, remission is not achieved, the control cytological study of the bone marrow is carried out by 45, 60 and 90 days.
Idarubicin or Downorubicin are prescribed in the form of a short (2-5 minutes) infusion in doses, respectively, 12 mg / m 2 and 60 mg / m 2 in 2, 4, 6 and 8 days. Patients over 60 years spend only three administrations.
Dexamethasone is prescribed 2.5 mg / m 2 every 12 hours from 1 to 15 days of course to all patients with leukocytes more than 15x10 9 / l.

Therapeutic tactics during the consolidating treatment.
Consolidation of remission is carried out by 3 courses depending on the risk group (see Figure). Anthraciklines are introduced in the form of a short intravenous infusion within 2-5 minutes. ARA-C at a dose of 1000 mg / m 2 In patients from a high risk group, under 60 years of age is introduced in the form of an intravenous 6-hour infusion. ARA-C at a dose of 200 mg / m 2 is introduced for 1 hour intravenously. Reception and correction of the ATRA dose is similar to the induction rate.
The break between courses is up to 30 days, it can be lengthened by no more than 45 days. Another course is beginning if there are signs of recovery of hematopois - neutrophils more than 1.5x10 9 / l, platelets are more than 100 x10 9 / l.

Therapeutic tactics during supporting treatment.

Supporting therapy is carried out up to 2.5 years from the day of the remission.
Treatment is carried out by three drugs at the same time - 6-mercaptopurine 50 mg / m 2 orally daily, methotrexate 15 mg / m 2 V / m or in / in or inside weekly and ATRA 45 mg / m 2 / day inside (in persons under 20 years old - 25 mg / m 2 / day) in 2 receptions within 15 days every 3 months.
Doses of mercaptopurine and methotrexate can be modified depending on peripheral blood indicators:
· The absolute number of neutrophils 1-1.5x10 9 / l - doses are reduced by 50% of the starting dose;
· Absolute number of neutrophils less than 1x10 9 / l - supporting therapy temporarily stops.
Bone marrow puncture is made 1 time in 3 months, or with suspected development of the recurrence of the disease (cytopenia, the emergence of tumor-like formations of various localizations, inexplicable headache and nausea).

Treatment of neurolecosis.

Neurolecosis prevention is not routine. When using a idarubicin, the likelihood of neurolemia development is significantly reduced, since, as opposed to a downorubicin, it penetrates through the hematorecephalic barrier.
Lumbal puncture is carried out in the case of suspicion of neurolemia. When cytose is detected 15/3 and more, as well as the detection of at least one atypical promoelocyte / blast cell, neurolekemia is diagnosed.
Treatment of neurolekemia is carried out by administering in the spinal channel of three drugs (ARA-C, methotrexate, dexamethasone - in the doses described above).
Lumbal puncture in patients with source neurolekemia after the completion of the treatment of neurolemia (after receiving three normal liquor indicators) is carried out in the future before each course of the scheduled protocol.

Arsenic trioxide *
It can be used in resistant cases: 10 mg per day, in the form of intravenous infusion, the course of treatment is no more than 60 days (until the achievement of complete remission). After reaching remission, a four-week break is given, and further, a consolidating course of chemotherapy is carried out: arsenic trioxide is 10 mg / day, V / B, 10 days per month, for 6 months. The frequency of achieving complete remission in the treatment of arsenic trioxide was 86%. Median observation amounted to 60 months; Disadvantageous survival rate - 69%, illegal survival - 80%, total survival rate of 74%.

Transfusion support
The testimony for transfusion therapy is primarily determined by clinical manifestations individually for each patient, taking into account the age of concomitant diseases, tolerability of chemotherapy and the development of complications at the previous stages of treatment.
Laboratory indicators to determine the indications have an auxiliary value, mainly to assess the non-leading prophylactic transfusions of platelet concentrate.
Indications for transfuses also depend on time, after the course of chemotherapy, the projected reduction in indicators in the next few days is taken into account.
Erythrocyte mass / suspension (level of evidenceD.):
· The hemoglobin level does not need to be raised until ordinary reserves and compensation mechanisms are sufficient to meet the needs of tissues in oxygen;
· There is only one indication for transfusions of erythrocycite-containing environments in chronic anemia - symptomic anemia (manifested tachycardia, shortness of breath, angina, syncope, de novo depression or element ST);
· Hemoglobin level of less than 30 g / l is an absolute indication for red blood cell transfusion;
· In the absence of decompensated diseases of the cardiovascular system and light indications for prophylactic transfusion of erythrocytes in chronic anemia, hemoglobin levels can be:

Platelet concentrate with OPL (level of proofD.) :
· With a decrease in platelet level of less than 30 x10 9 / l, transfusion of asphenic platelets is carried out in order to maintain their level not lower than 30-50 x 10 9 / l in particular in the first 10 days of the course.
· In the presence of high risk of hemorrhagic complications (age over 60 years, hyperlaycitosis (more than 10x10 9 / l), improving creatinine levels of more than 140 μmol / l), it is necessary to maintain platelet levels of more than 50x 10 9 / l.

Freshly frozen plasma (level of proofD.) :
· SPP transfusion is carried out in patients with bleeding or before carrying out invasive interventions;
· Patients with many ³2.0 (with neurosurgery interventions ³1.5) are considered as candidates for transfusion of SPP when planning invasive procedures.

Medical treatment rendered on an outpatient level:
- List of basic medicines indicating the form of release (having 100% probability of use):


· Downorubicin, lyophilisate for the preparation of a solution for infusions, 20 mg or idarubicin *, lyophilisate for the preparation of a solution for infusions, 5 mg;

· Methotrexat for intravenous administration;
· 6-mercaptopurine, Tablets 50 mg;
· Dexamethasone, solution for infusions, 4mg.

· Filgrastim, solution for injection 0.3 ml / ml, 1 ml;
· Ondansetron, solution for injection 8 mg / 4ml.

Antibacterial agents
· Azithromycin, tablet / capsule, 500 mg;


· Moxifloxacin, tablet, 400 mg;
· Offlsacin, tablet, 400 mg;
· Ciprofloxacin tablet, 500 mg;
· Metronidazole, tablet, 250 mg;

· Erythromycin, tablet 250mg.

· Anidulafungin, lyophilized powder for the preparation of the injection solution, 100 mg / bottle;
· Voriconazole, tablet, 50 mg;


· Clotrimazole, solution for outdoor use 1% 15ml;

· Fluconazole, capsule / Tablet 150 mg.

· Vangancycling, tablet, 450mg;
· Famciccovir, tablets, 500mg.

· Sulfamethoxazole / trinmetrium, 480 mg tablet.

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

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

· Treexamic acid, capsule / tablet 250 mg;
· Heparin, solution for injection of 5000 me / ml, 5 ml;
· Heparin, gel in a tube 100000th 50g;

· Econxaparine, solution for injection in syringes 4000 Anti-HE / 0.4 ml, 8000 anti-kh / 0.8 ml;
· Rivroxaban, tablet.

· Ambroxol, solution for intake and inhalation, 15mg / 2ml, 100ml;

· Atenolol, tablet 25mg;



· Drotaverin, tablet 40 mg;



· Lisinopril, 5mg tablet;


· Omeprazole, capsule 20 mg;

· Prednisolone, tablet, 5 mg;


· ToramSEMID, Tablet 10mg;
· Fentanyl, therapeutic transdermal system 75 μg / h; (for the treatment of chronic pains at oncological patients)

· Chlorhexidine, solution of 0.05% 100ml;


Medical treatment provided at the stationary level:
- List of basic medicines indicating the form of release (having 100% probability of use):

Antineoplastic and immunosuppressive drugs
· Tertinoin *, capsules, 10 mg;
· Downorubicin, lyophilisate for the preparation of solution for infusions, 20 mg;
· Idarubicin *, lyophilisate for the preparation of the solution for infusion, 5 mg;
· Citarabin, powder for the preparation of the solution for infusions, 100 mg;
· Arsenic trioxide *, lyophilisate for the preparation of a solution for infusions, 10 mg;
· Methotrexate, solution for infusions, 25 mg;
· 6-mercaptopurin, Tablets 50 mg.
· Dexamethasone, solution for infusions, 4mg.
- A list of additional drugs, indicating the form of release (less than 100% of the probability of application):
Drugs that weaken the toxic effect of antitumor drugs
· Filgrastim, solution for injection 0.3 ml / ml, 1 ml;
· Ondansetron, solution for injection 8 mg / 4ml.

Antibacterial agents
· Azithromycin, tablet / capsule, 500 mg, powder lyophilized for the preparation of solution for intravenous infusions, 500 mg;
· Amicacin, injection powder, 500 mg / 2 ml or powder for the preparation of the solution for injections, 0.5 g;
· Amoxicillin / clavulanic acid, tablet covered with film shell, 1000mg;
· Amoxicillin / clavulanic acid, powder for the preparation of solution for intravenous and intramuscular administration of 1000 mg + 500 mg;
· Vancomycin, powder / lyophilisate for the preparation of a solution for infusions of 1000 mg;
· Gentamicin, solution for injection 80mg / 2ml 2ml;
· Imipine, cilastatin powder for preparing a solution for infusions, 500 mg / 500 mg;
· Sodium quissatimetate *, lyophilisate for the preparation of a solution for infusions of 1 million units / vial;
· Levofloxacin, solution for infusion 500 mg / 100 ml;
· Levofloxacin, tablet, 500 mg;
· Lenezolid, solution for infusion2 mg / ml;
· Meropenem, lyophilisate / powder for the preparation of a solution for injections of 1.0 g;
· Metronidazole, tablet 250 mg, solution for infusion 0.5% 100ml;
· Moxifloxacin, tablet, 400 mg, solution for infusion 400 mg / 250 ml;
· Ofloxacin, tablet, 400 mg, solution for infusion 200 mg / 100 ml;
· PIPERACILLIN, TAZOBACTAM Powder for preparing a solution for injection 4.5g;
· Tigecycline *, lyophilized powder for preparing a solution for injection 50 mg / bottle;
· Tikartillalin / clavulanic acid, powder lyophilized for the preparation of the solution for infusion 3000mg / 200mg;
· Cefepim, powder for preparing a solution for injection of 500 mg, 1000 mg;
· Cefoperasazon, sulbactam powder for preparing a solution for injection 2 g;
· Ciprofloxacin, solution for infusion 200 mg / 100 ml, 100 ml; Tablet 500 mg;
· Erythromycin, tablet 250mg;
· Ertapenem lyophilisate, for preparing a solution for intravenous and intramuscular injections 1 g.

Antifungal medicines
· Amphotericin B *, lyophilized powder for the preparation of the injection solution, 50 mg / bottle;
· Anidulofungin, lyophilized powder for the preparation of the injection solution, 100 mg / bottle;
· Voriconazole, powder for preparing a solution for infusion 200 mg / bottle, tablet 50 mg;
· Itraconazole, a solution for receiving inside10mg / ml of 150.0;
· Caspophungin, lyophilisate for the preparation of a solution for infusion 50 mg;
· Clotrimazole, outdoor cream 1% 30g, solution for outdoor use 1% 15ml;
· Metronidazole, dental gel 20g;
· Mikafungin, powder lyophilized for the preparation of a solution for injection of 50 mg, 100 mg;
· Fluconazole, capsule / tablet 150 mg, solution for infusion 200 mg / 100 ml, 100 ml.

Antiviral drugs
· Acyclovir, outdoor cream, 5% - 5.0;
· Acyclovir, tablet, 400 mg;
· Acyclovir, powder for preparing a solution for infusions, 250 mg;
· Valcyclovir, tablet, 500mg;
· Valgancyclovir, tablet, 450mg;
· Gancyclovir *, lyophilisate for the preparation of solution for infusion 500mg;
· Famciclovir, tablets, 500mg №14.

Drugs used for pneumocystosis
· Sulfamethoxazole / trinmetrium, concentrate for preparing a solution for infusions (80mg + 16mg) / ml, 5 ml, 480 mg tablet.

Additional immunosuppressive drugs:
· Dexamethasone, solution for injection 4mg / ml 1 ml;
· Methylprednisolone, tablet, 16 mg;
· Prednisone, solution for injection of 30 mg / ml 1ml, 5 mg tablet.

Solutions used to correct disorders of water, electrolyte and acid-base balance, parenteral nutrition
· Albumin, solution for infusion 10% - 100ml, 20% - 100 ml;
· Water for injection, solution for injection 5ml;
· Dextrose, solution for infusion 5% - 250ml, 5% - 500 ml, 40% - 10 ml, 40% - 20 ml;
· Potassium chloride, solution for intravenous administration 40mg / ml, 10ml;
· Calcium gluconate, solution for injection 10%, 5 ml;
· Calcium chloride, solution for injection 10% 5ml;
· Magnesium sulfate, solution for injection of 25% 5 ml;
· Mannitol, solution for injection 15% -200.0;
· Sodium chloride, solution for infusion 0.9% 500ml, 250ml;
· Sodium chloride, potassium chloride, sodium acetic acid solution for infusions in a bottle of 200ml, 400ml;
· Sodium chloride, potassium chloride, sodium acetate solution for infusion 200ml, 400ml;
· Sodium chloride, potassium chloride, sodium hydrocarbonate solution for infusion 400ml;
· L-alanine, L-arginine, glycine, L-histidine, L-isoleucine, L-leucine, L-lysine hydrochloride, L-methionine, L-phenylalanine, L-proline, L-serine, L-threonine, L- Triptofan, L-Tyrosine, L-Vallin, sodium acetate trihydrate, sodium gliderophosphate Pentihydrate, potassium chloride, magnesium chloride hexahydrate, glucose, calcium chloride dihydrate, olive and beans Soy oils Mixture Emulsion d / inf.: Three-chamber containers 2 l
· Hydroxyethyl starch (pentacherchmal), solution for infusion 6% 500 ml;
· Amino acid complex, an infusion emulsion containing a mixture of olive and soybean oils in a ratio of 80:20, a solution of amino acids with electrolytes, a solution of dextrose, with a total caloric content of 1800 kcal 1,500 ml. Three-section container.

Drugs used for intensive heat treatment (cardiotonic means for the treatment of septic shock, Miorlaxants, Vazopressors and drugs for anesthesia):
· Aminophyllin, an injection solution 2.4%, 5 ml;
· Amiodaron, injection solution, 150 mg / 3 ml;
· Atenolol, tablet 25mg;
· Atrazurium of cheaper, solution for injections, 25mg / 2.5ml;
· Atropine, injection solution, 1 mg / ml;
· Diazepam, solution for intramuscular and intravenous use of 5mg / ml 2ml;
· Dobutamine *, solution for injection 250 mg / 50.0 ml;
· Dopamine, solution / concentrate for the preparation of a solution for injection 4%, 5 ml;
· Insulin simple;
· Ketamine, solution for injection of 500 mg / 10 ml;
· Morphine, solution for injection 1% 1ml;
· Norepinephrine *, solution for injection 20mg / ml 4.0;
· Pipecuronium bromide, powder lyophilized for injection 4 mg;
· Propofol, emulsion for intravenous administration of 10 mg / ml 20 ml, 10 mg / ml 50 ml;
· Rocuronia Bromide, solution for intravenous administration 10mg / ml, 5 ml;
· Tiopental sodium, powder for the preparation of solution for intravenous administration 500mg;
· Phenylephrine, solutions for injection 1% 1 ML;
· Phenobarbital, tablet 100mg;
· Human normal immunoglobulin, solution for infusion;
· Epinephrine, an injection solution 0.18% 1 ml.

Drugs affecting the blood coagulation system
· Aminocaproic acid, solution of 5% -100 ml;
· Antinfiber coagulant complex, lyophilized powder for the preparation of an injection solution, 500 Me;
· Heparin, an injection solution 5000 me / ml, 5 ml, gel in a tube 100000EB 50g;
· Hemostatic sponge, size 7 * 5 * 1, 8 * 3;
· Nadroparin, an injection solution in pre-filled with syringes, 2850 IU anti-ha / 0.3 ml, 5700 IU anti-ha / 0.6 ml;
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· Lisinopril, 5mg tablet;
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· ToramSEMID, Tablet 10mg;
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